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WO2025190158A1 - Composé spiro, procédé de préparation s'y rapportant et son utilisation - Google Patents

Composé spiro, procédé de préparation s'y rapportant et son utilisation

Info

Publication number
WO2025190158A1
WO2025190158A1 PCT/CN2025/081184 CN2025081184W WO2025190158A1 WO 2025190158 A1 WO2025190158 A1 WO 2025190158A1 CN 2025081184 W CN2025081184 W CN 2025081184W WO 2025190158 A1 WO2025190158 A1 WO 2025190158A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
phenyl
alkylene
cycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/081184
Other languages
English (en)
Chinese (zh)
Inventor
刘金明
任云
唐建川
田强
宋宏梅
俞文胜
葛均友
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Original Assignee
Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sichuan Kelun Biotech Biopharmaceutical Co Ltd filed Critical Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Publication of WO2025190158A1 publication Critical patent/WO2025190158A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/527—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim spiro-condensed
    • 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
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention belongs to the field of medicine, and in particular relates to a spirocyclic compound, a preparation method thereof and uses thereof.
  • RAS is a guanine nucleotide-binding protein with GTPase activity that anchors to the inner side of the cell membrane.
  • RAS proteins can transition between an inactive, GDP-bound state and an active, GTP-bound state, influencing downstream signaling pathways such as Raf, PI3K, and RalGDS, regulating protein synthesis, gene transcription, cell growth, differentiation, apoptosis, and migration.
  • RAS mutations lead to persistent activation of downstream signaling pathways, promoting tumor development and progression. Across all tumor types, RAS mutations primarily occur in KRAS (85%). In KRAS-mutated tumor cells, KRAS GTPase activity decreases, remaining persistently active. KRAS mutations are closely associated with the development of various cancers, including lung, pancreatic, and colorectal cancers.
  • PROTAC Proteolysis-Targeting Chimeras
  • PROTAC can recognize the target protein and E3 ubiquitin ligase respectively, shorten the distance between the target protein and the E3 ubiquitin ligase, and induce the ubiquitination process and degradation of the target protein by inducing the recruitment of the E3 ubiquitin ligase to the surface of the target protein.
  • PROTAC has the advantages of a wide range of pharmacological activities, high target selectivity, can be used to degrade difficult-to-drug target proteins, has strong degradation efficacy, and can maintain catalytic degradation at low concentrations.
  • the present invention provides compounds that can be used as degraders and/or inhibitors targeting the KRAS protein.
  • the compounds of the present invention are PROTACs, one end of which can bind to the target protein, while the high-affinity VHL ligand at the other end can recruit the target protein to the E3 ubiquitin ligase, leading to ubiquitination and subsequent degradation of the KRAS protein.
  • the compounds of the present invention can be used to treat and/or prevent cancers or diseases caused by aggregation and/or overactivation of the target protein.
  • the present invention provides a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein the compound has the structure of Formula (I):
  • Ring A is a C 3-6 cycloalkyl group or a 3-6 membered heterocyclyl group, wherein the cycloalkyl group or heterocyclyl group is optionally substituted by one or more substituents selected from halogen, C 1-6 alkyl group and C 1-6 haloalkyl group;
  • Ring B is a 3-12 membered nitrogen-containing heterocyclic group
  • X1 and X2 are each independently selected from O and N;
  • X 3 , X 4 and X 5 are each independently selected from CR 7 and N;
  • L is a covalent bond, or is selected from O, S and NR 8 ;
  • L 1 is selected from O, S and NR 9 ;
  • L 2 is a covalent bond, or is selected from C 1-6 alkylene and halogenated C 1-6 alkylene;
  • each R 1 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, -OC 3-6 cycloalkyl, and 3-6 membered heterocyclyl;
  • R 2 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, -C 1-6 alkylene-C 3-6 cycloalkyl, -C 1-6 alkylene-3-10 membered heterocyclyl and -C 1-6 alkylene-5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted by one or more selected from halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -OC 1-6 alkyl, -C 1-6 alkylene-OH, -OC 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, -NR 12a R 12
  • R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl;
  • R 4a and R 4b are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH and C 3-6 cycloalkyl; or,
  • R 4a and R 4b together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group or a 3-6 membered heterocyclic group;
  • R 5 is selected from halogen, phenyl and 5-6 membered heteroaryl, wherein the phenyl and heteroaryl are optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, C 1-6 alkyl and C 1-6 haloalkyl;
  • Each R 6 is independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl and C 1-6 haloalkyl; or,
  • Each R 7 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkoxy and C 1-6 haloalkyl-O-;
  • R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl;
  • R 9 is selected from hydrogen and C 1-6 alkyl
  • R 10 is selected from hydrogen and C 1-6 alkyl
  • R 11 is selected from hydrogen and C 1-6 alkyl
  • R 12a and R 12b are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-6 alkylene-OH and -C 1-6 alkylene-OC 1-6 alkyl, or R 12a and R 12b together with the nitrogen to which they are attached form a 3-6 membered nitrogen-containing heterocyclic group;
  • n is selected from 0, 1, 2, 3, 4, 5 and 6;
  • n is selected from 0, 1, 2, 3 and 4.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically and/or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.
  • the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a drug kit of the present invention, which targets KRAS protein and is used to degrade KRAS protein.
  • the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a drug kit of the present invention, for use in preventing and/or treating KRAS-mediated related diseases.
  • the present invention provides use of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical kit of the present invention in the preparation of a medicament for preventing and/or treating KRAS-mediated related diseases.
  • the present invention provides a method for preventing and/or treating KRAS-mediated related diseases, comprising administering to an individual in need thereof a preventively and/or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention or a pharmaceutical kit of the present invention.
  • the present invention provides methods of preparing the compounds of the present invention.
  • alkyl is defined as a straight-chain or branched saturated aliphatic hydrocarbon group.
  • C 1-6 alkyl refers to a straight-chain or branched group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted with one or more (such as 1, 2 or 3) suitable substituents such as halogen.
  • alkylene refers to a divalent saturated aliphatic hydrocarbon group derived from the corresponding "alkyl” by removing one hydrogen atom.
  • C 1-6 alkylene refers to an alkylene group having 1 to 6 carbon atoms, such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylene (-CH(CH 3 )CH 2 -), which is optionally substituted with one or more (such as 1, 2 or 3) suitable substituents such as halogen.
  • alkenyl refers to a straight or branched aliphatic hydrocarbon group with one or more carbon-carbon double bonds.
  • C2-6 alkenyl refers to an alkenyl group (such as vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl or 4-methyl-3-pentenyl, etc.) having 2 to 6 carbon atoms and one, two or three (preferably one) carbon-carbon double bonds, which is optionally substituted with one or more (such as 1, 2 or 3) suitable substituents such as halogen.
  • alkynyl refers to a straight or branched aliphatic hydrocarbon group having one or more carbon-carbon triple bonds.
  • C2-6alkynyl refers to an alkynyl group (such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl or 5-hexynyl) having 2 to 6 carbon atoms and one, two or three (preferably one) carbon-carbon triple bonds, which is optionally substituted with one or more (such as 1, 2 or 3) suitable substituents such as halogen.
  • cycloalkyl refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or cyclononyl, or a bicyclic ring, 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.), which is optionally substituted with one or more (such as 1 to 3) suitable substituents.
  • a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • C3-6 cycloalkyl refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring having 3 to 6 ring carbon atoms (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted by one or more (such as 1, 2 or 3) suitable substituents, for example methyl-substituted cyclopropyl.
  • cycloalkylene refers to a divalent group derived from a corresponding "cycloalkyl” by removing a hydrogen atom.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic group (including bridged, fused or spirocyclic rings), for example, having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms independently selected from N, O or S(O) t (wherein t is 0, 1 or 2) in the ring, such as a 3-12 membered heterocyclyl, a 3-7 membered heterocyclyl, a 3-6 membered heterocyclyl, a 5-6 membered heterocyclyl, etc.
  • heterocyclyl include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolidinyl, hexahydro-1H-pyrroline, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, or piperazinyl.
  • nitrogen-containing heterocyclic group refers to a heterocyclic group containing at least one N heteroatom, optionally containing one or more (e.g., 1, 2, 3 or 4) heteroatoms selected from O or S(O) t (wherein t is 0, 1 or 2), which may include nitrogen-containing monocyclic heterocyclic groups or polycyclic heterocyclic groups (e.g., nitrogen-containing bridged heterocyclic groups, nitrogen-containing heterocyclic groups, nitrogen-containing spiroheterocyclic groups), such as azetidinyl, piperidinyl, etc.
  • heterocyclylene refers to a divalent group obtained by removing a hydrogen atom from a corresponding "heterocyclyl”.
  • 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 containing 1, 2, 3, 4, 5, 6, 9 or 10 carbon atoms, and in each case may be benzo-fused.
  • the heteroaryl or heteroaromatic ring can be selected from thienyl (ring), furanyl (ring), pyrrolyl (ring), oxazolyl (ring), thiazolyl (ring), imidazolyl (ring), pyrazolyl (ring), isoxazolyl (ring), isothiazolyl (ring), oxadiazolyl (ring), triazolyl (ring), thiadiazolyl (ring) and the like, and benzo derivatives thereof; or pyridyl (ring), pyridazinyl (ring), pyrimidinyl (ring), pyrazinyl (ring), triazinyl (ring) and the like, and benzo derivatives thereof.
  • heteroarylene refers to a divalent group derived from a corresponding "heteroaryl” by removing a hydrogen atom.
  • substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and/or collectively, with independently selected substituents or unsubstituted. If a nitrogen of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected substituent or unsubstituted.
  • each substituent is selected independently of the other.
  • each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10, where reasonable.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature.
  • isotopes for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., 2H , 3H , deuterium D, tritium T); isotopes of carbon (e.g., 11C , 13C , and 14C ); isotopes of chlorine (e.g., 37Cl ); isotopes of fluorine (e.g., 18F ); isotopes of iodine (e.g., 123I and 125I ); isotopes of nitrogen (e.g., 13N and 15N ); isotopes of oxygen (e.g., 15O , 17O , and 18O ); isotopes of phosphorus (e.g., 32P ); and isotopes of sulfur (e.g., 35S ).
  • isotopes of hydrogen e.g., 2H , 3H , deuterium D, tri
  • Certain isotopically labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies (e.g., assays).
  • the radioisotopes tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose due to their ease of incorporation and ease of detection.
  • Substitution with positron-emitting isotopes e.g., 11 C, 18 F, 15 O, and 13 N
  • PET positron emission tomography
  • Isotopically labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying schemes and/or examples and preparations by using appropriate isotopically labeled reagents in place of the non-labeled reagents previously employed.
  • Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent is isotopically substituted, for example, D 2 O, acetone-d 6 , or DMSO-d 6 .
  • stereoisomer refers to an isomer formed due to at least one asymmetric center.
  • compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced.
  • Specific individual molecules can also exist as geometric isomers (cis/trans).
  • the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers).
  • Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is understood that the scope of this application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.
  • compositions of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention,” such various derivative forms of the compound are also intended to be encompassed.
  • 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 that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that 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 contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol.
  • the amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.
  • nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane.
  • MCPBA meta-chloroperbenzoic acid
  • alkyl hydroperoxides such as tert-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxirane such as dimethyldioxirane
  • metabolites of the compounds of the invention i.e., substances formed in vivo upon administration of the compounds of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound.
  • the present invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a period of time sufficient to produce a metabolic product thereof.
  • the present invention also encompasses compounds of the invention containing protecting groups.
  • protecting groups During any process for the preparation of the compounds of the invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference.
  • the protecting groups may be removed at an appropriate subsequent stage using methods known in the art.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof:
  • Ring A is a C 3-6 cycloalkyl group or a 3-6 membered heterocyclyl group, wherein the cycloalkyl group or heterocyclyl group is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl group and C 1-6 haloalkyl group;
  • Ring B is a 3-12 membered nitrogen-containing heterocyclic group
  • X1 and X2 are each independently selected from O and N;
  • X 3 , X 4 and X 5 are each independently selected from CR 7 and N;
  • L is a covalent bond, or is selected from O, S and NR 8 ;
  • L 1 is selected from O, S and NR 9 ;
  • L 2 is a covalent bond, or is selected from C 1-6 alkylene and halogenated C 1-6 alkylene;
  • L 3 is a covalent bond, or is selected from C 1-6 alkylene and halogenated C 1-6 alkylene;
  • L 4 is a covalent bond, or is selected from O, NR 10 , C 1-6 alkylene, -OC 1-6 alkylene-, -C 1-6 alkylene-O-, -C 1-6 alkylene-NR 10 -, -C 1-6 alkylene-OC 1-6 alkylene-, C 3-6 cycloalkyl and 3-10 membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, C 1-6 alkyl and C 1-6 haloalkyl;
  • each R 1 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OC 1-6 alkyl, -OC 1-6 haloalkyl, -OC 3-6 cycloalkyl, and 3-6 membered heterocyclyl;
  • R 2 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, -C 1-6 alkylene-C 3-6 cycloalkyl, -C 1-6 alkylene-3-10 membered heterocyclyl and -C 1-6 alkylene-5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted by one or more selected from halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -OC 1-6 alkyl, -C 1-6 alkylene-OH, -OC 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, -NR 12a R 12
  • R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl;
  • R 4a and R 4b are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-OH and C 3-6 cycloalkyl; or,
  • R 4a and R 4b together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group or a 3-6 membered heterocyclic group;
  • Each R 7 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkoxy and C 1-6 haloalkyl-O-;
  • R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl;
  • R 9 is selected from hydrogen and C 1-6 alkyl
  • R 10 is selected from hydrogen and C 1-6 alkyl
  • R 11 is selected from hydrogen and C 1-6 alkyl
  • R 12a and R 12b are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-6 alkylene-OH and -C 1-6 alkylene-OC 1-6 alkyl, or R 12a and R 12b together with the nitrogen to which they are attached form a 3-6 membered nitrogen-containing heterocyclic group;
  • n is selected from 0, 1, 2, 3, 4, 5 and 6;
  • n is selected from 0, 1, 2, 3 and 4.
  • the compound of formula (I) has the structure of formula (II-A), formula (II-B), formula (II-C) or formula (II-D):
  • Ring A, Ring B, R 2 , R 3 , R 4a , R 4b , R 5 , R 6 , L, L 1 , L 2 , L 3 , L 4 , L 5 and n are as defined above.
  • L 1 is -O-.
  • L 2 is -CH 2 -.
  • L 3 is C 1-3 alkylene.
  • L 3 is -CH 2 -.
  • Ring A is C 3-6 cycloalkyl.
  • Ring A is cyclopropyl
  • L 2 is C 1-3 alkylene
  • L 3 is C 1-3 alkylene
  • ring A is C 3-6 cycloalkyl
  • L 2 is -CH 2 -
  • L 3 is -CH 2 -
  • Ring A is C 3-6 cycloalkyl.
  • L 2 is -CH 2 -
  • L 3 is -CH 2 -
  • Ring A is cyclopropyl
  • Ring B is a 4-8 membered nitrogen-containing monoheterocyclic group.
  • Ring B is a 4-6 membered nitrogen-containing monoheterocyclic group.
  • Ring B is azetidinyl or piperidinyl.
  • Ring B is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L 4 is a covalent bond.
  • L 5 is a 5-10 membered heteroarylene.
  • L 5 is a 5-6 membered heteroarylene.
  • L 5 is a 5-6 membered nitrogen-containing heteroarylene group.
  • L 5 is a triazole group.
  • L5 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 3 is C 1-6 alkyl.
  • R 3 is C 3-6 alkyl.
  • R 3 is tert-butyl or isopropyl.
  • R 3 is tert-butyl
  • R 3 is isopropyl
  • R 4a and R 4b are each independently selected from hydrogen, C 1-3 alkyl, -C 1-3 alkylene-OH and C 3-6 cycloalkyl; or R 4a and R 4b form a C 3-6 cycloalkyl with the carbon atom to which they are attached.
  • R 4a and R 4b are each independently selected from hydrogen and C 1-3 alkyl; or R 4a and R 4b and the carbon atom to which they are attached together form a C 3-6 cycloalkyl.
  • R 5 is selected from phenyl and 5-6 membered heteroaryl, said phenyl and heteroaryl being optionally substituted with one or more substituents selected from halogen and C 1-4 alkyl.
  • R is selected from the group consisting of phenyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridinyl, and pyrimidinyl, wherein the phenyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridinyl, and pyrimidinyl groups are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, hydroxy, cyano, methyl, ethyl, isopropyl, and trifluoromethyl.
  • R 5 is selected from phenyl, thiazolyl, pyrazinyl, pyridinyl and pyrimidinyl, wherein the phenyl, thiazolyl, pyrazinyl, pyridinyl and pyrimidinyl are optionally substituted with one or two substituents selected from fluoro, chloro and methyl.
  • R 5 is selected from
  • R 5 is selected from
  • R 6 is selected from hydrogen and fluorine; and n is selected from 0 and 1.
  • L is a covalent bond, or is selected from -O- and -NR 8 -; R 8 is selected from hydrogen and C 1-3 alkyl.
  • L is a covalent bond, or is selected from -O-, -NH-, and -N(CH 3 )-.
  • L is a covalent bond
  • L is -O-.
  • L is selected from -NH- and -N(CH 3 )-.
  • R is selected from the group consisting of hydrogen, halogen, cyano, C1-6 alkyl, C3-6 cycloalkyl, phenyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, -C1-6 alkylene- C3-6 cycloalkyl, -C1-6 alkylene- 3-10 membered heterocyclyl, and -C1-6 alkylene-5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl, heterocyclyl, and heteroaryl groups are optionally replaced by one or more selected from the group consisting of halogen, hydroxy , cyano, C1-6 alkyl, C1-6 haloalkyl, -OC1-6 alkyl, -C1-6 alkylene-OH, -OC1-6 haloalkyl , C3-6 cycloalkyl, phenyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, -
  • R2 is selected from hydrogen
  • R2 is selected from hydrogen
  • fragment -LR 2 is selected from hydrogen
  • fragment -LR 2 is selected from hydrogen
  • the above-mentioned compound has the structure of Formula (IV-A), Formula (IV-B), Formula (IV-C) or Formula (IV-D):
  • Ring A, Ring B, R 2 , R 3 , R 4a , R 4b , R 5 , R 6 , L, L 1 , L 2 , L 3 , L 4 , L 5 and n are as defined above.
  • the present invention encompasses compounds obtained by any combination of the various embodiments. Embodiments obtained by combining the technical features or preferred technical features in one embodiment with the technical features or preferred technical features in another embodiment are also within the scope of the present invention.
  • Ring A, Ring B, R 2 , R 3 , R 4a , R 4b , R 5 , R 6 , L, L 1 , L 2 , L 3 , L 4 , L 5 and n are as defined above;
  • LG 1 , LG 2 and LG 3 each independently represent a leaving group, such as a halogen, a triflate group, a p-toluenesulfonate group or a methanesulfonate group;
  • the method comprises the following steps:
  • the reaction in step (1) is preferably carried out in a suitable organic solvent and in the presence of a suitable base.
  • the organic solvent may be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably N,N-dimethylformamide.
  • the base may be selected from N,N-diisopropylethylamine, triethylamine, potassium carbonate, cesium carbonate, and any combination thereof, preferably cesium carbonate.
  • the reaction is preferably carried out at a temperature of 0°C to 100°C for 0.5 to 48 hours.
  • the reaction of step (2) is preferably carried out in a suitable organic solvent and in the presence of a suitable base.
  • the organic solvent may be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably dimethyl sulfoxide or tetrahydrofuran.
  • the base may be selected from N,N-diisopropylethylamine, triethylamine, sodium hydride, potassium carbonate, cesium carbonate, sodium tert-butoxide or potassium tert-butoxide, preferably N,N-diisopropylethylamine, sodium tert-butoxide or cesium carbonate.
  • the reaction is preferably carried out at a temperature of 20°C-120°C for 2-48 hours; or the reaction of step (2) is preferably carried out in a suitable solvent and in the presence of a metal catalyst and a base.
  • the metal catalyst can be a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II), tetrakistriphenylphosphine palladium and palladium acetate, preferably [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium.
  • a palladium metal catalyst such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, methanesulfonic acid [n-butyldi(1-adam
  • the base can be an organic base or an inorganic base, for example, selected from sodium tert-butoxide, potassium carbonate, potassium phosphate, cesium carbonate and sodium carbonate, preferably potassium carbonate.
  • the solvent 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 preferably carried out at a temperature of 20-120°C for 2-16 hours.
  • the reaction of step (3) is preferably carried out in a suitable organic solvent and in the presence of a suitable reagent containing a -LG 3 group and a base.
  • the reagent containing a -LG 3 group can be selected from methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride or trifluoromethanesulfonic anhydride, preferably methanesulfonic anhydride.
  • the base can be selected from N,N-diisopropylethylamine or triethylamine, preferably triethylamine.
  • the organic solvent can be selected from tetrahydrofuran, dichloromethane, toluene, 1,2-dichloroethane and any combination thereof, preferably dichloromethane.
  • the reaction is preferably carried out at a temperature of 0-40°C for 2-16 hours.
  • the reaction of step (4) is preferably carried out in a suitable organic solvent and in the presence of an inorganic base and an inorganic salt.
  • the inorganic base may be selected from potassium carbonate or cesium carbonate, preferably potassium carbonate.
  • the inorganic salt may be selected from potassium iodide or sodium iodide, preferably potassium iodide.
  • the organic solvent may be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably acetonitrile.
  • the reaction is preferably carried out at a temperature of 25-100° C. for 2-16 hours.
  • the ring-closure reaction in step (5) is preferably carried out in a suitable organic solvent and in the presence of a suitable reagent.
  • the organic solvent may be selected from methanol, ethanol, isopropanol, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and any combination thereof, preferably ethanol.
  • the reagent is a combination of ammonium acetate and sulfur powder.
  • the reaction is preferably carried out at a temperature of 0-100° C. for 1-12 hours.
  • the present invention provides a second method for preparing a compound of formula (II-A), comprising the following steps:
  • Ring A, Ring B, R 2 , R 3 , R 4a , R 4b , R 5 , R 6 , L, L 1 , L 2 , L 3 , L 4 , L 5 and n are as defined above;
  • LG 1 , LG 2 and LG 3 each independently represent a leaving group, such as a halogen, a triflate group, a p-toluenesulfonate group or a methanesulfonate group;
  • the method comprises the following steps:
  • the reaction in step (1) is preferably carried out in a suitable organic solvent and in the presence of a suitable base.
  • the organic solvent may be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably tetrahydrofuran.
  • the base may be selected from N,N-diisopropylethylamine, triethylamine, potassium carbonate, cesium carbonate, sodium hydride, sodium tert-butoxide, or potassium tert-butoxide, preferably sodium hydride.
  • the reaction is preferably carried out at a temperature of 0°C to 100°C for 0.5 to 48 hours.
  • the reaction of step (3) is preferably carried out in a suitable organic solvent and in the presence of a suitable reagent containing a -LG 3 group and a base.
  • the reagent containing a -LG 3 group can be selected from methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride or trifluoromethanesulfonic anhydride, preferably methanesulfonic anhydride.
  • the base can be selected from N,N-diisopropylethylamine or triethylamine, preferably triethylamine.
  • the organic solvent can be selected from tetrahydrofuran, dichloromethane, toluene, 1,2-dichloroethane and any combination thereof, preferably dichloromethane.
  • the reaction is preferably carried out at a temperature of 0-40°C for 2-16 hours.
  • the reaction of step (4) is preferably carried out in a suitable organic solvent and in the presence of an inorganic base and an inorganic salt.
  • the inorganic base may be selected from potassium carbonate or cesium carbonate, preferably potassium carbonate.
  • the inorganic salt may be selected from potassium iodide or sodium iodide, preferably potassium iodide.
  • the organic solvent may be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably acetonitrile.
  • the reaction is preferably carried out at a temperature of 25-100° C. for 2-16 hours.
  • the ring-closure reaction in step (5) is preferably carried out in a suitable organic solvent and in the presence of a suitable reagent.
  • the organic solvent may be selected from methanol, ethanol, isopropanol, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and any combination thereof, preferably ethanol.
  • the reagent is a combination of ammonium acetate and sulfur powder.
  • the reaction is preferably carried out at a temperature of 0-100° C. for 1-12 hours.
  • the present invention provides a third method for preparing a compound of formula (II-A), comprising the following steps:
  • Ring A, Ring B, R 2 , R 3 , R 4a , R 4b , R 5 , R 6 , L, L 1 , L 2 , L 3 , L 4 , L 5 and n are as defined above;
  • LG 1 , LG 2 and LG 3 each independently represent a leaving group, such as a halogen, a triflate group, a p-toluenesulfonate group or a methanesulfonate group;
  • the method comprises the following steps:
  • the reaction in step (1) is preferably carried out in a suitable organic solvent and in the presence of a suitable base.
  • the organic solvent may be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably N,N-dimethylformamide.
  • the base may be selected from N,N-diisopropylethylamine, triethylamine, potassium carbonate, cesium carbonate, and any combination thereof, preferably cesium carbonate.
  • the reaction is preferably carried out at a temperature of 0°C to 100°C for 0.5 to 48 hours.
  • the reaction of step (2) is preferably carried out in a suitable organic solvent and in the presence of a suitable base.
  • the organic solvent may be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably acetonitrile or tetrahydrofuran.
  • the base may be selected from N,N-diisopropylethylamine, triethylamine, sodium hydride, potassium carbonate, cesium carbonate, sodium tert-butoxide or potassium tert-butoxide, preferably potassium carbonate or cesium carbonate.
  • the reaction is preferably carried out at a temperature of 20°C-120°C for 2-48 hours or the reaction of step (2) is preferably carried out in a suitable solvent and in the presence of a metal catalyst and a base.
  • the metal catalyst can be a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II), tetrakistriphenylphosphine palladium and palladium acetate, preferably [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium.
  • a palladium metal catalyst such as tris(dibenzylideneacetone)
  • the base can be an organic base or an inorganic base, for example, selected from sodium tert-butoxide, potassium carbonate, potassium phosphate, cesium carbonate and sodium carbonate, preferably potassium carbonate.
  • the solvent 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 preferably carried out at a temperature of 20-120°C for 2-16 hours.
  • the ring-closure reaction in step (3) is preferably carried out in a suitable organic solvent and in the presence of a suitable reagent.
  • the organic solvent may be selected from methanol, ethanol, isopropanol, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and any combination thereof, preferably ethanol.
  • the reagent is a combination of ammonium acetate and sulfur powder.
  • the reaction is preferably carried out at a temperature of 0-100° C. for 1-12 hours.
  • the reaction in step (4) is preferably carried out in a suitable organic solvent in the presence of N,N-dimethylformamide dimethyl acetal.
  • the organic solvent may be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably tetrahydrofuran.
  • the reaction is preferably carried out at a temperature of 25-100° C. for 2-16 hours.
  • the reaction of step (5) is preferably carried out in a suitable organic solvent and in the presence of a suitable reagent containing a -LG 3 group and a base.
  • the reagent containing a -LG 3 group can be selected from methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride or trifluoromethanesulfonic anhydride, preferably methanesulfonic anhydride.
  • the base can be selected from N,N-diisopropylethylamine or triethylamine, preferably triethylamine.
  • the organic solvent can be selected from tetrahydrofuran, dichloromethane, toluene, 1,2-dichloroethane and any combination thereof, preferably dichloromethane.
  • the reaction is preferably carried out at a temperature of 0-40°C for 2-16 hours.
  • the reaction of step (6) is preferably carried out in a suitable organic solvent and in the presence of an inorganic base and an inorganic salt.
  • the inorganic base may be selected from potassium carbonate or cesium carbonate, preferably potassium carbonate.
  • the inorganic salt may be selected from potassium iodide or sodium iodide, preferably potassium iodide.
  • the organic solvent may be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably acetonitrile.
  • the reaction is preferably carried out at a temperature of 25-100° C. for 2-16 hours.
  • the deprotection reaction in step (7) is preferably carried out in a suitable organic solvent and in the presence of a suitable deprotecting agent.
  • the organic solvent may be selected from methanol, ethanol, isopropanol, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, and any combination thereof, preferably tetrahydrofuran.
  • the deprotecting agent may be selected from hydrochloric acid, trifluoroacetic acid, acetic acid, and any combination thereof, preferably hydrochloric acid.
  • the reaction is preferably carried out at a temperature of 0-100° C. for 1-12 hours.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a preventively and/or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.
  • Another object of the present invention is to provide a drug kit comprising a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, and optionally instructions.
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit/risk ratio within the scope of reasonable medical judgment.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions or pharmaceutical formulations of this invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the pharmaceutical composition may be in the form of a solid preparation, a semisolid preparation, a liquid preparation, or a gaseous preparation.
  • solid preparations include tablets, capsules, powders, granules, or suppositories
  • liquid preparations include solutions, suspensions, or injections.
  • the composition may also be in the form of liposomes, microspheres, or other dosage forms.
  • compositions of the present invention can act systemically and/or locally.
  • they can be administered by suitable routes, for example, by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.
  • suitable routes for example, by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.
  • the content or dosage of the compound of the present invention in the pharmaceutical composition may be about 0.001 mg to about 1000 mg, suitably 0.01-800 mg, preferably 0.05-500 mg, more preferably 0.1-350 mg, particularly preferably 0.5-100 mg.
  • the present invention provides a method for preparing a pharmaceutical composition of the present invention, comprising combining a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof with one or more pharmaceutically acceptable carriers.
  • Another object of the present invention is to provide a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, for use in preventing and/or treating KRAS-mediated related diseases.
  • Another object of the present invention is to provide use of the compound of the present invention or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing and/or treating KRAS-mediated related diseases.
  • Another object of the present invention is to provide a method for preventing and/or treating KRAS-mediated related diseases, which comprises administering to an individual in need thereof a preventively or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.
  • the KRAS-mediated related disease is a tumor or cancer.
  • the term "effective amount” refers to an amount sufficient to achieve the desired prophylactic or therapeutic effect, for example, to achieve relief of one or more symptoms associated with the disease being treated.
  • the dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.
  • the amount of the compound of the present invention administered will depend on the severity of the individual, disease or the patient's condition, the speed of administration, the disposal of the compound and the judgment of the prescribing physician for treatment. Generally speaking, effective dose is about 0.0001 to about 50mg per kg body weight per day, for example, about 0.01 to about 10mg/kg/ day (single or divided administration). For 70kg people, this will add up to about 0.007mg/ day to about 3500mg/ day, for example, about 0.7mg/ day to about 700mg/ day.
  • the dosage level of the lower limit of the aforementioned range it can be enough to be not higher than the dosage level of the lower limit of the aforementioned range, and in other cases, it is still possible to adopt a larger dose in the case of not causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.
  • prevention includes suppressing and delaying the onset of a disease, and includes not only prevention before the development of a disease but also prevention of recurrence of a disease after treatment.
  • treat means to reverse, alleviate, or eliminate the progression of the disorder or condition to which such terms apply, or one or more symptoms of such disorder or condition.
  • subject includes humans and non-human animals.
  • exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals.
  • Non-human animals herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
  • the MS measuring instrument is Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.
  • Instrument model Agilent 1260; chromatographic column: Waters SunFire Prep C 18 OBD (19 mm ⁇ 150 mm ⁇ 5.0 ⁇ m); column temperature: 25°C; flow rate: 20.0 mL/min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: acetonitrile; mobile phase B: 0.05% formic acid in water;
  • Thin layer chromatography silica gel plates used aluminum plates (20 ⁇ 20 cm) produced by Merck, and the specifications used for thin layer chromatography separation and purification were GF 254 (1 mm) produced in Yantai.
  • the reaction is monitored by thin layer chromatography (TLC) or LC-MS; the developing solvent systems used include: dichloromethane and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system.
  • TLC thin layer chromatography
  • LC-MS LC-MS
  • the volume ratio of the solvent is adjusted according to the polarity of the compound or by adding triethylamine.
  • Column chromatography generally uses 200-300 mesh silica gel as a carrier.
  • Eluent systems include: dichloromethane and methanol systems, and petroleum ether and ethyl acetate systems. 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.
  • reaction temperature was room temperature (20°C-35°C).
  • the reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company, Teber Chemical and other companies.
  • Step 1 Preparation of (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl))ethyl)pyrrolidine-2-carboxamide
  • Step 2 Preparation of tert-butyl 4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl))ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate
  • Step 3 Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 1 Preparation of (S)-3-(4-(((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(pyrimidin-5-yloxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one
  • Step 2 Preparation of (S)-2-amino-3'-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(pyrimidin-5-yloxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile
  • Step 3 Preparation of (E)-N'-(3-cyano-3'-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(pyrimidin-5-yloxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N-dimethylformamide
  • Step 4 Preparation of (E)-(1-((2-(3-cyano-2-((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate
  • Step 1 Preparation of tert-butyl (S)-(1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)carbamate
  • Step 3 Preparation of tert-butyl (S)-1-((2S,4R)-2-(((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate
  • N,N-Diisopropylethylamine (820.7 mg, 6.35 mmol) was added dropwise under ice-cooling, and the mixture was allowed to react at room temperature for 2 hours.
  • Step 4 Preparation of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-N-(S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide
  • Step 5 Preparation of (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide
  • Step 7 Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide
  • Step 1 Preparation of (S)-1-(6-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)-1H-pyrazole-3-carboxylic acid methyl ester
  • Step 2 Preparation of (S)-1-(6-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)-1H-pyrazole-3-carboxylic acid methyl ester
  • Step 3 Preparation of methyl 1-(6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)-1H-pyrazole-3-carboxylate
  • Step 4 Preparation of 1-(6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)-1H-pyrazole-3-carboxylic acid
  • Step 2 Preparation of (R)-N-((S)-1-(4-bromo-3-fluorophenyl)ethyl)-2-methylpropane-2-sulfenamide
  • Step 3 Preparation of (R)-2-methyl-N-[(S)-1-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]propane-2-sulfenamide
  • Step 4 Preparation of (R)-2-methyl-N-[(S)-1-[3-fluoro-4-(4-methylthiazol-5-yl)phenyl]ethyl]propane-2-sulfenamide
  • Step 6 Preparation of tert-butyl ((S)-1-((2S,4R)-2-(((S)-1-(3-fluoro-4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl))-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate
  • Step 7 Preparation of (2S,4R)-4-hydroxy-1-[(S)-2-amino-3,3-dimethylbutyryl]-N-[(S)-1-[3-fluoro-4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide
  • Step 8 Preparation of (2S,4R)-4-hydroxy-1-[(S)-2-azido-3,3-dimethylbutanoyl]-N-[(S)-1-[3-fluoro-4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide
  • Step 9 Preparation of tert-butyl 4-[1-[(S)-2,2-dimethyl-1-[(2S,4R)-4-hydroxy-2-[[(S)-1-[3]-fluoro-4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]propyl]triazol-4-yl]piperidine-1-carboxylate
  • Step 10 Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(3-fluoro-4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide
  • Step 1 Preparation of tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate
  • Step 3 Preparation of tert-butyl ((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin)-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate
  • N-tert-Butyloxycarbonyl-L-valine 255 mg, 1.17 mmol
  • (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 432 mg, 1.17 mmol
  • N,N-diisopropylethylamine 380 mg, 2.94 mmol
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate 581 mg, 1.53 mmol
  • Step 4 Preparation of (2S,4R)-1-(L-valyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 5 Preparation of (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 6 Preparation of tert-butyl 4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl))ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate
  • Step 7 Preparation of (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 1 Preparation of (S)-3-(4-chloro-6-(2-methoxyethoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one
  • Step 2 Preparation of (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(2-methoxyethoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one
  • 1,1-Cyclopropane dimethanol (98 mg, 0.95 mmol) was dissolved in tetrahydrofuran (3 mL), and sodium hydride (38 mg, 0.95 mmol) was added. The mixture was stirred at 25°C for 0.5 hour.
  • (S)-3-(4-chloro-6-(2-methoxyethoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one 250 mg, 0.63 mmol was added, and the mixture was stirred at 25°C for 2 hours.
  • Step 3 Preparation of (S)-(1-(((6-(2-methoxyethoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate
  • Step 4 Preparation of (2S,4R)-4-hydroxy-1-((S)-2-(4-(1-(1-(((6-(2-methoxyethoxy))-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 5 Preparation of (2S,4R)-1-((S)-2-(4-(1-(((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 1 Preparation of tert-butyl (S)-4-((6-chloro-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)piperidine-1-carboxylate
  • Step 2 Preparation of tert-butyl (S)-4-((6-(((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)oxy)piperidine-1-carboxylate
  • 1,1-Cyclopropane dimethanol (44.4 mg, 0.44 mmol) was dissolved in tetrahydrofuran (3 mL), and sodium hydride (26.4 mg, 0.44 mmol) was added. The mixture was stirred at 25°C for 0.5 hour.
  • (S)-3-(4-chloro-6-(2-methoxyethoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one 150 mg, 0.29 mmol was added, and the mixture was stirred at 25°C for 2 hours.
  • Step 3 Preparation of tert-butyl (S)-4-((6-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)piperidine-1-carboxylate
  • Step 4 Preparation of tert-butyl 4-((6-((1-((4-(1-(S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)oxy)piperidine-1-carboxylate
  • Step 5 Preparation of tert-butyl 4-((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((1-((4-(1-(S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate
  • Step 6 Preparation of (2S,4R)-1-((S)-2-(4-(1-((((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(piperidin-4-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 1 Preparation of (S)-3-(4-cyclopropyl-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one
  • Step 2 Preparation of (S)-(1-(((6-cyclopropyl-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate
  • Step 3 Preparation of (2S,4R)-1-((S)-2-(4-(1-(((6-cyclopropyl-2-(S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexanone]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 4 Preparation of (2S,4R)-1-((S)-2-(4-(1-(((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-cyclopropylpyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 1 Preparation of (S)-3-(4-(3-(dimethylamino)azetidin-1-yl)-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one
  • Step 2 Preparation of (S)-(1-(((6-(3-(dimethylamino)azetidin-1-yl)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate
  • Step 3 Preparation of (2S,4R)-1-((S)-2-(4-(1-(1-(((6-(3-(dimethylamino)azetidin-1-yl))-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 4 Preparation of (2S,4R)-1-((S)-2-(4-(1-(((2-(((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(3-(dimethylamino)azetidin-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(((S)-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 1 Preparation of tert-butyl (R)-4-(6-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate
  • Step 2 Preparation of tert-butyl (R)-2-methyl-4-(6-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-2-(((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate
  • N,N-diisopropylethylamine (58.5 mg, 453 ⁇ mol) and methanesulfonic anhydride (39.4 mg, 226.5 ⁇ mol) were added sequentially, and the mixture was reacted at 25°C for 12 hours.
  • Step 3 Preparation of tert-butyl (R)-4-(6-((1-((4-(1-(S)-1-((2S,4R)-4-hydroxy-2-(((S)-1,4-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate
  • Step 4 Preparation of (R)-tert-butyl 4-(2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((1-((4-(1-(S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate
  • Step 5 Preparation of (2S,4R)-1-((S)-2-(4-(1-(((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((R)-3-methylpiperazin-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 1 Preparation of (S)-3-(4-chloro-6-methoxypyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one
  • Step 2 Preparation of (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-methoxypyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one
  • Step 3 Preparation of (S)-(1-((6-methoxy-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxymethyl)cyclopropyl)methyl methanesulfonate
  • Step 4 Preparation of (2S,4R)-N-(S)-1-(2-fluoro-[1,1-biphenyl]-4-yl)ethyl)-4-hydroxy-1-(S)-2-(4-(1-(6-methoxy-2-(S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide
  • Step 5 Preparation of (2S,4R)-1-((S)-2-(4-(1-((S)-(2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol-3-yl)-6-methoxypyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(2-fluoro-[1,1-biphenyl]-4-yl)ethyl)-4-hydroxypyrrolidine-2-carboxamide
  • Example 1 The synthetic route in Example 1 was used to replace the first step reaction raw material 2-methoxyethanol with tetrahydro-2H-pyran-4-ol to obtain the title compound (7 mg, yield: 18.6%).
  • Step 1 Preparation of (S)-3-(4-chloro-6-(pyrimidin-5-yloxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one
  • Step 2 Preparation of (S)-3-(4-(((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(pyrimidin-5-yloxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one
  • 1,1-Cyclopropane dimethanol (74.5 mg, 0.73 mmol) was dissolved in tetrahydrofuran (3 mL), and sodium hydride (43.8 mg, 0.73 mmol) was added. The mixture was stirred at 25°C for 0.5 hour.
  • (S)-3-(4-chloro-6-(pyrimidin-5-yloxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one 200 mg, 0.49 mmol was added, and the mixture was stirred at 25°C for 2 hours.
  • Step 3 Preparation of (S)-(1-(((2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexanone]-3-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate
  • Step 4 Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(1-(((2-(S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexanone]-3-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 5 Preparation of (2S,4R)-1-((S)-2-(4-(1-((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 1 Preparation of (S)-1-(6-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)-N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide
  • Step 2 Preparation of (S)-(1-(((6-(3-((2-methoxyethyl)carbamoyl)-1H-pyrazol-1-yl)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate
  • N,N-diisopropylethylamine (35.2 mg, 272 ⁇ mol) and methanesulfonic anhydride (23.7 mg, 136.1 ⁇ mol) were added sequentially, and the mixture was reacted at 25°C for 12 hours.
  • Step 3 Preparation of 1-(6-((1-((4-(1-(S)-1-((2S,4R)-4-hydroxy-2-(((S)-1,4-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)-N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide
  • Step 4 Preparation of 1-(2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrimidin-4-yl)-N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide
  • Step 1 Preparation of (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(thiazol-2-yloxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]]isoxazol-7,1'-cyclohexane]-2'-one
  • Step 2 Preparation of (S)-(1-(((2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)-6-(thiazol-2-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate
  • Step 3 Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(1-((1-(((2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)-6-(thiazol-2-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 4 Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6'),7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(thiazol-2-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 1 Preparation of (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one
  • Step 2 Preparation of (S)-(1-(((2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate
  • Step 3 Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(1-((1-(((2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 4 Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Example 1 The synthetic route in Example 1 was used to replace the first step reaction raw material 2-methoxyethanol with (1-(dimethylamino)cyclopropyl)methanol to obtain the title compound (15 mg, yield: 27.9%).
  • Example 3 The synthetic route in Example 3 was used to replace the cyclopropylboronic acid in the first step with trimethylcyclotriboroxine to obtain the title compound (30 mg, yield: 39.6%).
  • Example 12 The synthetic route in Example 12 was used to replace the first step reaction raw material 2-thiazolol with 5-aminopyrimidine to obtain the title compound (3 mg, yield: 18.6%).
  • Example 3 The synthetic route in Example 3 was used to replace the first step reaction raw material cyclopropylboronic acid with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to obtain the title compound (10 mg, yield: 13.3%).
  • Example 6 The synthetic route in Example 6 was used to replace the first step reaction raw material (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester with 2,6-diazaspiro[3.4]octyl-2-carboxylic acid tert-butyl ester to obtain the title compound (18 mg, yield: 53.8%).
  • Example 1 The synthetic route in Example 1 was used to replace the first step reaction raw material 2-methoxyethanol with (S)-tetrahydrofuran-3-ol to obtain the title compound (19 mg, yield: 13.9%).
  • Example 1 The synthetic route in Example 1 was used to replace the first step reaction raw material 2-methoxyethanol with 2-oxaspiro[3.3]heptan-6-ol to obtain the title compound (11 mg, yield: 16.2%).
  • Example 5 The synthetic route in Example 5 was used to replace the starting material N,N-dimethylazetidin-3-amine in the first step with morpholine to obtain the title compound (20 mg, yield: 29.3%).
  • Example 5 The synthetic route in Example 5 was used to replace the first step reaction raw material N,N-dimethylazetidin-3-amine with 1,4-oxazepane to obtain the title compound (15.4 mg, yield: 53.0%).
  • Example 6 The synthetic route in Example 6 was used to replace the starting material in the first step (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester with tert-butyl 1-piperazinecarboxylate to obtain the title compound (4.0 mg, yield: 42.3%).
  • Example 10 The synthetic route in Example 10 was used to replace the raw material 5-hydroxypyrimidine in the first step with 3-hydroxypyridine to obtain the title compound (1.82 mg, yield: 9.4%).
  • Example 2 The synthetic route in Example 2 was used to replace the first step reaction raw material 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester with (S)-1-N-tert-butyloxycarbonyl-3-hydroxypyrrolidine to obtain the title compound (2.47 mg, yield: 3.6%).
  • Step 1 Preparation of (S)-3-(4-(3-bromo-1H-pyrazol-1-yl)-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one
  • Step 2 Preparation of (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(3-((trimethylsilyl)ethynyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one
  • Trimethylsilylacetylene (202.7 mg, 2.06 mmol), bistriphenylphosphine palladium dichloride (28.9 mg, 41.3 ⁇ mol), cuprous iodide (15.7 mg, 82.6 ⁇ mol), and triethylamine (417.9 mg, 4.13 mmol) were added sequentially.
  • the atmosphere was purged with nitrogen three times and the reaction was carried out at 80°C for 12 h.
  • Water (10 mL) was added to the reaction solution, and the mixture was extracted twice with dichloromethane (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Step 3 Preparation of (S)-3-(4-(3-ethynyl-1H-pyrazol-1-yl)-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one
  • Step 4 Preparation of (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(3-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-1H-pyrazol-1-yl)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one
  • Step 5 Preparation of (S)-(1-(((2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexane]-3-yl)-6-(3-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-1H-pyrazol-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate
  • N,N-Diisopropylethylamine (129 mg, 100 ⁇ mol) was added, followed by methanesulfonic anhydride (13.1 mg, 75 ⁇ mol), and the mixture was reacted at 25°C for 2 hours.
  • Water (10 mL) was added to the reaction solution, and the mixture was extracted twice with dichloromethane (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (30 mg, yield: 88.5%).
  • Step 6 Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(1-((1-(((2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)-6-(3-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-1H-pyrazol-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 7 Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(3-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-1H-pyrazol-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 1 Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-3-cyano-2-(((E)-(dimethylamino)))methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide
  • Step 2 Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide
  • Example 32 Preparation of 1-(2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrimidin-4-yl)-N-methyl-1H-pyrazole-3-carboxamide (Compound 107)
  • Step 1 Preparation of 1-(6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)-N-methyl-1H-pyrazole-3-carboxamide
  • Methylamine hydrochloride (6.7 mg, 99.6 ⁇ mol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (18.9 mg, 49.8 ⁇ mol) and 1-(6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1- oxobutan-2-yl) methylamine hydrochloride (6.7 mg, 99.6 ⁇ mol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (18.9 mg, 49.8 ⁇ mol) and
  • Step 2 Preparation of 1-(2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrimidin-4-yl)-N-methyl-1H-pyrazole-3-carboxamide
  • the synthetic route in Example 31 was used to replace the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide with (2S,4R)-N-((S)-1-(4-(4-chloropyridin-3-yl)phenyl)ethyl)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxypyrrolidine-2-carboxamide (40 mg, yield: 46.6%).
  • Example 32 The synthetic route in Example 32 was used to replace the first step reaction raw material methylamine hydrochloride with dimethylamine hydrochloride to obtain the title compound (8 mg, yield: 32.4%).
  • Example 50 Preparation of 1-(2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrimidin-4-yl)-N-isopropyl-1H-pyrazole-3-carboxamide (Compound 109)
  • Step 1 Preparation of tert-butyl (S)-(4-((6-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)phenyl)carbamate
  • Step 2 Preparation of (S)-(1-(((6-(4-((tert-Butoxycarbonyl)amino)phenoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate
  • N,N-diisopropylethylamine 157 mg, 1.21 mmol
  • methanesulfonic anhydride 106 mg, 603.39 ⁇ mol
  • Saturated brine was added to the reaction solution, the layers were separated, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (250 mg, yield: 92.0%).
  • Step 3 Preparation of tert-butyl (4-((6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)phenyl)carbamate
  • Step 4 Preparation of tert-butyl (4-((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrimidin-4-yl)oxy)phenyl)carbamate
  • Step 5 Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((4-aminophenoxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Example 62 Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((3-methyl-1H-pyrazol-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 37)
  • Example 3 The synthetic route in Example 3 was used to replace the first step reaction raw material cyclopropylboronic acid with (1-(2-methoxyethyl)-1H-pyrazol-3-yl)boronic acid to obtain the title compound (4 mg, yield: 3.7%).
  • Example 68 Preparation of 1-(2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(1-((4-(1-(S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrimidin-4-yl)-N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide (Compound 36)

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Abstract

L'invention concerne un composé spiro, un procédé de préparation s'y rapportant et son utilisation. Plus particulièrement, la présente invention concerne un composé de formule (I) ou un sel, un stéréoisomère, un tautomère, un polymorphe, un solvate, un N-oxyde, un composé marqué isotopiquement, un métabolite ou un promédicament pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique comprenant le composé, son procédé de préparation et son utilisation dans la préparation d'un médicament pour la prévention ou le traitement de maladies associées à médiation par KRAS.
PCT/CN2025/081184 2024-03-14 2025-03-07 Composé spiro, procédé de préparation s'y rapportant et son utilisation Pending WO2025190158A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023099612A1 (fr) * 2021-12-01 2023-06-08 Boehringer Ingelheim International Gmbh 2-amino-3-cyano thiophènes annelés et leurs dérivés pour le traitement du cancer
WO2023099623A1 (fr) * 2021-12-01 2023-06-08 Boehringer Ingelheim International Gmbh 2-amino-3-cyano-thiophènes annelés et dérivés pour le traitement du cancer
WO2023099624A1 (fr) * 2021-12-01 2023-06-08 Boehringer Ingelheim International Gmbh 2-amino-3-cyano thiophènes annelés et leurs dérivés pour le traitement du cancer
WO2023099608A1 (fr) * 2021-12-01 2023-06-08 Boehringer Ingelheim International Gmbh 2-amino-3-cyano thiophènes annelés et leurs dérivés pour le traitement du cancer
WO2024001839A1 (fr) * 2022-06-29 2024-01-04 四川科伦博泰生物医药股份有限公司 Composé cyclique hétéroaromatique, son procédé de préparation et son utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023099612A1 (fr) * 2021-12-01 2023-06-08 Boehringer Ingelheim International Gmbh 2-amino-3-cyano thiophènes annelés et leurs dérivés pour le traitement du cancer
WO2023099623A1 (fr) * 2021-12-01 2023-06-08 Boehringer Ingelheim International Gmbh 2-amino-3-cyano-thiophènes annelés et dérivés pour le traitement du cancer
WO2023099624A1 (fr) * 2021-12-01 2023-06-08 Boehringer Ingelheim International Gmbh 2-amino-3-cyano thiophènes annelés et leurs dérivés pour le traitement du cancer
WO2023099608A1 (fr) * 2021-12-01 2023-06-08 Boehringer Ingelheim International Gmbh 2-amino-3-cyano thiophènes annelés et leurs dérivés pour le traitement du cancer
WO2024001839A1 (fr) * 2022-06-29 2024-01-04 四川科伦博泰生物医药股份有限公司 Composé cyclique hétéroaromatique, son procédé de préparation et son utilisation

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