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WO2024208187A1 - Composé azaaryle et son utilisation en tant qu'inhibiteur de lsd1 - Google Patents

Composé azaaryle et son utilisation en tant qu'inhibiteur de lsd1 Download PDF

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Publication number
WO2024208187A1
WO2024208187A1 PCT/CN2024/085484 CN2024085484W WO2024208187A1 WO 2024208187 A1 WO2024208187 A1 WO 2024208187A1 CN 2024085484 W CN2024085484 W CN 2024085484W WO 2024208187 A1 WO2024208187 A1 WO 2024208187A1
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Prior art keywords
mmol
reaction solution
alkyl
halogen
cycloalkyl
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English (en)
Chinese (zh)
Inventor
胡斌
刘鹏
张萌
郑敏
陆洪福
丁晓
严尚军
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Shanghai Fosun Pharmaceutical Group Co Ltd
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Shanghai Fosun Pharmaceutical Group Co Ltd
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Publication of WO2024208187A1 publication Critical patent/WO2024208187A1/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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—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 present application belongs to the field of medicine and relates to a compound of formula I and its use as a lysine-specific demethylase (LSD1) inhibitor.
  • Lysine specific demethylase 1 is the first reported protein lysine demethylase. It widely participates in transcriptional regulation by regulating the methylation state of histone lysine, affecting many processes such as cell proliferation and differentiation, embryonic stem cell pluripotency, etc.
  • LSD1 acts on different substrates and can play different regulatory roles on histone and gene expression: after binding to CoREST, LSD1 will preferentially act on histone H3K4, remove activation-related histone marks through demethylation, and inhibit gene transcription; after binding to androgen receptor protein, recombinant LSD1 will preferentially act on H3K9, and activate androgen receptor-related gene transcription through demethylation.
  • the present application provides a series of compounds which are LSD1 inhibitors and have preventive and therapeutic uses in the treatment of tumors such as leukemia, small cell lung cancer, etc.
  • the present application provides 1, a compound of formula I, a pharmaceutically acceptable salt thereof, an isomer thereof or an isotope-labeled substance thereof,
  • U, X, Y, and Z are each independently N or CR 2 ;
  • the two rings indicated by the dashed lines are fused bicyclic aromatic rings
  • R 1 is hydrogen, halogen, hydroxyl, cyano, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -NR 5 R 6 ;
  • n 0, 1, 2 or 3;
  • R 2 is hydrogen, halogen, hydroxy, cyano, C 1-6 alkyl optionally substituted by hydroxy or halogen, C 1-6 alkoxy optionally substituted by halogen, C 2-6 alkynyl, -S(O) 2 C 1-6 alkyl, -C(O)-C 1-6 alkyl, -NR 5 R 6 , -NHCOC 1-6 alkyl, -NHCOOC 1-6 alkyl;
  • L is a bond, O, S, -NH-, -CO-, or -CH 2 O-;
  • Ring A is C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 3-10 cycloalkenyl, 3-10 membered heterocyclyl and 5-6 membered heteroaryl, C 6-10 aryl and C 3-10 cycloalkyl, C 6-10 aryl and 3-10 membered heterocyclyl, C 6-10 aryl and C 3-10 cycloalkenyl, 5-10 membered heteroaryl and C 3-10 cycloalkyl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, 5-10 membered heteroaryl and C 3-10 cycloalkenyl, the heteroaryl is optionally oxoed, and Ring A is optionally substituted with 0 to 4 Ra ;
  • Ra is selected from halogen, -CN, hydroxy, C1-6 alkyl optionally substituted by a substituent selected from -OH and halogen, C1-6 alkoxy, C1-6 alkoxy substituted by C6-10 aryl, -OC3-10 cycloalkyl , C3-10 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, -NR5R6 , -NHCOC1-6 alkyl, - NHCOOC 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 NR 5 R 6 , 5-6 membered heteroaryl (containing heteroatoms selected from nitrogen and oxygen) optionally substituted by substituents selected from -CN, -CHF 2 and -CF 3 , wherein the alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl is optionally substituted by halogen, hydroxy, acetylene or cyano;
  • the two Ras may be linked together to form a C3-12 cycloalkyl or a 3-12 membered heterocyclyl, wherein the C3-12 cycloalkyl or the 3-12 membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 Ras ;
  • the two Ras may be linked together to form a C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a 5-12 membered heteroaryl or a C6-12 aryl group, wherein the C3-12 cycloalkyl, the 3-12 membered heterocyclyl, the 5-12 membered heteroaryl or the C6-12 aryl group is optionally substituted by 1, 2, 3 or 4 Ras ;
  • Raa is selected from halogen, -CN, hydroxy, C1-6 alkyl, halogen-substituted C1-6 alkyl, C1-6 alkoxy, halogen-substituted C1-6 alkoxy, C6-10 aryl-substituted C1-6 alkoxy, -OC3-10 cycloalkyl, C3-10 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl;
  • Ring B is C 6-10 aryl, C 5-10 heteroaryl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, or C3-10 cycloalkenyl, which may be substituted by 0 to 4 R b ;
  • Ring B is a 3- to 10-membered heterocyclyl group, optionally substituted by 0 to 4 R b ;
  • R b is selected from halogen, -CN, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy substituted by C 6-10 aryl, -OC 3-10 cycloalkyl, C 3-10 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -NR 5 R 6 , -NHCOC 1-6 alkyl, -NHCOOC 1-6 alkyl, wherein the alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl is optionally substituted by halogen, acetylene or cyano;
  • the two R b may be linked together to form a C 3-12 cycloalkyl or a 3-12 membered heterocyclyl, wherein the C 3-12 cycloalkyl or the 3-12 membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 R bb ;
  • the two R b may be linked together C 3-12 cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl or C 6-12 aryl, wherein the C 3-12 cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl or C 6-12 aryl is optionally substituted by 1, 2, 3 or 4 R bb ;
  • R bb is selected from halogen, -CN, hydroxy, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy, C 6-10 aryl-substituted C 1-6 alkoxy, -OC 3-10 cycloalkyl, C 3-10 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl; and
  • R 5 and R 6 are each independently selected from hydrogen, C 1-6 alkyl optionally substituted by -OH, halogen, and 3-5 membered oxygen-containing heterocyclic group.
  • the present application provides a compound represented by Formula II or Formula III, a pharmaceutically acceptable salt thereof, an isomer thereof, or an isotope-labeled substance thereof,
  • X, Y and Z are all selected from CR 7 ;
  • One of X, Y and Z is selected from N, and the others are selected from CR 8 ; or
  • R 7 , R 8 , and R 9 are each independently selected from hydrogen, halogen, hydroxy, cyano, C 2-6 alkynyl, C 1-6 alkyl optionally substituted by hydroxy or halogen, C 1-6 alkoxy optionally substituted by halogen, -NR 5 R 6 , -CONR 5 R 6 , COR 5 , C(O)OR 5 , -SO 2 NR 5 R 6 , for example selected from hydrogen, halogen (such as fluorine), cyano or C 1-6 alkyl (such as methyl) optionally substituted by hydroxy or halogen (such as fluorine).
  • one of W and V is selected from N, and the other is selected from CH;
  • R 10 and R 11 are each independently selected from hydrogen, halogen (such as fluorine), hydroxyl, cyano, C 2-6 alkynyl, C 1-6 alkyl optionally substituted by hydroxyl or halogen, C 1-6 alkoxy optionally substituted by halogen, -NR 5 R 6 , -CONR 5 R 6 , COR 5 , C(O)OR 5 , -SO 2 NR 5 R 6 , for example selected from hydrogen, C 1-6 alkyl optionally substituted by hydroxyl or halogen (such as fluorine).
  • halogen such as fluorine
  • R 1 is selected from hydrogen, halogen (e.g. -F), hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -NR 5 R 6 , for example , selected from halogen (e.g. fluorine).
  • halogen e.g. fluorine
  • L is selected from a bond, -CO-, and -CH 2 O-.
  • L is selected from a bond, -CO-.
  • Ra is selected from halogen, -CN, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy substituted with C6-10 aryl , -OC3-10 cycloalkyl, C3-10 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, -NR5R6 , -NHCOC1-6 alkyl, -NHCOOC1-6 alkyl, -SO2C1-6 alkyl , -SO2NR5R6 , and the alkyl , alkoxy, cycloalkyl , alkenyl and alkynyl are optionally substituted with halogen, hydroxyl, acetylene or cyano.
  • Ring B can be selected from C 6-10 aryl, C 5-6 heteroaryl, C 3-6 cycloalkyl, 3 to 10 membered heterocyclic group, the heteroatom of the heterocyclic group is selected from nitrogen atom and oxygen atom, it can be a double bridged ring, a double spiro ring, or a monocyclic ring (for example, a 5-6 membered heterocyclic group, specifically 1-piperidinyl, 1-pyrrolyl, or a nitrogen-containing double bridged ring, a nitrogen-containing double spiro ring), C 3-6 cycloalkenyl, the heteroaryl or heterocyclic group can contain an N heteroatom; if it contains an N heteroatom, the N heteroatom is connected to the fused bicyclic aromatic ring in Formula I, Formula II or Formula III; the above groups are optionally substituted by 0 to 4, for example 0 to 2 R b .
  • R 5 and R 6 can each be independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy.
  • Another aspect of the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present application or a pharmaceutically acceptable salt thereof, an isomer thereof or an isotope-labeled substance thereof, and a pharmaceutically acceptable carrier.
  • Another aspect of the present application provides a compound of the present application or a pharmaceutically acceptable salt thereof, an isomer thereof or an isotope-labeled substance thereof, or the above-mentioned pharmaceutical composition, which is a LSD1 inhibitor.
  • Another aspect of the present application provides a compound of the present application or a pharmaceutically acceptable salt, an isomer or an isotope-labeled substance thereof, or the above-mentioned pharmaceutical composition, which is used for preventing or treating diseases mediated by LSD1.
  • Another aspect of the present application provides a compound of the present application or a pharmaceutically acceptable salt thereof, an isomer thereof or an isotope-labeled substance thereof, or the above-mentioned pharmaceutical composition, which is used for preventing or treating tumors.
  • Another aspect of the present application provides a use of the compound of the present application or a pharmaceutically acceptable salt thereof, an isomer thereof or an isotope-labeled substance thereof, or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing or treating a disease mediated by LSD1.
  • Another aspect of the present application provides a use of a compound of the present application or a pharmaceutically acceptable salt thereof, an isomer thereof or an isotope-labeled substance thereof, or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing or treating a disease, wherein the disease includes a tumor.
  • One aspect of the present application provides a method for inhibiting LSD1 activity, which comprises administering a compound of the present application or a pharmaceutically acceptable salt, an isomer or an isotope-labeled substance thereof to an individual.
  • One aspect of the present application provides a method for preventing or treating a disease or condition in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt, an isomer or an isotope label thereof, wherein the disease is a LSD1-mediated disease.
  • One aspect of the present application provides a method for preventing or treating a disease or condition in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt, an isomer or an isotope label thereof, wherein the disease is a tumor.
  • LSD1-mediated diseases include diseases caused by high expression of LSD1.
  • the tumor includes but is not limited to neuroblastoma, breast cancer, blood tumor (such as leukemia), small cell lung cancer and Ewing's sarcoma.
  • the dosage of the compound can be in the range of about 0.001 mg/kg body weight/day to about 1000 mg/kg body weight/day. In other embodiments, dosage levels below the lower limit of the above range may be sufficient. In other embodiments, dosage levels higher than the upper limit of the above range may be required.
  • the compound is administered in a single dose, once a day. In other embodiments, the compound is administered in multiple doses, more than once a day.
  • the individual to whom the pharmaceutical composition is administered is a mammal. In some embodiments, the compound or pharmaceutical composition can be administered orally or parenterally. In some embodiments, the individual to whom the administration is administered can be a mammal, such as a primate, such as a human.
  • the manufacturer's instructions for the use of the kit can be used, or reactions and purifications can be carried out in a manner known in the art or as described in this application.
  • the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification.
  • groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds.
  • substituents When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2- .
  • alkyl as used herein includes optionally substituted alkyl.
  • optionally substituted alkyl refers to "unsubstituted alkyl” (alkyl not substituted by substituents) or “substituted alkyl” (alkyl substituted by substituents).
  • substituted means that one or more hydrogens on a specified atom are replaced with the specified radical and if the normal valency of the specified atom is not exceeded under existing conditions, the substitution results in a stable compound.
  • C 1-n includes C 1-6 and C 3-10 .
  • C 1-6 refers to a group having 1 to 6 carbon atoms.
  • alkyl refers to an optionally substituted straight chain or optionally substituted branched aliphatic hydrocarbon.
  • Alkyl herein, for example, has 1-10 carbon atoms, has 1-8 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms.
  • alkyl groups herein include, but are not limited to, methyl, ethyl, propyl, and the like.
  • C 1-6 alkyl refers to an alkyl group that can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
  • alkyl used in combination herein includes alkyl groups combined with other groups, for example, alkyl groups in alkoxy groups, alkyl groups in alkylthio groups, hydroxyalkyl groups, haloalkyl groups, cyanoalkyl groups, "alkyl” groups in alkylamino groups (such as monoalkylamino groups, dialkylamino groups), and the like.
  • alkoxy refers to an alkyl ether group (-O-alkyl).
  • alkoxy include methoxy, ethoxy, and the like.
  • the alkenyl group has, but is not limited to, 2-10 carbon atoms, or 2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms.
  • C 2-6 alkenyl refers to an alkenyl group that can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
  • halo or "halogen substitution” used herein, alone or in combination, refers to an optionally substituted group (such as an alkyl) wherein one or more hydrogen atoms are replaced with fluorine, chlorine, bromine, iodine atoms or a combination thereof.
  • two or more hydrogen atoms are replaced with halogen atoms that are identical to each other (e.g., difluoromethyl, trifluoromethyl); in other embodiments, two or more hydrogen atoms are replaced with halogen atoms that are not identical to each other (e.g., 1-chloro-1-fluoro-1-iodoethyl).
  • aromatic ring as used herein, alone or in combination, includes aryl and heteroaryl groups.
  • aryl used herein alone or in combination refers to an optionally substituted aromatic hydrocarbon group having 6-20, such as 6-12 or 6-10 ring-forming carbon atoms. It can be a fused aromatic ring or a non-fused aromatic ring.
  • the fused aromatic ring contains a ring of 2-4 aromatic rings fused together, and the other independent rings can be alicyclic (carbocyclic), heterocyclic, aromatic, aromatic heterocyclic (i.e., heteroaryl) or any combination thereof.
  • the aryl herein includes monocyclic, bicyclic, tricyclic or more cyclic aromatic groups.
  • Non-limiting examples of monocyclic aromatic groups include monocyclic aromatic groups of 6 to 12, 6 to 10 or 6 to 8 ring-forming carbon atoms, such as phenyl; fused ring aromatic groups include bicyclic, tricyclic or more cyclic aromatic groups, such as naphthyl, phenanthrenyl, anthracenyl; non-fused biaryl groups include biphenyl.
  • heteroaryl used herein alone or in combination refers to an arbitrarily substituted monovalent heteroaryl group, which contains about 5 to 20, such as 5 to 12 or 5 to 10 skeleton ring atoms, which contains at least one heteroatom (such as 1-4, 1-3, 1-2 heteroatoms) as a skeleton ring atom, and the heteroatom is independently selected from the heteroatoms in oxygen, nitrogen, and sulfur, but is not limited thereto.
  • the ring of the group does not contain two adjacent O or S atoms.
  • Heteroaryl includes monocyclic heteroaryl or polycyclic heteroaryl (e.g., bicyclic heteroaryl, tricyclic heteroaryl, etc.).
  • heteroaryl includes optionally substituted monovalent fused or non-fused heteroaryl groups having at least one heteroatom.
  • heteroaryl also includes fused and non-fused heteroaryl containing 5 to about 12 skeleton ring atoms, and fused and non-fused heteroaryl containing 5 to about 10 skeleton ring atoms. Can be combined with heteroaryl by carbon atoms or heteroatoms.
  • imidazole can be connected to the parent molecule by its arbitrary carbon atom (imidazole-2-yl, imidazole-4-yl or imidazole-5-yl) or its nitrogen atom (imidazole-1-yl or imidazole-3-yl).
  • heteroaryl groups can be further substituted by any or all of its carbon atoms and/or any or all of its heteroatoms.
  • the fused heteroaryl can include fused rings of 2-4 aromatic heterocycles, and other independent rings can be alicyclic, heterocyclic, aryl, heteroaryl or any combination thereof.
  • Non-limiting examples of monocyclic heteroaryl groups include monocyclic heteroaryl groups with 5 to 12, 5 to 10, 5 to 7 or 6 backbone ring atoms.
  • Examples of heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, and the like.
  • heterocycle or “heterocyclyl” used herein alone or in combination refers to a non-aromatic heterocycle, including heterocycloalkyl (saturated heterocyclyl) and heterocycloalkenyl (unsaturated heterocyclyl). It contains at least one heteroatom (such as 1-4, 1-3, 1-2 heteroatoms) as a skeleton ring atom, and the heteroatom is, for example, an oxygen, nitrogen or sulfur atom.
  • the heterocyclyl may include a monocyclic heterocyclyl (a heterocyclyl has one ring) or a polycyclic heterocyclyl (for example, a bicyclic heterocyclyl (a heterocyclyl has two rings), a tricyclic heterocyclyl, etc.).
  • the bicyclic heterocyclyl may be a spirocycle or a bridged ring.
  • the heterocyclyl may have 3 to 20, such as 3-10, 3-8, 5-8 or 5-6 ring atoms.
  • the heterocyclyl having one or more aromatic fusions may be connected to other groups through an aromatic ring or a non-aromatic ring portion. Other groups may be combined with the heterocycle through a heteroatom or a carbon atom (i.e., the heterocycle is connected to the parent molecule or further substituted).
  • cycloalkyl refers to a non-aromatic saturated carbocyclic ring.
  • a cycloalkyl group may be a monocyclic cycloalkyl group or a polycyclic cycloalkyl group (e.g., having 2, 3 or 4 rings; such as a bicyclic cycloalkyl group), which may be a spirocyclic ring or a bridged ring.
  • a cycloalkyl group may have 3-10 ring-forming carbon atoms, 3-8 or 3-6 ring-forming carbon atoms.
  • a cycloalkyl group may also include a ring having one or more aromatic rings fused (i.e., having a common bond).
  • a cycloalkyl group having one or more aromatic fusions may be connected to other groups through portions of aromatic or non-aromatic rings.
  • Examples of cycloalkyl groups include cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • cycloalkenyl refers to a non-aromatic double-bonded carbocyclic ring.
  • the cycloalkenyl group can be a monocyclic or polycyclic cycloalkenyl group (e.g., having 2, 3, or 4 rings), which can be a spirocyclic ring or a bridged ring.
  • the cycloalkenyl group can have 3-10 ring-forming carbon atoms, 3-8, or 3-6 ring-forming carbon atoms.
  • Halogen refers to fluorine, chlorine, bromine and iodine, for example fluorine.
  • Cyano refers to "-CN”.
  • Amino refers to " -NH2 ".
  • isomer refers to an isomer produced by different spatial arrangements of atoms in a molecule.
  • the compounds described herein include all isomers thereof.
  • the compounds of the present application include racemates, enantiomers, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., individual enantiomers) thereof.
  • stereochemical descriptions it is meant that there is an isomer therein and the compound is substantially free of another isomer.
  • “Substantially free of" another isomer means that the ratio of the two isomers is at least 80/20, more preferably 90/10, or 95/5 or higher. In some embodiments, an isomer will be present in an amount of at least 99%.
  • isotope label refers to a compound of the present application in which one or more constituent atoms are replaced by their isotope atoms.
  • the compound of the present application may contain an atomic isotope in a non-natural ratio on one or more atoms constituting the compound.
  • a radioactive isotope labelled compound may be used, such as deuterium ( 2H ), tritium ( 3H ), iodine 125 ( 125I ) or C14 ( 14C ). All isotopic composition changes of the compound of the present application, whether radioactive or not, are included in the scope of the present application.
  • H is deuterium or tritium.
  • subject refers to an individual suffering from a disease, disorder or condition, etc., including mammals and non-mammals.
  • the mammal is a human.
  • the term "treat” and other similar synonyms include alleviating, relieving or ameliorating symptoms of a disease or condition, inhibiting a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, making a disease or condition better, alleviating symptoms caused by a disease or condition, or stopping symptoms of a disease or condition, preventing other symptoms, improving or preventing the underlying metabolic causes of symptoms, and in addition, the term includes the purpose of prevention.
  • the term also includes obtaining a therapeutic effect and/or a prophylactic effect.
  • the therapeutic effect refers to the cure or improvement of the underlying disease being treated.
  • the cure or improvement of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, the patient's condition is observed to improve.
  • the composition can be administered to a patient at risk for a particular disease, or even if a disease diagnosis has not yet been made, the composition can be administered to a patient who has one or more physiological symptoms of the disease.
  • an "effective amount” or “therapeutically effective amount” refers to an amount of at least one active substance (such as a compound of the present application) sufficient to relieve to some extent one or more symptoms of the disease or condition being treated. The result may be signs, symptoms or causes of The reduction and/or alleviation of a disease, or any other desired change in a biological system.
  • an "effective amount” for treatment is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant symptom alleviation effect. Techniques such as dose escalation trials can be used to determine the effective amount suitable for any individual case.
  • administration refers to methods that enable a compound or composition to be delivered to the desired site for biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application and is relatively non-toxic, that is, the substance can be administered to a subject without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.
  • pharmaceutical composition refers to a mixture of the compound of the present application and at least one pharmaceutically acceptable substance.
  • the pharmaceutically acceptable substance includes, but is not limited to, a carrier, a stabilizer, a diluent, a dispersant, a suspending agent, a thickener and/or an excipient.
  • carrier refers to a relatively nontoxic substance that facilitates the introduction of a compound of the present application into cells or tissues.
  • pharmaceutically acceptable salt refers to a salt form in which the basic group in the parent compound is converted, which retains the biological effectiveness of the free base compound and has no adverse effects biologically or otherwise.
  • Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amine (amino) groups.
  • the compounds of the present application or salts, isomers or isotopically labeled thereof can be prepared using known organic synthesis techniques and can be prepared according to any of a number of possible synthetic routes, such as those described below.
  • EX4-06 (1.60 g, 4.54 mmol) and EX1-01 (1.26 g, 5.45 mmol) were dissolved in a solution of dioxane (20 mL) and water (5 mL), and Pd(dppf)Cl 2 (0.330 g, 0.454 mmol) and potassium carbonate (1.25 g, 9.08 mmol) were added.
  • the reaction solution was heated to 90°C under a nitrogen atmosphere and stirred for 12 hours.
  • the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL*3). The combined organic phases were washed with saturated brine (50 mL) and the mixture was stirred for 2 hours.
  • EX40-01a (5.0 g, 25.4 mmol) was dissolved in anhydrous N,N-dimethylformamide (50 mL), potassium hydroxide (5.0 g, 88.8 mmol) was added, and iodine (9.0 g, 35.5 mmol) was slowly added in an ice-water bath. The reaction solution was stirred at 25°C for 4 hours. After the reaction was completed, the reaction solution was poured into 1.5% ammonia water, filtered, and the filter cake was vacuum dried to obtain EX40-01 (7.0 g, yield 85.4%).
  • EX40-01 (3.00 g, 9.29 mmol) was dissolved in anhydrous dichloromethane (30 mL), and 4-cyano-3-fluorophenylboronic acid (3.10 g, 18.5 mmol) was added.
  • Molecular sieves (3.00g), pyridine (2.25mL, 27.8mmol) and copper acetate (3.40g, 18.6mmol)
  • the reaction solution was stirred at 25°C under an oxygen atmosphere for 16 hours. After the reaction was completed, the filtrate was filtered, diluted with water (30mL), and extracted with dichloromethane (50mL x 3).
  • EX52-03a (1.89 g, 7.89 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and LiBHEt 3 (8.68 mL, 8.68 mmol) was added in an ice bath under nitrogen atmosphere. The reaction solution was warmed to room temperature and stirred for 2 hours. The reaction was quenched with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered.
  • EX52-04a (379 mg, 1.571 mmol) was dissolved in anhydrous dichloromethane (4 mL) and trifluoroacetic acid (0.8 mL, 0.186 mmol) was added. The reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product EX52-05a (360 mg, 1.41 mmol).
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 8.85-8.26 (m, 2H), 3.95 (brs, 2H), 2.11–2.00 (m, 2H), 1.97-1.83 (m, 4H), 1.79-1.70 (m, 2H), 1.33 (s, 3H).
  • EX52-03b (253 mg, 1.06 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and LiBHEt 3 (1.16 mL, 1.16 mmol) was added in an ice bath under nitrogen atmosphere. The reaction solution was warmed to room temperature and stirred for 2 hours. The reaction was quenched with saturated ammonium chloride solution (5 mL), and the tetrahydrofuran was removed by vacuum concentration, and then diluted with water (10 mL) and extracted with ethyl acetate (10 mL ⁇ 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • EX52-04b (148 mg, 0.613 mmol) was dissolved in anhydrous dichloromethane (3 mL) and TFA (0.6 mL, 0.613 mmol) was added. The reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product EX52-05b.
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 8.81-8.27 (m, 2H), 4.02–3.85 (m, 2H), 2.33–2.24 (m, 2H), 1.92-1.80 (m, 4H), 1.79-1.72 (m, 2H), 1.07 (s, 3H).
  • EX53-02 (200 mg, 0.865 mmol) was dissolved in tetrahydrofuran (5 mL), sodium hydrogen (173.0 mg, 4.33 mmol) was added at 0 ° C and stirred for 15 minutes, then iodomethane (0.220 mL, 3.46 mmol) was slowly added at 0 ° C, and the reaction solution was stirred at 25 ° C for 2 hours under nitrogen protection. The reaction solution was quenched with saturated ammonium chloride (10 mL) and extracted with ethyl acetate (10 mL*3).
  • EX65-01 (100 mg, 0.407 mmol) was dissolved in anhydrous methanol (1 mL), and wet palladium carbon (100 mg, 0.940 mmol) was added. The reaction solution was stirred at room temperature for 12 hours under a hydrogen atmosphere (45 psi). After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound EX65-02 (30.0 mg, yield 47.4%).
  • EX69-01 (300 mg, 1.25 mmol) was dissolved in THF (3 mL), and 3 M methylmagnesium bromide solution (0.84 mL, 2.51 mmol) was slowly added dropwise under an ice-water bath. After the addition was completed, the reaction solution was stirred at room temperature for 2 hours. The reaction solution was quenched and diluted with water (10 mL), extracted with ethyl acetate (30 mL*3), the organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product EX69-02 (270 mg, yield 84.3%).
  • EX69-02 (300 mg, 1.175 mmol) was dissolved in 4M hydrochloric acid/dioxane (5 mL) and stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product EX69-03 (180 mg, yield 98.7%).
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 9.75-9.25 (m, 1H), 7.95-7.57 (m, 1H), 3.38-2.94 (m 1H), 2.21-1.73 (m, 3H), 1.72-1.36 (m, 5H), 1.27 (s, 3H).
  • EX71-02 (270 mg, 1.05 mmol) was dissolved in 4M hydrochloric acid/dioxane (3 mL) and stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure to obtain EX71-03 (200 mg, yield 98.4%).
  • EX53-01 (1.00 g, 4.65 mmol) was dissolved in methanol (30 mL), and sodium borohydride (280 mg, 6.50 mmol) was slowly added at 0 ° C. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, it was quenched and diluted with saturated aqueous ammonium chloride solution (50 ml) under an ice bath, and extracted with ethyl acetate (50 mL * 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product EX73-01a (1.10 g, yield 87.2%).
  • EX74-01 (804 mg, 2.30 mmol) and p-toluenesulfonic acid (594 mg, 3.45 mmol) were dissolved in water (2 ml), dimethyl sulfoxide (5 ml) and toluene (10 ml) at room temperature, and the temperature was raised to 100 ° C and stirred for 16 hours. After the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (5 ml), and extracted with ethyl acetate (20 mL * 3). After the organic phases were combined, they were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried.
  • EX74-02 (300 mg, 1.38 mmol) was dissolved in methanol (12 mL), and 10% wet palladium carbon (60 mg, 0.564 mmol) was added. The reaction solution was stirred at room temperature for 12 hours under a hydrogen atmosphere (45 psi). After the reaction was completed, the palladium carbon was recovered by filtration, and the filter cake was washed with methanol (30 mL). The filtrate was combined and concentrated under reduced pressure to dryness to obtain the target product EX74-03 (130 mg, yield 74.0%).
  • reaction solution was quenched with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (30 mL*3), the organic phases were combined, washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • EX79-02 (300 mg, 1.24 mmol) was dissolved in 4M hydrochloric acid/dioxane (3 mL) and stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure to obtain EX79-03 (hydrochloride) (220 mg, 99.6%).
  • EX88-01 (5.00 g, 34.22 mmol) was dissolved in ethyl acetate (5.0 mL), sodium ethoxide (11.7 g, 34.22 mmol) was added, and the reaction solution was stirred at 80°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain EX88-02 (6.6 g, yield 91.7%).
  • EX88-02 (5.60 g, 26.6 mmol) was dissolved in water (50 mL), and a mixture of 3-aminopyrazole (2.20 g, 26.6 mmol) in water (50 mL) and acetic acid (39.7 mL, 693 mmol) was added. The reaction solution was stirred at 85°C for 16 hours. After cooling to room temperature, the reaction solution was filtered and the filter cake was dried under vacuum to obtain EX88-03 (1.42 g, yield 25.7%).
  • EX88-03 (1.42 g, 6.85 mmol) was dissolved in toluene (24 mL), and DBU (1.23 mL, 8.22 mmol) was added. The reaction solution was stirred at 25 °C for 10 minutes, and then a toluene (12 mL) solution of phosphorus oxychloride (0.70 mL, 7.54 mmol) was added. The reaction solution was stirred at 110 °C for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed with petroleum ether/ethyl acetate (5/1, 5 mL), filtered, and the filter cake was removed under reduced pressure and dried to obtain EX88-04 (1.48 g, 95.7%).
  • EX88-05 (2.30 g, 6.54 mmol) was dissolved in dichloromethane (200 mL), and 4-cyano-3-fluorophenylboronic acid (2.16 g, 13.1 mmol), copper acetate (2.38 g, 13.1 mmol), 4A molecular sieve (2.00 g) and pyridine (1.58 mL, 19.6 mmol) were added.
  • the reaction solution was stirred at room temperature under an oxygen atmosphere for 48 hours.
  • reaction solution was adjusted to pH ⁇ 8 by adding sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (50 mL*3), and the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness.
  • EX101-01 (15.0 g, 90.3 mmol) was dissolved in acetic acid (100 mL) and water (100 mL), 1H-pyrazole-3-amine (7.50 g, 90.3 mmol) was added, and the reaction solution was stirred at 80°C for 8 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain EX101-02 (7.66 g, yield 45.8%).
  • EX101-04 (1.30 g, 3.95 mmol) was dissolved in dichloromethane (20 mL), and 4-cyano-3-fluorophenylboronic acid (1.30 g, 7.89 mmol), pyridine (0.96 mL, 11.8 mmol), 4A molecular sieve (1.30 g) and copper acetate (1.43 g, 7.89 mmol) were added.
  • the reaction solution was stirred at 25 ° C for 48 hours under an oxygen atmosphere.
  • EX102-01 (2.0 g, 11.2 mmol) was dissolved in THF (30 mL). The reaction solution was cooled to -78 ° C under nitrogen protection and then 2.5 M n-butyl lithium n-hexane solution (4.95 mL, 12.4 mmol) was slowly added. The reaction solution was stirred at -78 ° C for 30 minutes, and DMF (1.58 mL, 1.50 mmol) was slowly added. The reaction solution was stirred at -78 ° C for 3 hours. After the reaction was completed, saturated ammonium chloride solution (30 mL) was added to quench and dilute, and the reaction solution was extracted with ethyl acetate (30 mL * 3).
  • EX102-04 (600 mg, 1.94 mmol) was dissolved in dichloromethane (2 mL), and 4-cyano-3-fluorophenylboronic acid (639 mg, 3.88 mmol), pyridine (0.470 mL, 5.82 mmol), 4A molecular sieve (600 mg) and copper acetate (704 mg, 3.88 mmol) were added.
  • the reaction solution was stirred at 25 ° C for 48 hours under an oxygen atmosphere.
  • LCMS: MS m/z (ESI) [M+H] + 429.0.
  • Example EX2 was prepared by using EX1-01 and (2-methylphenyl)boric acid as raw materials through the same synthesis route as EX1.
  • EX10-01 (0.57 g, 1.47 mmol) was dissolved in 4M hydrochloric acid 1,4-dioxane solution (10 mL), and tert-butyl N-(4-piperidinyl)carbamate (0.740 g, 3.68 mmol), cesium carbonate (1.44 g, 4.42 mmol), sodium iodide (40.0 mg, 0.294 mmol) and RuPhos-Pd-G2 (110 mg, 0.147 mmol) were added.
  • the reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 hours.
  • the reaction solution was cooled to room temperature, diluted with water (3 mL), and extracted with ethyl acetate (10 mL*3).
  • Example EX14 was prepared by the same route as EX13 using EX14-01 and 4,4-difluoropiperidine as raw materials.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 19%-59%, 9 minutes).
  • Example EX16 was prepared by the same route as EX11 using EX4-01 and MeMgBr as raw materials.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 47%-77%, 8 minutes).
  • Example EX17 was prepared by the same route as EX13 using EX9-01 and 4-methoxy-4-methylpiperidine hydrochloride as raw materials.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 20%-60%, 9 minutes).
  • EX9-01 500 mg, 1.43 mmol was dissolved in dioxane (5 mL), and tert-butyl piperidine-4-carbamate (286 mg, 1.43 mmol), Pd(dba) 3 (115 mg, 0.143 mmol), Xantphos (165 mg, 0.285 mmol) and cesium carbonate (1.40 g, 4.28 mmol) were added.
  • the reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 hours.
  • the reaction solution was diluted with ethyl acetate (10 mL) and water (5 mL).
  • EX18-01 (420 mg, 0.894 mmol) was dissolved in 4M hydrochloric acid 1,4-dioxane solution (10 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried to obtain EX18-02 (310 mg).
  • LCMS: MS m/z (ESI) [M+H] + 370.1.
  • EX18-04 (30.0 mg, 0.052 mmol) was dissolved in 4M hydrochloric acid 1,4-dioxane solution (1 mL) and stirred at room temperature for 1 hour.
  • the reaction solution was subjected to preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 7%-37%, 8 minutes) to obtain EX18.
  • Example EX19 was prepared by the same route as EX18 using EX18-02, methyl chloroformate and piperidine-4-carbamic acid tert-butyl ester as raw materials.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 5%-32%, 8 minutes).
  • EX20-02 (0.96 g, 3.15 mmol) was dissolved in 1,4-dioxane (20 mL), and bis(boronic acid) pinacol ester (1.20 g, 3.15 mmol), potassium acetate (0.93 g, 9.46 mmol) and Pd(dppf)Cl 2 (0.12 g, 0.320 mmol) were added.
  • the reaction solution was heated to 100 °C and stirred for 3 hours under nitrogen protection.
  • the reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (100 mL x 3).
  • EX20-03 (230 mg, 0.856 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL), and EX9-01 (300 mg, 0.87 mmol), potassium carbonate (237 mg, 1.71 mmol) and Pd(dppf)Cl 2 (62.6 mg, 90.0 umol) were added.
  • the reaction solution was heated to 100 °C and stirred for 3 hours under nitrogen protection.
  • the reaction solution was cooled to room temperature, diluted with water (6 mL), and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried.
  • EX20-04 200 mg, 0.40 mmol was dissolved in 1,4-dioxane (2 mL), and tert-butyl piperidine-4-carbamate (243 mg, 1.21 mmol), cesium carbonate (395 mg, 1.21 mmol), NaI (12.1 mg, 0.08 mmol) and RuPhos Pd G 2 (31.4 mg, 40.0 mmol) were added.
  • the reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection.
  • the reaction solution was cooled to room temperature, diluted with water (6 mL), and extracted with ethyl acetate (20 mL x 3).
  • Example EX21 was prepared by the same route as EX20 using EX21-03, EX9-01 and piperidine-4-carbamic acid tert-butyl ester as raw materials.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-40%, 11 minutes).
  • Example EX22 was prepared by the same route as EX20 using EX21-03, EX14-01 and piperidine-4-carbamic acid tert-butyl ester as raw materials.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 15%-35%, 11 min).
  • Example EX23 was prepared by the same route as EX13 using EX14-01, 4,4-difluoropiperidine and (3S,4S)-4-tert-butylcarbamate-3-fluoropiperidine as raw materials.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-50%, 8 minutes).
  • Example EX25 was prepared by the same route as EX24 using EX24-02, methyl chloroformate and tert-butyl piperidine-4-carbamate as raw materials.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 25%-45%, 11 minutes).
  • EX26-05 (202 mg, 0.294 mmol) was dissolved in methanol (4 mL) and p-toluenesulfonic acid (253 mg, 1.47 mmol) was added. The reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the crude product was subjected to preparative HPLC (column: Boston Prime C18150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 18%-48%, 8 minutes) to obtain a mixture of EX26 and EX27. EX26 and EX27 were separated and purified by SFC (column: DAICEL CHIRALPAK AS (250mm*30mm, 10um); mobile phase: [0.1% ammonia/ethanol]; B%: 50%-50%, 45min).
  • Example EX28, EX29 was prepared by the same route as EX26 using (S)-piperidin-3-ylcarbamic acid tert-butyl ester as raw material.
  • Preparative HPLC columnumn: C18-1 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 19%-59%, 9 minutes).
  • Preparative SFC columnumn: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [0.1% ammonia. n-Heptane-IPA]; B%: 55%-55%).
  • Examples EX30 and EX31 were prepared by using (R)-3-(Boc-amino)pyrrolidine as raw material through the same route as EX26.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 18%-48%, 8 minutes).
  • SFC columnumn: DAICEL CHIRALPAK AS (250mm*30mm, 10um); mobile phase: [0.1% ammonia/ethanol]; B%: 55%-55%, 45min).
  • Examples EX32 and EX33 were prepared by using (S)-3-(Boc-amino)pyrrolidine as raw material through the same route as EX26.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 25%-55%, 8 minutes).
  • SFC columnumn: DAICEL CHIRALCEL OD (250mm*30mm, 10um); mobile phase: [0.1% ammonia.ethanol]; B%: 45%-45%).
  • EX34-01 (5 g, 43.8 mmol) was dissolved in DCM (100 mL), and diisopropylethylamine (13.2 g, 87.6 mmol) and tert-butyldimethylsilyl chloride (7.26 g, 48.2 mmol) were added. The reaction solution was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). After the organic phases were combined, they were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness.
  • the reaction solution was quenched with saturated ammonium chloride solution (50 mL) at 0 °C, extracted with ethyl acetate (80 mL x 3), and the organic phases were combined, washed with saturated brine (50 mL), dried, filtered, and concentrated under reduced pressure.
  • EX34-03 (1.0 g, 2.77 mmol) was dissolved in 1,4-dioxane (50 mL), and bis-boronic acid pinacol ester (0.80 g, 3.33 mmol) and potassium acetate (0.50 g, 5.55 mmol) were added.
  • the reaction solution was heated to 80 ° C under nitrogen protection and stirred for 12 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried.
  • EX34-04 (290 mg, 0.856 mmol) was dissolved in 1,4-dioxane (2.4 mL) and water (0.6 ml), and EX9-01 (300 mg, 0.856 mmol), Pd(dppf)Cl 2 (62.6 mg, 0.086 mmol) and potassium carbonate (355 mg, 2.57 mmol) were added.
  • the reaction solution was heated to 100°C under nitrogen protection and stirred for 12 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried.
  • EX34-05 (170 mg, 0.353 mmol) was dissolved in 1,4-dioxane (2 mL), and tert-butyl piperidine-4-carbamate (77.7 mg, 0.388 mmol), RuPhos Pd G2 (27.4 mg, 0.035 mmol), sodium iodide (26.4 mg, 0.176 mmol) and cesium carbonate (345 mg, 1.06 mmol) were added.
  • the reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 hours. After the reaction was completed, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3).
  • EX34-06 (130 mg, 0.201 mmol) was dissolved in methanol (0.5 mL), and p-toluenesulfonic acid (173 mg, 1.01 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Phenomenex C1875*30mm*3um; mobile phase: [water (ammonia)-acetonitrile]; B%: 33%-73%, 9 minutes) to obtain EX34 (18.91 mg, yield 21.6%).
  • Example EX36 was prepared by the same route as EX35 using EX5-02, (3S, 4R)-3-fluoropiperidin-4-yl)carbamic acid tert-butyl ester as raw material.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 20%-60%, 9 minutes).
  • Example EX37 was prepared by the same route as EX35 using EX5-02, (3R, 4R)-3-fluoropiperidin-4-yl)carbamic acid tert-butyl ester as raw material.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 38%-68%, 9 minutes).
  • Example EX38 was prepared by the same route as EX16 using EX9-01 and EX16-05 as raw materials.
  • Preparative HPLC column: phenomenex C18 (75 mm*30 mm, 3 um); mobile phase: [water (ammonia water)-acetonitrile]; B%: 43%-83%, 9 minutes).
  • Example EX39 was prepared by the same route as EX13 using EX9-01,4,5,6,7-tetrahydropyrazolo[1,5-A]pyrazine dihydrochloride as raw material.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-40%, 11 minutes).
  • Example EX41 was prepared by the same route as EX40 using EX40-03, 2-oxa-5-azabicyclo[2.2.2]octane hemioxalate as raw material.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 16%-46%, 8min).
  • Example EX42 was prepared by the same route as EX40 using EX40-03,6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride as raw material.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 61%-100%, 9 minutes).
  • Example EX43 was prepared by the same route as EX40 using EX40-03 and EX43-02 as raw materials.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 30%-50%, 16 min).
  • Example EX44 was prepared by the same route as EX43 using EX40-03 and EX44-02 as raw materials.
  • Example EX45 was prepared from EX40-03, 7-oxa-2-azaspiro[3.5]nonane hydrochloride by the same route as EX40.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 18%-58%, 9min).
  • Example EX46 was prepared from EX40-03, 2-oxa-7-azaspiro[3.5]nonane by the same route as EX40.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 40%-70%, 8 minutes).
  • Example EX47 was prepared by the same route as EX10 using EX9-01, 4-(trifluoromethyl)piperidin-4-ol as raw material.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 42%-72%, 8 minutes).
  • EX40-03 120 mg, 0.233 mmol was dissolved in dioxane (1 mL), and EX49-04 (50.0 mg, 0.278 mmol), RuPhos Pd G2 (16.3 mg, 21.0 umol), sodium iodide (6.30 mg, 42.0 umol) and cesium carbonate (205 mg, 0.628 mmol) were added.
  • EX50-05 (150 mg, 0.282 mmol) was dissolved in 1,4-dioxane (2 mL), and 4-methoxy-4-methylpiperidine hydrochloride (56.1 mg, 0.338 mmol), RuPhos Pd G 2 (21.9 mg, 0.028 mmol), cesium carbonate (184 mg, 0.563 mmol) and sodium iodide (8.40 mg, 0.056 mmol) were added.
  • the reaction solution was heated to 100 ° C under nitrogen protection and stirred for 18 hours.
  • the reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL*3).
  • EX51-01 200 mg, 0.843 mmol was dissolved in 1,4-dioxane (2 mL), and 4 M hydrochloric acid/dioxane solution (2 mL) was added. The reaction solution was stirred at 25°C for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain EX51-02 (130 mg, yield 88.3%).
  • Example EX51 was prepared by the same route as EX40 using EX51-02 and EX40-03 as raw materials.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 42%-72%, 8 minutes).
  • Example EX52 was prepared by the same route as EX40 using EX52-05b and EX40-03 as raw materials.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 5%-45%, 9 minutes).
  • Example EX53 was prepared by the same route as EX40 using EX53-03 and EX40-03 as raw materials.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 18%-48%, 8min).
  • Example EX54 was prepared from EX10-01, tert-butyl (R)-pyrrolidin-3-ylcarbamate, by the same route as EX10.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 33%-63%, 8 minutes).
  • Example EX55 was prepared from EX5-02,2-methylpropane-2-yl ⁇ [(1R,5S)-8-azabicyclo[3.2.1]octan-3-yl]carbamate by the same route as EX5.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 50%-70%, 11 minutes).
  • Example EX56 was prepared from EX5-02,2-methylpropane-2-yl ⁇ [(1S,5R,8s)-3-azabicyclo[3.2.1]octan-8-yl]carbamate by the same route as EX5.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 53%-73%, 11 minutes).
  • Example EX57 was prepared from EX5-02,2-methylpropane-2-yl ⁇ [(1S,5R,8r)-3-azabicyclo[3.2.1]octan-8-yl]carbamate by the same route as EX5.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 53%-73%, 11 minutes).
  • EX59-01 (5.61 g, 24.2 mmol) was dissolved in N, N-dimethylformamide (100 mL), and N-iodosuccinimide (6.60 mL, 135 mmol) was added. The reaction solution was stirred at room temperature for 18 hours. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (200 mL), and washed with a mixed solution of sodium bicarbonate (50 mL) and sodium thiosulfate (50 mL), and saturated brine (50 mL) in sequence.
  • EX59-05 (100 mg, 81.0 umol) was dissolved in 1,4-dioxane (1.5 mL) and water (0.3 mL), and EX4-06 (42.7 mg, 0.121 mmol), Pd(dppf)Cl 2 (5.90 mg, 8.00 umol) and potassium carbonate (33.5 mg, 0.242 mmol) were added.
  • the reaction solution was heated to 100 °C under nitrogen protection and stirred for 18 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL*3).
  • EX60-01 (3.00 g, 14.2 mmol) was dissolved in N,N-dimethylformamide (100 mL), and N-iodosuccinimide (4.80 g, 21.3 mmol) was added under ice-water bath, and the reaction solution was stirred at 25°C for 4 hours.
  • EX60-02 (4.70 g, 14.0 mmol) was dissolved in dichloromethane (100 mL), and 4-cyano-3-fluorophenylboronic acid (4.60 g, 27.9 mmol) and copper acetate (5.10 g, 27.9 mmol) were added.
  • Molecular sieves (4.50 g) and pyridine (3.38 mL, 41.8 mmol)
  • the reaction solution was stirred at 25 ° C for 16 hours under an oxygen atmosphere.
  • EX60-03 (4.60 g, 10.1 mmol) was dissolved in dioxane (300 mL), and tert-butyl N-(piperidin-4-yl)aminomethyl ester (2.02 mg, 10.1 mmol), Pd 2 (dba) 3 (923 mg, 1.01 mmol), Xantphos (1.17 g, 2.02 mmol) and cesium carbonate (6.57 g, 20.2 mmol) were added. The reaction solution was heated to 100°C under nitrogen atmosphere and stirred for 12 hours.
  • EX60-04 (1.30 g, 2.46 mmol) was dissolved in water (5 mL) and dioxane (30 mL), and EX4-06 (1.30 g, 3.69 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (II) (180 mg, 0.246 mmol), and potassium carbonate (680 mg, 4.92 mmol) were added.
  • the reaction solution was heated to 100 ° C under nitrogen atmosphere and stirred for 16 hours.
  • EX60-05 (300 mg, 0.445 mmol) was dissolved in methanol (2 mL), 4-toluenesulfonic acid (383 mg, 2.23 mmol) was added, and the reaction solution was stirred at 25°C for 16 hours.
  • LCMS detected that the reaction was complete, and the reaction solution was purified by preparative HPLC (column: Xtimate C18 150*40mm*5um; mobile phase: [water (ammonia water + ammonium bicarbonate)-acetonitrile]; B%: 30%-70%, 9 minutes) to obtain EX60.
  • Example EX62 was prepared by the same route as EX10 using EX10-01, piperidin-3-ylcarbamic acid tert-butyl ester as raw material.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 33%-63%, 8 minutes).
  • Example EX63 was prepared from EX40-03, 8-oxo-3-azabicyclo[3.2.1]octane hydrochloride by the same route as EX40.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 20%-60%, 9 minutes).
  • EX12-03a (1.00 g, 2.51 mmol) and EX53-03 (0.800 g, 2.83 mmol) were dissolved in 1-methyl-2-pyrrolidone (15.0 mL), and cesium carbonate (1.00 g, 7.53 mmol) was added.
  • the reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was diluted with water (20 mL) and extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with water (15 mL x 3) and saturated brine (15 mL) in turn, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried.
  • EX64-02 (280 mg, 0.486 mmol) was dissolved in methanol (2.0 mL), and p-toluenesulfonic acid (418 mg, 2.43 mmol) was added. The reaction solution was stirred at room temperature for 12 hours. After the reaction solution was concentrated under reduced pressure, it was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia water, ammonium bicarbonate)-acetonitrile]; B%: 60%-90%, 8 minutes) to obtain EX64.
  • Example EX65 was prepared by the same route as EX64 using EX12-03a and EX65-02 as raw materials.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 28%-58%, 8 minutes).
  • EX66-03 200 mg, 0.500 mmol
  • EX66-03 196 mg, 0.550 mmol
  • N-methylpyrrolidone 2 mL
  • potassium carbonate 208 mg, 1.50 mmol
  • the reaction solution was heated to 100 ° C and stirred for 12 hours.
  • water 5 mL
  • ethyl acetate 4 mL*3
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried.
  • EX66-04 100 mg, 0.200 mmol was dissolved in dioxane (2 mL), and 4-tert-butyloxycarbonyl-amino-piperidine (47.7 mg, 0.24 mmol), Xantphos (5.7 mg, 0.010 mmol), Pd 2 (dba) 3 (18.20 mg, 0.020 mmol) and cesium carbonate (129.2 mg, 0.397 mmol) were added.
  • the reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 hours.
  • EX67-01 (3.78 g, 19.1 mmol) was dissolved in ethanol (56 mL), and 9% sodium hypochlorite solution (63.2 mL, 195 mmol) was slowly added under ice-water bath. The reaction solution was stirred at 25°C for 10 minutes. TLC showed a new spot was generated. The mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL*3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • EX67-03 400 mg, 1.138 mmol was dissolved in 1,4-dioxane (2.5 ml) and water (0.5 mL), and EX4-06 (441.0 mg, 1.251 mmol), potassium carbonate (471.7 mg, 3.413 mmol) and Pd(dppf)Cl 2 (83.2 mg, 0.114 mmol) were added, and the reaction solution was stirred at 100°C for 3 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • EX67-04 250 mg, 0.503 mmol was dissolved in anhydrous 1,4-dioxane (3 mL), and tert-butyl piperidin-4-ylcarbamate (110.8 mg, 0.553 mmol), RuPhos Pd G2 (39.1 mg, 0.050 mmol), sodium iodide (15.1 mg, 0.101 mmol) and cesium carbonate (491.6 mg, 1.509 mmol) were added. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 12 hours.
  • EX67-05 (130 mg, 0.197 mmol) was dissolved in methanol (1 mL), p-toluenesulfonic acid (187 mg, 0.984 mmol) was added, and the mixture was stirred at 25°C for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure and dried, and the crude product was purified by preparative HPLC (column: Boston Prime C18150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 20%-60%, 9 minutes) to obtain EX67.
  • Example EX68 was prepared by the same route as EX64 using EX64-01, ((3S, 4R)-3-fluoropiperidin-4-yl)carbamic acid tert-butyl ester as raw material.
  • Preparative HPLC columnumn: YMC Triart 30*150mm*7um; mobile phase: [water (ammonia)-acetonitrile]; B%: 60%-90%, 8 minutes).
  • Example EX69, EX70 was synthesized by the same route as EX64 using EX12-03a and EX69-03 as raw materials.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 20%-60%, 9 minutes).
  • the mixture of EX69 and EX70 was further separated and purified by preparative SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [0.1% ammonia.ethanol]; B%: 50%-50%) to obtain EX69 and EX70.
  • EX71 and EX72 were prepared by using EX12-03a and EX71-03 as raw materials through the same route as EX64.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; Condition: water (ammonia hydroxide v/v)-ACN; B%: 29%-69%, 9minute).
  • the mixture of EX71 and EX72 was further separated and purified by preparative SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); Condition: [CO2-EtOH (0.1% NH3H2O)]; B%: 55%-55%, 45minute) to obtain EX71 and EX72.
  • Example EX73 was prepared by the same route as EX64 using EX12-03a and EX73-02 as raw materials.
  • Preparative HPLC columnumn: Boston Prime C18 75*30mm*3um; mobile phase: [water (ammonia hydroxide)-acetonitrile]; B%: 44%-84%, 9 minutes).
  • Example EX74 was prepared by the same route as EX64 using EX12-03a and EX74-03 as raw materials.
  • Preparative HPLC columnumn: Boston Prime C18 75*30mm*3um; mobile phase: [water (formic acid)-acetonitrile]; B%: 13%-53%, 9 minutes).
  • Example EX75 was prepared by the same route as EX64 using EX12-03a and EX52-05a as raw materials.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia)-acetonitrile]; B%: 36%-76%, 9 minutes) EX75.
  • Example EX76 was prepared by the same route as EX64 using EX12-03a and EX76-05 as raw materials.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 48%-88%, 2 minutes).
  • Example EX78 was prepared by the same route as EX64 using EX12-03a and piperidine-4-ol as raw materials.
  • Preparative HPLC columnumn: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 10%-40%, 9 minutes).
  • EX79-04 (150 mg, 0.298 mmol) was dissolved in 1,4-dioxane (2 mL), and tert-butyl piperidine-4-carbamate (89.5 mg, 0.447mmol), cesium carbonate (194mg, 0.596mmol) and Ruphos Pd G 2 (23.1mg, 0.0300mmol).
  • the reaction solution was heated to 100°C under nitrogen protection and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure.
  • LCMS: MS m/z (ESI) [M+H] + 574.3.
  • EX79-06 (25.0 mg, 0.043 mmol) was dissolved in methanol (1 mL), p-toluenesulfonic acid (37.4 mg, 0.217 mmol) was added, and the reaction solution was stirred at 25°C for 18 hours. After the reaction, the reaction solution was purified by HPLC (column: Boston Prime C18 150*30mm*5um; Condition: water (ammonia hydroxide v/v)-ACN; B%: 43%-83%, 9 minutes) to obtain a single isomer EX79.
  • HPLC columnumn: Boston Prime C18 150*30mm*5um; Condition: water (ammonia hydroxide v/v)-ACN; B%: 43%-83%, 9 minutes
  • EX64-01 200 mg, 0.397 mmol was dissolved in 1,4-dioxane (2 mL), and tert-butyl ((1R, 5S, 8S)-3-azabicyclo[3.2.1]octan-8-yl)carbamate (117 mg, 0.517 mmol), cesium carbonate (388 mg, 1.19 mmol) and Ruphos Pd G2 (30.9 mg, 40.0 umol) were added. The reaction solution was heated to 100 °C under nitrogen protection and stirred for 18 hours.
  • EX80-01 120 mg, 0.199 mmol was dissolved in methanol (1 mL), p-toluenesulfonic acid (171 mg, 0.995 mmol) was added, and the reaction solution was stirred at 25°C for 18 hours. After the reaction, the reaction solution was purified by HPLC (column: Boston Prime C18 150*40mm*5um; Condition: water (NH 3 H 2 O + NH 4 HCO 3 )-ACN; B%: 55%-95%, 9 minutes) to obtain a white solid EX80 (35.77 mg, yield 35.8%).
  • EX81-01 (1.00 g, 2.85 mmol) was dissolved in tetrahydrofuran (20.0 mL), sodium hydride (0.1 g, 3.71 mmol) was slowly added at 0 ° C, and iodomethane (0.20 mL, 3.14 mmol) was added after stirring for 0.5 hours. The reaction solution was stirred at room temperature for 1 hour.
  • reaction solution was quenched by adding saturated aqueous ammonium chloride solution (20 ml) under an ice-water bath, extracted with ethyl acetate (20 mL * 3), the organic layers were combined, washed with saturated aqueous salt solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried.
  • EX83-01 (13.0 g, 69.5 mmol) was dissolved in anhydrous dichloromethane (80 mL), and 1 M DIBALH toluene solution (69.5 mL, 69.5 mmol) was slowly added at -78 ° C, and the reaction solution was stirred at 25 ° C for 2 hours.
  • LCMS detected the formation of the target product.
  • the reaction solution was quenched with saturated ammonium chloride (160 mL) at 0 ° C, and the reaction solution was stirred at 0 ° C for 1 hour and then acidified with 1 M hydrochloric acid. The liquid was separated, and the aqueous phase was extracted with dichloromethane (120 mL x 3).
  • EX83-06 300 mg, 0.580 mmol was dissolved in dioxane (4 mL), and tert-butyl piperidine-4-carbamate (174 mg, 0.870 mmol), cesium carbonate (567 mg, 1.74 mmol) and Ruphos Pd G2 (45.0 mg, 0.0580 mmol) were added.
  • the reaction solution was heated to 100 ° C and stirred for 12 hours under a nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure.
  • EX83-07 140 mg, 0.237 mmol was dissolved in methanol (1 mL) and p-toluenesulfonic acid (204 mg, 1.19 mmol) was added. The reaction solution was stirred at 25°C for 12 hours. After the reaction, the reaction solution was purified by preparative HPLC (column: Xtimate C18 150*40mm*10um; Condition: water (ammonia water + ammonium bicarbonate)-acetonitrile; B%: 45%-85%, 9 minutes) to obtain EX83 (20.1 mg, yield 17.3%).
  • reaction solution was quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL * 3), the organic phases were combined, washed with saturated brine (20 mL * 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried to obtain EX86-01 (450 mg, yield 89.3%).
  • EX86-05 (80.0 mg) was separated and purified by preparative SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um); mobile phase: [0.1% ammonia water. ethanol]; B%: 50%-50%) to obtain EX86 (12.05 mg, yield 15.1%) and EX87 (6.27 mg, yield 7.8%).
  • EX88-06 (2.70 g, 5.74 mmol) was dissolved in 1-methyl-2-pyrrolidone (30 mL), and EX53-03 (1.02 g, 5.74 mmol) and potassium carbonate (1.59 g, 11.5 mmol) were added. The reaction solution was stirred at 100 ° C for 12 hours. After cooling to room temperature, the reaction solution was diluted with EtOAc (80 mL) and water (50 mL), and the aqueous phase was extracted with EtOAc (50 mL x 3). The organic phases were combined, washed with water (50 mL x 2) and saturated brine (50 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • EX88-08 (850 mg, 1.31 mmol) was dissolved in tetrahydrofuran (5 mL). After the reaction solution was cooled to -15 °C, 1 M lithium triethylborohydride solution (2.62 mL, 2.62 mmol) was slowly added. The reaction solution was stirred at -15 °C for 10 minutes. The reaction solution was quenched with water (5 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • EX88-11 (40.0 mg, 67.0 umol) was dissolved in methanol (0.5 mL), 4-toluenesulfonic acid (57.4 mg, 0.334 mmol) was added, and the reaction solution was stirred at 25°C for 16 hours. After the reaction was completed, the reaction was purified by HPLC (column: Phenomenex Gemini NX 150 ⁇ 30 mm, 5 ⁇ m; Condition: water (FA)-ACN; B%: 25%-65%, 9 minutes) to obtain EX88 (formate) (3.79 mg, yield 11.4%).
  • 1 H NMR 400 MHz, DMSO-d6) ⁇ 8.33 (s, 1H), 8.31-8.23 (m, 2H), 8.22-8.12 (m, 2H), 7.60 (s, 1H).
  • EX89-03 300 mg, 0.708 mmol was dissolved in 1-methyl-2-pyrrolidone (3 mL), EX53-03 (125 mg, 0.708 mmol) and potassium carbonate (196 mg, 1.42 mmol) were added, and the mixture was stirred at 100 °C for 12 hours. After the reaction, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (15 mL x 3), and the organic phases were combined, washed with water (10 mL x 3) and saturated brine (10 mL) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • EX89-04 200 mg, 0.379 mmol was dissolved in dioxane (2 mL), and tert-butyl piperidine-4-carbamate (151.7 mg, 0.757 mmol), cesium carbonate (246.7 mg, 0.757 mmol) and Pd-PEPPSI-HeptCl (36.8 mg, 38.0 umol) were added.
  • the reaction solution was heated to 110°C under nitrogen protection and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure.
  • EX89-05 120 mg, 0.200 mmol was dissolved in 4M hydrochloric acid/dioxane (0.5 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (column: Boston Prime C18 150*30mm*5um; Condition: water(FA)-ACN; B%: 10%-40%, 9 minutes) to obtain EX89 (24.1 mg, 24.1%).
  • reaction solution was quenched with saturated sodium bicarbonate aqueous solution and adjusted to pH ⁇ 9, extracted with ethyl acetate (50 mL*3), the organic phases were combined, washed with saturated brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried.
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 13.81(s,1H),6.93(s,1H),2.28(s,3H).
  • EX93-01 (80.0 mg, 0.168 mmol) was dissolved in 1,4-dioxane (1.0 mL), and tert-butyl piperidine-4-carbamate (43.6 mg, 0.218 mmol), RuPhos Pd G2 (13.0 mg, 0.017 mmol) and cesium carbonate (109 mg, 0.335 mmol) were added.
  • the reaction solution was heated to 100 ° C and stirred for 16 hours under nitrogen protection.
  • the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3).
  • EX93-02 (30 mg, 0.055 mmol) was dissolved in 4M hydrochloric acid dioxane (1.0 mL), and the reaction solution was stirred at 25°C for 1 hour. After the reaction solution was filtered, it was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 25%-45%, 11 minutes) to obtain EX93 (formate) (3.25 mg, yield 13.2%).
  • EX88-06 (3.00 g, 6.38 mmol) was dissolved in 1-methyl-2-pyrrolidone (30 mL), and EX71-03 (1.23 g, 6.38 mmol) and potassium carbonate (1.76 g, 12.8 mmol) were added. The reaction solution was stirred at 100 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was diluted with EtOAc (80 mL) and water (50 mL).
  • EX94-01 (3.60 g, 6.09 mmol) was dissolved in dioxane (50 mL), and tert-butyl piperidine-4-carbamate (2.44 g, 12.2 mmol), cesium carbonate (3.40 g, 12.2 mmol) and Pd-PEPPSI-IHeptCl (592 mg, 0.609 mmol) were added. The reaction mixture was heated to 110 °C under nitrogen protection and stirred for 12 hours.
  • EX94-05 (280 mg, 0.455 mmol) was dissolved in 4M hydrochloric acid/dioxane (3 mL), and the reaction solution was stirred at 25°C for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure and purified by HPLC (column: ACSSH-CK C18 150 ⁇ 30 mm; Condition: water (FA)-ACN; B%: 8%-38%, 9 minutes) and then purified by SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um); Condition: CO 2 -MeOH (0.1% NH 3 H 2 O); B%: 60%-60%, 20 minutes) to obtain EX94 (1.61 mg, yield 0.7%) and EX95 (20.9 mg, yield 8.9%).
  • HPLC columnumn: ACSSH-CK C18 150 ⁇ 30 mm; Condition: water (FA)-ACN; B%: 8%-38%, 9 minutes
  • SFC columnumn: DAICEL
  • EX98-01 (1.00 g, 3.53 mmol) was dissolved in 1,4-dioxane (0.5 mL), and 4 M hydrochloric acid/dioxane solution (2 mL) was added. The reaction solution was stirred at 25 °C for 1 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain EX98-02 (750 mg, yield 96.7%).
  • EX98-02 (444 mg, 2.42 mmol) and EX83-05 (500 mg, 1.21 mmol) were dissolved in 1-methyl-2-pyrrolidone (5.0 mL), and potassium carbonate (502 mg, 3.64 mmol) was added.
  • the reaction solution was heated to 100 ° C and stirred for 12 hours.
  • the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried.
  • EX98-03 200 mg, 0.358 mmol was dissolved in 1,4-dioxane (4.5 mL), and NaI (10.7 mg, 0.072 mmol), tert-butyl piperidin-4-ylcarbamate (86.0 mg, 0.429 mmol), Pd-PEPPSI-IHeptCl (34.8 mg, 0.036 mmol) and cesium carbonate (350 mg, 1.07 mmol) were added.
  • the reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection.
  • the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3).
  • EX98-04 (40 mg, 0.063 mmol) was dissolved in 4M hydrochloric acid/1,4-dioxane solution (2 mL) and stirred at room temperature for 1 hour.
  • the reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 23%-53%, 8 minutes) to obtain EX98 (formate) (13.9 mg, yield 41.3%).
  • EX99-01 400 mg, 0.735 mmol was dissolved in dioxane (1 mL), and tert-butyl piperidin-4-ylcarbamate (294 mg, 1.47 mmol), Pd-PEPPSI-IHeptCl (71.5 mg, 73.0 umol) and cesium carbonate (479 mg, 1.47 mmol) were added.
  • the reaction solution was heated to 110 ° C under nitrogen protection and stirred for 12 hours.
  • the reaction solution was cooled to room temperature and concentrated under reduced pressure.
  • EX99-02 (100 mg, 0.162 mmol) was dissolved in 4M hydrochloric acid/dioxane (2 mL), and the reaction solution was stirred at 25°C for 1 hour. After the reaction, the reaction solution was dried under reduced pressure, and the crude product was purified by HPLC (column: ACSSH-CP C18 150 ⁇ 30 mm; Condition: water (FA)-ACN; B%: 0%-40%, 9 minutes), and then purified by SFC (column: DAICEL CHIRALPAK IC (250mm*30mm, 10um); Condition: CO 2 -EtOH (0.1% NH 3 H2O); B%: 60%-60%, 20 minutes) to obtain EX99 (9.83 mg, yield 11.8%) and EX100 (2.52 mg, yield 3.0%).
  • EX101-05 (2.37 g, 5.28 mmol) was dissolved in 1-methyl-2-pyrrolidone (20 mL), and EX53-03 (936 mg, 5.28 mmol) and potassium carbonate (1.46 g, 10.6 mmol) were added.
  • EX101-07 400 mg, 0.639 mmol was dissolved in 4M hydrochloric acid/dioxane (4 mL), and the reaction solution was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (column: ACSSH-CAC18 150 ⁇ 40 mm; Condition: water (FA)-ACN; B%: 23%-63%, 9 minutes) to obtain EX101 (formate) (81.55 mg, yield 24.3%).
  • EX102-05 (800 mg, 1.87 mmol) was dissolved in 1-methyl-2-pyrrolidone (10 mL), and EX53-03 (332 mg, 1.87 mmol) and potassium carbonate (516 mg, 3.73 mmol) were added.
  • EX105-01 (110 mg, 0.182 mmol) was dissolved in 4M hydrochloric acid/1,4-dioxane (5 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-60%, 9 minutes) to obtain EX105 (formate) (23.20 mg, yield 25.3%).
  • reaction solution was slowly quenched with saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL*3), the organic phase was washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried.
  • EX107-01 300 mg, 0.629 mmol was dissolved in 1,4-dioxane (5.0 mL), and tert-butyl piperidine-4-carbamate (164 mg, 0.817 mmol), RuPhos Pd G2 (97.6 mg, 0.126 mmol) and cesium carbonate (410 mg, 1.26 mmol) were added.
  • the reaction solution was heated to 100 ° C and stirred for 16 hours under nitrogen protection.
  • the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried.
  • EX107-02 (100 mg, 0.182 mmol) was dissolved in 4 M dioxane hydrochloride (2.0 mL), and the reaction solution was stirred at 25°C for 1 hour.
  • the reaction solution was concentrated under reduced pressure and dried by spin drying, and the crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 21%-51%, 8 minutes) to obtain EX107 (formate) (37.9 mg, yield 46.4%).
  • EX83-05 300 mg, 0.727 mmol
  • (R)-2-methylmorpholine 36.8 mg, 0.364 mmol
  • K 2 CO 3 302 mg, 2.18 mmol
  • the reaction solution was heated to 100°C and stirred for 12 hours.
  • the reaction solution was cooled to room temperature and diluted with water (30 mL). Filtered.
  • the filter cake was concentrated and dried under reduced pressure to obtain EX108-01 (300 mg, yield 86.4%).
  • EX108-01 300 mg, 0.629 mmol was dissolved in 1,4-dioxane (3.0 mL), and tert-butyl piperidine-4-carbamate (151 mg, 0.754 mmol), RuPhos Pd G2 (48.8 mg, 0.063 mmol) and cesium carbonate (614 mg, 1.89 mmol) were added.
  • the reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection.
  • the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3).
  • EX108-02 (60.0 mg, 0.109 mmol) was dissolved in dioxane (0.5 mL), and 4 M dioxane hydrochloride (1.0 mL) was added. The reaction solution was stirred at 25°C for 1 h. The reaction solution was concentrated under reduced pressure and dried by spin drying. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 19%-49%, 8 minutes) to obtain EX108 (14.6 mg, yield 29.7%).
  • reaction solution was quenched and diluted with water (50 mL), extracted with ethyl acetate (50 mL*3), and the organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness.
  • EX110-02 (4.10 g, 19.04 mmol) was dissolved in dichloromethane (40 mL), triethylamine (10.56 mL, 76.2 mmol) was added, and then methanesulfonic anhydride (9.94 g, 57.1 mmol) was slowly added, and the reaction was allowed to react at 25°C for 1 hour.
  • the reaction solution was quenched and diluted with water (50 mL), extracted with dichloromethane (40 mL*3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product EX110-03 (6.10 g).
  • EX110-04 (1.1 g, 4.15 mmol) was dissolved in 4 M dioxane hydrochloride (5 mL) and reacted at 25° C. for 2 hours. The reaction solution was concentrated under reduced pressure and dried to obtain EX110-05 (830 mg, crude product).
  • EX110-05 (1.3 g, 6.45 mmol) was dissolved in 1-methylpyrrolidone (15 mL), and potassium carbonate (1.78 g, 12.9 mmol) and EX88-06 (3.03 g, 6.45 mmol) were added. The reaction temperature was raised to 100 °C for 12 hours. The reaction solution was diluted with water (30 mL), and ethyl acetate (50 mL*3) was added for extraction. The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • EX110-06 400 mg, 0.667 mmol was dissolved in dioxane (4 mL), 4-Boc-aminopiperidine (267.3 mg, 1.34 mmol), cesium carbonate (435 mg, 1.34 mmol) and Pd-PEPPSI-Iheptcl (64.9 mg, 0.067 mmol) were added, and the reaction was heated to 100 ° C under a nitrogen atmosphere for 12 hours.
  • the reaction solution was diluted with water (5 mL), and ethyl acetate (5 mL*3) was added to extract three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and dried.
  • EX110-07 (270 mg, 0.429 mmol) was dissolved in tetrahydrofuran (2 mL), and 1 M lithium triethylborohydride (1.33 mL, 1.33 mmol) solution was slowly added at -30 °C, followed by stirring at -30 °C for 10 minutes.
  • the reaction solution was quenched with saturated ammonium chloride (5 mL), extracted with ethyl acetate (5 mL*3), and the organic phase was dried with anhydrous sodium sulfate, filtered, and dried.
  • EX110-08 (130 mg, 0.206 mmol) was dissolved in dioxane hydrochloride (1 mL), and the reaction solution was stirred at room temperature for 1 hour.
  • the reaction solution was concentrated under reduced pressure and dried by spin drying, and then separated and purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 13%-53%, 9 minutes), and then by preparative SFC (column: DAICEL CHIRALPAK AS (250mm*30mm, 10um); mobile phase: [CO 2 -isopropanol (0.1% ammonia water)]; B%: 40%-40%,) to obtain EX110 (10.05 mg, yield 38.7%).
  • EX110-06 200 mg, 0.334 mmol was dissolved in dioxane (1 mL), methyl (piperidin-4-yl) carbamic acid tert-butyl ester (71.5 mg, 0.668 mmol), cesium carbonate (217 mg, 0.667 mmol) and Pd-PEPPSI-Iheptcl (32.5 mg, 0.033 mmol) were added, and the reaction was heated to 100 ° C under a nitrogen atmosphere for 12 hours. After the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (5 mL), and ethyl acetate (5 mL*3) was added for extraction.
  • EX111-02 (70 mg, 0.109 mmol) was dissolved in dioxane hydrochloride (1 mL), and the reaction solution was stirred at room temperature for 1 hour.
  • the reaction solution was concentrated under reduced pressure and dried by spin drying, and then separated and purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 0%-40%, 15 minutes), and then by preparative SFC (column: DAICEL CHIRALPAK AS (250mm*30mm, 10um); mobile phase: [CO 2 -isopropanol (0.1% ammonia water)]; B%: 40%-40%,) to obtain EX111 (3.75 mg, yield 6.1%).
  • EX83-05 300 mg, 0.727 mmol
  • 7-aza-2-oxaspiro[3.5]nonane 139 mg, 1.09 mmol
  • K 2 CO 3 302 mg, 2.18 mmol
  • the reaction solution was heated to 100°C and stirred for 12 hours.
  • the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried.
  • EX113-01 100 mg, 0.199 mmol was dissolved in 1,4-dioxane (1.0 mL), and tert-butyl piperidine-4-carbamate (47.8 mg, 0.238 mmol), RuPhos Pd G2 (15.4 mg, 0.020 mmol) and cesium carbonate (194 mg, 0.596 mmol) were added.
  • the reaction solution was heated to 100 ° C and stirred for 12 hours under nitrogen protection.
  • the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3).
  • EX113-02 (60 mg, 0.104 mmol) was dissolved in dichloromethane (1.0 mL), and trifluoroacetic acid (20.4 mg, 0.208 mmol) was added. The reaction solution was stirred at 25°C for 1 h. The reaction solution was concentrated under reduced pressure and then spin-dried. It was then purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 21%-51%, 8 minutes) to obtain a pale yellow solid EX113 (5.57 mg, yield 11.2%).
  • EX120-01 (5.00 g, 23.4 mmol) was dissolved in tetrahydrofuran (100 mL), (trifluoromethyl) trimethylsilane (6.70 g, 46.9 mmol) and 1 M tetrabutylammonium fluoride tetrahydrofuran solution (46.9 mL, 46.9 mmol) were added at 0 ° C, and the reaction solution was stirred at 25 ° C for 2 hours. Saturated ammonium chloride solution (300 ml) was added to the reaction solution and stirred for 30 minutes. After concentrating under reduced pressure, dichloromethane (300 ml) was added for extraction, and then washed with water (300 ml).
  • EX120-03 600 mg, 2.02 mmol was dissolved in 4M dioxane hydrochloride (5.0 mL), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain EX120-04.
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 9.55-9.17 (m, 2H), 3.56 (s, 3H), 3.50–3.39 (m, 1H), 3.31-3.19 (m, 1H), 3.04-2.89 (m, 1H), 2.23-2.13 (m, 2H), 2.13-1.78 (m, 2H), 1.37-1.29 (m, 3H).
  • EX120-04 (650 mg, 2.78 mmol) and EX83-05 (956 mg, 2.32 mmol) were dissolved in 1-methyl-2-pyrrolidone (5.0 mL), and potassium carbonate (961 mg, 6.95 mmol) was added.
  • the reaction solution was heated to 100 °C and stirred for 18 hours.
  • the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried.
  • EX120-05 (80.0 mg, 0.140 mmol) was dissolved in 1,4-dioxane (1.0 mL), and tert-butyl piperidine-4-carbamate (36.3 mg, 0.181 mmol), RuPhos Pd G2 (21.7 mg, 28.0 umol) and cesium carbonate (90.9 mg, 0.279 mmol) were added.
  • the reaction solution was heated to 100 ° C and stirred for 18 hours under nitrogen protection.
  • the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried.
  • EX120-06 (100 mg, 0.155 mmol) was dissolved in 4 M dioxane hydrochloride (3.0 mL). The reaction solution was stirred at 25 °C for 1 hour. After the reaction solution was filtered, it was purified by preparative HPLC (column: Boston Prime C18 150*40 mm; mobile phase: [water (formic acid)-acetonitrile]; B%: 34%-74%, 8 minutes) to obtain a pale yellow solid EX120 (formate) (31.2 mg, yield 36.9%).
  • EX121-02 (3.48 g, 16.6 mmol) was dissolved in 1,2-dichloroethane (35 mL), and 1-chloroethyl chloroformate (18.0 mL, 166 mmol) was added. The reaction solution was heated to 80 ° C and stirred for 16 hours. After the reaction solution was cooled to room temperature, methanol was added until no bubbles were generated, and the reaction mixture was heated to reflux and stirred for 1 hour. Then it was cooled to room temperature, and n-heptane (2*35 mL) was added and concentrated. After washing with ethyl acetate, the crude product EX121-03 (1.15 g, yield 44.4%) was obtained.
  • EX83-05 (1 g, 2.42 mmol) and EX121-03 (447 mg, 2.91 mmol) were dissolved in NMP (10 mL) and potassium carbonate (1005 mg, 7.27 mmol) was added. The reaction mixture was heated to 100 °C and stirred for 12 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (20 mL ⁇ 3).
  • EX88-07 700 mg, 1.22 mmol was dissolved in ethanol (7 mL), and 5 M NaOH (1.95 mL) was added to the solution. The reaction solution was stirred at room temperature for 2.5 h. The reaction solution was adjusted to pH 1 with 1 M HCl and solids were precipitated. The filter cake was concentrated under reduced pressure and dried to obtain EX122-01 (610 mg, yield 91.6%).
  • EX122-02 200 mg, 0.386 mmol
  • 4-Boc-aminopiperidine 116 mg, 0.579 mmol
  • cesium carbonate 251 mg, 0.772 mmol
  • Pd-PEPPSI-IHept-Cl 37.5 mg, 39.0 ⁇ mol
  • EX102-05 250 mg, 0.583 mmol was dissolved in NMP (5 mL), EX73-02 (169 mg, 0.700 mmol) and potassium carbonate (242 mg, 1.75 mmol) were added, and the reaction solution was stirred at 100 ° C for 12 hours.
  • the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL x 2), and the organic phases were combined, washed with water (10 mL x 2) and saturated brine (10 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • EX102-05 50 mg, 0.079 mmol was dissolved in dioxane (1 mL), and tert-butyl piperidine-4-carbamate (23.7 mg, 0.118 mmol), Pd-PEPPSI-HeptCl (7.7 mg, 0.008 mmol) and cesium carbonate (77.1 mg, 0.237 mmol) were added.
  • EX123-02 (40.0 mg, 0.057 mmol) was dissolved in hydrochloric acid-dioxane (4M, 1.0 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and dried by spin drying. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-60%, 9 minutes) to obtain EX123.
  • EX109-05 (800 mg, 1.63 mmol) was dissolved in dioxane (10 mL), and 4-N-BOC-4-N-methyl-aminopiperidine (152 mg, 0.757 mmol), cesium carbonate (1.59 g, 4.89 mmol) and Pd-PEPPSI-HeptCl (64.5 mg, 0.081 mmol) were added.
  • the reaction solution was heated to 100°C under nitrogen protection and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure.
  • LCMS: MS m/z (ESI) [M+H] + 578.2.
  • EX127-01 200 mg, 0.346 mmol was dissolved in 4M hydrochloric acid/dioxane (10 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(FA)-ACN]; B%: 30%-50%, 11 min) to obtain EX127.
  • EX128-02 (1 g, 2.99 mmol) was dissolved in 4M hydrochloric acid/dioxane (5 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and dried to give compound EX128-03.
  • EX128-04 (800 mg, 1.20 mmol) was dissolved in dioxane (10 mL), and methyl (piperidin-4-yl) carbamic acid tert-butyl ester (385 mg, 1.80 mmol), cesium carbonate (1.17 g, 3.60 mmol) and Pd-PEPPSI-HeptCl (233 mg, 0.240 mmol) were added.
  • the reaction solution was heated to 110 ° C and stirred for 12 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure.
  • EX128-06 200 mg, 0.281 mmol was dissolved in 4M hydrochloric acid/dioxane (5.0 mL), and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (column: Boston Prime C18 150*40 mm; Condition: water (FA)-ACN; B%: 26%-66%, 9 minutes) to obtain EX128.
  • EX110-01 (304 mg, 0.947 mmol) was dissolved in toluene (5 mL) and (R)-N-Boc-3-hydroxymethyl-pyrrolidine (202 mg, 1.00 mmol), CuI (159 mg, 0.834 mmol), 1,10-phenanthroline (150 mg, 0.834 mmol) and cesium carbonate (815 mg, 2.50 mmol) were added. The reaction mixture was heated to 110°C under nitrogen protection and stirred for 12 hours.
  • EX129-01 (114 mg, 0.309 mmol) was dissolved in tetrahydrofuran (3 mL), and LiBHEt 3 (0.71 mL, 0.713 mmol) was slowly added at -78 °C in a nitrogen atmosphere and stirred for 10 minutes.
  • Saturated ammonium chloride solution (3 mL) was added to the reaction system in an ice bath for quenching. Dilute with water (3 mL) and extract with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • EX129-02 (90 mg, 0.143 mmol) was dissolved in hydrochloric acid-dioxane (2 M, 2 mL), and the reaction solution was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, it was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (formic acid)-acetonitrile]; B%: 17%-47%, 8 minutes) to obtain EX-120.

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Abstract

La présente invention concerne un composé tel que représenté par la formule I, un sel pharmaceutiquement acceptable, un isomère ou un marqueur isotopique de celui-ci. Le composé peut être utilisé en tant qu'inhibiteur de LSD1, et peut également être utilisé pour prévenir ou traiter des tumeurs telles que des néoplasmes hématologiques et un cancer du poumon à petites cellules.
PCT/CN2024/085484 2023-04-03 2024-04-02 Composé azaaryle et son utilisation en tant qu'inhibiteur de lsd1 Pending WO2024208187A1 (fr)

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WO2018149986A1 (fr) * 2017-02-16 2018-08-23 Oryzon Genomics, S.A. Dérivés de 2-(bicyclo-hétéroaryl)-isonicotinique en tant qu'inhibiteurs d'histone déméthylase
CN110914265A (zh) * 2017-05-15 2020-03-24 密歇根大学董事会 作为lsd-1抑制剂的吡咯并[2,3-c]吡啶和相关类似物
CN112119080A (zh) * 2018-05-15 2020-12-22 密歇根大学董事会 作为lsd-1抑制剂的咪唑并[4,5-c]吡啶化合物
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WO2018149986A1 (fr) * 2017-02-16 2018-08-23 Oryzon Genomics, S.A. Dérivés de 2-(bicyclo-hétéroaryl)-isonicotinique en tant qu'inhibiteurs d'histone déméthylase
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