WO2023143249A1 - Composé de dégradation de protéine ciblant malt1 - Google Patents

Composé de dégradation de protéine ciblant malt1 Download PDF

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WO2023143249A1
WO2023143249A1 PCT/CN2023/072620 CN2023072620W WO2023143249A1 WO 2023143249 A1 WO2023143249 A1 WO 2023143249A1 CN 2023072620 W CN2023072620 W CN 2023072620W WO 2023143249 A1 WO2023143249 A1 WO 2023143249A1
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覃华
孙大庆
付家胜
辛正远
陈昫
石谷沁
池波
冯昊
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Shanghai Qilu Pharmaceutical Research and Development Centre Ltd
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Shanghai Qilu Pharmaceutical Research and Development Centre Ltd
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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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C07D471/10—Spiro-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
    • 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
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention belongs to the field of medicinal chemistry, and in particular relates to a compound inhibiting and/or promoting MALT1 degradation by recruiting E3 ubiquitin ligase, a pharmaceutical composition containing the compound and a method for using the compound of the present invention to treat cell proliferation diseases, such as cancer.
  • DLBCL Diffuse large B-cell lymphoma
  • GCB germinal center B cells
  • ABSC activated B cells
  • MALT1 Mucosa-associated lymphoid tissue lymphoma translocator 1
  • ABC-DLBCL interleukin 2
  • IL-2 interleukin 2
  • T and B lymphocytes T and B lymphocytes.
  • CARD11 triple signaling adapter
  • MALT1 MALT1 and BCL10.
  • CBM complex that is associated with antigen-dependent activation of NF- ⁇ .
  • MALT1 also contains proteolytic activities that are constitutively activated in ABC-DLBCL.
  • MALT1 inhibitors are known to inhibit NF- ⁇ B target gene expression and ABC-DLBCL viability, making MALT1 inhibition an attractive therapeutic target for the treatment of ABC-DLBCL.
  • E3 ubiquitin ligase is combined with E2 ubiquitin ligase to promote the connection of ubiquitin to lysine on the target protein through isopeptide bonds. Ubiquitination of proteins usually leads to degradation of target proteins by the proteasome.
  • VHL The von Hippel-Lindau tumor suppressor
  • VHL includes the substrate recognition subunit/E3 ubiquitin ligase complex VCB, which includes elongins B and C, and complexes, including Cullin-2 and Rbx1.
  • the major substrate of VHL is hypoxia-inducible factor Ia (HIF-1a), a transcription factor that upregulates genes such as the pro-angiogenic growth factor VEGF and the erythrocyte-inducing cytokine erythropoietin in response to low oxygen levels.
  • VCB is a known target of cancer, chronic anemia and ischemia.
  • Cereblon (CRBN), another E3 ubiquitin ligase, forms E3 ubiquitin linkages with regulators of damaged DNA-binding protein 1 (DDB 1), cullin-4A (CUL4A) and cullins 1 (ROC 1) enzyme complex. This complex ubiquitinates many other proteins. Through mechanisms that have not been fully elucidated, cereblon ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 in turn regulates many developmental processes such as limb and auditory vesicle formation. In addition, studies have shown that small molecules that bind to and inhibit Cereblon (such as lenalidomide) have direct anti-tumor activity on DLBCL cells, preferably ABC-DLBCL cells.
  • DDB 1 DNA-binding protein 1
  • CUL4A cullin-4A
  • ROC 1 cullins 1
  • FGF8 fibroblast growth factor 8
  • FGF10 fibro
  • Protein degradation targeting chimera is a technology that uses the ubiquitin-proteasome system to target specific proteins and induce their degradation in cells.
  • the ubiquitin-proteasome system is the main pathway for intracellular protein degradation. Its normal physiological function is mainly responsible for removing denatured, mutated or harmful proteins in cells. The degradation of more than 80% of proteins in cells depends on the ubiquitin-proteasome system.
  • PROTAC is a bifunctional small molecule triplet compound, which can be divided into three parts: target protein small molecule inhibitor, Linker (linker), and E3 ubiquitin ligase ligand.
  • the target protein (Protein of Interest, POI) ligand in its structure can specifically bind to the corresponding target protein, and the other end can recruit E3 ligase to form a POI-Linker-E3ligase ternary complex Object, in which E3 ligase can mediate ubiquitin-conjugating enzyme E2 to ubiquitination of POI.
  • POIs labeled with ubiquitin are recognized and degraded by the proteasome.
  • the present invention describes bifunctional or proteolysis-targeting chimeric compounds (PROTAC) compounds that act as MALT1 inhibitors targeting ubiquitination and / or degradants.
  • PROTAC proteolysis-targeting chimeric compounds
  • the invention provides a novel bifunctional compound that can be used to inhibit and/or degrade MALT1, a pharmaceutical composition containing the compound, a preparation method and an application for treating cancer.
  • the compound is a triplet compound comprising a small molecule ligand of the target protein, a linker and a ligand of E3 ubiquitin ligase, as shown in the following formula,
  • the small-molecule ligand of the target protein can specifically bind the target protein, and is connected to the linker through a covalent bond in the triplet compound;
  • the linker is the connecting group between the small-molecule ligand of the target protein and the ligand of E3 ubiquitin ligase Group, one end binds to the small molecule ligand of the target protein, and the other end binds to the ligand of E3 ubiquitin ligase;
  • the ligand of E3 ubiquitin ligase can bind ubiquitin ligase, such as E3 ubiquitin ligase, and linker Covalently bound.
  • the present invention provides the compound shown in formula (I'):
  • TGL binds to a MALT1 target ligand
  • E is a degron that binds ubiquitin ligase, selected from
  • B 1 is a C 1-15 alkylene chain, wherein the hydrogen atoms in the C 1-15 alkylene chain are optionally substituted by 1-3 R a , and the carbon atoms in the C 1-15 alkylene chain are optionally is replaced by -NR b -, -O-, carbonyl;
  • R a is C 1-4 alkyl;
  • R b is H or C 1-4 alkyl;
  • B 1 is C 1-15 alkylene chain, wherein the hydrogen atoms in the C 1-15 alkylene chain are optionally replaced by 1-3 R a , and the carbon atoms in the C 1-15 alkylene chain are optionally replaced by -NR b -, -O-, replaced by carbonyl;
  • R a is C 1-4 alkyl;
  • R b is H or C 1-4 alkyl;
  • B2 is a chemical bond, optionally substituted following groups: C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 7-11 spirocycloalkyl, 7-11 membered spiroheterocycloalkyl ;
  • B 3 is a chemical bond, a C 1-4 alkylene chain in which carbon atoms are optionally replaced by -NR b -, -O-, carbonyl;
  • B4 is a chemical bond, optionally substituted following groups: C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 7-11 spirocycloalkyl, 7-11 membered spiroheterocycloalkyl;
  • B 5 is a chemical bond, a C 1-5 alkylene chain, the carbon atoms in the alkylene chain are optionally replaced by NR c , carbonyl or oxygen, and R c is H or C 1-4 alkyl;
  • n 1 , n 2 , n 3 , and n 4 are 0 or 1.
  • above-mentioned E is selected from
  • the above-mentioned L has the structure of formula (II'a).
  • the above-mentioned L has the structure of formula (II'b).
  • the above-mentioned L has the structure of formula (II'c).
  • the above-mentioned L has the structure of formula (II'd).
  • the above-mentioned L has the structure of formula (II'e).
  • the above-mentioned L has the structure of formula (II'f).
  • the above-mentioned B 2 , B 3 , B 4 , and B 5 are each independently a chemical bond.
  • the above-mentioned B 1 is a C 1-15 alkylene chain, hydrogen atoms in the C 1-15 alkylene chain are optionally substituted by 1-2 R a , and in the C 1-15 alkylene chain Optionally 2 to 4 carbon atoms are replaced by -NR b -, -O-, carbonyl, R a is C 1-4 alkyl; R b is H or C 1-4 alkyl.
  • the above-mentioned B 1 is a C 1-11 alkylene chain, and the hydrogen atoms in the C 1-11 alkylene chain are optionally replaced by 1-2 R a , and the carbon atoms are optionally replaced by -NR b -, -O-, carbonyl instead, R b is H or C 1-4 alkyl.
  • the above-mentioned B 1 is a C 1-11 alkylene chain, and the hydrogen atoms in the C 1-11 alkylene chain are optionally substituted by 1-2 R a , optionally 2 to 4 carbon atoms are replaced by -NR b -, -O-, carbonyl, R b is H or C 1-4 alkyl.
  • the above-mentioned B 1 is a C 1-6 alkylene chain, and the hydrogen atoms in the C 1-6 alkylene chain are optionally replaced by 1-2 R a , and the carbon atoms are optionally replaced by -NR b -, -O-, -C(O)- instead, R b is H or C 1-4 alkyl.
  • the above B 1 is a C 7-11 alkylene chain, the hydrogen atoms in the C 7-11 alkylene chain are optionally replaced by 1-2 R a , and the carbon atoms are optionally replaced by -NR b -, -O-, carbonyl instead, R b is H or C 1-4 alkyl;
  • the above B 1 is a C 1-6 alkylene chain, and the hydrogen atoms in the C 1-6 alkylene chain are optionally substituted by 1-2 R a , optionally 2 to 4 Carbon atoms are optionally replaced by -NR b -, -O-, carbonyl, R b is H or C 1-4 alkyl.
  • the above-mentioned B 1 is a C 7-11 alkylene chain, and the hydrogen atom in the C 7-11 alkylene chain is optionally substituted by 1-2 R a , optionally 1-2 carbon Atoms are replaced by -NR b -, -O-, carbonyl, R b is H or C 1-4 alkyl.
  • the above-mentioned B 1 is a C 7-11 alkylene chain, and the hydrogen atoms in the C 7-11 alkylene chain are optionally substituted by 1-2 R a , optionally 3 to 5 carbon Atoms are replaced by -NR b -, -O-, carbonyl, R b is H or C 1-4 alkyl.
  • R a is methyl
  • R b is hydrogen or methyl
  • above-mentioned B 1 is selected from
  • the above-mentioned B is selected from C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl contains 1-2 N heteroatoms, and the cycloalkane A group, a heterocycloalkyl group are optionally substituted by a C 1-4 alkyl group.
  • the above-mentioned B2 is selected from C 7-11 spirocycloalkyl and 9-11 membered spiroheterocycloalkyl, wherein the spiroheterocycloalkyl contains 1-2 N heteroatoms.
  • the above-mentioned B2 is selected from C 9-11 spirocycloalkyl and 7-11 membered spiroheterocycloalkyl, wherein the spiroheterocycloalkyl contains 1-2 N heteroatoms.
  • the above-mentioned B2 is selected from 7-11 membered spiroheterocycloalkyl, wherein the spiroheterocycloalkyl contains 1-2 N heteroatoms.
  • the above-mentioned B 3 is a C 1-4 alkylene chain whose carbon atoms are optionally replaced by -NR b -, -O-, carbonyl; preferably -CH 2 -, -CH 2 - N(CH 3 )-, -CO-.
  • the above-mentioned B 3 is selected from -N(CH 3 )-, -(CH 2 ) 2 -.
  • the above-mentioned B 4 is the following groups optionally substituted: C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 7-11 spirocycloalkyl, 7-11 membered spiroheterocycloalkyl.
  • the above-mentioned B is selected from C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl contains 1-2 N heteroatoms, and the cycloalkane A group, a heterocycloalkyl group are optionally substituted by a C 1-4 alkyl group.
  • the above-mentioned B 4 is selected from C 7-11 spirocycloalkyl and 9-11 membered spiroheterocycloalkyl, wherein the spiroheterocycloalkyl contains 1-2 N heteroatoms.
  • the above-mentioned B 4 is selected from 7-11 membered spiroheterocycloalkyl, wherein the spiroheterocycloalkyl contains 1-2 N heteroatoms.
  • the above-mentioned B 4 is selected from C 9-11 spirocycloalkyl and 7-11 membered spiroheterocycloalkyl, wherein the spiroheterocycloalkyl contains 1-2 N heteroatoms.
  • the above-mentioned B 5 is a C 1-5 alkylene chain, carbon atoms are optionally replaced by NR c , carbonyl or oxygen, and R c is H or C 1-4 alkyl.
  • R c is hydrogen
  • the above-mentioned R c is -CH 3 .
  • above-mentioned B 5 is selected from
  • above-mentioned B 5 is selected from
  • the above-mentioned L is a C 1-11 alkylene chain, wherein the hydrogen atoms in the C 1-11 alkylene chain are optionally substituted by 1-3 R a , C 1- 11
  • the carbon atoms in the alkylene chain are optionally replaced by -NR b -, -O-, carbonyl;
  • R a is C 1-4 alkyl;
  • R b is H or C 1-4 alkyl.
  • the above-mentioned L is a combination of a C 1-7 alkylene chain and a C 6-9 cycloalkane, wherein the hydrogen atoms in the C 1-7 alkylene chain are optionally replaced by 1- 3 R a are substituted, and the carbon atoms in the C 1-7 alkylene chain are optionally replaced by -NR b -, -O-, carbonyl; R a is C 1-4 alkyl; R b is H or C 1-4 alkyl.
  • the above-mentioned L is a combination of a C 1-7 alkylene chain and a 4-9 membered heterocycloalkane, wherein the hydrogen atoms in the C 1-7 alkylene chain are optionally replaced by 1 -3 R a substitutions, the carbon atoms in the C 1-7 alkylene chain are optionally replaced by -NR b -, -O-, carbonyl; R a is C 1-4 alkyl; R b is H Or C 1-4 alkyl.
  • the above-mentioned L is selected from
  • the above-mentioned L is selected from
  • the above-mentioned L is selected from
  • the present invention also provides the following compound or its isomer or pharmaceutically acceptable salt, which is selected from,
  • the present invention also provides the preparation method of compound:
  • R a is hydrogen or C 5-6 nitrogen-containing heteroaryl
  • R b is halogen or halogenated C 1-4 alkyl
  • L' is a straight alkane or a combination of straight alkane and heterocycloalkyl, wherein The carbon atoms in the alkane are optionally substituted by heteroatoms, and L' is optionally substituted by C 1-4 alkyl
  • Y is selected from structures that are bound to CRBN, VHL or the like.
  • PG is a protecting group for hydroxyl, which can be optionally substituted with the following groups: C 1-6 alkyl (such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl, etc.), phenyl , C 7-10 aralkyl (such as benzyl, etc.), C 1-6 alkylcarbonyl (such as acetyl and propionyl, etc.), formyl, phenoxycarbonyl, C 7-10 aralkyloxycarbonyl ( For example, benzyloxycarbonyl, etc.), tetrahydropyranyl, tetrahydrofuranyl, silyl and the like.
  • C 1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl, etc.
  • phenyl C 7-10 aralkyl
  • C 1-6 alkylcarbonyl such as
  • the substituent may be, for example, a halogen atom (such as fluorine, chlorine, bromine and iodine), C 1-6 alkyl, phenyl, C 7-11 aralkyl and nitro, etc., and the number of substituents may be 1-4 pieces.
  • a halogen atom such as fluorine, chlorine, bromine and iodine
  • Intermediate IN-1 is generated from compound A through deprotection reaction.
  • the specific deprotection conditions include hydrochloric acid (HCl)/methanol (MeOH) or dioxane (dioxane), H 2 /palladium on carbon (Pd-C), trifluoroacetic acid (TFA) and the like.
  • the product was obtained from IN-1 and compound B via known condensation conditions.
  • R a , R b , L', Y are as defined above; X is halogen;
  • the product is obtained by substitution reaction of compound C with compound B under basic conditions.
  • bases are inorganic bases such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and thallium hydroxide, etc.; and organic bases such as triethylamine, diisopropyl Ethylamine and pyridine, etc.
  • R a , R b , L', Y are as defined above;
  • the product is produced by reacting compound D and compound B in the presence of base and further reduced.
  • base examples of “base” are inorganic bases such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and thallium hydroxide, etc.; and organic bases such as triethylamine, diisopropyl Ethylamine and pyridine, etc.
  • the reaction solvent used in this reaction is, for example, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, DMSO, tetrahydrofuran, etc.; wherein, the reducing conditions are such as Pd/C, etc.
  • the present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of the compound shown in (I'), or its isomer or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carriers, diluents and excipients agent.
  • Pharmaceutical compositions can be formulated for specific routes of administration, such as oral, parenteral, rectal, and the like. Oral, e.g. tablets, capsules (including sustained-release or time-release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions) , syrups and emulsions; sublingual administration; buccal administration; parenteral administration, e.g.
  • nasally including to the nasal mucosa, for example, by inhalation spray; topically, for example, in the form of a cream or ointment; or rectally, for example, in the form of suppositories.
  • inhalation spray e.g., sterile injectable aqueous or non-aqueous or suspensions
  • nasally including to the nasal mucosa, for example, by inhalation spray
  • topically for example, in the form of a cream or ointment
  • rectally for example, in the form of suppositories.
  • a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • “Pharmaceutically acceptable carrier” refers to a medium generally acceptable in the art for delivering biologically active agents to animals, especially mammals, including, for example, adjuvants, excipients or excipients according to the mode of administration and the nature of the dosage form. Diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants agents and dispersants. Pharmaceutically acceptable carriers are formulated according to a number of factors that are within the purview of those of ordinary skill in the art.
  • compositions containing the agent include, but are not limited to: the type and nature of the active agent being formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the intended therapeutic indication.
  • Pharmaceutically acceptable carriers include aqueous Both media and non-aqueous media and a variety of solid and semi-solid dosage forms. Such carriers include many different ingredients and additives in addition to the active agent, such additional ingredients being included in formulations for a variety of reasons (e.g., stabilizing the active agent, binders, etc.) are well known to those of ordinary skill in the art .
  • Dosage regimens for the compounds of the invention may of course vary according to known factors, such as the pharmacodynamic profile of the particular agent and its mode and route of administration, the species, age, sex, health, medical condition and weight of the recipient , nature and extent of symptoms, types of concurrent treatments, frequency of treatments, route of administration, patient's renal and hepatic function, and desired effects.
  • the therapeutically effective dose of the compound, pharmaceutical composition or combination thereof depends on the species, body weight, age and individual condition of the subject, the condition or disease being treated or its severity. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of a condition or disease.
  • the present invention also provides the use of the compound represented by (I'), or its isomer or pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a drug for the treatment of related diseases mediated by the MALT1 target.
  • the related disease mediated by the MALT1 target is a disease of abnormal cell proliferation; preferably, the disease of abnormal cell proliferation is cancer.
  • the present invention also provides the application of the compound shown in (I'), or its isomer or pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of drugs for the treatment of abnormal cell proliferation diseases; preferably, the The abnormal proliferation of cells is cancer.
  • the above use wherein the cancer comprises bile duct, bone, bladder, central nervous system, breast, colorectal, stomach, head and neck, liver, lung, neurons, esophagus, ovary, pancreas, prostate , kidney, skin, testis, thyroid, uterus and vulva and other solid tumors.
  • the present invention also provides a method for treating cancer diseases, the method comprising administering to a subject a therapeutically effective amount of a compound represented by formula (I'), or an isomer thereof or a pharmaceutically acceptable salt thereof .
  • the present invention also provides a compound represented by formula (I'), which is used for treating cancer diseases.
  • the compound of the invention has remarkable protein degradation activity and cell proliferation inhibitory activity, and can be used for the treatment of cancer.
  • pharmaceutically acceptable means, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction or other problems or complications, and with a reasonable benefit/risk ratio Comparable to those compounds, materials, compositions and/or dosage forms.
  • pharmaceutically acceptable salt refers to derivatives prepared from the compounds of the present invention with relatively non-toxic acids or bases. These salts can be prepared during compound synthesis, isolation, purification, or alone by reacting the free form of the purified compound with an appropriate acid or base.
  • the compound contains relatively acidic functional groups, it can react with alkali metal, alkaline earth metal hydroxide or organic amine to obtain base addition salts, including cations based on alkali metals and alkaline earth metals and non-toxic ammonium, quaternary ammonium and amine cations, Salts of amino acids and the like are also contemplated.
  • the compound contains a relatively basic functional group, it reacts with an organic acid or an inorganic acid to form an acid addition salt.
  • break position of each structural unit described in the present invention is only for the convenience of describing the content of the present invention, and it does not have a limiting effect on the synthesis method of the compound or the independent structure of each fragment.
  • the isomers mentioned in the present invention include geometric isomers and stereoisomers, such as cis-trans isomers, enantiomers, diastereoisomers, racemic mixtures and other mixtures thereof, all These mixtures are within the scope of the present invention.
  • enantiomer refers to stereoisomers that are mirror images of each other.
  • diastereomer refers to stereoisomers whose molecules have two or more chiral centers and which are in a non-mirror-image relationship.
  • cis-trans isomer refers to the configuration in which the double bond or the single bond of the ring carbon atom in the molecule cannot freely rotate.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and Straight dotted key Indicates the relative configuration of a stereocenter, such as a double straight solid-line bond or double straight dotted key Indicates a cis structure, a straight solid line bond and straight dashed key Indicates the trans structure.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and Straight dotted key Indicates the relative configuration of a stereocenter, such as a double straight solid-line bond or double straight dotted key Indicates a cis structure, a straight solid line bond and straight dashed key Indicates the trans structure.
  • Stereoisomers of the compounds of the present invention may be prepared by chiral synthesis or chiral reagents or other conventional techniques.
  • one enantiomer of a certain compound of the present invention can be prepared by asymmetric catalytic technology or chiral auxiliary derivatization technology.
  • a compound with a single stereo configuration can be obtained from a mixture by chiral resolution technology.
  • it can be directly prepared by using chiral starting materials.
  • the separation of optically pure compounds in the present invention is usually accomplished by using preparative chromatography, and a chiral chromatographic column is used to achieve the purpose of separating chiral compounds.
  • the absolute stereo configuration of the compound can be confirmed by conventional technical means in the art.
  • the single crystal X-ray diffraction method can also confirm the absolute configuration of the compound through the chiral structure of the raw material and the reaction mechanism of the asymmetric synthesis.
  • Compounds marked as "absolute configuration not determined” herein are usually resolved into single isomers by chiral preparative SFC from racemic compounds, which are then characterized and tested.
  • excipient generally refers to a carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.
  • prophylactically or therapeutically effective amount refers to a sufficient amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to treat a disorder at a reasonable effect/risk ratio applicable to any medical treatment and/or prevention.
  • total daily dosage of the compound represented by formula (I') of the present invention or its pharmaceutically acceptable salt and composition must be determined by the attending physician within the scope of reliable medical judgment.
  • the particular therapeutically effective dosage level will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; The age, weight, general health, sex and diet of the patient; the timing, route of administration, and rate of excretion of the specific compound employed; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed; and Similar factors are well known in the medical arts. For example, it is practice in the art to start doses of the compound at levels lower than that required to obtain the desired therapeutic effect and to gradually increase the dosage until the desired effect is obtained.
  • the term “optionally substituted” means that the hydrogen atoms in a given group may or may not be substituted, and unless otherwise specified, the type and number of substituents are on a chemically realizable basis above can be arbitrary, for example, the term "optionally substituted by one or more R a " means that it can be substituted by one or more R a , or not substituted by R a .
  • alkyl means a straight-chain or branched saturated hydrocarbon group, including a C 1-6 alkyl group, a C 1-4 alkyl group, and the numerical value indicates the number of carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, and the like.
  • hydrocarbylene chain refers to a group derived from a straight or branched chain hydrocarbon by removing a hydrogen atom, and the chain hydrocarbon includes alkanes, alkenes, and alkynes. Specific alkanyl examples include, but are not limited to: wait.
  • ring refers to saturated, partially saturated or unsaturated monocyclic rings and polycyclic rings
  • polycyclic rings includes spiro rings, fused rings or bridged rings.
  • Representative “ring” includes substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl.
  • hetero refers to substituted or unsubstituted heteroatoms and oxidized forms of heteroatoms, said heteroatoms are generally selected from N, O, S, oxidized forms generally include NO, SO, S(O) 2 , nitrogen atoms can be is substituted, that is, NR (R is H or other substituents defined herein); the number of atoms on the ring is usually defined as the number of ring members, for example, "3-6 membered heterocycloalkyl” refers to 3-6 rings arranged around atoms, each ring optionally contains 1 to 3 heteroatoms, namely N, O, S, NO, SO, S(O) 2 or NR, and each ring is optionally replaced by R Substituted by a group, R is a group as defined herein.
  • cycloalkyl means a saturated monocyclic or polycyclic hydrocarbon group.
  • the cycloalkyl group is preferably a 3-6 membered monocycloalkyl group. Examples of these monocycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • heterocycloalkyl refers to a monoheterocycloalkyl group and a polyheterocycloalkyl group containing a certain number of heteroatoms in the ring, and the heteroatoms are generally selected from N, NR, O, S, NO, SO , S(O) 2 , preferably 1-2 N and/or NR and/or O.
  • the heterocycloalkyl group is preferably a 3-6 membered monoheterocycloalkyl group, more preferably a 5-6 membered monoheterocycloalkyl group.
  • Examples of these monoheterocycloalkyl groups include, but are not limited to, oxiranyl, tetrahydropyrrolyl , piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, 1,3-dioxolane, 1,4-dioxane, etc.
  • spirocycloalkyl means that two carbon rings share one carbon atom to form a spirocyclyl, and the spirocycloalkyl is preferably a 5-13 membered spiroheterocyclyl, a 6-12 membered spiroheterocyclyl, or 7-11 membered spiroheterocyclyl.
  • spirocycloalkyl include, but are not limited to
  • spiroheterocyclic group refers to a spirocyclic group in which one or more carbon atoms in the spirocyclic skeleton structure are replaced by heteroatoms, and the heteroatoms are selected from N, NR, O, S, 1-2 N, NR and/or O are preferred.
  • the spiroheterocyclyl is preferably a 5-13 membered spiroheterocyclyl, a 6-12 membered spiroheterocyclyl, or a 7-11 membered spiroheterocyclyl. Examples of spiroheterocyclyls include, but are not limited to
  • heteroaryl means a stable monocyclic or polycyclic aromatic hydrocarbon containing at least one heteroatom (N, O, S, NO, SO, S(O) 2 or NR) . Preference is given to 5- or 6-membered monocyclic heteroaryl groups.
  • the nitrogen-containing heteroaryl group means that the heteroaryl group contains at least one N heteroatom.
  • heteroaryl include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl.
  • a stable compound or stable structure is one that is sufficiently stable to undergo chemical reactions, be isolated to a useful degree of purity, and be formulated as an effective therapeutic drug.
  • the name of the title compound was converted from the compound structure by means of Chemdraw. If there is any inconsistency between the name of the compound and the structure of the compound, it can be determined by comprehensively related information and reaction routes; if it cannot be confirmed by other methods, the structural formula of the given compound shall prevail.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS), or ultra-high performance liquid chromatography-mass chromatography (UPLC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm).
  • the determination of NMR is to use Bruker Neo 400M or Bruker Ascend 400 nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), heavy water (D 2 O), internal standard is tetramethylsilane (TMS).
  • Agilent 1260-6125B single quadrupole mass spectrometer is used for liquid chromatography-mass chromatography LC-MS, the column is Welch Biomate column (C18, 2.7um, 4.6*50mm) or waters H-Class SQD2, the column is Welch Ultimate column (XB- C18, 1.8um, 2.1*50mm), mass spectrometer (the ion source is electrospray ionization).
  • HPLC uses Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.
  • Preparative HPLC uses Waters 2555-2489 (10 ⁇ m, ODS 250cm ⁇ 5cm) or GILSON Trilution LC, and the column is Welch XB-C18 column (5um, 21.2*150mm).
  • Chiral HPLC uses waters acquisition UPC2; the column is Daicel chiralpak AD-H (5um, 4.6*250mm), Daicel chiralpak OD-H (5um, 4.6*250mm), Daicel chiralpak IG-3 (3um, 4.6*150mm), Chiral Technologies Europe AD-3 (3um, 3.0*150mm) and Trefoil TM Technology Trefoil TM AMY1 (2.5um, 3.0*150mm).
  • Supercritical fluid chromatography uses waters SFC 80Q, and the column is Daicel Chiralcel OD/OJ/OZ (20x 250mm, 10um) or Daicel Chiralpak IC/IG/IH/AD/AS (20x 250mm, 10um).
  • Thin-layer chromatography silica gel plates use Yantai Jiangyou Silica Gel Development Co., Ltd. GF254 silica gel plates or Rushan Shangbang New Materials Co., Ltd. GF254 silica gel plates.
  • the specifications used by TLC are 0.15mm to 0.20mm, preparative 20x 20cm, column chromatography is general Use 200-300 mesh silica gel in Yucheng Chemical as the carrier.
  • the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or following methods known in the art.
  • Step B Compound INT-1-1 (1.6 g, 8.3 mmol) was dissolved in ethanol (15 ml), and after argon replacement, Pd/C (10%, 0.2 g) was added. The system was replaced with hydrogen and stirred at room temperature for three hours under a hydrogen balloon. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 0.9 g of compound INT-1-2. The crude product was directly used in the next reaction.
  • Step C Compound INT-1-2 (0.9 g, 8.2 mmol) was dissolved in THF (10 mL), and N,N'-carbonyldiimidazole (1.5 g, 9.0 mmol) was added at 0°C. The ice bath was removed, the temperature was raised to 28 degrees Celsius, and stirred under this condition for 3 hours. (reaction solution one);
  • Step D Compound INT-1-3 (0.5 g, 2.7 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (1.25 ml), and the system was heated at 120 degrees Celsius for 1 hour , and then cooled to 80 degrees Celsius.
  • Step E Compound INT-1-4 (600 mg, 1.93 mmol) was dissolved in trifluoroacetic acid (5 mL), and the solution was stirred at room temperature for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain 400 mg of intermediate INT-1.
  • Step A 5-chloro-3-nitropyridin-2-ol (1.7 g, 10.0 mmol), tert-butyl (2-hydroxyethyl) carbamate ( 1.6 g, 10.0 mmol), triphenylphosphine (5.2 g, 20.0 mmol) was dissolved in tetrahydrofuran (30 ml), and diethyl azodicarboxylate (3.5 g, 20.0 mmol) was added. After the dropwise addition was completed, the reaction system was stirred at room temperature for 18 hours. The reaction solution was quenched with water (50 mL), extracted with ethyl acetate (50 mL ⁇ 3).
  • Step C Intermediate INT-1 (45.0 mg, 0.2 mmol) was dissolved in 1,4-dioxane (2 mL). Diphenylphosphoryl azide (0.1 mL, 0.5 mmol) and triethylamine (0.1 mL, 0.7 mmol) were added. The system was stirred at room temperature for half an hour. Compound INT-2-2 (100.0 mg, 0.3 mmol) was added to the above reaction system. The reaction was heated to 100°C and stirred for 1 hour. The reaction solution was cooled to room temperature, quenched by adding water (10 mL), and extracted with ethyl acetate (10 mL ⁇ 3).
  • Step D Compound INT-2-3 (200.0 mg, 0.4 mmol) was dissolved in ethyl acetate (5 mL) and hydrochloric acid in dioxane (4 mol, 5 mL). The system was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain (S)-1-(2-(2-aminoethoxy)-5-chloropyridin-3-yl)-3-(2-chloro-7-(1-methoxyethyl) base) pyrazolo[1,5-a]pyrimidin-6-yl)urea hydrochloride 120.0 mg intermediate INT-2.
  • the preparation method refers to the preparation example of intermediate INT-2, and finally the target product (S)-1-(2-(2-aminoethoxy)-5-(trifluoromethyl)pyridin-3-yl)-3- (2-Chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)urea hydrochloride intermediate INT-3.
  • the preparation method refers to the preparation example of INT-2, and finally the target product intermediate INT-4 is obtained.
  • Step A Add 40 grams (0.2 moles) of (S)-1-(4-bromophenyl)ethan-1-amine to a mixed solution of ethyl acetate (400 milliliters) and water (400 milliliters), dicarbonate Di-tert-butyl ester (64 g, 0.3 mol), sodium bicarbonate (24 g, 0.4 mol) were added to the above mixture. The resulting mixture was stirred at 25 °C for 1 hour. LCMS monitoring showed disappearance of starting material (complete dissolution). 1 liter of water and 1 liter of ethyl acetate were added and the reaction mixture was vigorously stirred for 5 minutes.
  • Step B Dissolve compound INT-5-1 (5 g, 16 mmol), palladium acetate (35.8 mg, 0.16 mmol) in N,N-dimethylacetamide (80 ml), and add to the solution Potassium acetate (3.1 g, 32 mmol) and 4-methylthiazole (3.2 g, 32 mmol) were added.
  • the resulting reaction mixture was stirred at 90 °C for 16 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was quenched with purified water (50 mL), and extracted with dichloromethane (50 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The resulting mixture was purified twice by silica gel column chromatography to obtain 2.5 g of compound INT-5-2.
  • Step C 20 mL of hydrochloric acid in 1,4-dioxane was added to a mixed solution of compound INT-5-2 (5.8 g, 18.2 mmol) and dichloromethane (40 mL). The reaction mixture was stirred at 25 °C for 1 hour. LCMS monitoring showed disappearance of starting material. The reaction solution was concentrated under reduced pressure, 7 g of compound INT-5-3 was obtained, which was directly used in the next step without purification. MS (ESI) M/Z: 219.3 [M+H] + .
  • Step D Compound N-BOC-trans-4-hydroxy-D-proline (4.2 g, 18.2 mmol), compound INT-5-3 (7 g), 2-(7-azabenzo Triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.9 g, 18.2 mmol) and N,N-diisopropylethylethylamine (11.7 g, 90.7 mmol) was added to THF (100 mL), and stirred at 20°C for 18 hours. LCMS monitoring showed disappearance of starting material. The reaction solution was quenched with purified water (200 mL), extracted with ethyl acetate (100 mL ⁇ 3).
  • Step E A solution of hydrochloric acid in 1,4-dioxane (4M, 4 mL) and compound INT-5-4 (350 mg, 0.8 mmol) were added into dichloromethane (4 mL). The reaction mixture was stirred at 25 °C for 1 hour. LCMS monitoring showed disappearance of starting material. The reaction mixture was concentrated to remove the solvent to obtain 420 mg of INT-5-5.
  • Step F Mix (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (293 mg, 1.3 mmol), compound INT-5-5 (420 mg, 1.3 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (483 mg, 1.3 mmol) and, N-diiso Propylethylethylamine (818 mg, 6.3 mmol) was added separately to the THF (5 mL) solution, and stirred at 20°C for 18 hours. LCMS monitoring showed disappearance of starting material.
  • reaction solution was quenched with purified water (200 mL), and extracted with ethyl acetate (100 mL ⁇ 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The resulting mixture was purified by silica gel column chromatography to obtain 510 mg of compound INT-5-6.
  • Step G A solution of hydrochloric acid in 1,4-dioxane (4M, 2 mL) was added to a mixture of compound INT-5-6 (240 mg, 0.4 mmol) and dichloromethane (2 mL). The mixture was stirred at 25 °C for 1 h, LCMS monitoring showed disappearance of starting material. The mixture was stripped of the solvent to give 196 mg of intermediate INT-5.
  • the preparation method refers to the preparation example of intermediate INT-5, and finally the target product intermediate INT-6 is obtained.
  • Step A Intermediate INT-5 (390.0 mg, 0.9 mmol), 7-tert-butoxy-7-oxoheptanoic acid (190.0 mg, 0.9 mg), N,N-diisopropylethylamine (566.0 mg , 4.4 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (501.0 mg, 1.3 mmol) were dissolved in N, N-Dimethylformamide (150 mL). The reaction was stirred at room temperature for 2 hours.
  • reaction solution was quenched with water (10 mL), and extracted with ethyl acetate (10 mL ⁇ 3). The organic phases were combined, washed with water (10 mL ⁇ 3) and saturated brine (10 mL ⁇ 3), and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The resulting mixture was purified by reverse phase column chromatography (mobile phase: 70% acetonitrile, 30% distilled water, distilled water containing 0.025% formic acid) to obtain 240.0 mg of compound 1-1.
  • Step B Compound 1-1 (240.0 mg, 0.4 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (2 mL). The reaction was stirred at room temperature for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure to obtain 200 mg of compound 1-2. This compound was used directly in the next step.
  • Step C Desalted intermediate INT-2 (95.0 mg, 0.2 mmol), compound 1-2 (120.0 mg, 0.2 mmol), N,N-diisopropylethylamine (0.16 mL, 1.0 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (82.0 mg, 0.2 mmol) dissolved in N,N-dimethyl Formamide (3 mL). The reaction was stirred at room temperature for 2 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was quenched with water (10 mL), and extracted with ethyl acetate (10 mL ⁇ 3).
  • Step A The hydrochloride salt of intermediate INT-3 (80.0 mg, 0.2 mmol), compound 1-2 (102.3 mg, 0.2 mmol), N,N-diisopropylethylamine (112.6 mg, 0.9 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (99.5 mg, 0.3 mmol) dissolved in N,N- Dimethylformamide (5 mL). The reaction was stirred at room temperature for 2 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was quenched with water (10 mL), and extracted with ethyl acetate (10 mL ⁇ 3).
  • Step A Add diethyl azodicarboxylate (2 g, 11.5 mmol) to a mixture of (5-chloro-3-nitro-2-hydroxy)pyridine (1 g, 5.7 mmol) at zero degrees Celsius , tert-butyl 2-hydroxyacetate (752 mg, 5.7 mmol) and triphenylphosphine (6.6 g, 25.3 mmol) in tetrahydrofuran (20 mL). Stirring at room temperature overnight, LCMS monitoring showed disappearance of starting material. The reaction solution was poured into water (50 mL), and extracted with ethyl acetate (100 mL ⁇ 3).
  • Step C Add diphenylphosphoryl azide (0.1 mL) and triethylamine (150 ⁇ L, 1.2 mmol) to 1,4-dioxan containing intermediate INT-1 (100 mg, 0.4 mmol) alkane (4 mL) solution.
  • the resulting yellow solution was stirred at room temperature for 30 minutes, 200 mg of compound 3-2 was added, and the mixture was heated under reflux for 1 hour.
  • LCMS monitoring showed disappearance of starting material.
  • the mixture was diluted with water (50 mL), extracted with ethyl acetate (30 mL ⁇ 3). The combined organic phases were washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to obtain 40 mg of compound 3-3.
  • Step D Trifluoroacetic acid (2 mL) was added to a solution of Intermediate 3-3 (200 mg, 0.4 mmol) in dichloromethane (5 mL) at 0 °C. The resulting yellow solution was stirred at room temperature for 2 hours. LCMS monitoring showed disappearance of starting material. Concentrate the mixture. 120 mg of compound 3-4 were obtained without purification.
  • Step E 7-((tert-butoxycarbonyl)amino)heptanoic acid (108 mg, 0.4 mmol), intermediate INT-5 (196 mg, 0.4 mmol), 2-(7-azabenzo Triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (167.6 mg, 0.4 mmol) and N,N-diisopropylethylethylamine (172 mg, 1.3 mmol) were added to tetrahydrofuran (5 mL), and stirred at 20°C for 18 hours. LCMS monitoring showed disappearance of starting material.
  • Step F A solution of hydrochloric acid in 1,4-dioxane (4M, 4 mL) was added to a solution of compound 3-5 (192 mg, 0.3 mmol) in dichloromethane (4 mL). The mixture was stirred at 25 °C for 1 hour. LCMS monitoring showed disappearance of starting material. The reaction solution was spin-dried to obtain 187 mg of compound 3-6.
  • Step G Compound 3-6 (187 mg, 0.3 mmol), compound 3-4 (96 mg, 0.2 mmol), 2-(7-azabenzotriazole)-N,N,N' , N'-Tetramethyluronium hexafluorophosphate (79.8 mg, 210 micromol) and N,N-diisopropylethylethylamine (94.8 mg, 740 micromol) were dissolved in THF (10 mL) , and the resulting solution was stirred at 20 °C for 1 h. LCMS monitoring showed disappearance of starting material. The reaction solution was quenched with purified water (20 mL), and then extracted with ethyl acetate (15 mL ⁇ 3).
  • Step A intermediate INT-2 (95.0 mg, 0.2 mmol), compound 4-1 (120.0 mg, 0.2 mmol), N,N-diisopropylethylamine (0.2 mL, 1.0 mmol) and 2 -(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (82.0 mg, 0.2 mmol) dissolved in N,N-dimethylformamide (3 ml). The reaction was stirred at room temperature for 2 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was quenched with water (10 mL), and extracted with ethyl acetate (10 mL ⁇ 3).
  • Embodiment 5 is a diagrammatic representation of Embodiment 5:
  • Step A Dissolve 7-bromoheptanoic acid (1.1 g, 5.3 mmol) in N,N-dimethylformamide (20 ml) at room temperature, add 2-(7 -Azabenzotriazole)-N,N,N',N'--Tetramethyluronium hexafluorophosphate (2.0 g, 5.3 mmol), after stirring for 10 minutes, add the intermediate INT-5 in sequence (2.0 g, 4.5 mmol) and N,N-diisopropylethylamine (2.2 ml, 12.9 mmol). The reaction solution was stirred for 30 minutes in an ice-water bath under the protection of argon. LC-MS showed complete reaction of starting material.
  • Step B Compound 5-1 (60 mg, 94.4 micromol), intermediate INT-2 hydrochloride (23 mg, 45.2 micromol), N,N-diisopropylethylamine (59 mg , 453.1 micromoles), potassium iodide (19 mg, 113.3 micromoles) and N,N-dimethylformamide (2 ml) were sequentially added to a one-necked flask. The reaction solution was heated to 70° C. and stirred for 4 hours. LC-MS showed product formation. Water (5 mL) was added to the cooled reaction solution and extracted with ethyl acetate (5 mL ⁇ 3).
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • Step A Dissolve the desalted intermediate INT-4 (21 mg, 41 micromole) in N,N-dimethylformamide (2 ml) at room temperature, and add compound 5-1 (52 mg, 82 micromole), potassium iodide (21 mg, 124 micromole) and N,N-diisopropylethylamine (16 mg, 124 micromole), the reaction solution was heated to 70 degrees Celsius and stirred for 4 hours.
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • Step A 7-Hydroxyheptanoic acid (1.2 g, 7.9 mmol) was dissolved in DMSO (20 mL), and 2-iodobenzoic acid (3.3 g, 11.9 mmol) was added. The reaction was stirred at room temperature for 4 hours. After LCMS monitoring showed that the starting material disappeared, the reaction liquid was quenched by adding water (8 mL), filtered, and the filtrate was extracted with ethyl acetate (40 mL). The organic phase was washed with water (20 mL) and saturated brine (30 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 1.0 g of compound 7-1.
  • Step B The desalted intermediate INT-2 (200.0 mg, 455.0 ⁇ mol) and compound 7-1 (85.0 mg, 0.6 mmol) were dissolved in 1,2-dichloroethane (5 mL). Acetic acid (1 drop), titanium tetraisopropoxide (258.0 mg, 0.9 mmol) and sodium triacetate borohydride (289.0 mg, 1.4 mmol) were added. The reaction system was reacted at 25 degrees Celsius for 6 hours.
  • reaction solution was quenched with water (10 mL), extracted with ethyl acetate (15 mL), and the organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting mixture was purified by reverse phase column chromatography (mobile phase: 28% acetonitrile, 72% purified water, 0.025% formic acid in purified water) to obtain 80.0 mg of compound 7-2.
  • Step C In N,N-dimethylformamide (5 mL), add compound 7-2 (200.0 mg, 352.0 ⁇ mol), 2-(7-azabenzotriazole)-N,N , N',N'-tetramethylurea hexafluorophosphate (134.0 mg, 0.4 mmol), N,N-diisopropylethylamine (0.3 mL, 1.8 mmol) and the desalted intermediate INT-6 (151.0 mg, 0.4 mmol). The reaction was stirred at 25°C for 1.5 hours.
  • reaction solution was quenched with water (10 mL), extracted with ethyl acetate (20 mL), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • Step A Compound 8-1 (96 mg, 511.0 micromole) was dissolved in N,N-dimethylformamide (2.0 mL), and 2-(7-azabenzotriazole) was added at zero degrees Celsius -N,N,N',N'-Tetramethyluronium hexafluorophosphate (212 mg, 557 micromol). The reaction solution was stirred at zero degrees Celsius for 10 minutes. The desalted intermediate INT-6 (200 mg, 465 ⁇ mol) and N,N-diisopropylethylamine (180 mg, 1.4 mmol) were added at zero degrees Celsius. The reaction was stirred at 0°C for 10 minutes. LC-MS showed complete reaction of starting material.
  • Step B Compound 8-2 (70 mg, 116 micromole) was dissolved in THF (7 mL) and water (1.4 mL), and lithium hydroxide monohydrate (49 mg, 1.2 mmol) was added in an ice-water bath . The reaction solution was slowly returned to room temperature and stirred overnight. LC-MS showed complete reaction of starting material.
  • Step C Compound 8-3 (40 mg, 70 micromole) was dissolved in N,N-dimethylformamide (2.0 mL) at zero degrees Celsius, and 2-(7-azabenzotriazole) was added -N,N,N',N'-Tetramethyluronium hexafluorophosphate (29 mg, 76.2 micromol). The reaction solution was stirred at zero degrees Celsius for 10 minutes, and intermediate INT-2 (30 mg, 63 micromoles) and N,N-diisopropylethylamine (25 mg, 190 micromoles) were added at zero degrees Celsius. The reaction solution was stirred at zero degrees Celsius for 10 minutes. LC-MS showed complete reaction of starting material.
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • Step A 8-Hydroxyoctanoic acid (1.0 g, 6.2 mmol) was dissolved in DMSO (20 mL), and 2-iodobenzoic acid (2.6 g, 9.4 mmol) was added. The reaction was stirred at room temperature for 4 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was quenched with water (20 mL), filtered, and the filtrate was extracted with ethyl acetate (20 mL ⁇ 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 0.7 g of compound 9-1.
  • Step B The intermediate INT-2 (120.0 mg, 252.0 ⁇ mol) was dissolved in N,N-dimethylformamide (1 mL) and THF (1 mL), and triethylamine (77.0 mg, 757.0 ⁇ mol) was added mol), the system was stirred at room temperature for half an hour. Compound 9-1 (40.0 mg, 252.0 micromole) and acetic acid (one drop) were added to the above reaction solution, and the stirring was continued for 1 hour. Sodium triacetate borohydride (107.0 mg, 504.0 micromole) was added to the reaction, and the reaction was stirred at room temperature for 12 hours.
  • Step C In N,N-dimethylformamide (2 mL), add compound 9-2 (40.0 mg, 69 ⁇ mol), the desalted intermediate INT-6 (48.0 mg, 0.1 mmol), 2 -(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (39.0 mg, 0.1 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.3 mmol). The reaction system was stirred at 20°C for 18 hours.
  • reaction solution was poured into ice water (5 ml), extracted with ethyl acetate (10 ml ⁇ 3), the organic phases were combined, washed with brine (10 ml ⁇ 3), and dried over anhydrous sodium sulfate , concentrated under reduced pressure.
  • Step A Intermediate INT-4 (18 mg, hydrochloride, 35.3 micromole), compound 10-1 (44 mg, 70.7 micromole), N,N-diisopropylethylamine (44 mg , 339.3 ⁇ mol), potassium iodide (14 mg, 84.8 ⁇ mol) and N,N-dimethylformamide (1 ml) were added to a one-necked flask. The reaction solution was stirred at 70°C for 4 hours. LC-MS showed product formation. Water (10 mL) was added to the cooled reaction solution, followed by extraction with ethyl acetate (10 mL ⁇ 3).
  • Step A Compound 11-1 (80 mg, 128 micromole) was dissolved in N,N-dimethylformamide (2 ml) at room temperature, and intermediate INT-2 (31 mg, hydrochloride , 65 ⁇ mol) and potassium iodide (25 mg, 154 ⁇ mol). The reaction solution was heated to 70° C. and stirred for 4 hours. LC-MS showed the production of QL-MDC2026. Ethyl acetate (20 ml) was added to the cooled reaction solution, washed with water (5 ml ⁇ 6), dried over anhydrous sodium sulfate and filtered.
  • Step A Dissolve 5-chloropentanoic acid (152 mg, 1.1 mmol) in N,N-dimethylformamide (4 ml) at room temperature, add 2-(7 -Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (706 mg, 1.9 mmol). After stirring in an ice-water bath for 30 minutes, intermediate INT-6 (400 mg, 0.9 mmol) and N,N-diisopropylethylamine (0.8 mL, 1.9 mmol) were sequentially added. The reaction solution was stirred at room temperature for 1 hour. LC-MS showed starting material was consumed.
  • Step B Compound 12-1 (110 mg, 0.20 mmol), desalted intermediate INT-2 (44 mg, 0.10 mmol), potassium iodide (40 mg, 0.24 mmol) and N,N-di Isopropylethylamine (129 mg, 1.0 mmol) was dispersed in N,N-dimethylformamide (1 mL), heated to 80°C under argon protection and stirred for 16 hours. LC-MS showed that most of the starting material was consumed and the product QL-MDC2018 was formed. Water (10 mL) was added to the cooled reaction solution, followed by extraction with ethyl acetate (5 mL ⁇ 3).
  • Step A compound 13-1 (60 mg, 0.1 mmol), compound rac-INT-2 (22 mg, 0.05 mmol), potassium iodide (20 mg, 0.1 mmol) and N,N-diiso Propylethylamine (64 mg, 0.5 mmol) was dispersed in N,N-dimethylformamide (1 mL), and the reaction solution was heated to 80°C under the protection of argon and stirred for 16 hours. LC-MS showed that most of the starting material was consumed and the product QL-MDC2019 was formed. Water (10 mL) was added to the cooled reaction solution, followed by extraction with ethyl acetate (5 mL ⁇ 3).
  • Step A compound 10-1 (60 mg, 0.1 mmol), compound rac-INT-2 (21 mg, 50 micromol), potassium iodide (19 mg, 0.1 mmol) and N,N-diiso Propylethylamine (62 mg, 0.5 mmol) was dispersed in N,N-dimethylformamide (1 mL), heated to 80°C under argon protection and stirred for 16 hours.
  • LC-MS showed that most of the starting material was consumed and the product QL-MDC2020 was formed. Water (10 mL) was added to the cooled reaction solution, followed by extraction with ethyl acetate (5 mL ⁇ 3).
  • Step A Intermediate INT-6 (100 mg, 0.2 mmol) and triethylamine (0.1 mL, 0.7 mmol) were dissolved in anhydrous dichloromethane (1 mL) at room temperature, protected by argon, in an ice-water bath And a solution of acryloyl chloride (21 mg, 0.23 mmol) in anhydrous dichloromethane (1 mL) was added with stirring. The reaction solution was stirred at room temperature under argon protection for 16 hours. LC-MS showed disappearance of starting material. Water (10 mL) was added to the reaction solution, followed by extraction with dichloromethane (10 mL ⁇ 3).
  • Step B Compound 15-1 (46 mg, 95 ⁇ mol), compound rac-INT-2 (33 mg, 76 ⁇ mol) and sodium carbonate (50 mg, 47 ⁇ mol) were dispersed in methanol (1 mL) at room temperature ), the reaction solution was heated to 65 degrees Celsius under the protection of argon and stirred for 48 hours. LC-MS showed disappearance of most starting material and formation of product. The cooled reaction solution was concentrated. Water (10 ml) was added to the resulting residue, followed by extraction with ethyl acetate (5 ml ⁇ 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate and filtered.
  • Step A Desalted intermediate INT-2 (100.0 mg, 0.2 mmol), 6-(methoxycarbonyl)spiro[3.3]heptane-2-carboxylic acid (42.0 mg, 0.2 mmol), HATU (80.0 mg, 0.2 mmol) and diisopropylethylamine (0.2 ml, 1.1 mmol) were dissolved in N,N-dimethylformamide (2 ml), and the reaction system was stirred at room temperature for 1.5 hours.
  • reaction solution was poured into ice water and extracted with dichloromethane (10 mL), washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was washed over silica gel. Purified by column chromatography to obtain 60.0 mg of compound 16-1.
  • Step B Compound 16-1 (60.0 mg, 0.1 mmol) and lithium hydroxide monohydrate (6.1 mg, 0.1 mmol) were dissolved in THF/water (1 mL/1 mL) at 0°C. The resulting solution was stirred at zero degrees Celsius for 1.5 hours. After LCMS monitoring showed that the raw material disappeared, the pH of the solution was adjusted to 2-3 with 1 M aqueous hydrochloric acid, extracted with ethyl acetate (5 mL), washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, and filtered and concentrated, the crude product was directly used for the next step without further purification.
  • Step C compound 16-2 (50 mg, 82.6 micromol), intermediate INT-6 (42.0 mg, 0.09 mmol), HATU (80.0 mg, 0.2 mmol) and diisopropylethylamine (0.2 mL, 1.1 mmol) was dissolved in dichloromethane (2 mL), and the resulting solution was stirred at room temperature for 15 hours.
  • Embodiment 17 is a diagrammatic representation of Embodiment 17:
  • Step A Dissolve 2-fluoro-3-nitrobenzoic acid (20 g, 108 mmol) and methylamine hydrochloride (8.7 g, 129 mmol) in ethanol (200 ml), then add N,N- Diisopropylethylamine (70 g, 540 mmol). Stir overnight at room temperature. LCMS monitoring showed that the starting material disappeared, concentrated, added water (100 ml), adjusted the pH value to 3 with concentrated hydrochloric acid, filtered the yellow precipitate, and dried to obtain 10.5 g of compound 17-1.
  • Step B Compound 17-1 (11.6 g, 59 mmol) was dissolved in tert-butanol (200 mL), and N,N-diisopropylethylamine (15.3 g, 118.3 mmol) and phosphoric azide were added Diphenyl ester (17.9 g, 65.0 mmol). The reaction system was stirred overnight at 90°C. After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated. The crude product was added with water (500 ml), crushed, filtered, the filter cake was washed with ethyl acetate (10 ml), and dried to obtain compound 17-2 (11.0 g, yellow solid, yield 95%).
  • Step D Compound 17-3 (140 mg, 460 ⁇ mol) was dissolved in THF (15 mL) and methanol (15 mL), and 5% Pd/C (40 mg, 50% H2O) was added. The hydrogenation reaction was carried out overnight at room temperature. Filtration, washing and concentration gave compound 17-4 (80 mg). The crude product was directly used in the next reaction without further reaction.
  • Step E Under nitrogen protection, slowly add oxalyl chloride (541 mg, 4.3 mmol) to a solution of anhydrous dimethyl sulfoxide (666 mg, 8.5 mmol) in dichloromethane (2 mL) at -78 °C dichloromethane solution (20 mL). After stirring at -78°C for half an hour, a solution of compound 17-5 (500 mg, 2.1 mmol) in dichloromethane (2 mL) was slowly added dropwise, and stirring was continued for 1 hour. Triethylamine (1293 mg, 12.8 mmol) was added slowly, and stirring was continued for 1 hour at constant temperature. Naturally raised to room temperature, concentrated.
  • Step F Compound 17-6 (81 mg, 340 ⁇ mol) and compound 17-4 (80 mg, 0.3 mmol) were dissolved in DMSO (4 mL) under nitrogen atmosphere, and acetic acid (0.2 mL) was added , react at 60°C for 1 hour, add sodium cyanoborohydride (27 mg, 430 micromole) in portions, and continue stirring at constant temperature overnight. Dilute with water (50 mL), extract with ethyl acetate (20 mL ⁇ 2), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate. The crude product was separated by silica gel column chromatography to obtain 42 mg of compound 17-7.
  • Step G Compound 17-7 (42 mg, 85 ⁇ mol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added. After reacting at room temperature for 3 hours, the reaction solution was concentrated to obtain 40 mg of compound 17-8.
  • Step H under nitrogen protection, to compound 17-8 (40 mg, 0.09 mmol) and intermediate INT-2 hydrochloride (52 mg, 0.1 mmol) in dry N,N-dimethylformamide ( 4 ml) solution, add N, N-diisopropylethylamine (35 mg, 0.27 mmol), 2-(7-azabenzotriazole)-N, N, N', N' - Tetramethylurea hexafluorophosphate (53 mg, 140 micromol). After reacting at room temperature for 2 hours, water (50 mL) was added, extracted with ethyl acetate (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • N, N-diisopropylethylamine 35 mg, 0.27 mmol
  • 2-(7-azabenzotriazole)-N, N, N', N' - Tetramethylurea hexafluorophosphate 53 mg, 140 micromol
  • Step A tert-butyl acrylate (tert-butyl acrylate, 3.3 g, 25.8 mmol) and piperidin-4-ylmethanol (2.0 g, 21.7 mmol) were dissolved in methanol (20 ml), and the reaction system was heated at room temperature Stirring was continued for 18 hours. After LCMS monitoring showed that the raw material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting mixture was purified by reverse phase column chromatography (mobile phase: 50% acetonitrile, 50% distilled water, distilled water containing 0.01% ammonium bicarbonate) to obtain compound 18-1 (3.9 g , white solid, yield 92.0%).
  • Step B Dissolve oxalyl chloride (0.6 g, 4.5 mmol) in dichloromethane (3 mL) and dimethyl sulfoxide (0.7 mL, 9.1 mmol) (in 2 mL dichloromethane) was slowly added dropwise to the above solution. The system was stirred for 5 minutes. Compound 18-1 (1.0 g, 4.1 mmol) (dissolved in 2.5 mL of dichloromethane) was slowly added dropwise to the reaction solution. The reaction was stirred at -78°C for 15 minutes. Triethylamine (2 mL, 14.8 mmol) was slowly added dropwise to the reaction system, and the reaction solution was slowly raised to room temperature and stirred at room temperature for 45 minutes.
  • Step C Dissolve compound 18-2 (120.0 mg, 0.5 mmol), compound 18-3 (136.0 mg, 0.5 mmol), acetic acid (0.5 ml) and sodium cyanoborohydride (47.0 mg, 0.8 mmol) in dimethyl sulfoxide (5 mL).
  • the system was stirred at 60°C for 18 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was quenched with ice water (50 mL), and extracted with dichloromethane (50 mL ⁇ 3). The organic phases were combined, washed successively with water (50 mL ⁇ 3) and saturated brine (50 mL ⁇ 3), and dried over anhydrous magnesium sulfate.
  • Step D Compound 18-4 (120.0 mg, 0.2 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1 mL). The system was stirred at room temperature for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure. Compound 18-5 (100.0 mg) was obtained. This compound was used directly in the next step.
  • Step E Compound 18-5 (100.0 mg, 0.2 mmol), intermediate INT-2 (99.2 mg, 0.2 mg), N,N-diisopropylethylamine (145.4 mg, 1.1 mmol) and 2 -(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (128.5 mg, 0.3 mmol) dissolved in N,N-dimethylformamide (5 ml). The reaction was stirred at room temperature for 1 hour. After LCMS monitoring showed that the starting material disappeared, the reaction solution was quenched with water (50 mL), and extracted with ethyl acetate (50 mL ⁇ 3).
  • Step A Dissolve compound 19-1 (2.3 g, 8.3 mmol) in N-methylpyrrolidone (20 ml) at room temperature, then add 4-aminobutyraldehyde dimethyl acetal (1.0 g, 7.5 mmol) and N,N-diisopropylethylamine (5.2 mL, 30.0 mmol).
  • the reaction solution was buried in an oil bath preheated to 140°C, and stirred at 140°C for 30 minutes under the protection of argon. LC-MS showed that no starting material remained, and the main product was compound 19-2. Water (100 mL) was added to the cooled reaction solution, followed by extraction with ethyl acetate (100 mL, 50 mL).
  • Step C Compound 19-3 (15 mg, 44 ⁇ mol) and the desalted intermediate INT-2 (10 mg, 23 ⁇ mol) were dissolved in THF (2 ml) at room temperature, and tris was added under stirring at zero degrees Celsius. Sodium acetoxyborohydride (24.4 mg, 115 micromol). The reaction solution was stirred at room temperature for 2 hours. LC-MS showed that the main product was QL-MDC2040. The reaction solution was quenched with saturated aqueous sodium bicarbonate (20 mL), and the resulting mixture was extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phases were washed with saturated brine (20 mL ⁇ 3), dried over anhydrous sodium sulfate and filtered.
  • Step A Compound 20-1 (18 mg, 47 ⁇ mol) and desalted intermediate INT-2 (20 mg, 45 ⁇ mol) were dissolved in THF (2 mL) at zero degrees Celsius with stirring Sodium triacetoxyborohydride (38 mg, 180 ⁇ mol) was added. The reaction was then stirred at room temperature for 2 hours. The reaction solution was quenched with saturated aqueous sodium bicarbonate (20 mL), and the resulting mixture was extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phases were washed with saturated brine (50 mL ⁇ 3), dried over anhydrous sodium sulfate and filtered.
  • Step A Compound 21-1 (80 mg, 224 ⁇ mol) and the desalted intermediate INT-2 (30 mg, 68 ⁇ mol) were dissolved in THF (5 ml) at room temperature, and tris was added under stirring at zero degrees Celsius. Sodium acetoxyborohydride (72 mg, 341 micromol). The reaction was then stirred at room temperature for 2 hours. LC-MS showed that the main product was QL-MDC2042. Saturated aqueous sodium bicarbonate (20 mL) was added to the reaction solution, followed by extraction with ethyl acetate (20 mL ⁇ 3). The combined organic phases were washed with saturated brine (20 mL ⁇ 3), dried over anhydrous sodium sulfate and filtered.
  • Step A tert-butyl 7-aminoheptanoate (100.0 mg, 0.5 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3- Diketone (138.0 mg, 0.5 mmol), N,N-diisopropylethylamine (0.4 mL, 2.4 mmol) was dissolved in dimethylsulfoxide (2 mL). The reaction system was stirred at 90°C for 18 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (10 mL ⁇ 3).
  • Step B Compound 22-1 (100 mg, 0.2 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL). The reaction was stirred at room temperature for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure, and the resulting mixture was purified by silica gel column chromatography to obtain 50.0 mg of compound 22-2.
  • Step C intermediate INT-2 (77.0 mg, 0.2 mmol), compound 22-2 (65.0 mg, 0.2 mmol), N,N-diisopropylethylamine (103.2 mg, 0.8 mmol) and 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (62.0 mg, 0.2 mmol) dissolved in N,N-dimethylformaldehyde Amide (3 mL). The reaction was stirred at room temperature for 2 hours.
  • reaction solution was quenched with water (10 ml), extracted with ethyl acetate (10 ml ⁇ 3) and the combined organic phase was washed with water (10 ml ⁇ 3) and saturated brine (10 ml ⁇ 3). Dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure.
  • Embodiment 23 is a diagrammatic representation of Embodiment 23.
  • Step A To stirred compound 23-1 (33 mg, 77 micromole) in N,N-dimethylformamide (1 mL) at zero degrees Celsius under argon atmosphere 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 40 mg, 0.1 mmol) was added to the solution. The reaction solution was stirred at zero degrees Celsius and under argon protection for 30 minutes. Compound rac-INT-4 (crude hydrochloride, 35.4 mg, 65.1 ⁇ mol) and N,N-diisopropylethylamine (27.1 mg, 0.2 mmol) were added.
  • HATU 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • reaction solution was then stirred at room temperature under argon protection for 1 hour.
  • the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL ⁇ 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered.
  • Step A Dissolve compound 24-1 (45 mg, 92.5 micromole) in N,N-dimethylformamide (1 ml) at room temperature, add 2-(7- Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 47 mg, 123.3 ⁇ mol). under ice water bath After stirring for 30 minutes, compound rac-INT-4 (17 mg, 33.5 ⁇ mol) and N,N-diisopropylethylamine (DIPEA, 12 mg, 92.5 ⁇ mol) were added sequentially. The reaction solution was stirred in an ice-water bath and under the protection of argon for 1 hour. LC-MS showed disappearance of starting material.
  • HATU 2-(7- Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DIPEA N,N-diisopropylethylamine
  • Step A Dissolve compound 25-1 (23 mg, 50 micromol) and triethylamine (7 mg, 70 micromol) in dichloromethane (2 ml) at room temperature, add 2-( 7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 19 mg, 50 ⁇ mol). The reaction was then stirred at room temperature for 0.5 hours. Compound rac-INT-4 (18 mg, crude hydrochloride, 30 ⁇ mol) was added under ice-water bath and stirring. The reaction solution was stirred at room temperature for 8 hours. LC-MS showed disappearance of starting material.
  • HATU 2-( 7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • Step A Compound 26-1 (1 g, 3.1 mmol) was dissolved in N,N-dimethylformamide (20 ml) at room temperature, and 7-octynol (586 mg, 4.6 mmol), cesium carbonate (2.02 g, 6.2 mmol), cuprous iodide (118 mg, 618.9 micromol) and bis(triphenyl phospho)palladium dichloride (217 mg, 309.5 micromole). The reaction solution was stirred at 80° C. for 2 hours under the protection of argon. LC-MS showed complete reaction of starting material. Water (200 mL) was added to the cooled reaction solution, followed by extraction with ethyl acetate (150 mL ⁇ 3).
  • Step B Compound 26-2 (100 mg, 271.4 ⁇ mol) was dissolved in ethyl acetate (25 mL) at room temperature, and Dess-Martin oxidant (158 mg, 372.6 ⁇ mol) was added at 0°C. The reaction solution was slowly returned to room temperature and stirred overnight. Saturated sodium bicarbonate (10 mL) and water (10 mL) were added to the reaction solution, followed by extraction with ethyl acetate (20 mL ⁇ 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was purified by preparative thin-layer chromatography to obtain 44 mg of compound 26-3.
  • Step C Dissolve compound 26-3 (44 mg, 120.1 ⁇ mol) and the desalted intermediate INT-2 (48 mg, 109.2 ⁇ mol) in THF (2 mL) at room temperature, and add triacetoxy sodium borohydride (69 mg, 327.5 micromol). The reaction solution was slowly returned to room temperature and stirred for 2 hours. LC-MS showed a small amount of starting material remaining and product formed. Saturated aqueous sodium chloride solution (2 mL) and saturated aqueous sodium bicarbonate solution (2 mL) were added to the reaction solution, followed by extraction with ethyl acetate (10 mL ⁇ 3).
  • Step A Dissolve compound 27-1 (25 mg, 77.1 ⁇ mol) and the desalted intermediate INT-2 (31 mg, 70.1 ⁇ mol) in THF (2 mL) at room temperature, and add triacetoxy Sodium borohydride (45 mg, 210.2 micromol). The reaction solution was slowly returned to room temperature and stirred for 2 hours. LC-MS showed a small amount of starting material remaining and product formed. Saturated aqueous sodium chloride solution (2 mL) and saturated aqueous sodium bicarbonate solution (2 mL) were added to the reaction solution, followed by extraction with ethyl acetate (10 mL ⁇ 3).
  • Embodiment 28 is a diagrammatic representation of Embodiment 28:
  • Step B Compound 28-2 (650 mg, 1.7 mmol) was dissolved in methanol (10 mL) at room temperature, and Pd/C (65 mg, 10%) was added. After the addition, the hydrogen gas was replaced three times, protected by a hydrogen balloon and stirred overnight at room temperature. LC-MS showed disappearance of starting material and compound 28-3 as main product. The reaction solution was filtered through celite, and the filter cake was washed with methanol. The combined filtrate was concentrated to obtain an oil, which was then separated by silica gel column chromatography to obtain 423 mg of compound 28-3.
  • Step C Disperse compound 28-4 (1.2 g, 6.5 mmol) in glacial acetic acid (25 ml) at room temperature, add 3-amino-piperidine-2,6-dione hydrochloride (1.1 g , 6.8 mmol) and potassium acetate (0.7 g, 7.2 mmol). The reaction was warmed to 90°C and stirred overnight. LC-MS showed disappearance of starting material. After cooling the reaction solution to room temperature, it was slowly added to water (500 ml), stirred for 2 hours, and then filtered. The filter cake was washed well with water, collected and dried to yield 1.7 g of compound 28-5.
  • Step D Dissolve compound 28-5 (273 mg, 0.9 mmol) in N-methylpyrrolidone (10 ml) at room temperature, add compound 28-3 (110 mg, 0.5 mmol) and N,N-di Isopropylethylamine (853 mg, 6.6 mmol).
  • the reaction solution was buried in an oil bath preheated to 140°C and stirred for 30 minutes. LC-MS showed that the starting material was consumed almost completely and the main product was compound 28-6.
  • the reaction solution was cooled to room temperature and extracted with ethyl acetate (20 mL ⁇ 2) after adding water. The combined organic phases were washed with saturated brine (30 mL ⁇ 10), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was separated by preparative thin-layer chromatography to obtain 143 mg of compound 28-6.
  • Step E Compound 28-6 (75 mg, 0.2 mmol) was dissolved in acetone (10 mL) at room temperature, and dilute hydrochloric acid (1M, 10 mL, 10 mmol) was added. The reaction solution was stirred overnight at room temperature. LC-MS showed disappearance of starting material. Saturated aqueous sodium carbonate solution (20 mL) and ethyl acetate (20 mL) were carefully added to the reaction solution, and the organic phase was separated. The aqueous phase was further extracted with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine (20 mL ⁇ 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was purified by preparative thin-layer chromatography to obtain 54 mg of compound 28-7.
  • Step F Dissolve compound 28-7 (50 mg, 0.1 mmol) in tetrahydrofuran (10 ml) in an ice-water bath, add desalted intermediate INT-2 (61 mg, 0.1 mmol), and stir in an ice-water bath Sodium triacetoxyborohydride (112 mg, 0.5 mmol) and anhydrous sodium acetate (11 mg, 0.1 mmol) were added, and the reaction solution was warmed to room temperature and stirred for 5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution and extracted with ethyl acetate (20 mL ⁇ 3).
  • Step A 1-[1-(diphenylmethyl)azetidin-3-yl]pyrrolidin-3-alcohol 1-(diphenylmethyl)azetidin-3-yl Methanesulfonate (3.1 g, 9.8 mmol) was dissolved in acetonitrile (35 mL). 1,4-dioxa-8-azaspiro[4.5]decane (1.7 g, 12 mmol) and triethylamine (1.2 g, 12 mmol) were added to the above solution, and the resulting solution was heated to 90 for the night.
  • Step B Compound 29-1 (2.5 g, 6.8 mmol) was dissolved in dry dichloromethane (100 mL) under nitrogen, and chloroethyl 1-chloroformate (2.3 mL, 21 mmol). The mixture was stirred for 1.5 h, then methanol was added. Heat the solution to reflux 20 minutes, then the solvent was removed by evaporation. The residue was dissolved in acetone, and the filtered precipitate was recrystallized from isopropanol to obtain 1.2 g of compound 29-2.
  • Step C Compound 29-2 (0.5 g, 2.5 mmol) was dissolved in N-methylpyrrolidone (15 mL) under nitrogen protection. Compound 28-5 (722 mg, 2.5 mmol) and N,N-diisopropylethylamine (980 mg, 7.5 mmol) were added. The system was stirred at 140°C for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting mixture was separated by thin-layer chromatography to obtain 520 mg of compound 29-3.
  • Step D Compound 29-3 (520 mg, 1.1 mmol) was dissolved in THF (5 mL), water (5 mL) and hydrochloric acid solution (5 mL, 4M in 1,4-dioxane) , the reaction system was heated to 50 degrees and stirred for three hours. After LCMS monitoring showed that most of the raw materials disappeared, the reaction solution was adjusted to weak alkaline and the target components were collected by reverse phase purification and lyophilized to obtain 150 mg of compound 29-4.
  • Step E The desalted intermediate INT-2 (200 mg, 0.4 mmol) and compound 29-4 (200 mg, 0.4 mmol) were dissolved in 1,2-dichloroethane (6 mL) and methanol (1 ml), acetic acid (0.15 ml) and tetraisopropyl titanate (0.3 ml) were added to the above solution, then stirred at room temperature for 0.5 hours, then sodium triacetoxyborohydride (180.4 mg , 0.9 mmol).
  • Step B Compound 30-1 (1.0 g, 2.7 mmol) was dissolved in methanol (15 mL). Under the protection of nitrogen, palladium hydroxide/carbon (500.0 mg) was added, the reaction system was replaced with hydrogen, and stirred for 17 hours under the atmosphere of hydrogen balloon. After LCMS monitoring showed that the starting material disappeared, it was filtered and concentrated under reduced pressure. 450.0 mg of compound 30-2 was obtained. This compound was used directly in the next step.
  • Step C Compound 30-2 (330.0 mg, 1.4 mmol) was dissolved in N-methylpyrrolidone (15 mL) under nitrogen protection.
  • Compound 28-5 (403.0 mg, 1.4 mmol) and N,N-diisopropylethylamine (5.5 g, 55.0 mmol) were added.
  • the system was stirred at 140°C for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting mixture was separated by thin-layer chromatography to obtain 460 mg of compound 30-3.
  • Step D Compound 30-3 (120.0 mg, 0.2 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (4 mL). The system was stirred at room temperature for 4 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was filtered and concentrated under reduced pressure. 100 mg of compound 30-4 was obtained. This compound was used directly in the next step.
  • Step E In N,N-dimethylformamide (10 mL), add compound 30-4 (100.0 mg, 0.2 mmol), desalted intermediate INT-2 (97.0 mg, 0.2 mmol), 1 -Hydroxybenzotriazole (44.0 mg, 0.3 mmol), (1-ethyl-3(3-dimethylpropylamine) carbodiimide) (126.0 mg, 0.7 mmol) and triethylamine (3.1 g , 30.6 mmol). The reaction was stirred at room temperature for 17 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure.
  • Step A In N,N-dimethylformamide (5 mL), add compound 31-4 (80.0 mg, 0.2 mmol), the desalted intermediate INT-3 (80.0 mg, 0.2 mmol), 1 -Hydroxybenzotriazole (34.0 mg, 0.3 mmol), (1-ethyl-3(3-dimethylpropylamine) carbodiimide) (97.0 mg, 0.5 mmol) and triethylamine (51.0 mg , 0.5 mmol). The reaction was stirred at room temperature for 17 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure.
  • Step A Dissolve tert-butyl 4-oxocyclohexane-1-carboxylate (500.0 mg, 2.5 mmol) and benzyl piperazine-1-carboxylate (555.0 mg, 2.5 mmol) in methanol (5 mL), acetic acid (1 mL) and sodium cyanoborohydride (238.0 mg, 3.8 mmol) were added. The reaction was stirred at room temperature for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure, and the resulting mixture was purified by reverse-phase column chromatography to obtain 159.0 mg of compound 32-1.
  • Step B Compound 32-1 (1.0 g, 2.5 mmol) was dissolved in THF (5 mL) and methanol (0.5 mL). Under nitrogen protection, add Palladium/carbon (10%, 100.0 mg) was added, the reaction system was replaced with hydrogen, and stirred for 3 hours under a hydrogen balloon environment. After LCMS monitoring showed that the starting material disappeared, it was filtered and concentrated under reduced pressure. 750 mg of compound 32-2 were obtained. This compound was used directly in the next step.
  • Step C Compound 32-2 (455.6 mg, 1.7 mmol) was dissolved in N-methylpyrrolidone (5 mL) under nitrogen protection. Compound 28-5 (500.0 mg, 1.7 mmol) and N,N-diisopropylethylamine (657.5 mg, 5.1 mmol) were added. The system was stirred at 140°C for 2 hours.
  • reaction solution was quenched by adding water (15 ml), extracted with ethyl acetate (30 ml), the organic phase was washed with saturated brine (20 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was decompressed After concentration, the resulting mixture was separated by silica gel column chromatography to obtain 323 mg of compound 32-3.
  • Step D Compound 32-3 (323.0 mg, 0.6 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL). The system was stirred at room temperature for 1 hour. After LCMS monitoring showed that the starting material disappeared, it was filtered and concentrated under reduced pressure. The resulting mixture was separated by high performance liquid chromatography to obtain 224.0 mg of Compound 32-4.
  • Step E In N,N-dimethylformamide (3 mL), add compound 32-4 (70.0 mg, 0.1 mmol), the desalted intermediate INT-2 (57.0 mg, 0.1 mmol), 1 -Hydroxybenzotriazole (23.0 mg, 0.2 mmol), (1-ethyl-3(3-dimethylpropylamine) carbodiimide) (31.0 mg, 0.2 mmol) and N,N-diiso Propylethylamine (56.0 mg, 0.4 mmol). The reaction was stirred at room temperature for 3 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure.
  • Step A In N,N-dimethylformamide (3 mL), add compound 32-4 (70.0 mg, 0.1 mmol), the desalted intermediate INT-3 (61.0 mg, 0.1 mmol), 1 -Hydroxybenzotriazole (23.0 mg, 0.2 mmol), (1-ethyl-3(3-dimethylpropylamine) carbodiimide) (31.0 mg, 0.2 mmol) and N,N-diiso Propylethylamine (56.0 mg, 0.4 mmol). The reaction was stirred at room temperature for 3 hours.
  • reaction solution was quenched with water (50 mL), and 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, and concentrated under reduced pressure.
  • Step A In N,N-dimethylformamide (3 mL), add compound 31-4 (105.0 mg, 0.2 mmol), compound 34-1 (116.0 mg, 0.2 mmol), 2-(7 -Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (135.8 mg, 0.4 mmol), N,N-diisopropylethylamine (153.6 mg , 1.2 mmol). The reaction was stirred at room temperature for 1 hour. After LCMS monitoring showed that the starting material disappeared, water (100 mL) was added to quench, and ethyl acetate (100 mL ⁇ 3) was extracted.
  • Step A Add cuprous iodide (12 mg, 0.06 mmol), triethylamine (120 mg, 1.20 mmol), 2-propyn-1-ol (68 mg, 1.20 mmol) and 1,1' - Bisdiphenylphosphinoferrocenepalladium dichloride (44 mg, 0.06 mmol) was added to a solution of compound 26-1 (200 mg, 0.60 mmol) in N,N-dimethylformamide (5 mL) middle. Under nitrogen protection, after stirring at 80°C for 16 hours.
  • Step B Dissolve compound 35-1 (90 mg, 0.3 mmol) in dimethyl sulfoxide (1 mL), add 2-iodobenzoic acid (530 mg, 1.9 mmol), and react overnight at room temperature. After LCMS monitoring showed disappearance of starting material, the reaction mixture was diluted with water, and the aqueous phase was extracted with ethyl acetate (20 mL ⁇ 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was separated by silica gel column chromatography to obtain 60 mg of compound 35-2.
  • Step C Compound 35-2 (60 mg, 0.2 mmol), intermediate INT-2 (92 mg, 0.2 mmol), triethylamine (19 mg, 0.2 mmol) were dissolved in dichloromethane (10 mL ), the resulting solution was stirred at room temperature for 10 minutes, then acetic acid (0.5 mL) and sodium triacetoxyborohydride (110 mg, 0.57 mmol) were added. Stir overnight at room temperature. After LCMS monitoring showed that the starting material disappeared, saturated aqueous sodium bicarbonate solution (20 mL) was added and extracted with dichloromethane (10 mL ⁇ 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated.
  • Step A Compound 28-5 (500.0 mg, 1.7 mmol) and tert-butyl 2-(piperidin-4-yl)acetate (500.0 mg, 2.5 mmol) were dissolved in N-methylpyrrolidone (5 mL) , N,N-diisopropylethylamine (668.0 mg, 5.2 mmol) was added. The reaction system was stirred at 140°C for 1 hour. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, quenched by adding water (50 ml), extracted with ethyl acetate (80 ml), the organic phase was washed with saturated brine (80 ml), and dried over anhydrous magnesium sulfate.
  • N-methylpyrrolidone 5 mL
  • N,N-diisopropylethylamine 668.0 mg, 5.2 mmol
  • Step B Compound 36-1 (300.0 mg, 0.6 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, and the reaction system was stirred at room temperature for 2 hours. After LCMS monitoring showed disappearance of starting material, it was concentrated under reduced pressure. The resulting mixture was purified by HPLC (mobile phase: 64% acetonitrile, 36% distilled water, distilled water containing 0.01% formic acid) to obtain 195.0 mg of compound 36-2.
  • HPLC mobile phase: 64% acetonitrile, 36% distilled water, distilled water containing 0.01% formic acid
  • Step C Compound 36-2 (70.0 mg, 0.2 mmol) and the desalted intermediate INT-3 (79.5 mg, 0.2 mmol) were dissolved in N,N-dimethyl in methyl formamide (5 mL). Add 2-(7azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (67. mg, 0.2 mmol) and N,N-diisopropyl Ethylamine (64.0 mg, 0.5 mmol). The system was stirred at room temperature for 2 hours.
  • reaction solution was quenched by adding water (15 ml), extracted with ethyl acetate (30 ml), the organic phase was washed with saturated brine (20 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was decompressed concentrate.
  • Step A Compound 37-1 (50.0 mg, 0.1 mmol), the desalted intermediate INT-3 (60.0 mg, 0.1 mmol) were dissolved in methanol (4 mL). Acetic acid (0.01 mL) was added. The system was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (20.0 mg, 0.4 mmol) was added to the above reaction solution. The reactant. The system was reacted at 25 degrees Celsius for 3 hours.
  • reaction solution was quenched with water (20 mL), and extracted with dichloromethane (20 mL ⁇ 3). Combine the organic phases with It was washed with water (20 mL ⁇ 3) and saturated brine (20 mL ⁇ 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
  • Step A Compound 38-1 (0.7 g, 2.6 mmol) and 2-(bromomethyl)-1,3-dioxolane (0.5 g, 3.1 mmol) were dissolved in acetonitrile (15 mL) at room temperature )middle. Potassium carbonate (1.1 g, 8.0 mmol) was added. The system was raised to 90°C and reacted at this temperature for 16 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, quenched by adding saturated aqueous sodium bicarbonate solution (50 mL), and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step B Dissolve compound 38-2 (900.0 mg, 2.5 mmol) in methanol (5 mL) at room temperature, replace with nitrogen, and add palladium/carbon (90.0 mg, 10%). The system was replaced with hydrogen and stirred at room temperature for 16 hours under a balloon of hydrogen. After LCMS monitoring showed that the starting material disappeared, it was filtered, and the filtrate was concentrated under reduced pressure to obtain 500.0 mg of compound 38-3.
  • Step C Compound 38-3 (500.0 mg, 2.2 mmol) was dissolved in N-methylpyrrolidone (15 mL) under nitrogen protection. Compound 28-5 (650.0 mg, 2.2 mmol) and N,N-diisopropylethylamine (850.0 mg, 6.6 mmol) were added. The system was stirred at 120°C for 1 hour. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature and separated by a reverse-phase column (mobile phase: 40% acetonitrile, 60% distilled water, containing 0.01% formic acid in distilled water) to obtain 500.0 mg of compound 38-4.
  • Step D Compound 38-4 (400.0 mg, 0.8 mmol) was dissolved in concentrated hydrochloric acid (20 mL). The system was stirred at 50°C for 3 hours. After LCMS monitoring showed that the raw material disappeared, the reaction solution was cooled to room temperature, quenched by adding saturated sodium bicarbonate solution (100 ml), extracted with ethyl acetate (100 ml), the organic phase was washed with saturated brine (50 ml), and anhydrous sulfuric acid Sodium dry.
  • Step E Dissolve compound 38-5 (130.0 mg, 0.3 mmol) and desalted intermediate INT-2 (150.0 mg, 0.3 mmol) in THF (8 mL), add acetic acid (0.25 mL) and tetraiso Titanium propoxide (243.0 mg, 0.9 mmol). The system was stirred at room temperature for 1 hour. Sodium triacetate borohydride (181.0 mg, 0.9 mmol) was added to the above reaction system. The reaction solution was stirred at room temperature for 5 hours.
  • Step A Compound 39-1 (50.0 mg, 0.1 mmol), desalted intermediate INT-3 (50.0 mg, 0.1 mmol), N,N-diisopropylethylamine (43.0 mg, 0.3 mmol ) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (41.8 mg, 0.1 mmol) were dissolved in dichloromethane (5 mL ). The reaction was stirred at room temperature for 4 hours.
  • reaction solution was diluted with ethyl acetate (20 mL), and the organic phase was washed with water (20 mL ⁇ 3) and saturated brine (20 mL ⁇ 3). The organic phases were combined, washed with water (10 mL ⁇ 3) and saturated brine (10 mL ⁇ 3), and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure.
  • the preparation of compound 40-1 refers to the preparation scheme of intermediate INT-2.
  • Step A Compound 40-1 (400.0 mg, 0.7 mmol) was dissolved in THF (5 mL), and hydrogen fluoride in triethylamine (566.0 mg, 3.5 mmol) was added. The system was stirred at room temperature for 3 hours.
  • Step B Compound 40-2 (300.0 mg, 0.7 mmol) was dissolved in dimethyl sulfoxide (10 mL), and 2-iodobenzoic acid (369.0 mg, 1.3 mmol) was added. The reaction system was stirred at 28°C for 4 hours. After LCMS monitoring showed that the raw material disappeared, ethyl acetate (20 ml) was added to the reaction solution to dilute, followed by saturated sodium thiosulfate solution (20 ml ⁇ 3), sodium bicarbonate solution (20 ml ⁇ 3), water (20 ml ⁇ 3) and saturated brine (20 ml ⁇ 3), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 260.0 mg of compound 40-3.
  • Step C Compound 40-4 (500.0 mg, 2.0 mmol) was dissolved in N-methylpyrrolidone (5 mL) under nitrogen protection. Compound 28-5 (573.8 mg, 2.0 mmol) and N,N-diisopropylethylamine (1 mL, 6.0 mmol) were added. The system was stirred at 130°C for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was directly separated by a reverse-phase column (mobile phase: 50% acetonitrile, 50% distilled water, 0.01% formic acid in distilled water) to obtain 580.0 mg of compound 40-5.
  • Step D Compound 40-5 (480.0 mg, 0.9 mmol) was suspended in a solution of hydrochloric acid in dioxane (4 mol, 30 mL). The system was stirred at room temperature for 2 hours. After LCMS monitoring showed that the starting material disappeared, it was concentrated under reduced pressure to obtain 410.0 mg of the hydrochloride of compound 40-6.
  • Step E Dissolve the hydrochloride salt of compound 40-6 (235.0 mg, 0.5 mmol) and compound 40-3 (260.0 mg, 0.6 mmol) in methanol (30 ml), add acetic acid (62.5 mg, 1.0 mmol Moore). The system was stirred at room temperature for 1 hour. Sodium cyanoborohydride (98.0 mg, 1.6 mmol) was added to the above reaction system. The reaction was stirred at room temperature for 3 hours. After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction liquid to quench, and ethyl acetate (20 mL ⁇ 3) was extracted.
  • Step A Dissolve tert-butyl piperazine-1-carboxylate (1.9 g, 10.0 mmol) in N-methylpyrrolidone (30 mL), add N,N-diisopropylethylamine (4.9 mL, 28.1 mmol) and compound 41-1 (2.8 g, 10.0 mmol). The reaction system was stirred at 140°C for 1 hour. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature, quenched by adding water (50 mL), and extracted with ethyl acetate (50 mL ⁇ 3).
  • Step B Compound 41-2 (3.5 g, 7.9 mmol) was dissolved in ethyl acetate (15 mL), and a solution of hydrochloric acid in 1,4-dioxane (4 mol, 15 mL) was added. The system was stirred at room temperature for 3 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure to obtain 2.6 g of the hydrochloride of compound 41-3.
  • Step C At room temperature, the hydrochloride salt of compound 41-3 (350.0 mg, 0.9 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (218.0 mg, 1.0 mmol) were dissolved in N, To N-dimethylformamide (5 mL) and tetrahydrofuran (5 mL), was added acetic acid (306.0 mg, 5.1 mmol). The system was stirred at room temperature for 0.5 hours. Sodium triacetate borohydride (649.0 mg, 3.1 mmol) was added to the above reaction system. The reaction was stirred at room temperature for 3 hours.
  • Step D Compound 41-4 (450.0 mg, 0.8 mmol) was dissolved in dichloromethane (10 mL). A solution of hydrochloric acid in dioxane (4 M, 3 mL) was added. The system was stirred at room temperature for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the mixture was filtered, and the filter cake was washed with dichloromethane and dried to obtain 300.0 mg of the hydrochloride of compound 41-5.
  • Step E Dissolve the hydrochloride salt of compound 41-5 (50.0 mg, 0.1 mmol) and compound 41-6 (54.0 mg, 0.1 mmol) in methanol (2 ml) at room temperature, add acetic acid (0.1 ml ) and titanium tetraisopropoxide (0.2 ml). The system was stirred at room temperature for 1 hour. 2-picoline borane complex (37.0 mg, 0.3 mmol) was added to the above reaction system. The reaction was stirred at room temperature for 3 hours.
  • Step A Dissolve 1,4-dioxa-8-azaspiro[4.5]decane (5.0 g, 32.1 mmol), benzyl piperazine-1-carboxylate (7.1 g, 32.2 mmol) in To methanol (50 mL), acetic acid (1 drop) was added. The reaction was stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (3.0 g, 48.0 mmol) was added to the above reaction solution. The reaction was stirred at room temperature for 2 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was quenched with water (100 mL), and extracted with dichloromethane (100 mL ⁇ 3).
  • Step B Compound 42-1 (3.0 g, 8.3 mmol) was dissolved in dry THF (30 mL), replaced with nitrogen, and added into palladium on carbon (0.3 g, 10%). The reaction was stirred under a hydrogen balloon at room temperature for 6 hours. After LCMS monitoring showed that the starting material disappeared, it was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.7 g of compound 42-2.
  • Step C Compound 42-2 (1.7 g, 7.6 mmol)) was dissolved in N-methylpyrrolidone (25 mL). Compound 28-5 (2.3 g, 7.6 mmol) and N,N-diisopropylethylamine (3.0 g, 23.1 mmol) were added. The reaction system was stirred at 120°C for 1 hour. After LCMS monitoring showed that the starting material disappeared, the reaction solution was quenched with water (100 mL), and extracted with ethyl acetate (100 mL ⁇ 3).
  • Step D Compound 42-3 (800.0 mg, 1.6 mmol) was dissolved in hydrochloric acid (2.4 mL) and ethyl acetate (12 mL). The reaction was stirred at room temperature for 1 hour. After LCMS monitoring showed that the starting material disappeared, the reaction solution was quenched with ice water (50 mL), and extracted with ethyl acetate (50 mL ⁇ 3). The organic phases were combined, washed with water (50 ml) and saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 222.0 mg of compound 42-4.
  • Step E Compound 42-4 (150.0 mg, 0.3 mmol), intermediate INT-2 (144.6 mg, 0.3 mmol) and tetraisopropyl titanate (0.3 mL) were dissolved in 1,2-dichloroethane alkane (10 mL). Acetic acid (0.3 mL) and 1-boryl-2-methyl-1-pyridine (70.3 mg, 0.7 mmol) were added. The system was stirred at room temperature for 1 hour.
  • reaction solution was quenched with water (50 ml), extracted with dichloromethane (50 ml ⁇ 3), the organic phases were combined, and the organic phase was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, Filter and concentrate under reduced pressure.
  • the resulting mixture was purified by reverse phase (45% acetonitrile: 55% water: 0.025% formic acid) yielded 7.3 mg of compound 42-P1 (retention time 2.12 min) and 11.9 mg of compound 42-P2 (retention time 2.26 min).
  • Step A The desalted intermediate INT-3 (200.0 mg, 0.4 mmol) and compound 43-1 (201.0 mg, 0.4 mmol) were dissolved in 1,2-dichloroethane (10 mL) and methanol (1.5 ml). Acetic acid (0.1 mL) and titanium tetraisopropoxide (0.4 mL, 1.4 mmol) were added. The reaction system was reacted at 25 degrees Celsius for 0.5 hours. Sodium triacetate borohydride (180.4 mg, 0.9 mmol) was added to the above reaction system, and the reaction solution was reacted at 25 degrees Celsius for 2 hours.
  • Step A Compound 44-1 (100.0 mg, 0.2 mmol), the desalted intermediate INT-2 (92.0 mg, 0.2 mmol) and tetraisopropyl titanate (0.4 mL) were dissolved in 1,2-bis in ethyl chloride (5 mL). Acetic acid (0.02 mL) was added. The system was stirred at room temperature for 30 minutes. Sodium acetate borohydride (88.6 mg, 2.4 mmol) was added to the above reaction solution. The reaction system was reacted at 25 degrees Celsius for 2 hours.
  • reaction solution was quenched with water (10 mL), extracted with ethyl acetate (15 mL), and the organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step A The starting material 4-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazole -2-Kone (500 mg, 1.4 mmol), 1-tert-butoxycarbonylpiperazine (261 mg, 1.4 mmol), sodium tert-butoxide (400 mg, 4.2 mmol), 2-bicyclohexylphosphine- 2',6'-diisopropoxybiphenyl (65 mg, 140 micromol), tridibenzylideneacetone dipalladium (64 mg, 70 micromol), were added to a three-necked flask, and dioxane was added (10 mL), and replace nitrogen 3 times.
  • Step B Compound 45-1 (600 mg, 1.3 mmol) was dissolved in 1M tetrabutylammonium fluoride/THF (10.4 mL) at room temperature. The reaction solution was heated to reflux overnight. After LCMS monitoring showed disappearance of starting material, water (50 mL) was added to the reaction system to quench. The mixture was extracted with ethyl acetate (50 ml ⁇ 3), the organic phases were combined, washed with water (20 ml ⁇ 2) and saturated brine (20 ml), then dried over anhydrous sodium sulfate, filtered, and finally reduced pressure concentrate. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate) to obtain 330 mg of compound 45-2.
  • Step C Compound 45-2 (270 mg, 0.8 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), cooled to zero degrees Celsius under nitrogen protection, and potassium tert-butoxide (182 mg, 1.6 mmol) was added, And stirring for 5 minutes after the addition was complete, then dropwise added 1-(4-methoxybenzyl)-2,6-dioxopiperidine-3-trifluoromethylsulfonate (450 mg, 1.2 mmol) THF solution (2 ml) was stirred at this temperature for 30 minutes after the addition was complete. After LCMS monitoring showed disappearance of starting material, saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction.
  • Step D Compound 45-3 (160 mg, 0.3 mmol) was dissolved in TFA (10 mL) at room temperature under nitrogen protection. Subsequently, trifluoromethanesulfonic acid (480 mg, 3.2 mmol) was added thereto. The reaction solution was stirred overnight at 60°C. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated to obtain 500 mg of compound 45-4. The compound was directly subjected to the next reaction without further purification.
  • Step E Compound 45-4 (500 mg) was dissolved in acetonitrile (10 mL). At zero degrees Celsius, triethylamine (324 mg, 3.2 mmol) was added thereto, followed by ethyl acrylate (205 mg, 1.6 mmol), and stirring was continued overnight at room temperature. After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated. Water (40 mL) was added, extracted with ethyl acetate (20 mL ⁇ 3), and the combined organic phases were washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel column chromatography (dichloromethane/methanol) to obtain 140 mg of compound 45-5.
  • Step F Compound 45-5 (70 mg, 0.2 mmol) was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (2 mL) was added thereto at zero degrees Celsius, and stirring was continued overnight at room temperature. After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated. 80 mg of compound 45-6 were obtained.
  • Step G Compound 45-6 (80 mg, 0.2 mmol) and the desalted intermediate INT-2 (72 mg, 0.2 mmol) were dissolved in N,N-dimethylformamide (5 mL). At zero degrees Celsius, N, N-diisopropylethylamine (97 mg, 0.8 mmol) and 2-(7-azabenzotriazole)-N,N,N',N '-Tetramethyluronium hexafluorophosphate (95 mg, 0.3 mmol). After reacting at room temperature for 2 hours, water (50 mL) was added, extracted with ethyl acetate (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step A 5-Bromo-3H-isobenzofuran-1-one (5.0 g, 23.5 mmol) and tert-butylpiperazine-1-carboxylate (4.8 g, 25.8 mmol) were dissolved in toluene ( 50 ml). Cesium carbonate (15.3 g, 46.9 mmol)), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (73.9 mg, 0.2 mmol) and palladium(II) acetate ( 0.1 g, 0.4 mmol). The reaction system was stirred at 100° C. for 16 hours under nitrogen protection.
  • Step B Compound 46-1 (4.7 g, 14.7 mmol) was dissolved in THF/methanol/water (1/1/1 by volume) (90 mL). Sodium hydroxide (2.2 g, 55.6 mmol) was added at zero degrees Celsius, and the mixture was stirred at room temperature overnight. After LCMS monitoring showed that the raw materials disappeared, the pH value of the reaction solution was adjusted to 4-5 with 2 moles of dilute hydrochloric acid. Extracted with ethyl acetate (100 mL x 4). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.2 g of compound 46-2. This compound was used directly in the next step.
  • Step C Compound 46-2 (3.2 g, 9.4 mmol) was dissolved in a solution of methanol (20 mL) and ethyl acetate (20 mL). At minus 10°C, (trimethylsilyl)diazomethane (2 moles, 20 ml) was added dropwise to the solution, and stirring was continued for 15 minutes after the addition was complete. After LCMS monitoring showed that the starting material disappeared, the reaction solution was quenched with water (50 mL), and extracted with ethyl acetate (100 mL ⁇ 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3.1 g of compound 46-3.
  • Step E Compound 46-4 (3.1 g, 7.4 mmol) was dissolved in N,N-dimethylformamide (30 mL), and 3-aminopiperidine-2,6-dione salt was added to the solution salt (2.5 g, 14.9 mmol) and N,N-diisopropylethylamine (3.8 g, 29.8 mmol), and the reaction was stirred overnight at 100°C. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was poured into water (50 mL), filtered, the filter cake was washed with acetonitrile (100 mL), and 2.3 g of compound 46-5 was obtained after drying.
  • Step F Compound 46-5 (2.3 g, 5.4 mmol) was dissolved in 1,4-dioxane (30 ml), and a solution of hydrochloric acid in 1,4-dioxane (4 moles, 22.5 ml ), and the mixture was stirred at room temperature for 16 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was filtered, and the obtained solid was washed with ethyl acetate (20 mL ⁇ 2) and dichloromethane (20 mL ⁇ 2), and dried to obtain 2.0 g of compound 46-6.
  • Step G Compound 46-7 (100.0 mg, 0.2 mmol) was dissolved in THF (5 mL) and water (1 mL), and lithium hydroxide monohydrate (21.0 mg, 0.5 mmol) was added. The reaction system was stirred at zero degrees Celsius for 5 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was quenched with ice water (3 ml), and adjusted to a pH value of 2 with 1 molar hydrochloric acid. Extracted with ethyl acetate (6 mL ⁇ 3), combined organic phases, washed with saturated brine (6 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 85.0 mg of compound 46-8. The crude product can be directly used in the next reaction.
  • Step H In N,N-dimethylformamide (5 mL), add compound 46-8 (85.0 mg, 0.1 mmol), compound 46-6 (109.0 mg, 0.3 mmol), 1-hydroxybenzene Triazole (30.0 mg, 0.2 mmol), (1-ethyl-3 (3-dimethylpropylamine) carbodiimide) (86.0 mg, 0.5 mmol) and triethylamine (45.0 mg, 0.5 mmol Moore). The reaction was stirred at room temperature for 17 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure.
  • Step A Under nitrogen protection conditions, mix 1-bromo-4-nitrobenzene (500.0 mg, 2.5 mmol) and tert-butyl (4-(4,4,5,5-tetramethyl-1,3 ,2-Dioxybenzaldehyde-2-yl)cyclohex-3-en-1-yl)carbamate (803 mg, 2.5 mmol) dissolved in 1,4-dioxane (10 mL), Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (183.0 mg, 0.3 mmol) and aqueous potassium carbonate (2 mL, 10%) were added. The reaction system was stirred at 90°C for 1 hour.
  • Step B Compound 47-1 (560.0 mg, 1.8 mmol) was dissolved in THF (100 mL). The reaction system was replaced with nitrogen, palladium/carbon (56 mg, 10%) was added, the reaction system was replaced with hydrogen, and stirred at room temperature for 16 hours under a hydrogen balloon environment. After LCMS monitoring showed that the starting material disappeared, it was filtered, and the filtrate was concentrated under reduced pressure to obtain 450 mg of compound 47-2.
  • Step C In a 5 ml microwave tube, sequentially add compound 47-2 (450.0 mg, 1.6 mmol), 3-bromopiperidine-2,6-dione (703.0 mg, 3.7 mmol), N,N - Diisopropylethylamine (460.0 mg, 3.5 mmol) and 1,4-dioxane (1 mL). After sealing, the reaction solution was stirred at 80°C for 14 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature, and ethyl acetate (50 mL) was added for dilution.
  • Step D Compound 47-3 (290.0 mg, 0.7 mmol) was dissolved in ethyl acetate (10 mL), and a solution of hydrochloric acid in 1,4-dioxane (4 mol, 10 mL) was added. The system was stirred at room temperature for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated under reduced pressure to obtain 210.0 mg of compound 47-4.
  • Step E Under nitrogen protection, compound 47-4 (210.0 mg, 0.7 mmol) and compound 47-5 (329.0 mg, 0.7 mmol) were dissolved in methanol (20 ml), and acetic acid (0.2 ml, 0.1 millimoles) and tetraisopropyl titanate. The system was stirred at 50°C for 1 hour. The reaction solution was cooled to room temperature, and 2-picoline borane (112.0 mg, 1.1 mmol) was added. The reaction was stirred at room temperature for 16 hours.
  • Step A Dissolve 1-chloro-4-nitrobenzene (5.0 g, 31.8 mmol), methyl 2-cyanoacetate (7.9 g, 79.3 mmol), potassium carbonate (11.8 g, 85.5 mmol) in N,N-Dimethylformamide (25 ml).
  • the reaction system was stirred at 110°C for 1 hour. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature and quenched by adding water (50 mL). Add dilute sulfuric acid dropwise to adjust the pH of the solution to 2. After filtering, the filter cake was washed with water, and the filtrate was extracted with ethyl acetate (100 ml ⁇ 2).
  • Step B Compound 48-1 (0.5 g, 2.2 mmol) was dissolved in THF (10 mL). Methyl acrylate (190.0 mg, 2.2 mmol) and N-methylmorpholine (222.0 mg, 2.2 mmol) were added, and the reaction system was stirred at 60°C for 3 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature, quenched with water (20 mL), and extracted with ethyl acetate (20 mL ⁇ 2).
  • Step C Compound 48-2 (700.0 mg, 2.3 mmol) was dissolved in acetic acid (10 mL). Concentrated sulfuric acid (800.0 mg, 8.2 mmol) was added. The system was stirred at 110°C for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and 3 molar sodium hydroxide aqueous solution was slowly added to adjust the solution to weak acidity. Extracted with ethyl acetate (25 mL x 2).
  • Step D Compound 48-3 (400.0 mg, 1.7 mmol), ammonium chloride (130.0 mg, 2.5 mmol) and iron powder (400.0 mg, 7.1 mmol) were dissolved in ethanol (5 ml) and water (0.5 ml). The system was stirred at 100°C for 1 hour. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), and the organic phase was washed with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting mixture was purified by silica gel column chromatography to obtain 300.0 mg of compound 48-4.
  • Step E (1R,4R)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (393.0 mg, 2.1 mmol), desalted intermediate INT-3 (1.0 g, 2.1 mmol), N,N-Diisopropylethylamine (1.4 g, 10.6 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate Esters (1.2 g, 3.2 mmol) was dissolved in N,N-dimethylformamide (10 mL). The reaction was stirred at room temperature for 1 hour.
  • reaction solution was quenched with water (100 mL), and extracted with ethyl acetate (100 mL ⁇ 3). The organic phases were combined, washed with saturated brine (100 mL ⁇ 3), and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The resulting mixture was purified by high performance liquid chromatography to obtain 1.4 g of compound 48-5.
  • Step F Compound 48-5 (1.0 g, 1.6 mmol) was dissolved in THF (16 mL) at -78 °C under argon protection. Diisopropylaluminum hydride (2 molar tetrahydrofuran solution, 4.1 ml) was slowly added dropwise. After the addition was complete, the reaction system was slowly raised to room temperature and stirred for 2 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was quenched with water (50 mL). After filtration, the filtrate was extracted with ethyl acetate (50 mL ⁇ 3).
  • Diisopropylaluminum hydride (2 molar tetrahydrofuran solution, 4.1 ml) was slowly added dropwise. After the addition was complete, the reaction system was slowly raised to room temperature and stirred for 2 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was quenched with water (50 mL). After filtration, the filtrate was extracted with
  • Step G Compound 48-6 (350.0 mg, 0.6 mmol) was dissolved in dimethyl sulfoxide (5 mL), and 2-iodobenzoic acid (319.2 mg, 1.1 mmol) was added. The reaction system was stirred at 30°C for 2 hours. After LCMS monitoring showed that the starting material disappeared, water (50 mL) was added to the reaction solution to quench it. After filtration, the filtrate was extracted with ethyl acetate (50 mL ⁇ 3).
  • Step H Compound 48-7 (200.0 mg, 0.3 mmol), Compound 48-4 (66.0 mg, 0.3 mmol) were dissolved in methanol (8 mL) at room temperature. Acetic acid (39.2 mg, 0.7 mmol) was added. The reaction solution was stirred at 50°C for 1 hour. The borane complex of 2-picoline (70.0 mg, 0.7 mmol) was added to the above reaction solution. The system was stirred at room temperature for 1 hour. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was poured into water (100 mL), and extracted with ethyl acetate (100 mL ⁇ 3).
  • Step A Under the condition of nitrogen protection, 4-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H- Benzo[d]imidazol-2-one (2.0 g, 5.6 mmol), tert-butyl piperazine-1-carboxylate (1.3 g, 6.8 mmol), sodium tert-butoxide (808.0 mg, 8.4 mmol) , 2-bicyclohexylphosphino-2',6'-diisopropoxybiphenyl (20.0 mg, 0.04 mmol) and chloro(2-dicyclohexylphosphino-2',6'-di-isopropyl Oxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (32.0 mg, 0.04 mmol) was dissolved in toluene (20 mL).
  • Step B Compound 49-1 (2.2 g, 4.8 mmol) was dissolved in tetrabutylammonium fluoride in tetrahydrofuran (1 mol, 48 mL) under nitrogen protection. The reaction system was stirred at 80°C for 16 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, quenched by adding saturated ammonium chloride solution (200 mL), and extracted with ethyl acetate (200 mL).
  • Step C Dissolve compound 49-2 (1.8 g, 5.4 mmol) in tetrahydrofuran (50 ml) under nitrogen protection at 0°C, slowly add potassium tert-butoxide (1 mol, 8 ml) dropwise, After the dropwise addition was complete, the system was stirred at 0°C for 1 hour.
  • 1-(4-Methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (2.4 g, 6.3 mmol) and THF (50 mL) were mixed at 0 °C The mixed solution was slowly added dropwise to the above solution, and stirred at this temperature for 2 hours.
  • Step D Dissolve compound 49-3 (1.2 g, 2.1 mmol) in ethyl acetate (50 ml) at room temperature, add hydrochloric acid in 1,4-dioxane (4 mol, 5 ml), The system was stirred at room temperature for 2 hours. After LCMS monitoring showed that the raw material disappeared, ethyl acetate (100 ml) was added to the reaction solution for dilution, the organic phase was washed with water (100 ml ⁇ 3) and saturated brine (100 ml ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrate under reduced pressure. The resulting mixture was purified by silica gel column chromatography to obtain 950 mg of Compound 49-4.
  • Step E Under nitrogen protection, compound 49-4 (200.0 mg, 0.4 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (91.0 mg, 0.4 mmol), acetic acid (51.6 mg, 0.9 mmol) and titanium tetraisopropoxide (244.0 mg, 0.9 mmol) were dissolved in methanol (20 ml), and the system was stirred at 50°C for 0.5 hour. The reaction solution was cooled down to room temperature, borane complex of 2-picoline (70.0 mg, 0.5 mmol) was added, and the reaction solution was stirred at room temperature for 3 hours.
  • Step F Under nitrogen protection, compound 49-5 (130.0 mg, 0.2 mmol) was dissolved in trifluoroacetic acid (5 mL), and trifluoromethanesulfonic acid (0.5 mL) was added. The system was stirred at 60°C for 16 hours. After LCMS monitoring showed that the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure. 360 mg of compound 49-6 were obtained.
  • Step G Under nitrogen protection, compound 49-6 (130.0 mg, 0.2 mmol) was dissolved in acetonitrile (5 ml), triethylamine (4.0 g, 4.0 mmol) and di-tert-butyl carbonate (65.4 mg, 0.3 mmol). The system was stirred at room temperature for 3 hours. LCMS monitoring showed that after the raw material had reacted completely, dichloromethane (50 ml) was added to the reaction solution for dilution, and the organic phase was washed with water (50 ml ⁇ 3) and saturated brine (50 ml ⁇ 3), dried over anhydrous magnesium sulfate, filtered, The filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to obtain 77 mg of Compound 49-7.
  • Step H Under nitrogen protection, compound 49-7 (130.0 mg, 0.2 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was added. The system was stirred at room temperature for 3 hours. After LCMS monitoring showed that the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure to obtain 60 mg of compound 49-8.
  • Step I Under nitrogen protection, compound 49-8 (60.0 mg, 0.1 mmol), compound 49-9 (64.0 mg, 0.1 mmol), acetic acid (17.0 mg, 0.3 mmol) and tetraisopropyl titanate
  • the ester (80.0 mg, 0.3 mmol) was dissolved in methanol (5 ml), and the system was stirred at 50°C for 0.5 hour.
  • the reaction solution was cooled down to room temperature, borane complex of 2-picoline (23.0 mg, 0.2 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours.
  • Step A Under the condition of nitrogen protection, tert-butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate (1.0g, 4.2 mmol), 4-bromo-3-methyl yl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (1.5g, 4.2mmol) , sodium tert-butoxide (599.0 mg, 6.2 mmol), 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (194.0 mg, 0.4 mmol) and chloro(2-dicyclohexyl Phosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (323.0 mg, 0.4 mmol) was dissolved in to
  • Step B Under nitrogen protection, compound 50-1 (1.2 g, 2.3 mmol) was dissolved in THF (5 mL), and tetrabutylammonium fluoride in THF (1 mol, 23 mL) was added. The reaction system was stirred at 90°C for 16 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, quenched by adding saturated ammonium chloride solution (200 mL), and extracted with ethyl acetate (200 mL).
  • Step C Dissolve compound 50-2 (800 mg, 2.1 mmol) in tetrahydrofuran (10 ml) under nitrogen protection at 0°C, slowly add potassium tert-butoxide (1 mol, 2.1 ml) dropwise , the dropwise addition was completed, and the system was stirred at 0° C. for 1 hour.
  • 1-(4-Methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate 1.6 g, 4.1 mmol
  • tetrahydrofuran 5 mL
  • Step D Under nitrogen protection, compound 50-3 (1.2 g, 1.8 mmol) was dissolved in trifluoroacetic acid (10 mL), and trifluoromethanesulfonic acid (1 mL) was added. The system was stirred at 60°C for 16 hours. After LCMS monitoring showed that the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure. 746 mg of compound 50-4 were obtained.
  • Step E Under nitrogen protection, compound 50-4 (746.0 mg, 1.8 mmol) was dissolved in acetonitrile (5 ml), triethylamine (379.6 mg, 3.8 mmol) and di-tert-butyl carbonate (491.6 mg, 2.3 mmol). The system was stirred at room temperature for 3 hours. LCMS monitoring showed that after the raw material had reacted completely, dichloromethane (50 ml) was added to the reaction solution for dilution, and the organic phase was washed with water (50 ml ⁇ 3) and saturated brine (50 ml ⁇ 3), dried over anhydrous magnesium sulfate, filtered, The filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to obtain 510 mg of Compound 50-5.
  • Step F Under nitrogen protection, compound 50-5 (510.0 mg, 1.0 mmol) was dissolved in dichloromethane (4 mL), and 1,4-dioxane hydrochloride (1 mL) was added. The system was stirred at room temperature for 2 hours. After LCMS monitoring showed that the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure to obtain 400 mg of compound 50-6.
  • Step G Under nitrogen protection, compound 50-6 (120.0 mg, 0.3 mmol), (S)-1-(2-chloro-7-(1-methoxyethyl)pyrazol[1,5 -a]pyrimidin-6-yl)-3-(2-(2-oxyethoxy)-5-(trifluoromethyl)pyridin-3-yl)urea (compound 50-7, 142.7.0 mg, 0.3 mg mol), acetic acid (0.05 ml) and titanium tetraisopropoxide (0.1 ml) were dissolved in methanol (5 ml), and the system was stirred at 50° C. for 0.5 hour.
  • reaction solution was cooled down to room temperature, borane complex of 2-picoline (69.0 mg, 0.2 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours.
  • dichloromethane 50 ml was added to the reaction solution for dilution, quenched with sodium sulfate decahydrate and stirred for 0.5 hours. After filtration, the filtrate was washed with water (50 mL ⁇ 3) and saturated brine (50 mL ⁇ 3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step A Dissolve 1-bromo-2-fluoro-4-nitrobenzene (1.0 g, 4.5 mmol) and tert-butyl piperazine-1-carboxylate (0.83 g, 4.5 mmol) in N,N- To dimethylformamide (20 ml), triethylamine (1.36 g, 13.5 mmol) was added. The system was stirred at 100°C for 16 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature and extracted with ethyl acetate (50 mL ⁇ 3).
  • Step B Compound 51-1 (720.0 mg, 2.21 mmol) and ammonium chloride (120.0 mg, 2.6 mmol) were dissolved in ethanol (10 mL) and water (1 mL), and iron powder (1.0 g, 22.1 mmol). The system was warmed to 100°C and stirred at this temperature for 18 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure.
  • Step C Under the condition of nitrogen protection, compound 51-2 (560.0 mg, 1.89 mmol), 3-bromopiperidine-2,6-dione (903.0 mg, 4.73 mmol) was dissolved in N,N- To dimethylformamide (10 mL), N,N-diisopropylethylamine (731.0 mg, 5.67 mmol) was added. The system was warmed to 80°C and stirred at this temperature for 16 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature and extracted with ethyl acetate (50 mL ⁇ 3).
  • Step D Under nitrogen protection, compound 51-3 (100.0 mg, 0.246 mmol) was dissolved in dichloromethane (3 mL), and hydrochloric acid in 1,4-dioxane (1 mL) was added . The reaction was stirred at room temperature for 1 hour. After LCMS monitoring showed that the raw materials disappeared, dichloromethane (10 ml) was added to the reaction solution for dilution, and the reaction solution was concentrated under reduced pressure to obtain 80 mg of compound 51-4.
  • Step F Under nitrogen protection, compound 51-5 (110.0 mg, 0.218 mmol) was dissolved in dichloromethane (3 mL), and hydrochloric acid in 1,4-dioxane solution (1 mL) was added . The reaction was stirred at room temperature for 1 hour. After LCMS monitoring showed that the raw materials disappeared, dichloromethane (10 ml) was added to the reaction solution for dilution, and the reaction solution was concentrated under reduced pressure to obtain 60 mg of compound 51-6.
  • Step A 3-nitro-5-(trifluoromethyl)pyridin-2-alcohol (2.2g, 9.6 mmol), 4-(2-hydroxyethyl)piperidine were added at 0 degrees centigrade under nitrogen protection conditions Pyridine-1-carboxylic acid tert-butyl ester (2.0 g, 9.6 mmol), triphenylphosphine (5.0 g, 19.2 mmol) were dissolved in tetrahydrofuran (50 ml), and diethyl azodicarboxylate ( 3.5 g, 20.2 mmol). After the dropwise addition was completed, the reaction system was stirred at room temperature for 16 hours.
  • Step B Compound 52-1 (3.2 g, 7.64 mmol) and ammonium chloride (0.83 g, 15.28 mmol) were dissolved in ethanol (100 mL) and water (10 mL). Iron powder (4.29 g, 76.4 mmol) was added, and the reaction system was stirred at 85° C. for 3 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (100 mL ⁇ 3). The organic phases were combined, washed with saturated brine (100 mL ⁇ 3), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting mixture was purified by silica gel column chromatography to obtain 2.8 g of compound 52-2.
  • Step C Compound 52-2 (1.62 g, 6.37 mmol) was dissolved in 1,4-dioxane (50 mL). Diphenylphosphoryl azide (2.48 g, 5.0 mmol) and triethylamine (3.1 mL, 22.2 mmol) were added. The system was stirred at room temperature for half an hour. tert-butyl 4-(2-(3-amino-5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)piperidine-1-carboxylate (2.8 g, 7.4 mmol) was added In the above reaction system. The reaction was heated to 100°C and stirred for 3 hours.
  • reaction solution was cooled to room temperature, quenched by adding saturated aqueous sodium bicarbonate solution (100 mL), and extracted with ethyl acetate (100 mL ⁇ 3). The organic phases were combined, washed with water (100 ml ⁇ 3) and saturated brine (100 ml ⁇ 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting mixture was purified by silica gel column chromatography to obtain 1.95 g of compound 52- 3.
  • Step D Compound 52-3 (600.0 mg, 0.9 mmol) was dissolved in dichloromethane (10 mL), and hydrogen chloride in 1,4-dioxane (5 mL, 4 mol) was added to the above solution middle. The resulting reaction solution was stirred and reacted at room temperature for 4 hours. LCMS monitoring showed that the raw materials disappeared, and the reaction solution was concentrated to obtain 500 mg of compound 52-4.
  • Step E Dissolve piperidine-4-methanol (626.0 mg, 5.4 mmol) in N-methylpyrrolidone (15 mL), add N,N-diisopropylethylamine (1.8 mL, 10.9 mmol) and Compound 52-5 (1.0 g, 3.6 mmol). The reaction system was stirred at 140°C for 2 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature, quenched by adding water (50 mL), and extracted with ethyl acetate (50 mL ⁇ 3).
  • Step F The compound starting material compound 52-6 (350.0 mg, 0.95 mmol) was dissolved in dimethyl sulfoxide (6 mL), and 2-iodobenzoic acid (530.0 mg, 1.9 mmol) was added in the above solution. The resulting reaction solution was stirred and reacted at room temperature for 16 hours. LCMS monitoring showed disappearance of starting material, quenched with water (30 mL), extracted with ethyl acetate (30 mL ⁇ 3).
  • Step G The compound starting material compound 52-4 (176.0 mg, 0.3 mmol) was dissolved in THF and N,N-dimethylformamide (4.0 mL/4.0 mL), and triethylamine (0.13 mL , 0.98 mmol) and stirred at room temperature for 30 minutes, then acetic acid (0.1 ml) and compound 52-7 (120 mg, 0.3 mmol) were added to the above solution and stirred at room temperature for 15 minutes, then triacetoxyboron Sodium hydride (138.0 mg, 0.7 mmol) was added to the above solution. The resulting reaction solution was stirred and reacted at room temperature for 3 hours. LCMS monitoring showed that the raw materials disappeared.
  • the reaction solution was added to a mixed solution of water and ethyl acetate and filtered.
  • the filtrate was separated to obtain an organic layer.
  • the organic layer was dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by reverse phase.
  • Step A 5-Fluoroisobenzofuran-1,3-dione (1.0 g, 6.0 mmol) was dissolved in acetic acid (2 mL). 3-Aminopiperidine-2,6-dione (1.1 g, 6.6 mmol) and potassium acetate (1.8 g, 18.6 mmol) were added. The system was stirred at 90°C for 16 hours. LCMS monitoring showed that the starting material disappeared, and the reaction solution dropped to room temperature. At zero degrees Celsius, add water (20 ml) to quench, concentrate under reduced pressure to remove the supernatant, transfer the remaining crude product to a 250 ml single-necked bottle with methanol, and concentrate under reduced pressure. The resulting mixture is purified by silica gel column chromatography to obtain 700 mg Compound 53-1.
  • Step B Under nitrogen protection, compound 53-2 (1.0 g, 4.3 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (916.0 mg, 4.3 mmol) were dissolved in methanol (5 mL ), acetic acid (0.5 ml) was added, and the reaction solution was stirred at room temperature for 0.5 hours.
  • Sodium triacetoxyborohydride (1.4 g, 6.4 mmol) was added to the above reaction system, and the reaction solution was stirred at room temperature for 3 hours. After LCMS monitoring showed that the raw materials disappeared, dichloromethane and sodium sulfate decahydrate were added to the reaction solution, and stirring was continued for 0.5 hours.
  • Step C Compound 53-3 (1.2 g, 2.8 mmol) was dissolved in methanol (50 mL). After replacing the system with nitrogen, palladium/carbon (100 mg) was added to replace the reaction system with hydrogen, and the reaction solution was stirred at room temperature for 3 hours under a hydrogen balloon environment. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 900 mg of compound 53-4. This compound was directly used in the next reaction.
  • Step D Dissolve compound 53-4 (240.0 mg, 0.8 mmol) and compound 53-1 (230.0 mg, 0.8 mmol) in N-methylpyrrolidone (10 ml) at room temperature, add N,N- Diisopropylethylamine (322.0 mg, 2.5 mmol), the system was heated to 140 degrees Celsius and stirred for 1 hour. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature, quenched by adding water (100 mL), and extracted with dichloromethane (50 mL ⁇ 3).
  • Step E Compound 53-5 (400.0 mg, 1.4 mmol) was dissolved in dichloromethane (5 mL), and hydrochloric acid in ethyl acetate (4 mol, 1 mL) was added. The reaction was stirred at room temperature for 1 hour. After LCMS detection showed that the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure to obtain 300. mg of compound 53-6.
  • Step F Compound 53-6 (100.0 mg, 0.2 mmol) was dissolved in THF (5 mL) and N,N-dimethylformamide (5 mL) at room temperature, and triethylamine (0.5 mL) was added , and the system was stirred at room temperature for 0.5 h. Then acetic acid (0.5 ml), compound 53-7 (104.0 mg, 0.2 mmol) and sodium triacetoxyborohydride (55.8 mg, 0.3 mmol) were added to the above reaction system in turn, and the reaction solution was stirred at room temperature for 2 Hour.
  • Step A 4-Bromo-3-methyl-1-(2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazole-2 - Ketone (1.5 g, 4.2 mmol) and tert-butyl (2-(piperidin-4-yl) ethyl) carbamate (1.2 g, 5.2 mmol), sodium tert-butoxide (1.0 g, 10.5 mmol), 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (98 mg, 0.2 mmol) was dissolved in 1,4-dioxane (20 mL) and replaced with nitrogen Three times, tris(dibenzylideneacetone)dipalladium (192 mg, 0.2 mmol) was added to the above solution.
  • the resulting reaction solution was stirred at 90° C. for 2 hours. LCMS monitoring showed that the raw material disappeared, the reaction solution was cooled and filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by normal phase to obtain 0.6 g of compound 54-1.
  • Step B Compound 54-1 (0.6 g, 1.2 mmol) was dissolved in tetrabutylammonium fluoride (11.9 ml, 1 molar solution in THF), and the resulting mixture was stirred at 80°C for 16 hours.
  • LCMS monitors the disappearance of raw materials, and the reaction solution is cooled and poured into a mixed solution of ethyl acetate and saturated ammonium chloride, the organic layer is washed with saturated ammonium chloride, washed with water, washed with brine, dried, filtered, and the filtrate is spin-dried to obtain 0.4 grams of compound 54-2.
  • Step C Compound 54-2 (470 mg, 1.3 mmol) was dissolved in tetrahydrofuran (15 ml), the reaction system was placed in an ice bath, potassium tert-butoxide (1.9 ml, 1.9 mmol) was added dropwise to In the above solution, the resulting mixture was stirred at zero for one hour, and then 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl-trifluoromethanesulfonate (506 mg, 2.5 mmol) was dissolved in tetrahydrofuran (10 ml), and added dropwise to the above solution, and the reaction system was slowly raised to room temperature and stirred for two hours.
  • LCMS detects that most of them are products, and there is also a small amount of raw materials.
  • the reaction solution is poured into a mixed solvent of water and ethyl acetate, separated, the organic layer is dried with anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. Normal phase purification afforded 600 mg of compound 54-3.
  • Step D Compound 54-3 (0.6 g, 1.0 mmol) was dissolved in trifluoroacetic acid (7 ml), and trifluoromethanesulfonic acid (0.7 ml, 7.9 mmol) was added to the above solution, heated to 60 degrees Celsius overnight. LCMS showed that the raw materials disappeared, and the reaction solution was cooled to room temperature and spin-dried to obtain 380 mg of compound 54-4.
  • Step E Compound 54-4 (380 mg, crude product) was dissolved in acetonitrile (10 ml), triethylamine was added dropwise at zero temperature until the pH value of the reaction solution was 8-9, and di-tert-butyl carbonate ( 324 mg, 1.5 mmol) was added to the above solution, and the resulting mixture was stirred at room temperature for 2 hours. LCMS monitoring showed that the reaction was complete. The reaction solution was spin-dried, and then water and ethyl acetate were added. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain 170 mg of compound 54-5. .
  • Step F Compound 54-5 (140 mg, 0.3 mmol) was dissolved in dichloromethane (5 mL), and hydrochloric acid in ethyl acetate (2 mL) was added to the above solution, and the resulting mixture was heated at room temperature Stirring was continued for 2 hours. LCMS showed that the starting material disappeared, and it was directly spin-dried to obtain 110 mg of compound 54-6.
  • Step G Compound 54-6 (110 mg, 0.3 mmol), Compound 54-7 (119 mg, 0.3 mmol), acetic acid (0.2 mL), and tetraisopropyl titanate (0.3 mL) were dissolved in methanol (5 ml), heated to 50 degrees Celsius and stirred for half an hour, then cooled to room temperature, and 2-picoline borane (60 mg, 0.6 mmol) was added to the above solution. The resulting reaction solution was stirred and reacted at room temperature for 3 hours.
  • Step A Compound 55-1 (60 mg, 0.09 mmol), pyridine (32 mg, 0.4 mmol) were dissolved in methanol (5 mL) at room temperature. The reaction solution was heated to 60°C and stirred for 10 minutes. The reaction solution was cooled to room temperature, and (S)-1-(2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(2 -(2-Carbonylethoxy)-5-(trifluoromethyl)pyridin-3-yl)urea (32 mg, 0.07 mmol) and 2-picoline borane (58 mg, 0.5 mmol) were added into the reaction solution, replaced by nitrogen, and stirred at room temperature for 16 hours.
  • Step A Compound 55-1 (55 mg, 0.05 mmol) was dissolved in a mixed solution of trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.1 mL) at room temperature. The reaction solution was heated to 70°C and stirred for 12 hours under nitrogen protection.
  • Step A Compound 57-1 (86 mg, 0.16 mmol) was dissolved in THF (2 mL) and N,N-dimethylformamide (2 mL) at room temperature. Subsequently, N,N-diisopropylethylamine (41 mg, 0.3 mmol) was added thereto, stirred at room temperature for 10 minutes, and then acetic acid (0.5 ml) and (S)-1-(2-chloro-7 -(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(2-(2-oxoethoxy)-5-(trifluoromethyl) Pyridin-3-yl)urea (76 mg, 0.2 mmol), the reaction solution was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (51 mg, 0.24 mmol) was added.
  • Step A Under nitrogen protection, compound 58-1 (100.0 mg, 0.2 mmol), 1-(2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a] pyrimidin-6-yl)-3-(2-oxoethoxy)-5-trifluoromethylpyridin-3-ylurea (107.7 mg, 0.2 mmol), acetic acid (27.9 mg, 0.5 mmol) and Tetraisopropyl titanate (64.8 mg, 0.2 mmol) was dissolved in methanol (5 ml), and the system was stirred at room temperature for 0.5 hour.
  • reaction solution was cooled down to room temperature, sodium triacetoxyborohydride (96.8 mg, 0.5 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours.
  • dichloromethane 50 ml was added to the reaction solution for dilution, quenched with sodium sulfate decahydrate and stirred for 0.5 hours. After filtration, the filtrate was washed with water (50 mL ⁇ 3) and saturated brine (50 mL ⁇ 3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure.

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Abstract

La présente invention concerne un composé qui inhibe MALT1 et favorise la dégradation de MALT1 au moyen du recrutement de l'ubiquitine ligase E3, et l'utilisation du composé dans la préparation d'un médicament pour le traitement de maladies associées à médiation par une cible MALT1. L'invention concerne spécifiquement un composé tel que représenté par la formule (I') et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2023/072620 2022-01-28 2023-01-17 Composé de dégradation de protéine ciblant malt1 Ceased WO2023143249A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2023224879B2 (en) * 2022-02-25 2025-10-09 Tegid Therapeutics, Inc. Protacs of malt1
US12459920B2 (en) 2023-07-25 2025-11-04 Monte Rosa Therapeutics Ag Targeted protein degradation

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106170489A (zh) * 2014-05-28 2016-11-30 诺华股份有限公司 新的吡唑并嘧啶衍生物及其作为malt1抑制剂的用途
WO2018085247A1 (fr) * 2016-11-01 2018-05-11 Cornell University Composés pour la dégradation de malt1
CN109641874A (zh) * 2016-05-10 2019-04-16 C4医药公司 用于靶蛋白降解的c3-碳连接的戊二酰亚胺降解决定子体
WO2020264499A1 (fr) * 2019-06-28 2020-12-30 Kymera Therapeutics, Inc. Agents de dégradation d'irak et leurs utilisations
CN113412259A (zh) * 2018-10-15 2021-09-17 紐力克斯治疗公司 通过泛素蛋白酶体途径降解btk的双官能化合物
CN113710661A (zh) * 2019-04-02 2021-11-26 上海睿跃生物科技有限公司 治疗癌症的化合物和方法
WO2022235698A1 (fr) * 2021-05-03 2022-11-10 Nurix Therapeutics, Inc. Composés pour inhiber ou dégrader des protéines cibles, compositions les comprenant, leurs procédés de fabrication et leurs procédés d'utilisation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106170489A (zh) * 2014-05-28 2016-11-30 诺华股份有限公司 新的吡唑并嘧啶衍生物及其作为malt1抑制剂的用途
CN109641874A (zh) * 2016-05-10 2019-04-16 C4医药公司 用于靶蛋白降解的c3-碳连接的戊二酰亚胺降解决定子体
WO2018085247A1 (fr) * 2016-11-01 2018-05-11 Cornell University Composés pour la dégradation de malt1
CN113412259A (zh) * 2018-10-15 2021-09-17 紐力克斯治疗公司 通过泛素蛋白酶体途径降解btk的双官能化合物
CN113710661A (zh) * 2019-04-02 2021-11-26 上海睿跃生物科技有限公司 治疗癌症的化合物和方法
WO2020264499A1 (fr) * 2019-06-28 2020-12-30 Kymera Therapeutics, Inc. Agents de dégradation d'irak et leurs utilisations
WO2022235698A1 (fr) * 2021-05-03 2022-11-10 Nurix Therapeutics, Inc. Composés pour inhiber ou dégrader des protéines cibles, compositions les comprenant, leurs procédés de fabrication et leurs procédés d'utilisation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2023224879B2 (en) * 2022-02-25 2025-10-09 Tegid Therapeutics, Inc. Protacs of malt1
US12459920B2 (en) 2023-07-25 2025-11-04 Monte Rosa Therapeutics Ag Targeted protein degradation

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