WO2023226950A1 - Agent de dégradation de protéine stat peptidomimétique, composition et utilisation associées - Google Patents

Agent de dégradation de protéine stat peptidomimétique, composition et utilisation associées Download PDF

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WO2023226950A1
WO2023226950A1 PCT/CN2023/095625 CN2023095625W WO2023226950A1 WO 2023226950 A1 WO2023226950 A1 WO 2023226950A1 CN 2023095625 W CN2023095625 W CN 2023095625W WO 2023226950 A1 WO2023226950 A1 WO 2023226950A1
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amino
carbamoyl
esi
methyl
synthesis
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PCT/CN2023/095625
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Chinese (zh)
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吴一哲
周星露
朱建荣
刘兴国
胡苗
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杭州和正医药有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1027—Tetrapeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention belongs to the technical field of drug synthesis, and specifically relates to a class of peptoid STAT protein degradation agents, compositions and applications thereof.
  • the JAK-STAT signaling pathway is an important tumor-related signaling pathway. After the cytokine receptor, hormone receptor or growth factor receptor on the cell surface binds to the corresponding ligand, the intracellular JAK kinase is activated, thereby inducing the phosphorylation of the downstream transcription factor STAT and forming a homodimer, thereby entering the cell nucleus. , initiating or inhibiting the transcription of a series of tumor-related genes.
  • the transcription factor STAT regulates a variety of tumor-related genes, such as: cMyc, Survivin, BCL-XL, VEGF, HIF, NF-kB, etc.
  • Gain-Of-Function mutations of STAT are often associated with tumor cells, leading to over-activation of the pathway. Over-activation of the STAT pathway can lead to: increased proliferation and survival of tumor cells, abnormal proliferation of blood vessels, invasion and migration of tumor cells, and Immune evasion and maintenance of cancer stem cell-like appearance.
  • STAT3 is closely related to the suppressive immune microenvironment of tumor tissues. Excessive activation of STAT in DC cells leads to a decrease in the expression of MHC type II molecules and costimulatory factors, thereby reducing their ability to present antigens and activate T cells. Expression in neutrophils, NK cells, and effector T cells will reduce their ability to recognize, activate and kill tumor cells. At the same time, it can promote the M2 polarization of tumor-associated macrophages, the maturation and expansion of myeloid suppressor cells, induce the differentiation of T cells into regulatory T cells, and induce PD- The expression of L1 increases, thereby forming a suppressive immune microenvironment and promoting tumor immune escape.
  • the JAK-STAT signaling pathway can promote tumor proliferation through multiple pathways and is therefore a potential target for anti-tumor drug development.
  • targeted protein degradation technology which achieves target protein degradation by inducing ubiquitination of target proteins.
  • Drugs using this technology do not need to continuously occupy the target protein, and the catalytic concentration can achieve target degradation. Therefore, the development of targeted degradation molecules for STAT3 is expected to solve the shortcomings of insufficient efficacy of current small molecule STAT3 inhibitors.
  • the purpose of the present invention is to provide a novel, unreported STAT3-degrading molecule with high-efficiency STAT3-degrading activity and its stereoisomers or stereoisomer mixtures or pharmaceutically acceptable salts thereof.
  • the object of the present invention is to also provide a compound including the above compound or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt.
  • the present invention also provides an application of the above compound or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt for preparing drugs for treating diseases, disorders or conditions that benefit from degrading STAT3. .
  • a first aspect of the present invention is to provide a structure as shown in (I):
  • R 1 and R 2 are each independently selected from: H, -Me, -Et,
  • X 1 is selected from: -CH 2 -, -CF 2 -, -CO-;
  • X 2 is selected from: S, NRd, O;
  • X 3 , X 4 , X 5 , X 6 are independently selected from: CRa, N;
  • R 3 is selected from: H, R 7 , R 7 -(CH 2 ) p -, R 7 -(CH 2 ) p -CO-, R 7 -(CH 2 ) p -O-CO-, R 7 -( CH 2 ) p -NH-CO-, R 7 -(CH 2 ) p -SO 2 -. Any one or more methylene groups (-CH 2 -) mentioned above (i.e.
  • R 7 is selected from: H, halogen, -CN, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, halogenated C 3 -C 6 cycloalkyl, 3-10 membered heterocyclyl, phenyl, heteroaryl, E3;
  • Ring A is selected from: C 6 -C 10 aryl, 5-10 membered heteroaryl, and the heteroaryl contains 1 to 4 heteroatoms selected from O, S, and N;
  • R 6 is selected from: -(CH 2 ) p -P(O)R 8 R 9 ;
  • R 5 is selected from: H, halogen, CN, -OH, nitro, carboxyl, amino, amide, -P(O)R 8 R 9 , acyl, -SO 2 , sulfonamide, C 1 -C 6 alkane Oxygen group, halo C 1 -C 6 alkoxy group, C 1 -C 6 alkyl group, C 1 -C 6 haloalkyl group, hydroxyalkyl group, aminoalkyl group, C 1 -C 6 alkyl-sulfonamide group, C 1 -C 6 haloalkyl-sulfonamide, C 3 -C 8 cycloalkyl, halo C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, alkylamino, haloalkylamino, C 3 -C 8 cycloalkylamino, C 1 -C 6 alkyl -SO 2 -, C 1 -
  • R 8 and R 9 are each independently selected from: H, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl;
  • Ra and Rb are each independently selected from: H, halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 3-10 membered heterocyclyl, phenyl, heteroaryl, -CN, -NHRd, -ORd;
  • Rd, Rj, and Rk are each independently selected from: H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, 3-10 membered heterocyclyl, phenyl, hetero Aryl;
  • n is selected from: 0, 1, 2, 3;
  • n is selected from: 0, 1, 2, 3;
  • p is selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8;
  • r is selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8;
  • s is selected from: 0, 1, 2;
  • E3 is selected from:
  • Re is selected from: -Me, -Et, -CF 3 , -OMe, -OH, -F, -Cl, -CN;
  • W 1 , W 2 , W 3 and W 4 are each independently selected from: CH, N.
  • R 8 (or R 9 ) appears in both R 6 and R 5.
  • R 8 (or R 9 ) in R 6 and R 5 are independent of each other and can be the same or different.
  • Ra (or Rb) appearing in different groups or positions are independent of each other and can be the same or different.
  • Rd (or R j , R k ) appearing in different groups or positions are independent of each other and can be the same or different; similarly, m (or n, p, s, r) appearing in different positions, etc., Independent of each other, they can be the same or different.
  • n' and n" are 0,1,2,3.
  • Re is selected from: H, -Me, -Et, -CF 3 , -OMe, -OH, -F, -Cl, -CN.
  • E3 is selected from
  • X 16 is selected from: CH, N.
  • X 3 , X 4 , X 5 , and X 6 are each independently selected from: CH, CF, C, CCH 3 , and N.
  • the preferred compounds of the present invention have the general formula Partially selected from: X 2 is selected from: S, NRd, O.
  • the preferred compound of the present invention has the structure represented by general formula III:
  • X 1 is selected from: -CH 2 -, -CF 2 -, -CO-;
  • X 2 is selected from: S, NH, O, NCH 3 .
  • X 16 is selected from: CH, N.
  • n is selected from: 0, 1, 2, 3;
  • n’ or n are each independently selected from: 0, 1, 2, 3;
  • R 8 is selected from: methyl, ethyl, propyl, isopropyl
  • R 9 is selected from: methyl, ethyl, propyl, isopropyl.
  • preferred compounds of the present invention have the structure of general formula V(a) or V(b) or V(c) or V(d):
  • R 14 is selected from: R 7 -(CH 2 ) p -, R 7 -(CH 2 ) p -CO-, R 7 -(CH 2 ) p -O-CO-, R 7 -(CH 2 ) p -NH-CO-, R 7 -(CH 2 ) p -SO 2 -.
  • R 8 and R 9 are each independently selected from ethyl and isopropyl.
  • the C atom connected to R4 is a chiral carbon atom with R or S configuration.
  • R 7 is selected from: E3.
  • r is selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8.
  • X 1 is selected from: -CF 2 - or -CO-;
  • X 2 is selected from: S, NH or NCH 3 ;
  • R 3 is selected from: CF 3 CH 2 -, CF 3 -, CF 2 HCH 2 -, -Me, -Et, -iPr, -Ac, CH 3 OCO-, CH 3 CO-, CH 3 NHCO-, CH 3 SO 2 - or iPrSO 2 -;
  • R 5 is selected from: H, halogen, CN, -OH, nitro, carboxyl, amino, amide, -P(O)R 8 R 9 , acyl, -SO 2 , sulfonamide, hydroxyalkyl, aminoalkyl base, C 1 -C 6 alkoxy group, C 1 -C 6 haloalkoxy group, C 1 -C 6 alkyl group, C 1 -C 6 haloalkyl group, C 1 -C 6 alkyl-sulfonamide group, C 1 -C 6 haloalkyl-sulfonamido, C 3 -C 8 cycloalkyl, halo C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, alkylamino, haloalkylamino, C 3 -C 8 cycloalkylamino, C 1 -C 6 alkyl-SO 2 -, C 1 -C 6
  • R 7 is selected from: E3.
  • R 5 is preferably: H, fluorine, chlorine, bromine, CN, -OH, nitro, carboxyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, Propoxy, isopropoxy, difluoromethyl, difluoromethoxy, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy , cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the C 3 -C 10 cycloalkylene group may be selected from: cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, cyclononylene, cyclodecylene base,, cyclobutylidene and cyclobutyl, cyclobutylidene and cyclopentyl, cyclobutylidene and cyclohexyl, cyclopentylidene and cyclohexyl, cyclopentylidene and cyclohexyl, cyclopentylidene and cyclohexyl, cyclohexylidene and Cyclohexyl, cyclopropylidenecyclobutyl, cyclopropylidenecyclopentyl, cyclopropylidenecyclohexyl, cyclobutylidenespirocyclo
  • heterocyclic ring is selected from: azetidinyl, pyrrolidine, piperidine, piperazine, morpholine, azetidinyl, azetipentyl, piperidine, morpholine , piperazine, pyrrole, pyrazole, imidazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, tetrazole, cyclopropyl azetidinyl, cyclopropyl azetidinyl , cyclopropyl azetidine, cyclopropyl piperidine, cyclobutyl azetidinyl, cyclobutyl azetipentyl, cyclobutyl azetihexyl, cyclobutyl piperidine, cyclopentaazetidinyl,
  • E3 is selected from:
  • E3 is further preferably:
  • E3 is preferably
  • the structure is preferably:
  • the compound or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt is selected from the following compounds:
  • “Bond” means that the indicated substituent does not exist, and the two end portions of the substituent are directly connected to form a bond.
  • Alkyl when used as a group or part of a group means a C 1 -C 20 linear or branched aliphatic hydrocarbon group. Preferably it is a C 1 -C 10 alkyl group, more preferably a C 1 -C 8 alkyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl wait.
  • Alkyl groups may be substituted or unsubstituted.
  • Alkenyl refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond, which can be straight or branched. Preferred is C 2 -C 10 alkenyl, more preferred is C 2 -C 8 alkenyl. Representative examples include, but are not limited to, vinyl, wait. Alkenyl groups may be substituted or unsubstituted.
  • Alkynyl refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which can be straight or branched. It is preferably a C 2 -C 10 alkynyl group, more preferably a C 2 -C 8 alkynyl group, and most preferably a C 2 -C 4 alkynyl group. Examples of alkynyl groups include, but are not limited to, ethynyl, wait. Alkynyl groups may be substituted or unsubstituted.
  • Cycloalkyl refers to saturated or partially saturated monocyclic, fused, bridged and spiro carbocyclic rings. Preferred is C 3 -C 12 cycloalkyl, more preferred is C 3 -C 8 cycloalkyl, and most preferred is C 3 -C 6 cycloalkyl.
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyltri Alkenyl group, cyclooctyl group, etc., preferably cyclopropyl group and cyclohexenyl group. Cycloalkyl groups may be substituted or unsubstituted.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one carbon atom (called a spiro atom) with each other.
  • the ring may contain 1 or more Multiple double bonds, but none of the rings are aromatic. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spirocycloalkyl group is divided into single spiro, double spiro or polyspiral cycloalkyl, preferably single spiro and double spiro cycloalkyl, preferably 4-membered/5-membered, 4-membered Yuan/6 Yuan, 5 Yuan/5 Yuan or 5 Yuan/6 Yuan.
  • spirocycloalkyl include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.
  • Condensed cycloalkyl refers to an all-carbon polycyclic group with 5 to 18 members and containing two or more cyclic structures sharing a pair of carbon atoms with each other.
  • One or more rings may contain one or more double bonds. However, none of the rings has aromaticity, and it is preferably 6 to 12 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed ring alkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl groups.
  • fused cycloalkyl examples include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decalin base or tetradecahydrophenanthyl base.
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group with 5 to 18 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other.
  • One or more rings may contain one or more Multiple double bonds, but none of the rings are aromatic, preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl examples include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicycloo[ 3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl, bicyclo[1.1.1]pentyl.
  • Heterocyclyl “heterocycle” or “heterocyclic” are used interchangeably in this application and all refer to non-aromatic heterocyclyl, in which one or more ring-forming atoms are heteroatoms, such as N, O, S, P, Se, including single ring, fused ring, bridged ring and spiro ring, the ring may contain one or more double bonds.
  • ring atoms Preferably it has 3 to 12 ring atoms, more preferably 4 to 7 membered monocyclic ring or 7 to 10 membered bi- or tricyclic ring, which may contain 1, 2 or 3 selected from N, O, S(O) n (where n is selected from 0, 1 or 2), P(O) m (where m is selected from 0 or 1), Se atoms.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,,1-dioxo-thiomorpholinyl, pipera Aldinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl , piperazinyl, 1,2,3,6-tetrahydropyridyl or 3,6-dihydro-2H-pyranyl.
  • Heterocyclyl groups may be substituted or unsubstituted.
  • “Spiroheterocyclyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one atom with each other.
  • the ring may contain 1 or more double bonds, but No ring is aromatic in which one or more ring atoms are selected from wherein one or more ring atoms are selected from N, O, S(O) n (where n is selected from 0, 1 or 2), P(O) m (where m is selected from 0 or 1), heteroatoms of Se, and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiroheterocyclyl group is divided into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a polyspiroheterocyclyl group, and is preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiroheterocyclic group.
  • spiroheterocyclyl examples include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[ 3.5]nonyl and 5-oxaspiro[2.4]heptyl.
  • Condensed heterocyclyl refers to an all-carbon polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other.
  • One or more rings may contain one or more double bonds, but none of the rings is aromatic.
  • property in which one or more ring atoms are selected from N, O, S(O) n (where n is selected from 0, 1 or 2), P(O) m (where m is selected from 0 or 1), Se hetero atoms, and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclyl include, but are not limited to: octahydropyrro[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1. 0]Hexyl, octahydrobenzo[b][1,4]dioxin (dioxine).
  • “Bridged heterocyclyl” refers to a polycyclic group with 5 to 18 members, containing two or more cyclic structures, sharing two atoms that are not directly connected to each other.
  • One or more rings may contain one or more Double bonds, but neither ring is aromatic, and one or more ring atoms are selected from N, O, S(O) n (where n is selected from 0, 1 or 2), P(O) m (where m is selected From 0 or 1), the heteroatom of Se, and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl examples include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[3.3 .2] Decyl.
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner.
  • Aryl includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferred aryl groups are C 6 -C 10 aryl groups, more preferred aryl groups are phenyl and naphthyl, and most preferred are phenyl groups.
  • Aryl groups may be substituted or unsubstituted.
  • Heteroaryl and “heteroaryl ring” are used interchangeably in this application, and both refer to a monocyclic or polycyclic aromatic ring group containing 5 to 14 ring atoms, which may contain 1 to 4 selected from Atoms of N, O, S, and Se. Preferably it contains 5 to 12 ring atoms, more preferably 5 to 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl.
  • heteroaryl examples include but are not limited to furan base, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, Pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, Benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, indazolyl, benzisothiazolyl, benzoxazolyl, benziiso Oxazolyl, Heteroaryl groups may be substituted or unsubsti
  • “Fused ring” refers to a polycyclic group in which two or more cyclic structures share a pair of atoms with each other.
  • One or more rings may contain one or more double bonds, but at least one ring is not aromatic.
  • at least one ring is aromatic, in which 0, 1 or more ring atoms are selected from N, O, S(O) n (where n is selected from 0, 1 or 2), P(O) m (where m is selected from 0 or 1), heteroatoms of Se, and the remaining ring atoms are carbon.
  • the fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclyl group or a monocyclic cycloalkyl group. It is preferably 7 to 14 yuan, more preferably 9 to 10 yuan. Examples of "fused rings" include, but are not limited to:
  • Fused rings may be substituted or unsubstituted.
  • Alkoxy refers to the group (-O-alkyl). Among them, alkyl group is as defined in this article. C 1 -C 8 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentoxy, neo Pentyloxy etc. Alkoxy groups may be substituted or unsubstituted.
  • Alkylthio refers to a (-S-alkyl) group. Among them, alkyl group is as defined in this article. C 1 -C 8 alkylthio groups are preferred. Examples include, but are not limited to: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, etc. "Alkylthio" may be substituted or unsubstituted.
  • Alkenyloxy refers to the group (-O-alkenyl). Among them, alkenyl group is as defined in this article. Alkenyloxy groups of C 2 to C 8 are preferred. Alkenyloxy groups may be substituted or unsubstituted.
  • Hydroalkyl is the group (-alkyl-OH). Among them, alkyl group is as defined in this article. C 1 -C 8 hydroxyalkyl groups are preferred. Examples include, but are not limited to: hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, etc. Hydroxyalkyl groups may be substituted or unsubstituted.
  • Alkylamino refers to the group (-NH-alkyl). Among them, alkyl group is as defined in this article. C 1 -C 8 alkylamino groups are preferred. Examples include, but are not limited to: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutoxy, tert-butoxy, etc.
  • the alkylamino group can be substituted or unsubstituted, and the substituent can be on the alkyl group or on N, such as dimethylamino and diethylamino.
  • Alkyl refers to the group (-alkyl- NH2 ). Among them, alkyl group is as defined in this article. Examples include, but are not limited to: aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, aminopentyl, etc.
  • the aminoalkyl group can be substituted or unsubstituted, and the substituent can be on the alkyl group or on N, such as: dimethylaminoalkyl group.
  • Alkylcarbonyl refers to the group (-C(O)-alkyl). Among them, alkyl group is as defined in this article. Examples include, but are not limited to: methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, etc. Alkylcarbonyl groups may be substituted or unsubstituted.
  • Alkoxycarbonyl refers to the group (-C(O)-O-alkyl). Among them, alkyl group is as defined in this article. Examples include, but are not limited to: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, etc. Alkoxycarbonyl groups may be substituted or unsubstituted.
  • Haloalkyl refers to an alkyl group substituted by halogen. Among them, halogen and alkyl are defined in this article.
  • Haloalkoxy refers to an alkoxy group substituted by halogen. Among them, halogen and alkoxy are defined in this article.
  • Halohydroxyalkyl refers to a hydroxyalkyl group substituted by halogen. Among them, halogen and hydroxyalkyl are defined in this article.
  • Haloalkylamino refers to an alkylamino group substituted by halogen. Among them, halogen and alkylamino are defined in this article.
  • Cycloalkoxy refers to the group (-O-cycloalkyl).
  • the cycloalkyl group is as defined in this article.
  • Heterocyclyloxy refers to a (-O-heterocyclyl) group.
  • the heterocyclyl group is as defined in this article.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • Substituted means that one or more hydrogen atoms in the group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art is able to determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • Substituted or “substituted” mentioned in this specification, unless otherwise specified, means that the group can be substituted by one or more groups selected from the following: hydrogen, halogen, amino, cyano, nitro, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3 -C 12 cycloalkyl, 5-12 membered heterocyclyl, C 6 -C 10 aryl, 5-12 membered Heteroaryl, -OR a' , -C(O)R a' , -C(O)OR a' , -C(O)N(R b' )R c' , -NR b' R c' , -N(R b' )C(O)R c' , -N(R b' )C(O)NR c' R d' , -N(R b' )C(O)OR c' , ,
  • the 2 R o 's When 2 R o 's are substituted on the same atom, the 2 R o 's form a 3-6 membered ring together with the atoms they are connected to, or when the 2 R o 's are substituted on adjacent atoms, the 2 R o 's 'Together with the atoms to which it is connected, it forms a 3-12 membered ring;
  • R a' , R b' , R c' , R d' , R e' , R f' , and R o ' are each independently selected from hydrogen, halogen, amino, cyano, nitro, C 1-8 alkyl , C 2-8 alkenyl, C 2-8 alkynyl, C 3 -C 12 cycloalkyl, 5-12 membered heterocyclyl, C 6 -C 10 aryl, 5-12 membered heteroaryl, -OR a” , -C(O)R a” , -C(O)OR a” , -C(O)N(R b” )R c” , -NR b” R c” , -N(R b” )C(O)R c” , -N(R b” )C(O)NR c” R d” , -N(R b” )C(O)OR c
  • R a” , R b” , R c” , R d” , R e” , R f” , and R o” are each independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, C 1-8 Alkyl , C 1-8 alkoxy, halo C 1-8 alkyl, halo C 1-8 alkoxy, C 1-8 alkylamino, C 2-8 alkenyl, C 2-8 alkynyl , C 3 -C 12 cycloalkyl, 5-12 membered heterocyclyl, C 6 -C 10 aryl, 5-12 membered heteroaryl, carboxyl, carboxylate group.
  • “Pharmaceutically acceptable salts” refer to salts of compounds of the present invention with acids or bases suitable for use as pharmaceuticals.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • One preferred class of salts are the salts of the compounds of the invention with acids.
  • Acids suitable for forming salts include, but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydriodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid and other inorganic acids, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, amber Organic acids such as acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid; and Acidic amino acids such as aspartic acid and glutamic acid.
  • salts of compounds of the invention with bases, including but not limited to sodium, potassium, magnesium, and ammonium salts.
  • Bases suitable for forming salts include, but are not limited to: sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, magnesium carbonate, potassium bicarbonate, potassium phosphate, magnesium phosphate and other inorganic Alkali, ammonia, triethylamine, diethylamine, piperazine, guanidine, diethanolamine and other organic bases.
  • the second object of the present invention is to provide a pharmaceutical composition including one or more of the compounds described in any of the above technical solutions.
  • the pharmaceutical composition of the present invention may be composed of one or more of the compounds described in any of the above technical solutions and other compounds, or one or more of the compounds described in any of the above technical solutions. composition.
  • the present invention provides a pharmaceutical preparation, which contains at least one active component, and the active component is one or more of the compounds described in any of the above technical solutions.
  • the pharmaceutical preparation contains at least one active component and one or more pharmaceutically acceptable carriers or excipients.
  • the active component may be the STAT3 inhibitor compound of the present invention, a stereoisotope of the compound. Any one or more of the configurations, pharmaceutically acceptable salts of the compound or its stereoisomer, and solvates of the compound or its stereoisomer.
  • the carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption accelerators, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field, and fragrances can also be added if necessary. agents, sweeteners, etc.
  • the medicine of the present invention can be made into various forms such as tablets, powders, granules, capsules, oral liquids and injections, granular preparations, sprays, etc.
  • the medicines in each of the above dosage forms can be prepared according to conventional methods in the pharmaceutical field.
  • the present invention provides a disease that benefits from degrading STAT3 using the compounds described in Formulas I to VI disclosed herein and their optical isomers or pharmaceutically acceptable salts or solvates thereof. , disorder or illness.
  • the invention provides a method of degrading STAT3 in a subject in need thereof by administering to the subject a composition containing a therapeutically effective amount of at least one compound, wherein the compound The structural formulas are general formula I to general formula VI.
  • the subject in need thereof has cancer.
  • the compounds of formulas I to VI provided by the present invention are used in combination with immune checkpoint inhibitors, chemotherapy or targeted drugs.
  • the immune checkpoint inhibitor includes but is not limited to: PD-1 monoclonal antibody, PD-L1 monoclonal antibody or CTLA-4 monoclonal antibody.
  • the chemotherapeutic drugs include, but are not limited to: mitosis inhibitors (such as vinblastine, vindesine and vinorelbine); tubulin decomposition inhibitors (such as Taxol)); alkylating reagents (such as cisplatin, carbin).
  • antimetabolites such as 5-fluorouracil, tegafur, methotrexate, cytarabine, and hydroxyurea
  • insertable antibiotics such as areresin, mitomycin and strobomycin
  • topoisomerase inhibitors such as etoposide and camptothecin
  • the targeted drugs include but are not limited to: BTK inhibitors (such as ibrutinib, acalabrutinib); Bcl-2 inhibitors (such as Venetoclax); anti-CD20 monoclonal antibodies (such as rituximab, ofatumumab, atuzumab); mTOR inhibitors (such as rapamycin, AZD8055), mTORC1 inhibitors (such as everolimus, temsirolimus), AKT inhibitors (such as MK-2206 , GSD690693), PI3K inhibitors (such as Idelalisib, Duvelisib); proteasome inhibitors (such as bortezomib, carfilzomib, ixazomib); EGFR inhibitors (such as erlotinib, gefitinib, Osimertinib), VEGFR inhibitors (sorafenib, cabozantinib, refut
  • the subject in need thereof has cancer including, but not limited to:
  • Hematologic malignancies including lymphoma, leukemia, multiple myeloma, myelodysplastic syndromes such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell Prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia ( macroglobulinemia), splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma lymph node marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma lymphoma), AML, CML, multiple myeloma, or lymphomatoid granulomatosis.
  • Autoimmune diseases or conditions including autoimmune conditions of a single organ or single cell type, such as Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis with pernicious anemia, autoimmune encephalomyelitis, autoimmune Orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic invasive hepatitis, ulcerative colitis and membranous glomerulopathies, those involving systemic autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, Reiter's syndrome, polymyositis dermatomyositis, systemic sclerosis, tuberculosis polyarteritis, multiple sclerosis, and bullous pemphigoid) and other O-cell (hum
  • Solid tumors include, including gastrointestinal/gastrointestinal cancer, colorectal cancer, liver cancer, skin cancer (including mast cell tumor and squamous cell carcinoma), breast and breast cancer, ovarian cancer, prostate cancer, kidney cancer, lung cancer, muscle cancer, Cancer, bone cancer, bladder cancer, brain cancer, melanoma (including oral and metastatic melanoma), Kaposi's sarcoma, thyroid cancer, retinoblastoma, rhabdomyosarcoma, urinary tract tumors, central nervous system tumors, respiratory system Malignant tumors, nasopharyngeal cancer, pancreatic cancer, head and neck cancer;
  • the inventor of the present invention has confirmed through experiments that the compound of the present invention can degrade the transcription factor STAT3.
  • the inventors of the present invention have confirmed through experiments that the compounds of the present invention have obvious proliferation inhibitory activity on MOLM16 and SU-DHL-1 tumor cells.
  • the inventor of the present invention has confirmed through experiments that the compound of the present invention has good pharmacokinetic properties.
  • the inventor of the present invention has confirmed through experiments that the compound of the present invention has significant anti-tumor efficacy in vivo.
  • Step 1 (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2- a][1,5]Diazepine-8-carboxylic acid methyl ester (01-1)
  • Step 2 (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2- a][1,5]diazacycline-8-carboxylic acid (intermediate 01)
  • Step 4 Benzyl 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate ((02-4)
  • the first step 4-(3-oxypropyl)piperidine-1-carboxylic acid tert-butyl ester (03-1)
  • Step 2 4-(butyl-3-yn-1-yl)piperidine-1-carboxylic acid tert-butyl ester (03-2)
  • Step 3 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)but-3-yn-1-yl )Piperidine-1-carboxylic acid tert-butyl ester (03-3)
  • Step 4 3-(1-oxo-4-(4-(piperidin-4-yl)butyl-3-yn-1-yl)isoindolin-2-yl)piperidine-2, 6-diketone (intermediate 03)
  • Example 1 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan-3-yne- 1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2- Difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl )Difluoromethyl)phosphoric acid (001)
  • Synthesis step 5 2-(R)-5-amino-2-(5S,8S,10aR)-5-(tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazepine-8-carboxamido)-5-oxopentanoyl)-3-(4-(dimethylphosphonium) Methyl acyl)phenyl)propionate (001-5)
  • Synthesis step 6 2-(R)-5-amino-2-(5S,8S,10aR)-5-(tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazepine-8-carboxamido)-5-oxopentylamide)-3-(4-(dimethylphosphate) )Phenyl)propionic acid (001-6)
  • Synthesis step 7 tert-butyl ((5S,8S,10aR)-8-((2R)-5-amino-1-((2S)-3-(4-(4-(2,6-dioxo) Piperidin-3-yl)-1-oxoisoindolin-4-yl)butyl-3-ynyl-1-yl)-1-oxopropan-2-yl)amino)-1,5 -Dioxopent-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diaza Heterocyclooct-5-yl)carbamate (001-7)
  • Synthesis step 8 2R-2-(5S,8S,10aR)-5-amino-3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1 ,5]Diazepine-8-carboxamido)-N1-((2S)-3-(4-(4-(2,6-dioxopiperidin-3-yl)-1-oxo Isoindolin-4-yl)butyl-3-ynyl-1-yl)piperidin-1-yl)-1-oxopropan-2-yl)glutaramide (001-8)
  • Synthesis step 9 (2-((5S,8S,10aR)-8-(2R)-5-amino-1-((2S)-3-(4-(dimethylphosphoryl)phenyl)-1 -(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)but-3-ynyl-1-yl) -1-Oxopropan-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxo Decahydropyrro[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphate (001 -9)
  • Synthesis step 10 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S)-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan-3-yne- 1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2- Difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl )Difluoromethyl)phosphoric acid (001)
  • Example 2 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-((2S))-3-(4-(dimethylphosphoryl)benzene base)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)but-3-ynyl- 1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-ethyl-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid ( 002)
  • Example 3 ((2-(((5S,8S,10aR)-3-acetyl-8-(((2S)-5-amino-1-(((2S)-3-(4-(di Methylphosphoryl)phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan -3-yn-1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid ( 003)
  • Step 1 (5S,8S,10aR)-3-acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5] Diazacycline-8-carboxylic acid methyl ester (05-1)
  • Step 2 (5S,8S,10aR)-3-acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5] Diazacycline-8-carboxylic acid (Intermediate 05)
  • Example 5 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan-3-yne- 1-yl)piperazin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2- Difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl )Difluoromethyl)phosphoric acid (005)
  • Example 7 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(3-chloro-4-(dimethyl Phosphoryl)phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan- 3-yn-1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-( 2,2-Difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophene -5-yl)difluoromethyl)phosphoric acid (007)
  • Synthesis step 1 Synthesis of (S)-3-(4-bromo-3-chlorophenyl)-2-((tert-butoxycarbonyl)amino)propionic acid methyl ester (007-2)
  • Step 2 (S)-3-(4-Bromo-3-chlorophenyl)-2-((tert-butoxycarbonyl)amino)propionic acid methyl ester (007-2)
  • Example 8 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) -3-Fluorophenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan- 3-yn-1-yl)piperidin-1-yl)-1-oxopropan-2-yl)ammonium (yl)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (008)
  • Synthesis step 1 Synthesis of (S)-2-amino-3-(4-(dimethylphosphoryl)-3-fluorophenyl)propionic acid methyl ester (008-1):
  • Example 10 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)butan-3-yne- 1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2- Difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl )Difluoromethyl)phosphoric acid (010)
  • Example 11 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)butan-3 -Alkyn-1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2 ,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophene- 5-yl)difluoromethyl)phosphoric acid (011)
  • Example 12 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl (yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoro Ethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)bis Fluoromethyl)phosphoric acid (012)
  • Example 13 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl (yl)piperazin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoro Ethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)bis Fluoromethyl)phosphoric acid (013)
  • Example 14 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzimidazol-5-yl)but-3-yn-1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2- yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl) Carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (014)
  • Synthesis step 1 3-(3-methyl-2-oxo-5-(4-(piperidin-4-yl)but-1-yn-1-yl)-2,3-dihydro-1H- Synthesis of benzimidazol-1-yl)piperidine-2,6-dione (intermediate 14)
  • Example 15 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzimidazol-4-yl)but-3-yn-1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2- yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl) Carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (015)
  • Example 16 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzimidazol-4-yl)propyl-2-ynyl-1-oxy)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent -2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooctane-5 -yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)
  • Synthesis step 1 3-(3-methyl-2-oxo-4-(3-(piperidin-4-oxy)prop-1-yn-1-yl)-2,3-dihydro-1H -Synthesis of benzimidazol-1-yl)piperidine-2,6-dione (intermediate 16)
  • Example 17 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzimidazol-5-yl)butyl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)- 3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[ b]Thien-5-yl)difluoromethyl)phosphoric acid (017)
  • Example 18 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan-3-yne- 1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2- Difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl )Phosphoric acid(018)
  • Synthesis step 1 Synthesis of 5-((diethoxyphosphoryl)carbonyl)benzo[b]thiophene-2-carboxylic acid (intermediate 18)
  • the first step the compound of (2-acetylbenzo[b]thiophene-5-carbonyl)phosphonate diethyl ester and benzyl-L1-oxanide (18-1)
  • Synthesis step 1 Synthesis of 5-(diethoxyphosphate)carbonyl)-1H-indole-2-carboxylic acid (intermediate 19)
  • intermediate 19 For the synthesis of intermediate 19, refer to the synthetic route and method of intermediate 02, replace 5-bromobenzothiophene-2-carboxylic acid in the first step with 5-bromoindole-2-carboxylic acid, and replace 5-bromoindole-2-carboxylic acid in the fourth step.
  • the diethyl bromodifluoromethylphosphonate was replaced with diethyl phosphite and the adduct of carbon monoxide with tris(dibenzylideneacetone)dipalladium-chloroform was synthesized to obtain intermediate 19.
  • LC-MS: (ESI) [M+H] + 326.1.
  • Example 20 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan-3-yne- 1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2- Difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1-methyl-1H-indole -5-carbonyl)phosphate(020)
  • Synthesis step 1 Synthesis of 5-(diethoxyphosphate)carbonyl)-1H-indole-2-carboxylic acid (intermediate 20)
  • Example 21 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S)-3-(2-chloro-4-(dimethyl) Phosphoryl)phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan- 3-yn-1-yl)piperidin-1-yl)-1-oxopropan-2-yl)ammonium (yl)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (021)
  • Example 22 (2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S)-3-(4-(dimethylphosphoryl))benzene base)-1-(4-(4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)but-3-yn-1-yl) Piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoroethyl )-6-Oxodecahydropyrro[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid (022 )
  • Example 23 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)but-3-yn-1-yl )piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoroethyl) base)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoro Methyl)phosphate(023)
  • Example 24 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-((3-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)prop-2-ynyl-1 -yl)oxy)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2, 2-Difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophene-5 -Difluoromethyl)phosphoric acid (024)
  • Example 25 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-((2S)-3-(4-(dimethylphosphoryl))benzene base)-1-(4-(4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)but-3-yn-1-yl) Piperazin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoroethyl) )-6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl base) phosphoric acid (025)
  • Example 26 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(S)-3-(4-(dimethylphosphoryl))benzyl )Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -2-Oxo-2,3-dihydro-1H-benzimidazol-5-yl)heptanoyl-6-oxodecahydropyrrolo[1,2-a][1,5]diazacycle Oct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (026)
  • Step one 3-benzyl 8-methyl(5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1 ,5]Diazepine-3,8(4H)-dicarboxylate (24-1)
  • Step 2 (5S,8S,10aR)-3-((benzyloxy)carbonyl)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazoxide-8-carboxylic acid (intermediate 024)
  • Step 1 7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole- 5-yl)hept-6-ynoic acid (25-1)
  • Step 2 7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole- 5-yl)heptanoic acid (intermediate 25)
  • Step 1 4-nitrophenyl 5-((diethoxyphosphate)difluoromethyl)benzo[b]thiophene-2-carboxylate (26-1)
  • Synthesis step 3 tert-butyl ((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino)-1,5 -Dioxopent-2-yl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazolin-5-yl)carboxylate (026-3 )
  • Synthesis step 4 tert-butyl ((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino)-1,5 -Dioxopent Alk-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-di Hydrogen-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazolin-5-yl)carboxylate (026-4)
  • Synthesis step 5 2S-2-(5S, 8S, 10aR)-5-amino-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzimidazol-5-ylheptanoyl)-6-oxodecylhydropyrrolo[1,2-a][1,5]diazozine-8- Carboxamido)-N1-(4-(dimethylphosphoryl)benzyl)glutaramide (026-5)
  • Synthesis step 6 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo -2,3-Dihydro-1H-benzimidazol-5-yl)heptanoyl-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl) Carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (026)
  • Example 27 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzimidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1 ,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (027)
  • Steps 2 to 3 4-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole- 5-yl)ethyl)cyclohexane-1-carboxylic acid (Intermediate 27)
  • Example 28 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-((1-(2,6-dioxopiperidin-3-yl))-3-methyl- 2-Oxo-2,3-dihydro-1H-benzimidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1,2-a][1, 5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (028)
  • Synthesis step 1 2-(4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo Synthesis of imidazol-5-yl)methyl)cyclohexyl)acetic acid (intermediate 28)
  • 28-1 (9.80 g, 46.60 mmol, 1.0 eq.) was dissolved in EA (100 mL). 10% Pd/C (3.00g, 0.3m/m) was added to the mixture. Under hydrogen protection, the mixture was stirred at 25°C for 16 h. The sample was taken for NMR detection and the reaction was completed. The reaction solution was filtered, and the residue was concentrated under reduced pressure to obtain 28-2.
  • LC-MS: (ESI) [M+H] + 213.1.
  • Step 4 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5 -Methylene)cyclohexyl)tert-butyl acetate (28-4)
  • Step 5 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5 -Methyl)cyclohexyl)tert-butyl acetate (28-5)
  • Step 6 2-(4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo Imidazol-5-yl)methyl)cyclohexyl)acetic acid (Intermediate 28)
  • Example 29 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline- 4-yl)octyl-7-ynyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[ b]Thien-5-yl)difluoromethyl)phosphoric acid (029)
  • Synthesis step 1 Synthesis of 8-(1-(2,6-dioxopiperidin-3-yl)-2-oxoindolin-7-yl)oct-7-ynic acid (intermediate 29)
  • Example 30 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(8-(6-(2,6-dioxopiperidin-3-yl)-octyl-7-ynyl)- 6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl) Phosphoric acid (030)
  • Synthesis step 1 Synthesis of 8-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)oct-7-ynic acid (intermediate 30)
  • Step 2 8-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)oct-7-ynic acid (Intermediate 30)
  • Example 31 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)--3-(1-(7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoiso Indolin-4-yl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-6-oxodecahydropyrrolo[1,2-a][1, 5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (031)
  • Step 3 3-(4-(2-(4-hydroxypiperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-1-oxoisoindoline-2 -yl)piperidine-2,6-dione (31-3)
  • Step 4 1-(7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)-7-azaspiro[3.5]non- 2-yl)piperidin-4-yl 4-methylbenzenesulfonate (Intermediate 31)
  • Example 32 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)--3-(7-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoiso Indolin-4-yl)-7-azaspiro[3.5]nonan-2-yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooctane -5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (032)
  • Step 2 3-(4-(3-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)propyl-1-ynyl-1-yl)-1-oxoiso Indolin-2-yl)piperidine-2,6-dione(32-2)
  • Step 3 3-(4-(3-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)propyl)-1-oxoisoindolin-2-yl)piper Dipyridine-2,6-dione(32-3)
  • Step 4 7-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)propyl)-7-azaspiro[3.5 ]Non-2-yl 4-methylbenzenesulfonate (Intermediate 32)
  • Example 33 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline- 4-yl)octyl-7-ynyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole Indo-5-yl)difluoromethyl)phosphoric acid (033)
  • Synthesis step 1 Synthesis of (difluoro(2-((4-nitrophenoxy)carbonyl)-1H-indol-5-yl)methyl)phosphoric acid (intermediate 33)
  • Example 34 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylbenzene yl)octyl-7-ynyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b] Thiophen-5-yl)difluoromethyl)phosphoric acid (034)
  • Synthesis step 1 Synthesis of 8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)-octan-7-ynic acid (intermediate 34)
  • the first step 1-(4-bromo-2-methylphenyl)dihydropyrimidine-2,4(1H,3H(-dione(34-1)
  • Step 1 8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methoxyphenyl)-octan-7-ynic acid (Intermediate 34)
  • Example 35 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)octyl- 7-Alkynyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl )Difluoromethyl)phosphoric acid (035)
  • Synthesis step 1 Synthesis of 8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)-octan-7-ynic acid (intermediate 35)
  • Example 36 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((S)-3-(4-(dimethylphosphoryl))benzene base)-1-(4-(4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)but-3-yn-1-yl)piperazine-1 -yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid ( 036)
  • Synthesis step 1 Synthesis of 8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)-octan-7-ynic acid (intermediate 36)
  • Example 37 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((S)-3-(4-(dimethylphosphoryl))benzene base)-1-(4-(4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)but-3-yn-1-yl)piperidine-1 -yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid (037)
  • Synthesis step 1 Synthesis of 8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)-octan-7-ynic acid (intermediate 37)
  • Example 38 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((S)-3-(4-(dimethylphosphoryl))benzene base)-1-(4-(4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3methylphenyl)but-3-yn-1-yl) Piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoroethyl) )-6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid (038 )
  • Synthesis step 1 Synthesis of 8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)-octan-7-ynic acid (intermediate 34)
  • Example 39 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl )octyl-7-ynyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophene -5-yl)difluoromethyl)phosphoric acid (039)
  • Synthesis step 1 Synthesis of 8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-octan-7-ynic acid (intermediate 39)
  • Example 40 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methoxy Phenyl)octyl-7-ynyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b ]Thien-5-yl)difluoromethyl)phosphoric acid (040)
  • Example 41 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(8-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxy Phenyl)octyl-7-ynyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b ]Thien-5-yl)difluoromethyl)phosphoric acid (041)
  • Example 42 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(8-(4-(2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl )octyl-7-ynyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophene -5-yl)difluoromethyl)phosphoric acid (042)
  • Synthesis step 1 Synthesis of 8-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)oct-7-ynic acid (intermediate 42)
  • Example 47 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-2-fluorobenzyl)) Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]di Azepan-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (047)
  • Synthesis step 1 Synthesis of 4-aminomethyl-3-fluorophenyldimethylphosphine oxide (047-3)
  • the first step (4-bromo-2-fluorobenzyl)carbamic acid tert-butyl ester (047-1)
  • Step 2 (4-(Dimethylphosphoryl)-2-fluorobenzyl)carbamic acid tert-butyl ester (047-2)
  • Example 48 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-ylmethyl )Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5] Diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoro Methyl)phosphate(048)
  • Synthesis step 1 Synthesis of (5-(aminomethyl)pyridin-2-yl)dimethylphosphine oxide (048-2)
  • Example 49 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((3-(difluoromethoxy))-4-(dimethyl Phosphoryl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]Diazepine-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (049)
  • Synthesis step 1 Synthesis of 4-(aminomethyl)-2-(difluoromethoxy)phenyl)dimethylphosphine oxide (049-4)
  • Step 4 4-(aminomethyl)-2-(difluoromethoxy)phenyl)dimethylphosphine oxide (049-4)
  • Example 50 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-amino-3-(dimethylphosphoryl)benzyl)) Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]di Azepan-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (050)
  • Synthesis step 1 Synthesis of (2-amino-5-aminomethylphenyl)dimethylphosphine oxide (050-4)
  • the first step 4-aminomethyl-2-bromoaniline (050-1)
  • Example 51 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(4-(dimethylphosphoryl))-3-(trifluoromethyl )benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3 -Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1 ,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (051)
  • Synthesis step 1 Synthesis of (4-(aminomethyl)-2-(trifluoromethyl)phenyl)dimethylphosphine oxide (051-4)
  • Example 52 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(4-(dimethylphosphoryl))-3-(methoxybenzyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl Base-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5 ]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (052)
  • Synthesis step 1 (Synthesis of 4-(aminomethyl)-2-(methoxyphenyl)dimethylphosphine oxide (052-4)
  • Example 53 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(4-(dimethylphosphoryl))-3-(trifluoromethoxy yl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (053)
  • Synthesis step 1 Synthesis of (4-(aminomethyl)-2-(trifluoromethoxy)phenyl)dimethylphosphine oxide (053-4)
  • Example 54 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(4-(dimethylphosphoryl))-3-(difluoromethoxy yl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (054)
  • Steps 1 to 2 (5-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole) -5-yl)pentyl)carbamic acid tert-butyl ester (43-2)
  • Synthesis step 1-3 tert-butyl ((5S,8S,10aR)-8-((S)-5-amino-1-(3-(difluoromethoxy)-4-(dimethylphosphoryl) )benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-6-oxodecanylpyrrolo[1,2-a][1,5]diazacycle Oct-5-yl)carbamate (054-3)
  • Synthesis step 4 tert-butyl ((5S,8S,10aR)-8-((S)-5-amino-1-(3-(difluoromethoxy)-4-(dimethylphosphoryl)benzyl) yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)3-(5-(1-(2,6-dioxopiperidin-3-yl)-3-methyl Base-2-oxoindolin-5-yl)pentyl)carbamoyl)-6-oxodecylhydropyrrolo[1,2-a][1,5]diazepine-5- base) carbamate (054-4)
  • Synthesis step 5-6 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(4-(dimethylphosphoryl))-3-(difluoro Methoxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl) )-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (054)
  • Example 55 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(S)-1-(4-(dimethylphosphoryl))benzyl )Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(5-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pentyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (055)
  • Example 56 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(4-(dimethylphosphoryl))-2-(trifluoromethyl )benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3 -Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1 ,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (056)
  • Synthesis step 1 Synthesis of (4-(aminomethyl)-3-(trifluoromethyl)phenyl)dimethylphosphine oxide (056-4)
  • Example 57 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(4-(dimethylphosphoryl)benzyl)amino)-1, 5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo- 2,3-Dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepine- 5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (057)
  • Example 58 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(-3-(difluoromethoxy)-4-(dimethyl) Phosphoryl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (058)
  • Example 59 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(-3-(trifluoromethoxy))-4-(dimethyl Phosphoryl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo Imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole- 5-carbonyl)phosphate(059)
  • Example 60 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(-3-(difluoromethoxy)-4-(dimethyl) Phosphoryl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pentyl)carbamoyl)-6-oxodecahydropyrrolo[1, 2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (060)
  • Example 61 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(-4-(dimethylphosphoryl)benzyl)amino)-1 ,5-dioxopent-2-yl)carbamoyl)-3-(5-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo -2,3-dihydro-1H-benzo[d]imidazol-5-yl)pentyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]di Azepan-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (061)
  • Example 63 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (063)
  • Steps 1 to 2 4-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d ]imidazol-5-yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (45-2)
  • Step 3 4-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5- Ethyl)piperidine-1-carboxylic acid (Intermediate 45)
  • Synthesis step 1 ((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino)-1,5-dioxo Pentyl-2-yl)carbamoyl)-3-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2 ,3-Dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5] Diazacyclin-5-yl)carbamate (063-1)
  • Synthesis step 2-3 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino)) -1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(2-(2,6-dioxopiperidin-3-yl))-3-methyl -2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (063)
  • Example 64 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(2-(1-(2,6-dioxopiperidin-3-yl))-3-methyl Base-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidin-1-yl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid (064)
  • Synthesis step 4 2-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- Benzimidazol-5-yl)ethyl)piperidin-1-yl)acetic acid (064-4)
  • Synthesis step 5-7 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino)) -1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(2-(1-(2,6-dioxopiperidin-3-yl))-3 -Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidin-1-yl)acetyl)-6-oxodecahydropyrrole And[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid (064)
  • Example 65 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-2-(trifluoromethyl yl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidine-3- (yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydro Pyrro[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (065)
  • Example 66 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidine-3) -yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydro Pyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (066)
  • Example 67 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidine-3) -yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydro Pyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (067)
  • Example 68 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((4-((1-(2,6-dioxopiperidine-3- (yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)carbamoyl)-6-oxodecahydro Pyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (068)
  • Synthesis step 1 3-(5-(4-aminocyclohexyl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) Piperidine-2,6-dione (Intermediate 46)
  • Step 4 3-(5-(4-aminocyclohexyl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) Piperidine-2,6-dione (Intermediate 46)
  • Example 69 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2- Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (069)
  • Example 70 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (070)
  • Example 71 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (071)
  • Example 72 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (072)
  • Example 73 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(1-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)propyl)piperidine-4-carbonyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (073)
  • Step 4 1-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[ d]imidazole-5-propyl)piperidine-4-carboxylic acid (Intermediate 47)
  • Example 74 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(4-(1-(2,6-dioxopiperidin-3-yl))-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)butyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (074)
  • Example 75 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-1-yl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (075)
  • Example 76 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-2-(trifluoromethyl yl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidine-3- (yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydro Pyrro[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (076)
  • Example 77 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(4-(1-(2,6-dioxopiperidine-3) -yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)butyl)piperidine-1-carbonyl)-6-oxodeca Hydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (077)
  • Synthesis step 1 (S)-2-((5S,8S,10aR)-5-amino-6-oxodecylhydropyrrolo[1,2-a][1,5]diazopyrimidine-8-methyl Amide)-N1-(3-(difluoromethoxy)-4-(dimethylphosphoryl)benzyl)glutaramide (077-3)
  • Example 78 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidine-3) -yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodeca Hydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (078)
  • Example 79 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidine-3) -yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (079)
  • Example 80 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidine-3) -yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydro Pyrro[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (080)
  • Example 81 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((4-((1-(2,6-dioxopiperidine-3- (yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)carbamoyl)-6-oxodecahydro Pyrro[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (081)
  • Example 82 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2- Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (082)
  • Example 83 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(1-((1-(4-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)- 3-Methylphenyl)piperidin-4-yl)methyl)piperidin-4-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepine -5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (083)
  • Step 3 1-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piper Copyridine-4-carboxylic acid (Intermediate 49)
  • Example 84 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(1-((1-(4-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)- 3-methylphenyl)piperidin-4-yl)methyl)azetidine-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diaza Heterocyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (084)
  • Example 85 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-((2,6-dioxopiperidin-3-yl)-2-oxo-1,2 -Dihydrobenzo[cadmium]indol-6-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)ammonium Formyl)-1H-indole-5-carbonyl)phosphate (085)
  • the first step 3-bromo-2,6-dioxopiperidine-1-carboxylic acid tert-butyl ester (51-1)
  • Steps 4 to 5 7-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl) Heptanoic acid (intermediate 51)
  • Example 86 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-6-oxo-3-(3-(1-(4-(6-oxo-1,6-dihydropyridazine-3- yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)propionyl)decahydropyrro[1,2-a][1,5]diazacyclooct-5-yl) Carbamoyl)-benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (086)
  • Synthesis step 1 3-(1-(4-(6-oxo-1,6-dihydropyridazin-3-yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl) Synthesis of propionic acid (intermediate 52)
  • Step 2 3-(1-(4-(6-oxo-1,6-dihydropyridazin-3-yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl) Propionic acid (intermediate 52)
  • Example 87 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-6-oxo-3-(2-(1-(4-(6-oxo-1,6-dihydropyridazine-3- yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)acetyl)decahydropyrro[1,2-a][1,5]diazacyclooct-5-yl) Carbamoyl)-benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (087)
  • Synthesis step 1 2-(1-(4-(6-oxo-1,6-dihydropyridazin-3-yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl) Synthesis of acetic acid (intermediate 53)
  • Example 88 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-6-oxo-3-(4-(1-(4-(6-oxo-1,6-dihydropyridazine-3- yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)butyryl)decahydropyrro[1,2-a][1,5]diazacyclooct-5-yl) Carbamoyl)-benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (088)
  • Example 89 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(5-(dimethylphosphoryl))-2,3-dihydro- 1H-inden-1-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidine-3- methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzene And[d]imidazol-5-yl)heptanoyl-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[ b]Thien-5-yl)difluoromethyl)phosphoric acid (089)
  • Synthesis step 1 Synthesis of 4-aminomethyl-3-fluorophenyldimethylphosphine oxide (089-3)
  • Example 90 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(5-(dimethylphosphoryl))-2,3-dihydro- 1H-inden-1-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidine-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (090)
  • Example 91 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(5-(dimethylphosphoryl))-2,3-dihydro- 1H-inden-1-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)butyl)piperidine-1-carbonyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (091)
  • Synthesis step 1 (2S)-2-(5S,8S,10aR)-5-amino-6-oxodecylhydropyrrolo[1,2-a][1,5]diazopyrimidine-8-carboxamide base)-N1-(5-dimethylphosphoryl)-2,3-dihydro-1H-inden-1-yl)glutaramide (091-3)
  • Example 92 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(6-(dimethylphosphoryl)pyridin-3-yl)methyl) )Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl-6-oxodecahydropyrrolo[1,2-a][1,5]di Azepan-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (092)
  • Example 93 ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((6-(dimethylphosphoryl))pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3- Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl-6-oxodecahydropyrrolo[1,2-a][1,5 ]Diazepine-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (093)
  • Example 94 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(((6-(dimethylphosphoryl))pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (094)
  • Synthesis step 1 (S)-2-(5S,8S,10aR)-5-amino-6-oxodecylhydropyrrolo[1,2-a][1,5]diazoxide-8-carboxamide base)-N1-(5-dimethylphosphoryl)pyridine-3-methyl)glutaramide (094-3)
  • Example 95 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl)pyridin-3-yl)methyl) (base)amino)-1,5- Dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo -2,3-Dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1 ,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (095)
  • Example 96 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1 ,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (096)
  • Example 97 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((5-(1-(2,6-dioxopiperidin-3-yl)-3- Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pentyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (097)
  • Example 98 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(((6-(dimethylphosphoryl))pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (098)
  • Example 99 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (099)
  • Example 100 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl)pyridin-3-yl))methyl (base)amino)-1,5- Dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo -2,3-Dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1,2-a][1,5 ]Diazepine-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (100)
  • Example 101 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((5-(1-(2,6-dioxopiperidin-3-yl)-3- Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pentyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (101)
  • Intermediate 27 was separated by SFC to obtain two cis-trans isomers, namely intermediate 55 and intermediate 56.
  • Intermediate 55LC-MS: (ESI) [M+H] + 414.2.
  • Intermediate 56LC-MS: (ESI) [M+H] + 414.2.
  • Example 102 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (102)
  • Example 103 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (103)
  • Example 104 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (104)
  • Example 105 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (105)
  • Example 106 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (106)
  • Example 107 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (107)
  • Example 108 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid ( 108)
  • Example 109 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid ( 109)
  • Example 110 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((3-(difluoromethoxy))-4-(dimethyl Phosphoryl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-di Oxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl )-6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphoric acid (110)
  • Example 111 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((3-(difluoromethoxy))-4-(dimethyl Phosphoryl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-di Oxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl )-6-Oxodecahydropyrro[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (111)
  • Example 112 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((3-(difluoromethoxy))-4-(dimethyl Phosphoryl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-di Oxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl )-6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl base) phosphate(112)
  • Example 113 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((3-(difluoromethoxy))-4-(dimethyl Phosphoryl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-di Oxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl )-6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl base) phosphoric acid (113)
  • Example 114 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (114)
  • Example 115 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (115)
  • Example 116 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (116)
  • Example 117 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (117)
  • Example 118 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-ylmethyl )Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (118)
  • Example 119 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-ylmethyl )Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (119)
  • Example 120 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-ylmethyl )Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (120)
  • Example 121 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-ylmethyl )Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (121)
  • Example 122 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6- Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl) -6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (122)
  • Example 123 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6- Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl) -6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (123)
  • Example 124 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6- Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl) -6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl )Phosphoric acid (124)
  • Example 125 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6- Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl) -6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl )Phosphoric acid (125)
  • Example 126 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (126)
  • the first step 4-(diethylphosphoryl)benzyl)carbamic acid tert-butyl ester (126-1)
  • Example 127 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (127)
  • Example 128 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)-1-fluorocyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1 ,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (128)
  • Synthesis step 1 4-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5- Synthesis of ethyl)-1-fluorocyclohexane-1-carboxylic acid (intermediate 59)
  • Step 1 4-(((tert-butyldimethylsilyl)oxy)methyl)-1-fluorocyclohexane-1-carboxylic acid (59-1)
  • Step 2 4-(((tert-butyldimethylsilyl)oxy)methyl)-1-fluorocyclohexane-1-carboxylic acid tert-butyl ester (59-2)
  • Step 3 1-Fluoro-4-(hydroxymethyl)cyclohexane-1-carboxylic acid tert-butyl ester (59-3)
  • Step 4 1-Fluoro-4-formylcyclohexane-1-carboxylic acid tert-butyl ester (59-4)
  • Step 5 4-ethynyl-1-fluorocyclohexane-1-carboxylic acid tert-butyl ester (59-5)
  • Step 8 4-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5- Ethyl)-1-fluorocyclohexane-1-carboxylic acid (Intermediate 59)
  • Example 129 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)-1-fluorocyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1 ,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (129)
  • Example 130 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (130)
  • Synthesis step 1 (4-(aminomethyl)phenyl)diisopropylphosphine oxide (130-2)
  • Example 131 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (131)
  • Example 132 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)-1-fluorocyclohexane-1-carbonyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (132)
  • Example 133 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)-1-fluorocyclohexane-1-carbonyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (133)
  • Example 134 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(4-(1-(2,6-dioxopiperidin-3-yl))-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)butyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (134)
  • Example 135 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(4-(1-(2,6-dioxopiperidin-3-yl))-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)butyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (135)
  • Example 136 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)bicyclo[2.2.2]octane-1-carbonyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (136)
  • Step 1 1-(tert-butyl)4-methylbicyclo[2.2.2]octane-1,4-dicarboxylate (60-1)
  • Step 2 4-(tert-butoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (60-2)
  • Step 3 4-(hydroxymethyl)bicyclo[2.2.2]octane-1-carboxylic acid tert-butyl ester (60-3)
  • Steps 4 to 8 4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzene And[d]imidazol-5-yl)ethyl)bicyclo[2.2.2]octane-1-carboxylic acid (Intermediate 60)
  • Example 137 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)bicyclo[2.2.2]octane-1-carbonyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (137)
  • Example 138 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)butyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (138)
  • Example 139 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)butyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (139)
  • Example 140 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)bicyclo[2.2.2]octane-1-carbonyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (140)
  • Example 141 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)bicyclo[2.2.2]octane-1-carbonyl)-6-oxo Substituted decahydropyrro[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (141 )
  • Example 142 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (142)
  • Example 143 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (143)
  • Example 144 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclin-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (144)
  • Example 145 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (145)
  • Example 146 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (146)
  • Example 147 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (147)
  • Example 148 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazacyclin-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (148)
  • Example 149 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (149)
  • Example 150 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl))pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1 ,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (150)
  • Synthesis step 1 (5-(aminomethyl)pyridin-2-yl)diethylphosphine oxide (150-2)
  • Example 151 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl)pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1 ,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (151)
  • Example 152 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl))pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (152)
  • Example 153 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl)pyridin-3-yl)methyl) (base)amino)-1,5- Dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo -2,3-Dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1 ,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (153)
  • Example 154 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diisopropylphosphoryl)pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (154)
  • Synthesis step 1 (5-(aminomethyl)pyridin-2-yl)diisopropylphosphine oxide (154-2)
  • Example 155 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diisopropylphosphoryl)pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (155)
  • Example 156 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diisopropylphosphoryl)pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrole And[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (156)
  • Example 157 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diisopropylphosphoryl)pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrole And[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (157)
  • Example 158 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino)amino)-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (158)
  • Example 159 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (159)
  • Example 160 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (160)
  • Example 161 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (161)
  • Example 162 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (162)
  • Example 163 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (163)
  • Example 164 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (164)
  • Example 165 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (165)
  • Example 166 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperidin-3-yl) )-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclin-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (166)
  • Example 167 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperidin-3-yl) )-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (167)
  • Example 168 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperidin-3-yl) )-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (168)
  • Example 169 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperidin-3-yl) )-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (169)
  • Example 170 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrole And[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (170)
  • Example 171 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrole And[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (171)
  • Example 172 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrole And[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (172)
  • Example 173 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrole And[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (173)
  • Example 174 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperyl) (ridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (174)
  • Example 175 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl)pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperyl) (ridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (175)
  • Example 176 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperyl) (ridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxo Substituted decahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (176 )
  • Example 177 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperyl) (ridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxo Substituted decahydropyrro[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (177 )
  • Example 178 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl))pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-(4-(2-(1-(2,6-dioxopiperyl) (ridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6 -Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (178)
  • Example 179 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl)pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-(4-(2-(1-(2,6-dioxopiperyl) (ridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6 -Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (179)
  • Example 180 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl))pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-(4-(2-(1-(2,6-dioxopiperyl) (ridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6 -Oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (180)
  • Example 181 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl)pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-(4-(2-(1-(2,6-dioxopiperyl) (ridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6 -Oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (181)
  • Example 182 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diisopropylphosphoryl)pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxo) Piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (182)
  • Example 183 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diisopropylphosphoryl)pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxo) Piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (183)
  • Example 184 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diisopropylphosphoryl)pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxo) Piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid ( 184)
  • Example 185 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(((6-(diisopropylphosphoryl))pyridin-3-yl )methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxo Piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6 -Oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl) Carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (185)
  • Example 186 ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diisopropylphosphoryl)pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-(4-(2-(1-(2,6-dioxo) Piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)- 6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (186)
  • Example 187 (2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(((6-(diisopropylphosphoryl)pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-(4-(2-(1-(2,6-dioxo Piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)- 6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (187)
  • the tumor cell seeding plate density is 800,000-1 million/well
  • the PBMC seeding plate is 1.3 million/well
  • the cell suspension volume is 2mL/well
  • 12-well plate is seeded based on specific tumor cells.
  • Collect suspended cells Collect the cell suspension into a 2mL centrifuge tube, centrifuge at 1500rpm for 10min, discard the supernatant, add 1mL of PBS and pipet gently, transfer to a 1.5mL sterile centrifuge tube, centrifuge at 1500rpm for 10min, discard the supernatant , try to absorb the liquid as much as possible, and store at -20°C (storage for one week) or -80°C (storage for one month) for later use.
  • DC 50 calculation Use ImageJ to quantify the signal intensity of the corresponding band of STAT3/1, and compare it with the DMSO control group to calculate the protein degradation rate at the corresponding concentration. Draw a degradation curve based on the protein content at different concentrations of the compound to be tested, and calculate DC 50 .
  • the anti-tumor activity of the test compound is detected by detecting the inhibitory effect of the test compound on the cell proliferation of MOLM16 or SU-DHL-1.
  • the cell culture medium is RPMI-1640 medium + 10% fetal calf serum.
  • Different concentrations of test compound solutions 1000nM, 4-fold dilution, 8 concentration gradients
  • After incubation for 96 hours at 37°C, 5% CO2 add 20 ⁇ L MTS to each well.
  • 25 ⁇ L of 10% SDS was added to each well to terminate the reaction.
  • IC50 was calculated using GraphPad Prism 5.0.
  • Table 3 The inhibitory activity of compounds of the present invention on MOLM16 cell proliferation A:IC 50 ⁇ 10nM B:10nM ⁇ IC 50 ⁇ 50nM C:50nM ⁇ IC 50
  • Example 190 Anti-tumor efficacy in vivo
  • SU-DHL-1 cell line 10 million cells/mouse were inoculated into the right armpit of NSG mice. After the tumors grew to 80mm3 , the drugs were administered in groups. Mice in each group were given a corresponding dose of the compound to be tested. The dosage of each compound to be tested was as shown in the table below. The mice were administered once a week by intravenous injection (vehicle: 100% physiological saline). Tumor volume was measured on D1/D4 every week, and the tumor growth curve was drawn based on the measured volume. By comparing the tumor volume with the blank group, the tumor was peeled off and weighed, and the tumor inhibition coefficient was calculated.
  • a is the long diameter of the tumor
  • b is the short diameter of the tumor
  • TGI% (1- RTV of administration group/ RTV of blank group)*100%
  • mice Precisely weigh the compound to be tested and prepare a solution of corresponding concentration with physiological saline.
  • Male ICR mice were injected into the tail vein with a corresponding concentration of test compound solution at a volume of 10 mL/kg. After intravenous administration, 3 mice were taken at each time point at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h, and blood was collected through the orbital vein.
  • the collected blood samples were collected in EP tubes containing EDTA anticoagulation, placed on ice, and centrifuged to separate plasma within 1 hour (centrifugation conditions: 5000 rpm, 10 minutes, 2-8°C). Plasma samples were stored in a -80°C refrigerator before analysis.
  • DNAUC represents the ratio of the area under the drug curve (AUC) to the corresponding dose mpk.

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Abstract

La présente invention concerne un agent de dégradation de protéine STAT peptidomimétique, une composition et une utilisation associées. L'invention concerne une structure représentée par la formule générale (I), ou un stéréoisomère ou un mélange stéréoisomère ou un sel pharmaceutiquement acceptable de celle-ci, son procédé de préparation, et son utilisation en tant qu'agent de dégradation de protéine STAT. L'inventeur de la présente invention a confirmé par des expériences que le composé selon la présente invention peut dégrader un facteur de transcription STAT3. Le composé selon la présente invention a une activité inhibitrice de prolifération évidente sur les cellules tumorales MOLM16 et SU-DHL-1. Le composé selon la présente invention a de bonnes propriétés pharmacocinétiques. De plus, le composé selon la présente invention a une efficacité antitumorale remarquable in vivo.
PCT/CN2023/095625 2022-05-25 2023-05-22 Agent de dégradation de protéine stat peptidomimétique, composition et utilisation associées WO2023226950A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102317290A (zh) * 2008-12-08 2012-01-11 密执安大学评议会 Stat3抑制剂及使用stat3抑制剂的治疗方法
WO2020205467A1 (fr) * 2019-03-29 2020-10-08 The Regents Of The University Of Michigan Agents de dégradation de protéines stat3
WO2021195481A1 (fr) * 2020-03-26 2021-09-30 The Regents Of The University Of Michigan Agents de dégradation de protéine stat à petites molécules
CN114269763A (zh) * 2019-03-26 2022-04-01 美国密歇根州立大学试剂中心 Stat3的小分子降解剂

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102317290A (zh) * 2008-12-08 2012-01-11 密执安大学评议会 Stat3抑制剂及使用stat3抑制剂的治疗方法
CN114269763A (zh) * 2019-03-26 2022-04-01 美国密歇根州立大学试剂中心 Stat3的小分子降解剂
WO2020205467A1 (fr) * 2019-03-29 2020-10-08 The Regents Of The University Of Michigan Agents de dégradation de protéines stat3
WO2021195481A1 (fr) * 2020-03-26 2021-09-30 The Regents Of The University Of Michigan Agents de dégradation de protéine stat à petites molécules

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HAIBIN ZHOU, LONGCHUAN BAI, RENQI XU, YUJUN ZHAO, JIANYONG CHEN, DONNA MCEACHERN, KRISHNAPRIYA CHINNASWAMY, BO WEN, LIPENG DAI, PR: "Structure-Based Discovery of SD-36 as a Potent, Selective, and Efficacious PROTAC Degrader of STAT3 Protein", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 62, no. 24, 26 December 2019 (2019-12-26), US , pages 11280 - 11300, XP055701449, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.9b01530 *

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