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WO2025026218A1 - Composé arylamine ayant un effet de dégradation de protéine - Google Patents

Composé arylamine ayant un effet de dégradation de protéine Download PDF

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Publication number
WO2025026218A1
WO2025026218A1 PCT/CN2024/107819 CN2024107819W WO2025026218A1 WO 2025026218 A1 WO2025026218 A1 WO 2025026218A1 CN 2024107819 W CN2024107819 W CN 2024107819W WO 2025026218 A1 WO2025026218 A1 WO 2025026218A1
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Prior art keywords
ring
mmol
membered
alkyl
halogen
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English (en)
Chinese (zh)
Inventor
张智敏
陈敏
常玉杰
郑永勇
翟文强
刘东舟
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Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
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Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present disclosure relates to the field of chemical drugs, and in particular to a compound capable of regulating or degrading GSPT1 and uses thereof.
  • the MYC gene is one of the important proto-oncogenes. As a transcription factor, it regulates the expression of downstream target genes, thereby regulating various biological processes such as cell proliferation, differentiation, metabolism and apoptosis. About 15% of the genes in the human genome are transcriptionally regulated by MYC. More than 70% of tumors have MYC mutations or changes in expression, and at least one-third of cancer deaths are attributed to MYC activation.
  • the MYC protein is difficult to target due to its disordered structure and nuclear localization. It is a recognized difficult-to-drug target, and no drugs targeting the MYC target have been approved for marketing. Therefore, there is a high unmet clinical need for the treatment of MYC-driven tumors.
  • GSPT1 encodes eukaryotic peptide chain release factor 3 (eRF3), a translation termination factor that mediates protein translation and mRNA degradation, thereby regulating downstream gene expression.
  • eRF3 eukaryotic peptide chain release factor 3
  • GSPT1 is involved in a variety of biological processes, including regulating cell proliferation, migration, growth cycle and apoptosis. Recent studies have shown that GSPT1 is closely related to the occurrence and progression of a variety of common malignant tumors, especially MYC-driven tumors. GSPT1 high expression and MYC high expression tumor types highly overlap, and the expression levels of the two are positively correlated in most tumors. In vivo and in vitro studies have shown that GSPT1 degradation affects protein synthesis and interferes with the expression of MYC and its downstream target genes. In addition, in multiple PDX models with high MYC expression, GSPT1 degradation can significantly inhibit tumor growth, suggesting that GSPT1 degradation has a potential therapeutic effect on MYC-driven
  • the present disclosure provides novel GSPT1 protein regulators.
  • the novel GSPT1 regulators disclosed herein have high affinity and are capable of degrading GSPT1, and therefore have the potential to prevent and treat diseases, disorders or conditions associated with GSPT1.
  • the novel GSPT1 regulators disclosed herein also have improved pharmacokinetic properties (e.g., improved bioavailability, improved metabolic stability, suitable half-life and duration of action) and improved safety (lower toxicity (e.g., reduced cardiac toxicity) and/or fewer side effects), less prone to drug resistance and other more excellent properties.
  • the present disclosure provides a compound of formula (I') as defined below, or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from a 6-10 membered aryl ring, a 5-10 membered heteroaryl ring, a 3-11 membered carbocyclic ring and a 4-11 membered heterocyclic ring;
  • X is selected from N and CR a ;
  • W is selected from -NRa- , -CRaRb- and -O-;
  • L 0 is selected from a single bond, -NR a -, -CR a R b - and -O-;
  • L 1 is selected from a single bond, -NR a -, -CR a R b -, -CR a R b -CR a R b -, -CR a R b -O- and -O-;
  • L2 is selected from a single bond, -NR a -, -CR a R b - and -O-;
  • Ra and Rb are independently selected from hydrogen, amino, halogen, oxo, cyano, C1-3 alkyl and C3-4 cycloalkyl, wherein the C1-3 alkyl and C3-4 cycloalkyl may be optionally substituted 1-3 times by halogen;
  • R 1 is independently selected from halogen, hydroxy, NR a R b , cyano, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 haloalkyl;
  • R 2 is independently selected from halogen, hydroxy, CN, NR a R b , oxo, C 1-6 alkyl, C 1-6 alkoxy, SO 2 NR a R b , SONR a R b , SO 2 R a and C(O)R a , wherein the C 1-6 alkyl or C 1-6 alkoxy may be optionally substituted 1-3 times by halogen or hydroxy;
  • R c is H or an amino protecting group that can be removed under physiological conditions
  • R d is selected from -SO 2 R a , -SO 2 NR a R b and -P(O)R a R b ;
  • R 3 is selected from hydrogen, C 1-6 alkyl and C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy may be optionally substituted 1-3 times by halogen, and the carbon atoms in the alkyl and alkoxy in R 3 may be optionally replaced by N, O or S atoms under the conditions permitted by valence;
  • R4 is selected from C1-6 alkyl substituted 1-3 times by Rx , and R5 , -( CRaRb ) p - R5 , -C(O) -R5 , C1-6 alkoxy, C2-6 alkenyl and C2-6 alkynyl, wherein R5 , -( CRaRb ) p - R5 , -C(O) -R5 , C1-6 alkoxy, C2-6 alkenyl or C2-6 alkynyl in said R4 may be optionally substituted 1-3 times by Rx , and the carbon atoms in the alkyl, alkoxy, alkenyl and alkynyl in said R4 may be optionally replaced by N, O or S atoms under the condition that the valence permits; or
  • R4 may be connected to a ring member of ring A to form a ring B fused to the ring A, the ring B being a 5-6 membered nitrogen-containing aromatic heterocyclic ring or a 4-6 membered nitrogen-containing heterocyclic ring;
  • R 5 is selected from a 3-10 membered carbocyclic ring, a 4-10 membered heterocyclic ring, a 6-10 membered aryl ring and a 5-10 membered aromatic heterocyclic ring, the ring of R 5 may be a monocyclic ring, a condensed ring, a fused ring, a bridged ring and a spirocyclic ring, and the R 5 may be optionally substituted 1-3 times by R x ;
  • n is selected from 0, 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • p is selected from 1, 2 or 3;
  • R 2 may optionally form a 4-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring with L 0 ;
  • R 2 may optionally form a 4-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring with L 2 ;
  • Ra and/or R in W may independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and/or, under conditions where L1 is not a single bond, Ra and/or R in L1 may independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and/or, under conditions where L1 is not a single bond, Ra and/or R in W and Ra and/or R in L1 may independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring;
  • Ra and/or Rb in L0 can independently form a 3-6-membered carbocyclic ring or a 4-6-membered heterocyclic ring; and/or, under the condition that L2 is not a single bond, Ra and/or Rb in L2 can independently form a 3-6-membered carbocyclic ring or a 4-6-membered heterocyclic ring; and/or, under the condition that both L0 and L2 are not single bonds, Ra and/or Rb in L0 and Ra and/or Rb in L2 can independently form a 3-6-membered carbocyclic ring or a 4-6-membered heterocyclic ring;
  • Rx is independently selected from halogen, hydroxy, oxo, CN, C1-6 alkyl, C1-6 alkoxy, 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl and 6-10 membered aryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl of Rx may be optionally substituted 1-3 times by halogen, cyano, hydroxy, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl or C1-3 haloalkoxy, as valence permits;
  • the conditions are:
  • L1 is selected from a single bond or -CRaRb-
  • W is -CRaRb-
  • L0 and L2 are each a single bond
  • Ring A is phenyl
  • R4 is not -C1-6alkylene - OC1-6alkyl .
  • W and L2 are not simultaneously -NR a -, preferably The moiety is not -CH 2 -NH-C(O)-NH-.
  • L 1 is selected from a single bond, -NR a -, -CR a R b -, -CR a R b -CR a R b -, -CR a R b -O-, and -O-, wherein Ra and R b are each independently selected from hydrogen, halogen, and C 1-3 alkyl.
  • L1 is selected from -CH2- , -NH-, -N( CH3 )-, -CF2- , -CH2 -CH2- , -CH( CH3 )- , -C( CH3 ) 2- , -CHF-, -CH2 -O-, and -O-.
  • W is selected from -NR a -, -CR a R b -, and -O-, wherein Ra and R b are independently selected from hydrogen, halogen, and C 1-3 alkyl.
  • W is selected from -O-, -NH-, -CH 2 -, and -CF 2 -.
  • Ra and Rb of each CRaRb moiety in L1 can optionally form a C3-6 cycloalkyl ring with the C atom to which they are attached.
  • one of Ra and R b of L 1 and one of Ra and R b of W are optionally linked to form a C 3-6 cycloalkyl ring.
  • one of Ra and R b of -CR a R b - and Ra of NR a are optionally linked to form a 4-6 membered azacycloalkyl group.
  • the structural unit Selected from The key indicated by the symbol “*” is connected to section, and keys indicated by the "#" symbol connect to part.
  • the ring A is selected from a 6-10 membered aryl ring (preferably a benzene ring), a 5-10 membered aromatic heteroyl ring (preferably a 5- or 6-membered nitrogen-containing aromatic heteroyl ring), an 8-10 membered bicyclic carbocyclic ring and a 7-10 membered bicyclic heterocyclic ring, wherein one ring of the 8-10 membered bicyclic carbocyclic ring is a benzene ring, and one ring of the 7-10 membered bicyclic heterocyclic ring is a benzene ring or a 5- or 6-membered nitrogen-containing aromatic heterocyclic ring, and the ring A may be optionally substituted m times by R 2 .
  • a 6-10 membered aryl ring preferably a benzene ring
  • a 5-10 membered aromatic heteroyl ring preferably a 5- or 6-membered nitrogen-containing aromatic heteroyl ring
  • the ring A is selected from a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a benzo C 4-6 cycloalkyl ring, a benzo 4-6 membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl C 4-6 cycloalkyl ring, and a 5- or 6-membered heteroaryl 4-6 membered heterocycloalkyl ring, and the ring A may be optionally substituted m times by R 2.
  • the ring A is a benzene ring optionally substituted m times by R 2 .
  • the ring A is selected from The ring A may be optionally substituted m times by R 2. In a further preferred embodiment, the ring A is optionally substituted m times by R 2
  • R c is H or —CR a R b —OC(O)—C 1-4 alkyl, wherein Ra and R b are preferably independently selected from hydrogen and C 1-3 alkyl.
  • R c is H or -CH 2 -OC(O)-C(CH 3 ) 3 .
  • R c is H.
  • Rd is selected from -SO2Ra , -SO2NRaRb and -P (O) RaRb , wherein Ra and Rb are independently selected from hydrogen and C1-3 alkyl, and the C1-3 alkyl is optionally substituted 1 to 3 times by halogen.
  • Rd is selected from -SO 2 C 1-3 alkyl, -SO 2 NHC 1-3 alkyl, -SO 2 N(C 1-3 alkyl) 2 , and -P(O)(C 1-3 alkyl) 2 , wherein the C 1-3 alkyl is optionally substituted 1 to 3 times by -F, -Cl or -Br.
  • Rd is selected from -SO 2 CF 3 , -SO 2 NHCH 3 and -P(O)(CH 3 ) 2 .
  • Rd is
  • Rx is independently selected from halogen, hydroxy, oxo, CN, C1-6 alkyl, C1-6 alkoxy, 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl and 6-10 membered aryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl of Rx may be optionally substituted 1-3 times by halogen, cyano, hydroxy, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl or C1-3 haloalkoxy, as valence permits.
  • Rd is and
  • R 4 is selected from C 1-4 alkyl substituted 1-3 times with R x , and R 5 , -CH 2 -R 5 , C 2-4 alkenyl and C 2-4 alkynyl, wherein R 5 , -CH 2 -R 5 , -C(O)-R 5 , C 2-4 alkenyl and C 2-4 alkynyl in R 4 may be optionally substituted 1-3 times with R x .
  • R 4 is selected from C 1-4 alkyl substituted 1-3 times by halogen or C 1-3 alkoxy, and C 2-4 alkenyl and C 2-4 alkynyl optionally substituted 1-3 times by halogen or C 1-3 alkoxy.
  • R4 is preferably selected from:
  • R 4 is preferably selected from: R 5 and -CH 2 -R 5 , said R 5 being optionally substituted 1-3 times with R x .
  • R 5 is selected from a 3-10 membered carbocyclic ring, a 4-10 membered heterocyclic group, a phenyl group and a 5 or 6 membered aromatic heterocyclic group, and the ring of R 5 can be a monocyclic ring, a condensed ring, a fused ring, a bridged ring and a spirocyclic ring, and the ring of R 5 can be optionally substituted by R x 1-3 times.
  • R 5 is selected from a 3-10 membered monocyclic or bicyclic fused ring, a bridged ring or a spirocyclic carbocyclic ring, a phenyl group, a 5- or 6-membered aromatic heterocyclic group (preferably a nitrogen-containing heteroaryl group), a 4-10 membered monocyclic or bicyclic fused ring, a bridged ring or a spirocyclic heterocyclic group, and the ring of R 5 may be optionally substituted 1-3 times by R x .
  • R 5 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,
  • the ring of R 5 may be optionally substituted 1-3 times by halogen or C 1-3 alkyl, wherein the C 1-3 alkyl is substituted 1-3 times by halogen.
  • R 5 is selected from
  • R4 is optionally connected to a ring member of the ring A to form a ring B fused to the ring A, and the ring B is a 5-6-membered nitrogen-containing aromatic heterocyclic ring.
  • the 5-6-membered nitrogen-containing aromatic heterocyclic ring is selected from pyrrole, pyrazole, pyridine, pyrimidine, pyrazine or pyridazine, more preferably pyrrole and pyrazole.
  • the ring A is a benzene ring, which forms a ring B with the ring B.
  • the compound of formula (I') has the following formula (I):
  • L1 is selected from a single bond, -NR a -, -CR a R b -, -O-;
  • Ra and Rb are independently selected from hydrogen, amino, halogen, oxo, cyano, C1-3 alkyl and cyclopropyl, wherein the C1-3 alkyl and cyclopropyl may be optionally substituted 1-3 times by halogen;
  • R 2 is independently selected from halogen, hydroxy, NR a R b , oxo, C 1-6 alkyl, C 1-6 alkoxy, SO 2 NR a R b , SONR a R b and C(O)R a , wherein the C 1-6 alkyl and C 1-6 alkoxy may be optionally substituted 1-3 times by halogen or hydroxy;
  • R4 is selected from C1-6 alkyl substituted 1-3 times by Rx , and R5 , -( CRaRb ) p - R5 , -C(O) -R5 , C1-6 alkoxy, C2-6 alkenyl and C2-6 alkynyl, wherein R5 , -( CRaRb ) p - R5 , -C(O) -R5 , C1-6 alkoxy, C2-6 alkenyl or C2-6 alkynyl in said R4 may be optionally substituted 1-3 times by Rx , and the carbon atoms in the alkyl, alkoxy, alkenyl and alkynyl in said R4 may be optionally replaced by N, O or S atoms under the condition that the valence permits; and
  • R 5 is selected from 3-10 membered carbocyclic ring, 4-10 membered heterocyclic ring, 6-10 membered aromatic ring, 5-10 membered aromatic heterocyclic ring, the ring of R 5 can be a monocyclic ring, a condensed ring, a fused ring and a spirocyclic ring, and R 5 can be optionally substituted by R x 1-3 times.
  • Ra and R in W may form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring, under conditions where valence permits.
  • Ra and R in L may form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring, under conditions where L is not a single bond.
  • Ra or R in W may form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring , under conditions where L is not a single bond.
  • Ra or R in W may form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring, under conditions where L is not a single bond.
  • Ra and R in L may form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring, under conditions where L is not a single bond.
  • Ra and R in L may form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring, under conditions where L is not a single bond.
  • Ra or Rb in L0 and Ra or Rb in L2 may form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring.
  • X is selected from N, CH, C( CH3 ), CF, C( CH2F ), C( CHF2 ) and C( CF3 ). In preferred embodiments, X is selected from N and CH. In more preferred embodiments, X is CH.
  • said L 0 is selected from a single bond, -CH 2 -, and -NH-.
  • the L 1 is selected from -CH 2 -, -NH-, -N(CH 3 )-, -CF 2 -, -CHF-, -C(CH 3 ) 2 -, -CH(CH 3 )-, and -O-. In a preferred embodiment, the L 1 is -CH 2 -.
  • L 2 is selected from -CH 2 -, -NH-, -N(CH 3 )-, -CH(CH 3 )-.
  • Ra or Rb in L1 may form a cyclopropyl group with Ra or Rb in W.
  • said L 0 is a single bond.
  • R1 is independently selected from -F, -Cl, -Br, -OH , -CN, -NH2, -CH3 , -CH2CH3 , -OCH3 , -CF3 , -CH2F , -CHF2 , -CH2CF3 , -CH2CH2F , -OCH2CH3 , and -CH2CHF2 .
  • R 1 is independently selected from -F, -Cl and -OCH 3 .
  • the ring A is selected from a 6-10 membered aryl ring or a 5-10 membered aromatic heterocyclic ring, preferably a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring and a pyridazine ring, and the ring A may be optionally substituted m times by R 2.
  • the ring A is a benzene ring optionally substituted m times by R 2 .
  • the ring A is selected from The ring A may be optionally substituted m times by R 2. In a more preferred embodiment, the ring A is optionally substituted m times by R 2
  • R 3 is selected from hydrogen, C 1-3 alkyl and C 1-3 alkoxy, wherein the C 1-3 alkyl or C 1-3 alkoxy may be optionally substituted 1-3 times by -F, -Cl or -Br.
  • R3 is selected from -H, -CH3 , -CF3 , -CH2CH3 , -CH( CH3 ) CH3 , -OCH3, -OCH2CH3 , -CH2CF3 , -CH( CH3 ) CF3 , -C ( CH3 ) 2CF3 , -CH2CHF2 , -CH2CH2F , -CH( CH2F ) 2 , and -CH( CH2F )( CHF2 ) .
  • R 3 is selected from -H, -CH 3 , -CF 3 , -CH 2 CH 3 and -CH 2 CF 3 .
  • n is selected from 0, 1 or 2.
  • m is selected from 0, 1 or 2.
  • p is 1.
  • said R 4 is selected from R 5 and -CH 2 -R 5 , and said R 4 may be optionally substituted 1-3 times by R x .
  • the R 5 is selected from Said R 5 may be optionally substituted 1-3 times by R x .
  • said R 4 is selected from
  • said R 4 is selected from
  • the compound of formula (I') or the compound of formula (I) is a compound of formula (Ii) or (I-ii):
  • the compound of formula (I') or the compound of formula (I) is a compound of formula (II-1) or (II-2):
  • R 1 , n, L 1 , W, L 2 , L 0 , R 2 , R 3 and R 4 are each as defined above,
  • n1 0, 1 or 2;
  • n2 is 0 or 1
  • R 2 ' is halogen or CN
  • X 1 , X 2 and X 3 are each CH or N.
  • R 2 ′ is preferably F, Cl or CN, more preferably F.
  • X 1 , X 2 and X 3 are all CH. In other embodiments, only one of X 1 , X 2 and X 3 is N and the others are CH. In other embodiments, X 1 and X 2 are N and X 3 is CH.
  • X is CH.
  • R 1 is independently selected from halogen and C 1-3 alkoxy, more preferably F, Cl and methoxy.
  • n is 0 or 1.
  • L 1 is -CR a R b -, wherein Ra and R b are independently selected from hydrogen and halogen. In a more preferred embodiment, L 1 is -CH 2 - and -CF 2 -.
  • W is selected from -NH-, -CRaRb- , and -O-, wherein Ra and Rb are independently selected from hydrogen and halogen.
  • W is selected from -O-, -NH- , -CH2- , and -CF2- .
  • W is -CH2- .
  • W is -O-.
  • L2 is selected from a single bond and NH. In some embodiments, L2 is -NH-.
  • L 0 is a single bond.
  • R 2 is independently selected from halogen, hydroxy, CN, C 1-4 alkyl optionally substituted 1-3 times by halogen, and SO 2 R a .
  • R2 is independently selected from -F, -Cl, CN, -CH3 , -CH2CH3 , -C( CH3 ) 3 , -CF3, -CH2F , -CHF2 , -CH2CF3 , -CH2CH2F , and -SO2 -CH3 .
  • R 2 is independently selected from -F, -Cl, CN, -CH 3 , -CH 2 CH 3 , -C(CH 3 ) 3 , -CF 3 and -SO 2 -CH 3 .
  • R 3 is selected from hydrogen and C 1-3 alkyl optionally substituted 1-3 times by -F, -Cl or -Br.
  • R3 is selected from -H, -CH3 , -CH2CH3 , -CH( CH3 ) CH3 , -CF3, -CH2CF3 , -CH( CH3 ) CF3 , -C ( CH3 ) 2CF3 , -CH2CHF2 , -CH2CH2F , -CH ( CH2F ) 2 , and -CH ( CH2F )( CHF2 ), more preferably -H, -CH3 , -CH2CH3 , -CF3 , and -CH2CF3 .
  • R 4 is selected from C 1-4 alkyl substituted 1-3 times by halogen or C 1-3 alkoxy, and R 5 and -CH 2 -R 5 , wherein R 5 is selected from C 3-10 monocyclic or bicyclic fused cycloalkyl, 4-10 membered heterocyclyl and phenyl, and said R 5 may be optionally substituted 1-3 times by halogen or C 1-3 alkyl, wherein said C 1-3 alkyl is substituted 1-3 times by halogen.
  • R 4 is selected from -CH 2 CF 3 , -CH(CH 3 )CF 3 , -CH 2 CF 2 CH 2 OCH 3 ,
  • R4 is optionally linked to a ring to form a ring member fused to the ring Ring B is a 5-6 membered nitrogen-containing aromatic heterocyclic ring.
  • the 5-6 membered nitrogen-containing aromatic heterocyclic ring is selected from pyrrole, pyrazole, pyridine, pyrimidine, pyrazine or pyridazine, preferably pyrrole and pyrazole.
  • the compound of formula (I') or the compound of formula (I) is a compound of formula (II-3), or preferably a compound of formula (II-4):
  • R 1 , R 2 , R 3 and R 4 are each as defined above;
  • n1 is 0 or 1
  • n1 1 or 2.
  • R 1 is halogen or C 1-3 alkoxy, and even more preferably F or methoxy.
  • R 4 is selected from the group consisting of -CH 2 CF 3 , -CH(CH 3 )CF 3 , -CH 2 CF 2 CH 2 OCH 3 ,
  • the compound of formula (I') or the compound of formula (I) is a compound of formula (II-5) or formula (II-6):
  • R 1 , R 3 and Rx are each as defined above;
  • n1 is 0 or 1.
  • R 1 is halogen or C 1-3 alkoxy, further more preferably F or methoxy; and/or
  • R3 is H
  • Rx is halogen, more preferably F.
  • the present disclosure provides a compound of formula (I) as defined below, or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from a 6-10 membered aryl ring, a 5-10 membered heteroaryl ring, a 3-11 membered carbocyclic ring and a 4-11 membered heterocyclic ring;
  • X is selected from N or CR a ;
  • W is selected from the group consisting of -NRa- , -CRaRb- and -O-;
  • L0 is selected from a single bond, -NR a -, -CR a R b - and -O-;
  • L1 is selected from a single bond, -NR a -, -CR a R b - and -O-;
  • L2 is selected from a single bond, -NR a -, -CR a R b - and -O-;
  • Ra and Rb are independently selected from hydrogen, amino, halogen, oxo, cyano, C1-3 alkyl and cyclopropyl, wherein the C1-3 alkyl and cyclopropyl may be optionally substituted 1-3 times by halogen;
  • R 1 is independently selected from halogen, hydroxy, NR a R b , cyano, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 haloalkyl;
  • R 2 is independently selected from halogen, hydroxy, NR a R b , oxo, C 1-6 alkyl, C 1-6 alkoxy, SO 2 NR a R b , SONR a R b and C(O)R a , wherein the C 1-6 alkyl or C 1-6 alkoxy may be optionally substituted 1-3 times by halogen or hydroxy;
  • R 3 is selected from hydrogen, C 1-6 alkyl and C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy may be optionally substituted 1-3 times by halogen, and the carbon atoms in the alkyl and alkoxy in R 3 may be optionally replaced by N, O or S atoms under the conditions permitted by valence;
  • R4 is selected from C1-6 alkyl substituted 1-3 times by Rx , and R5 , -( CRaRb ) p - R5 , -C(O ) -R5 , C1-6 alkoxy, C2-6 alkenyl and C2-6 alkynyl, wherein R5 , -( CRaRb ) p - R5 , -C(O) -R5 , C1-6 alkoxy, C2-6 alkenyl or C2-6 alkynyl in said R4 may be optionally substituted 1-3 times by Rx , and the carbon atoms in the alkyl, alkoxy, alkenyl and alkynyl in said R4 may be optionally replaced by N, O or S atoms under the condition that the valence permits;
  • R 5 is selected from a 3-10 membered carbocyclic ring, a 4-10 membered heterocyclic ring, a 6-10 membered aryl ring, a 5-10 membered aromatic heterocyclic ring, the R 5 ring may be a monocyclic ring, a condensed ring, a fused ring, or a spirocyclic ring, and the R 5 may be optionally substituted 1-3 times by R x ;
  • n is selected from 0, 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • p is selected from 1, 2 or 3;
  • R 2 may optionally form a 4-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring with L 0 ;
  • R 2 may optionally form a 4-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring with L 2 ;
  • Ra and/or R in W may independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and/or, under conditions where L1 is not a single bond, Ra and/or R in L1 may independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and/or, under conditions where L1 is not a single bond, Ra and/or R in W and Ra and/or R in L1 may independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring;
  • Ra and/or Rb in L0 can independently form a 3-6-membered carbocyclic ring or a 4-6-membered heterocyclic ring; and/or under the condition that L2 is not a single bond, Ra and/or Rb in L2 can independently form a 3-6-membered carbocyclic ring or a 4-6-membered heterocyclic ring; and/or, under the condition that both L0 and L2 are not single bonds, Ra and/or Rb in L0 and Ra and/or Rb in L2 can independently form a 3-6-membered carbocyclic ring or a 4-6-membered heterocyclic ring;
  • Rx is independently selected from halogen, hydroxy, oxo, CN, C1-6 alkyl, C1-6 alkoxy, 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl and 6-10 membered aryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl of Rx can be optionally replaced by halogen, cyano, hydroxy, C1-3 alkyl, C1-3 alkoxy, C1-3 halo under the condition that the valence permits. Alkyl or C 1-3 haloalkoxy is substituted 1-3 times.
  • Ring A is selected from a 6-10 membered aryl ring, a 5-10 membered heteroaryl ring, a 3-11 membered carbocyclic ring, and a 4-11 membered heterocyclic ring;
  • X is selected from N or CR a ;
  • W is selected from the group consisting of -NRa- , -CRaRb- and -O-;
  • L0 is selected from a single bond, -NR a -, -CR a R b - and -O-;
  • L1 is selected from a single bond, -NR a -, -CR a R b - and -O-;
  • L2 is selected from a single bond, -NR a -, -CR a R b - and -O-;
  • Ra and Rb are independently selected from hydrogen, amino, halogen, oxo, cyano, C1-3 alkyl and cyclopropyl, wherein the C1-3 alkyl and cyclopropyl may be optionally substituted 1-3 times by halogen;
  • R 1 is independently selected from halogen, hydroxy, NR a R b , cyano, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 haloalkyl;
  • R 2 is independently selected from halogen, hydroxy, NR a R b , oxo, C 1-6 alkyl, C 1-6 alkoxy, SO 2 NR a R b , SONR a R b and C(O)R a , wherein the C 1-6 alkyl and C 1-6 alkoxy may be optionally substituted 1-3 times by halogen or hydroxy;
  • R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy may be optionally substituted 1-3 times by halogen, and the carbon atoms in the alkyl and alkoxy in R 3 may be optionally replaced by N, O or S atoms under the conditions permitted by valence;
  • R 4 is selected from R 5 and -(CR a R b ) p -R 5 ;
  • R 5 is selected from a 3-10 membered carbocyclic ring, a 4-10 membered heterocyclic ring, a 6-10 membered aromatic ring and a 5-10 membered aromatic heterocyclic ring, the R 5 ring may be a monocyclic ring, a condensed ring, a fused ring and a spirocyclic ring, and the R 5 may be optionally substituted by R x 1-3 times;
  • n is selected from 0, 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • p is selected from 1, 2 or 3;
  • Rx is independently selected from halogen, hydroxy, oxo, CN, C1-6 alkyl, C1-6 alkoxy, 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl and 6-10 membered aryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl of Rx may be optionally substituted 1-3 times by halogen, cyano, hydroxy, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl or C1-3 haloalkoxy under conditions permitting by valence.
  • the ring A is selected from a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring and a pyridazine ring, and the ring A may be optionally substituted m times by R 2 .
  • the ring A is selected from The ring A may be optionally substituted m times by R2 .
  • the ring A is selected from The ring A may be optionally substituted m times by R2 .
  • X is selected from N, CH, C(CH 3 ), CF, C(CH 2 F), C(CHF 2 ), and C(CF 3 ).
  • X is selected from N and CH.
  • W is selected from -CH2- , -NH-, and -O-.
  • said L 0 is selected from a single bond, -CH 2 -, -NH-, and -O-.
  • said L 0 is selected from a single bond, -CH 2 -, and -NH-.
  • L 1 is selected from -CH 2 -, -NH-, -N(CH 3 )-, -CF 2 -, -CHF-, -C(CH 3 ) 2 -, -CH(CH 3 )-, and -O-.
  • L 2 is selected from -CH 2 -, -NH-, -N(CH 3 )-, and -CH(CH 3 )-.
  • Ra or Rb in L1 may form a cyclopropyl group with Ra or Rb in W.
  • the R3 is selected from -H , -CN, -CH3 , -CF3 , -CH2CH3 , -CH( CH3 ) CH3 , -OCH3, -OCH2CH3 , -CH2CF3, -CH( CH3)CF3 , -C ( CH3 ) 2CF3 , -CH2CHF2 , -CH2CH2F , -CH ( CH2F ) 2 , and -CH( CH2F )( CHF2 ) .
  • the R 5 is selected from Said R 5 may be optionally substituted 1-3 times by R x .
  • said R 4 is selected from R 5 , -CH 2 -R 5 , and said R 4 may be optionally substituted 1-3 times by R x .
  • the R4 is selected from
  • the R4 is selected from
  • the -CH 2 -R 5 is selected from
  • the R 5 is selected from Said R 5 may be optionally substituted 1-3 times by R x .
  • the R 5 is selected from Said R 5 may be optionally substituted 1-3 times by R x .
  • R1 is independently selected from -F, -Cl, -Br, -OH , -CN, -NH2, -CH3 , -CH2CH3 , -OCH3 , -CF3 , -CH2F , -CHF2 , -CH2CF3 , -CH2CH2F , -OCH2CH3 , and -CH2CHF2 .
  • the present disclosure provides a compound of formula (I) as described above, wherein the compound of formula (I) is a compound of formula (I-i):
  • the present disclosure provides a compound of formula (I) as described above, wherein the compound of formula (I) is a compound of formula (I-ii):
  • the present disclosure provides a compound of formula (I) as described above, wherein the compound of formula (I) is a compound of formula (I-iii):
  • Ring A is selected from benzene or pyridine;
  • W is selected from -NH-, -CH 2 - and -O-;
  • L 0 is selected from a single bond and -CH 2 -;
  • L2 is selected from a single bond, -NH- and -O-;
  • R2 is independently selected from halogen
  • R 4 is selected from R 5 and -CH 2 -R 5 ;
  • R 5 is selected from benzene, pyridine or benzocyclopentane, and said R 5 may be optionally substituted 1-3 times by R x ;
  • n is selected from 0, 1 or 2;
  • n is selected from 0, 1 or 2;
  • Rx is independently selected from halogen and C1-6 alkyl, wherein the alkyl of Rx may be optionally substituted 1 to 3 times by halogen under conditions permitting by chemical valence.
  • the present disclosure encompasses compounds resulting from any combination of the various embodiments.
  • the present disclosure provides a compound selected from the following and a pharmaceutically acceptable salt thereof:
  • alkane means a straight-chain or branched saturated aliphatic hydrocarbon.
  • alkyl means a straight or branched monovalent saturated aliphatic hydrocarbon, which can be regarded as a group obtained by losing 1 hydrogen atom from an alkane.
  • the alkyl group has 1 to 12, such as 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms.
  • C 1-8 alkyl refers to a straight or branched group of 1 to 8 carbon atoms, including "C 1-6 alkyl", “C 2-6 alkyl", “C 2-5 alkyl”, “C 1-4 alkyl", “C 2-4 alkyl” and "C 1-2 alkyl".
  • C 1-6 alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.
  • the alkyl group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents such as halogen (in this case , the group is referred to as "haloalkyl", for example CF3 , C2F5 , CHF2 , CH2F , CH2CF3 , CH2Cl or -CH2CH2CF3 , etc.).
  • C1-4alkyl refers to an alkyl group having 1 to 4 carbon atoms (i.e. , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl or tert-butyl).
  • alkylene refers to a linear or branched divalent saturated aliphatic hydrocarbon.
  • the alkylene group has 1 to 12 carbon atoms, preferably 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, such as methylene, ethylene, propylene or butylene.
  • alkoxy refers to an -O-alkyl group, wherein the alkyl group is as defined above.
  • alkenyl means a linear or branched monovalent aliphatic hydrocarbon group containing one or more double bonds.
  • the alkenyl group has 2-8 carbon atoms (" C2-8 alkenyl"), for example, 2-6 carbon atoms (“ C2-6 alkenyl”) or 2-4 carbon atoms (“ C2-4 alkenyl”).
  • the compounds of the invention may be present in the pure E (ent ought) form, the pure Z (zusammen) form or any mixture thereof.
  • alkynyl means a linear or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds.
  • the alkynyl group has 2, 3, 4, 5, 6, 7 or 8 carbon atoms (" C2-8 alkynyl"), such as ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc.
  • the alkynyl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents.
  • fused means that two or more ring structures share two adjacent atoms with each other.
  • bridge means that two or more ring structures share two non-adjacent atoms with each other.
  • spiro or “spiro-connected” means that two or more ring structures share 1 atom with each other.
  • Carbocycle and “carbocyclyl” mean a monocyclic or polycyclic (such as a bicyclic) system in which all ring members are C atoms, which ring or ring system may be saturated (“cycloalkyl”), partially unsaturated (e.g., having one or more double bonds within the ring, i.e., "cycloalkenyl”), or aromatic (“aryl”).
  • Carbocycles have, for example, 3-12 (suitably 3-11, 3-10, 8-10, 3-8, 3-7, 3-6, 4-6, or 5-6) ring carbon atoms.
  • Carbocycles may be monocyclic or polycyclic, such as fused rings (e.g., “fused cycloalkyl”), bridged rings (e.g., “bridged cycloalkyl”), and spiro rings (e.g., "spirocycloalkyl”).
  • cycloalkyl and cycloalkylene refer to a saturated monocyclic or polycyclic (such as bicyclic) fused hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring such as ).
  • the cycloalkyl and cycloalkylene groups have 3 to 10 carbon atoms, suitably 3-8, for example 3-7, 3-6, 4-6 or 5-6.
  • xy-membered cycloalkyl is used interchangeably with “ Cxy- membered cycloalkyl", for example "3-10-membered cycloalkyl” is used interchangeably with “ C3-10 cycloalkyl”.
  • C4-10 fused cycloalkyl and “ C4-10 fused cycloalkylene” refer to fused rings containing 4 to 10 (e.g. 6-10 or 8-10) ring carbon atoms and formed by two or more rings sharing two adjacent carbon atoms.
  • the cycloalkyl and cycloalkylene groups are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g. methyl or halogen), for example methyl-substituted cyclopropyl.
  • spirocycloalkyl and “spirocycloalkylene” refers to a polycyclic (such as a bicyclic) saturated carbocyclic ring as defined above, wherein any two connected rings share one carbon atom.
  • examples of spirocycloalkyl include "C 7-12 spirocycloalkyl” and "C 7-12 spirocycloalkylene", which means a cyclic structure containing 7 to 12 (e.g., 5-12 or 7-11) carbon atoms and formed by at least two rings sharing one atom.
  • bridged cycloalkyl and “bridged cycloalkylene” refer to polycyclic (such as bicyclic) saturated carbocyclic rings as defined above, in which any two connected rings share two carbon atoms that are not adjacent to each other.
  • C7-10 bridged cycloalkyl and “ C7-10 bridged cycloalkylene” refer to a cyclic structure containing 7 to 12 (e.g., 6-10, 6-9, or 6-8) carbon atoms and formed by two rings that share two atoms that are not adjacent to each other.
  • the heterocyclyl group can be attached to the rest of the molecule via any of the carbon atoms or the nitrogen atom, if present.
  • the 3-10 membered heterocyclic group is a group having 3-10 (e.g., 4-10, 3-8, 3-7, 3-6, 4-6 or 5-6) carbon atoms and heteroatoms in the ring.
  • Examples that can be cited include, but are not limited to, oxirane, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, dioxolyl, pyrrolyl, thiazolin ...
  • pyrrolidinyl pyrrolidonyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, azocanyl, dihydropyrrolyl, dihydroimidazolyl, azooctenyl.
  • heterocycles described above include monocyclic rings, fused rings, bridged rings and spiro rings, i.e., monocyclic heterocycles, bridged heterocycles, spiro heterocycles and fused heterocycles.
  • the connection points of bridged heterocycles, spiro heterocycles and fused heterocycles with other groups can be on any ring in the structure.
  • fused heterocycle refers to a bicyclic heterocycle as defined above, wherein the two rings share two adjacent atoms.
  • Fused heterocycles include, but are not limited to, heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, such as 3-7-membered monoheterocyclyl and 3-7-membered monoheterocyclyl, 3-7-membered monoheterocyclyl and C 3-7 -cycloalkyl, 3-7-membered monoheterocyclyl and C 4-6 monocycloalkyl.
  • the fused heterocycle is 6 to 10 yuan, and more preferably 8-10 yuan.
  • fused heterocycles include, but are not limited to, pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl,
  • fused heterocyclyl also includes heteroaryl-fused heterocyclyl or cycloalkyl, and aryl-fused heterocyclyl, as long as the entire ring system is non-aromatic.
  • fused heterocyclyl includes 5-6 membered monocyclic heteroaryl-fused C 5-6 monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl-fused 5-6 membered monocyclic heterocyclyl, and phenyl-fused 5-6 membered monocyclic heterocyclyl, such as pyrrolotetrahydropyridinyl, pyrazolotetrahydropyridinyl and imidazotetrahydropyridinyl.
  • spiroheterocycle refers to a bicyclic heterocycle as defined above, wherein the two rings share one carbon atom.
  • the spiroheterocycle is 5-10 members, and more preferably 7-10 members.
  • Spiroheterocycles include 4/4, 3/5, 4/5, 4/6, 5/5, or 5/6 monospiroheterocycles.
  • a bridged heterocycle or bridged heterocycle refers to a bicyclic heterocycle as defined above, wherein the two rings share two non-adjacent atoms.
  • One or both rings of the bridged heterocycle may contain one or more double bonds, but neither ring has a completely conjugated ⁇ electron system.
  • the bridged heterocycle is 6 to 9-membered, and more preferably 6-8-membered.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ electron system.
  • C 6-14 aryl means an aromatic group containing 6 to 14 (e.g., 6 to 12, or 6 to 10) carbon atoms, such as phenyl or naphthyl.
  • the aryl group is optionally substituted with 1 or more (e.g., 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.).
  • heteroaryl refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having 5 to 14 ring atoms, e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and 1, 2, 3, 4 or 5 identical or different heteroatoms independently selected from N, O, S and S(O) 2 .
  • One or more ring carbon atoms in the heteroaryl may be replaced by C(O).
  • the heteroaryl may be benzo-fused.
  • 5-6 membered heteroaromatic ring and “5-6 membered heteroaryl” herein can be used interchangeably.
  • the term “5-6 membered heteroaryl” means a monocyclic group consisting of 5 to 6 ring atoms with a conjugated ⁇ electron system, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • the 5-6 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl.
  • halo or halogen group is defined to include F, Cl, Br, or I.
  • substituted means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form stable compounds.
  • a group is described as "optionally substituted by" or “optionally substituted", the group can be: (1) unsubstituted or (2) Substitution. If a carbon of a group is described as optionally substituted with one or more of the substituent lists, then one or more hydrogens on that carbon (to the extent of any hydrogens present) may be replaced, individually and/or together, with independently selected optional substituents. If a nitrogen of a group is described as optionally substituted with one or more of the substituent lists, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with independently selected optional substituents.
  • each substituent is selected independently of the other.
  • each substituent may be the same as or different from another (other) substituent.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D, 2 H), tritium (T, 3 H)); isotopes of carbon (e.g., 11 C, 13 C, and 14 C); isotopes of chlorine (e.g., 36 Cl); isotopes of fluorine (e.g., 18 F); isotopes of iodine (e.g., 123 I and 125 I); isotopes of nitrogen (e.g., 13 N and 15 N); isotopes of oxygen (e.g., 15 O, 17 O, and 18 O); isotopes of phosphorus (e.g., 32 P); and isotopes of sulfur (e.g., 35 S).
  • isotopes of hydrogen e.g., deuterium (D, 2 H), tritium (T, 3 H)
  • Certain isotopically labeled compounds of the invention can be used in drug and/or substrate tissue distribution studies (e.g., analysis).
  • the radioisotopes tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose because they are easily incorporated and easily detected.
  • Substitution with positron emitting isotopes e.g., 11 C, 18 F, 15 O, and 13 N
  • PET positron emission tomography
  • Isotopically labeled compounds of the invention can be prepared by methods similar to those described in the accompanying routes and/or examples and preparations by using appropriate isotopically labeled reagents instead of previously employed non-labeled reagents.
  • Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent can be isotopically substituted, for example, D 2 O, acetone-d 6 , or DMSO-d 6.
  • the isotopically labeled compounds of the invention are deuterated.
  • stereoisomer means an isomer formed due to at least one asymmetric center, which has the same chemical composition but different spatial arrangements of atoms or groups. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, it can produce a racemic mixture, a single enantiomer, a diastereomeric mixture, and a single diastereomer. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structures in rapid equilibrium in different forms.
  • tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of the present application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).
  • Diastereomers refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical methods such as electrophoresis and chromatography.
  • Enantiomers refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.
  • chiral refers to molecules that have the property of non-superimposability of mirror image pairs, whereas the term “achiral” refers to molecules that are superimposable on their mirror image pairs.
  • the compounds of the invention may be prepared in racemic form, or individual enantiomers may be prepared by enantioselective synthesis or by resolution.
  • cis-trans isomers or “geometric isomers” is caused by the inability to rotate freely around double bonds or single bonds of ring-forming carbon atoms.
  • the compounds provided herein include all cis, trans, cis (syn), anti (anti),
  • Z isomers and their corresponding mixtures.
  • solid lines can be used Solid wedge Virtual wedge Depicting chemical bonds of compounds of the invention.
  • the use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.) are included.
  • the use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that There are stereoisomers as shown. When present in a racemic mixture, the real and dashed wedges are used to define relative stereochemistry, rather than absolute stereochemistry.
  • the compounds of the invention are intended to exist as stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof.
  • the compounds of the invention may exhibit more than one type of isomerism, and consist of mixtures thereof, such as racemic mixtures and diastereomeric pairs.
  • compositions of the present invention may exist in free form for treatment, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which, after being administered to a patient in need thereof, can directly or indirectly provide a compound of the present invention or a metabolite or residue thereof. Therefore, when referring to "compounds of the present invention" herein, the above-mentioned various derivative forms of the compounds are also intended to be covered.
  • a wavy line Represents the point of attachment of a substituent to another group.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients making up the formulation and/or the mammal to be treated therewith.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • the substituent When a substituent has a bond that crosses two or more atoms in a ring, the substituent may be bonded to any atom in the ring, e.g. Indicates that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene.
  • the substituent can be bonded through any atom thereof.
  • a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.
  • linking direction is arbitrary, for example,
  • the connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of the reading order from left to right to form Combinations of linkers, substituents, and/or variations thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds to become a group with the corresponding valence.
  • the chemical bonds connecting the site to other groups can be represented by straight solid line bonds Straight dotted key or wavy line express.
  • the compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.
  • the compounds disclosed herein or their pharmaceutically acceptable salts are GSPT1 protein regulators and can degrade GSPT1. Therefore, the compounds disclosed herein can be used to prevent and/or treat diseases or conditions associated with GSPT1.
  • the present disclosure provides use of the compounds described herein or pharmaceutically acceptable salts thereof in the preparation of a medicament as a protein degrading agent.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions of the present disclosure may further comprise one or more additional therapeutically active agents.
  • the GSPT1-associated disease or disorder is a tumor (eg, cancer), including solid tumors and hematological tumors.
  • the present disclosure also provides the use of the above-mentioned compounds and pharmaceutically acceptable salts thereof in the preparation of a medicament for treating and/or preventing cancer/tumor-related diseases or conditions.
  • the cancer/tumor-related diseases or conditions include GSPT1-mediated diseases or conditions and related diseases or conditions.
  • the compounds provided by the present disclosure are GSPT1 modulators and can be used to treat one or more diseases or conditions associated with GSPT1 activity.
  • the present disclosure provides a method for treating GSPT1-mediated diseases or conditions and related diseases or conditions, comprising the step of administering a compound of the present disclosure or a pharmaceutically acceptable salt or composition thereof to a subject in need thereof.
  • GSPT1 -mediated disease or condition refers to any disease or condition in which GSPT1 or a mutant thereof is known to play a role.
  • the compounds provided by the present disclosure can be used for:
  • Inhibiting cancer or “inhibiting tumor cell proliferation” as described in the present disclosure refers to inhibiting the growth, division, maturation or survival of cancer cells, and/or causing the death of cancer cells by cytotoxicity, nutrient depletion or induction of apoptosis, either individually or together with other cancer cells.
  • cancer cells or tissues containing cells whose proliferation is inhibited by the compounds or pharmaceutically acceptable salts or compositions described herein and for which the methods described herein are applicable include, but are not limited to, breast, prostate, brain, blood, bone marrow, liver, pancreas, epidermis, kidney, colon, ovary, lung, testis, vagina, thyroid, parathyroid, pituitary, thymus, conjunctiva, spleen, head and neck, trachea, gallbladder, rectum, salivary glands, adrenal glands, pharynx, esophagus, lymph nodes, muscle, stomach, and heart.
  • the present disclosure also provides a method for treating a disease or condition, comprising administering a therapeutically effective amount of the compound as described above and a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the disease or condition is a GSPT1-mediated disease or condition and related diseases or conditions.
  • the GSPT1-mediated disease or condition is selected from melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, liposarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, esophageal cancer, brain cancer, lymphoma, colon cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilm's tumor.
  • the structure of the compounds disclosed herein can be confirmed by conventional methods known to those skilled in the art. If the disclosure relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction SXRD
  • the cultured single crystal is used to collect diffraction intensity data using a Bruker D8 venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning mode is: After collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.
  • Ref1 The reference compound used in the present disclosure (hereinafter referred to as "Ref1”) has the following structure:
  • the chemical formula is [2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-3-oxo-1H-isoindol-5-yl]methyl-N-[2-fluoro-5-(trifluoromethoxy)phenyl]carbamate, CAS No. 2803881-11-8.
  • the compound was first disclosed in patent application documents WO2022152821A1 and WO2022152822A1, and can be prepared according to the preparation methods described in the above patent applications.
  • Step 1 3-(6-bromo-1-oxoisoindol-2-yl)piperidine-2,6-dione (0.3 g, 0.92 mmol) and ethyl acrylate (0.121 g, 1.21 mmol) were dissolved in anhydrous N,N-dimethylformamide, and then potassium acetate (0.182 g, 1.62 mmol) and palladium acetate (0.021 g, 0.092 mmol) were added, and the mixture was reacted at 100 degrees Celsius for 12 hours.
  • Step 2 Dissolve INT3-1 (150.0 mg, 0.04 mmol) in tetrahydrofuran, add 10% palladium/carbon (15.0 mg), and react at room temperature for 16 hours. After the reaction is completed, filter and concentrate the organic phase to obtain INT3-2, which is directly used in the next step (149.0 mg).
  • Step 3 Dissolve INT3-2 (149.0 mg, 0.04 mmol) in tetrahydrofuran, add 6M hydrochloric acid (20 mL), and react for three hours. After the reaction is completed, concentrate the organic phase to obtain INT3 (110 mg, 79.7%), which is directly used in the next step.
  • Step 1 Dissolve INT4-1 (5 g, 15.68 mmol), 2-(azetidin-3-yl)acetic acid methyl ester triacetate (2.43 g, 18.82 mmol), tris(dibenzylideneacetone)palladium (1.44 g, 1.57 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (900 mg, 1.57 mmol), cesium carbonate (15.3 g, 47.04 mmol) in ultra-dry dioxane (100 mL), react at 90 °C for 2 hours under nitrogen protection.
  • Step 3 Dissolve NT4-3 (1.2 g, 2.26 mmol), palladium hydroxide/carbon (100 mg), and palladium/carbon (100 mg) in dioxane (20 ml), and react at 40°C for 2 hours under nitrogen protection. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain NT4-4 (760 mg, 95.5%).
  • Step 2 Compound C003-1 (300 mg, 1.140 mmol) was dissolved in 8 mL of tetrahydrofuran and 2 mL of methanol, and 1.0 M lithium hydroxide (2 mL) was added dropwise to the reaction solution. The reaction was stirred at room temperature for 3 hours. Water was added to quench the reaction mixture, and the reaction mixture was extracted three times with dichloromethane (25 mL) and discarded. The aqueous phase was adjusted to a weakly acidic pH with 1 M dilute hydrochloric acid, and then extracted three times with ethyl acetate (25 mL). The organic phase was dried with anhydrous sodium sulfate, filtered, and dried to obtain a crude compound C003-2 (1.189 g) which was directly used in the next step. LCMS [M+H] + m/z: 250.0.
  • Step 3 Dissolve the crude compound C003-2 (75 mg, 0.301 mmol) and INT-2 (99 mg, 0.361 mmol) in 5 mL of anhydrous DMSO, and then add DPPA (207 mg, 0.752 mmol) and TEA (37 mg, 0.366 mmol). The reaction was stirred at 120°C overnight. The reaction mixture was extracted with ethyl acetate (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to prepare and purify compound C003 (5.0 mg).
  • Step 2 Compound C004-1 (300 mg, 0.958 mmol) was dissolved in 8 mL of tetrahydrofuran and 2 mL of methanol, and 1.0 M LiOH (2 mL) was added dropwise to the above solution. The reaction was stirred at room temperature for 3 hours. Water was added to quench the reaction, the mixture was extracted with ethyl acetate, the pH of the aqueous phase was adjusted to weak acidity with 1 M dilute hydrochloric acid, and then extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and dried to obtain crude compound C004-2 (280 mg, 97.9%), which was directly used in the next step. LCMS [M+H] + m/z 300.0.
  • Step 3 Dissolve the crude compound C004-2 (140 mg, 0.468 mmol) in 5 mL of anhydrous DMSO, add DPPA (283 mg, 1.029 mmol), triethylamine (57 mg, 0.564 mmol) and INT-2 (154 mg, 0.562 mmol). The reaction solution was stirred at 120°C overnight. The reaction mixture was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was sent for preparation and purification to obtain compound C004 (19 mg). LCMS [M+H] + m/z: 571.4.
  • Step 1 Compound C005-0 (500 mg, 2.1 mmol), BINAP (107 mg, 0.17 mmol), Cs 2 CO 3 (1.4 g, 4.31 mmol), Pd(OAc) 2 (24.2 mg, 0.1 mmol) and 2,6-difluoroaniline (362 mg, 2.7 mmol) were dissolved in 5 mL of dioxane, ventilated three times under nitrogen, and reacted at 100° C. for 16 hours.
  • Step 2 Dissolve compound C005-1 (470 mg, 1.67 mmol) in 5 mL of tetrahydrofuran. Add 2M LiOH (5 mL) at 0°C under nitrogen protection. Stir the reaction at room temperature for 1 hour. After the reaction is completed, add dilute hydrochloric acid in an ice bath to adjust the pH. After the value reached 4, the filter cake was filtered and washed with ice water (20 mL) to obtain compound C005-2 (330 mg, 74%). LCMS [M+H] + m/z: 268.0
  • Step 2 Compound C006-1 (1 g, 3.55 mmol) was dissolved in THF/H2O (10 mL), LiOH (170 mg, 14.23 mmol) was added at 0°C, and stirred overnight. After the reaction was complete, water was added to dilute, and the pH was adjusted to neutral with 4 mmol/L hydrochloric acid. The mixture was extracted with ethyl acetate, dried, and concentrated to obtain compound C006-2 (1 g, yield: 87%). LCMS [M+H] + m/z: 268.0.
  • Step 2 Compound C007-1 (90 mg, 0.34 mmol) was dissolved in 4 mL THF, and 4 N aqueous lithium hydroxide solution (4 ml) was added. The reaction mixture was stirred at room temperature for 6 hours, and the reaction solution was neutralized with 2 N HCl to a pH of 5-6. THF was spin-dried, and the aqueous phase was freeze-dried. The obtained solid was dissolved in DCM/MeOH (10/1, 20 mL), and the inorganic salt was removed by filtration. The organic phase was concentrated to obtain compound C007-2 (70 mg). LCMS: [M+H]+m/z: 251.0.
  • Step 1 C009-0 (500 mg, 2.14 mmol), o-chloroaniline (327 mg, 2.57 mmol), Cs 2 CO 3 (976 mg, 3.0 mmol), BINAP (106 mg, 0.17 mmol), Pd(OAc) 2 (25 mg, 0.10 mmol) were dissolved in anhydrous toluene (10 mL), stirred at 120°C overnight under nitrogen protection, and after the reaction, DCM (20 mL) was added to wash away impurities. The aqueous phase was adjusted to pH 3-4 with dilute hydrochloric acid (1.0 M), extracted with dichloromethane (30 mL), dried, and spin-dried to obtain compound C009-1 (185 mg, 32.5%). LCMS [M+H] + m/z: 266.0.
  • Step 1 Dissolve INT-6 (10 mg, 0.023 mmol), o-fluorobenzaldehyde (6 mg, 0.046 mmol) and a drop of acetic acid in 5 mL of methanol, and add sodium cyanoborohydride (3 mg, 0.046 mmol) under ice bath. The reaction mixture was stirred at 0°C for 1 hour. Saturated sodium bicarbonate solution was added to quench, and ethyl acetate (20 mL) was used for extraction to prepare and purify compound C010 (2.25 mg, 18%). LCMS [M+H] + m/z: 535.5.
  • Step 2 Dissolve compound C011-1 (150 mg, 0.54 mmol) in 20 mL THF/MeOH (3/1), add 5 mL of saturated solution of LiOH. Stir at room temperature for 1 h. Add DCM (20 mL) to wash away impurities, acidify the aqueous phase with dilute hydrochloric acid (1.0 M, 10 mL), extract with DCM (30 mL), and spin dry to obtain the crude product compound C011-2 (110 mg, 77%). LCMS [M+H] + m/z: 264.0.
  • Step 3 Dissolve the crude product compound C011-2 (110 mg,), INT-2 (274 mg, 0.5 mmol), DPPA (206 mg, 0.63 mmol), TEA (0.18 mL, 1.2 mmol) in 30 mL DMSO, and stir the reaction solution at 120°C for 1 hour. Cool the reaction mixture to room temperature, add EA, extract with water, prepare and purify to obtain compound C011 (23.35 mg, 10%). LCMS [M+H] + m/z: 535.2.
  • Step 2 Dissolve compound C012-1 (100 mg, 0.28 mmol) in 2 mL of methanol and 2 mL of tetrahydrofuran, and add 10% Pd/C (100 mg). The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain compound C012-2 (100 mg, 99%).
  • Step 3 Dissolve compound C012-2 (80 mg, 0.2 mmol) in 4 mL of dichloromethane and add trifluoroacetic acid (2 mL). Stir the reaction mixture at room temperature for 0.5 hours. After the reaction is completed, concentrate the reaction solution to obtain compound C012-3 (80 mg, 94%).
  • Step 4 Compound C004-2 (130 mg, 0.44 mmol) was dissolved in 3 mL of toluene and 3 mL of tert-butanol, triethylamine (53 mg, 0.52 mmol) was added at room temperature, DPPA (143 mg, 0.52 mmol) was added after heating to 80°C, and the reaction mixture was stirred at 80°C for 16 hours. After the reaction was completed, it was diluted with water, extracted with ethyl acetate (50 mL x 3), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product compound C012-4 (100 mg).
  • Step 1 C013-4 (2 g, 0.013 mol) and SM (1.75 mg, 0.014 mol) were dissolved in 30 mL of methanol and stirred at room temperature for 30 min. NaBH 3 CN was added at 0°C under N 2 protection, and the reaction was stirred at 25°C for 2 hours. LCMS monitoring showed that the product was generated. The reaction solution was quenched with water, extracted with ethyl acetate three times, and the organic phase was dried with anhydrous sodium sulfate, filtered, and dried to obtain the product compound C013-5. (3g, 89%). LCMS[M+H]+m/z:265.0
  • Step 4 Compound C013-7 (21 mg, 0.06 mmol) and compound C013-3 (20 mg, 0.06 mmol) were dissolved in 1.5 mL of Py, and EDCI (15.8 mg, 0.08 mmol) was added at 0°C under nitrogen protection. After the reaction was stirred at 25°C for 30 min, LCMS monitored the formation of the product. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying, and used directly in the next step. LCMS [M + H] + m / z: 533.0
  • Step 1 Zn (5.5 g, 84.9 mmol) was placed in anhydrous THF (50 ml), TMSCl (9.2 g, 84.9 mmol), C017-0 (3.7 g, 15 mmol) was added, and SM2 (4.8 g, 18.5 mmol) was added after reacting at room temperature for 15 minutes, and reacted at room temperature for 2 hours. After the reaction was completed, 10% NaHCO 3 solution was added to quench, the reaction solution was filtered, and the filtrate was extracted three times with ethyl acetate (40 ml). The organic phases were combined, dried, and concentrated, and the residue was purified by silica gel column chromatography (100% PE) to obtain C017-1 (3 g, 49.4%).
  • Step 4 C017-3 (800 mg, 2.6 mmol) was dissolved in MeOH (10 ml), Pd(OH) 2 (400 mg) and HCl-EA (0.03 mL) were added at room temperature, the gas was replaced three times under hydrogen atmosphere, and the reaction was continued with stirring for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain C017-4 (300 mg, 91.5%).
  • Step 6 Dissolve C017-5 (80 mg, 0.28 mmol) in THF (3 ml), add 2N LiOH (3 ml), react at room temperature for 2 hours under N2 protection, adjust the pH of the reaction solution to weak acidity with HCl-EA. Concentrate to obtain C017-6 (60 mg, 79%).
  • Step 7 C017-6 (60 mg, 0.2 mmol), SM4 (82 mg, 0.3 mmol), DPPA (83 mg, 0.3 mmol), TEA (73 mg, 0.7 mmol) were dissolved in ultra-dry DMSO (2 mL), and reacted at 90 ° C for 2 hours under N 2 protection. After the reaction, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by reverse phase column chromatography to obtain the target compound C017 (5.5 mg, 4.5%).
  • Step 1 In a microwave tube, C018-0 (1.96 g, 12.02 mmol) and t-BuONa (3.46 g, 36.06 mmol) were dissolved in 15 mL of anhydrous dioxane, nitrogen was bubbled for 5 minutes, RuPhos Pd G3 (700 mg, 0.837 mmol) was added, nitrogen was bubbled for 5 minutes, and 4,4-difluorocyclohexylamine hydrochloride (2.48 g, 14.43 mmol) was added. The reaction solution was microwaved at 100°C for 2 hours.
  • Step 2 C018-1 and C018-2 (1.2 g) were dissolved in dioxane (2 mL), 6.0 mol/L hydrochloric acid (20 mL) was added, and the reaction solution was stirred at 100°C for 18 hours. After the reaction was completed, the reaction solution was cooled to room temperature, ethyl acetate (30 mL*3) was added for extraction and discarded. The aqueous phase was concentrated under reduced pressure, dried in vacuo, and the residue was directly used in the next step.
  • Step 4 C018-4 (133 mg, 0.5 mmol), TEA (152 mg, 1.5 mmol) and PdCl 2 dppf (36.8 mg, 0.05 mmol) were dissolved in 10 mL of methanol, and the reaction solution was reacted at 55°C for 18 hours under a CO atmosphere.
  • DCM/MeOH 10/1
  • Step 4 C019-3 (100 mg, 0.345 mmol), SM2 (108 mg, 0.41 mmol), DPPA (108 mg, 0.41 mmol) and TEA (105 mg, 1.02 mmol) were dissolved in 2 mL of anhydrous DMSO.
  • the reaction solution was heated to 90 ° C under nitrogen protection and stirred for 1 hour.
  • the reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL * 3), the organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by spin drying.
  • Step 1 C020-1 (20 g, 0.082 mol) was dissolved in 200 mL of 10 wt% H 2 SO 4. At 0°C, an aqueous solution of NaNO 2 (7 g, 0.010 mol) was added dropwise. The reaction was slowly heated to room temperature and stirred for 1 hour. After reacting for 1 hour, 400 mL of 50 wt% H 2 SO 4 was added and reacted at 100°C for 1 hour.
  • reaction liquid was filtered, and the filter cake was washed three times with a saturated NaHCO 3 aqueous solution, extracted three times with ethyl acetate (50 mL), and the organic phase was dried with anhydrous sodium sulfate, filtered, and dried to obtain the product C020-2 (13 g, 65%).
  • Step 6 C020-6 (100 mg, 0.33 mmol) and SM-3 (99 mg, 0.36 mmol) were dissolved in 5 mL of anhydrous DMSO. DPPA (108 mg, 0.39 mmol) and TEA (0.14 mL, 0.99 mmol) were added at 0°C under nitrogen protection. The reaction was reacted at 90°C for 1 hour.
  • Step 1 Dissolve the raw material C021-0 (70 mg, 0.239 mmol) in anhydrous DMSO (3 mL), add C019-3 (75 mg, 0.285 mmol), DPPA (80 mg, 0.290 mmol) and triethylamine (0.1 mL), and heat to 120 degrees for 1 hour. After the reaction is complete, add water (5 ml) and ethyl acetate (10 mL*3) to extract the product, dry the organic phase and concentrate, and the residue is purified by reverse phase column chromatography to obtain C021 (8.19 mg, 6.21%)
  • Step 2 C022-1 (1.0 g, 2.82 mmol) and zinc powder (732.0 mg, 11.3 mmol) were dissolved in 10 mL of acetic acid solution, and the reaction solution was reacted at 80 degrees under nitrogen protection for five hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the resulting crude product was dissolved in 10 mL of dichloromethane solution, and 10.0 mL of trifluoroacetic acid and 5.0 mL of triethylsilane were added in sequence, and stirred at room temperature for one hour.
  • Step 1 C019-3 (470 mg, 1.6 mmol) was dissolved in 5 mL 1,4-dioxane, cooled to 0 °C, dibromosulfoxide (670 mg, 3.2 mmol) was added, and then the reaction solution was returned to room temperature and stirred for 16 hours. After the reaction was completed, the solvent in the reaction solution was dried, and petroleum ether and ethyl acetate (1:1) were added for washing, and the filter cake was collected by filtration to obtain C023-1 (460 mg, 81.3%).
  • Step 2 C023-1 (460 mg, 1.3 mmol) was dissolved in 5 mL DMF, cooled to 0 °C, sodium azide (126 mg, 1.94 mmol) was added, and then the reaction solution was returned to room temperature and stirred for 2 hours. After the reaction was completed, the reaction solution was poured into ice water to quench, and solid precipitated. The filter cake was collected by filtration to obtain C023-2 (400 mg, 97.0%).
  • Step 3 C023-2 (400 mg, 1.26 mmol) was dissolved in 20 mL of methanol, and then palladium carbon (40 mg) and concentrated hydrochloric acid (0.57 mL) were added, and the reaction solution was stirred at room temperature overnight under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered through diatomaceous earth and washed with methanol, and then the filtrate was dried to obtain the target compound C023-3 (110 mg, 30.0%).
  • Step 4 C023-3 (95 mg, 0.33 mmol) was dissolved in 2 mL of pyridine, and then SM1 (107 mg, 0.39 mmol) and EDCI (83 mg, 0.43 mmol) were added to the reaction solution, and the reaction solution was stirred at room temperature for 2 hours under nitrogen protection.
  • the liquid was extracted with water (10 mL) and ethyl acetate (10 mL*3), the organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried.
  • Step 1 Dissolve the raw material C024-0 (2.67 g, 15.798 mmol) in DMF (20 mL), add potassium carbonate (6.6 g, 47.826 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (11.0 g, 47.413 mmol), and heat to 50 degrees for 6 hours. After the reaction is complete, add water (30 ml) and ethyl acetate (30 mL*3) to extract the product, dry the organic phase and concentrate, and the residue is purified by column chromatography to obtain C024-1 (2.72 g, 68.0%)
  • Step 2 C025-1 (200 mg, 0.69 mmol) was dissolved in a mixed solution of 10 mL of THF and MeOH. 8 mL of LiOH aqueous solution was added to the reaction under nitrogen protection. The reaction was reacted at 25 ° C for 2 h. The pH was adjusted to 4 with dilute hydrochloric acid, and ethyl acetate (15 mL) was extracted three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and dried to obtain the product C025-2 (150 mg, 79%).
  • Step 3 C025-2 (150 mg, 0.54 mmol) and INT-2 (150 mg, 0.54 mmol) were dissolved in 10 mL of DMSO. DPPA (0.14 mL, 0.65 mmol) and TEA (0.23 mL, 1.62 mmol) were added at 0°C under nitrogen protection. The reaction was reacted at 90°C for 1 h.
  • Step 2 C026-1 (200 mg, 0.730 mmol) was dissolved in 10 mL of a mixed solvent of EA and EtOH, Pd-C (20 mg) was added, and the reaction system was ventilated three times to allow the reaction to proceed under a H2 atmosphere, and the reaction was stirred at 25°C overnight. Pd-C was filtered off with diatomaceous earth, and the product C026-2 (100 mg, 56%) was obtained by spin drying.
  • Step 2 C027-1 (70 mg, 0.28 mmol) was dissolved in a mixed solution of 2 mL of THF, 1 mL of MeOH, and 0.5 mL of H 2 O, and lithium hydroxide (13.3 mg, 0.56 mmol) was added, and the reaction was carried out at room temperature for 30 minutes. After the reaction was completed, the mixture was quenched with 1M HCl aqueous solution and the pH was adjusted to 3-4, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the white solid obtained by spin drying was the target product C027-2 (60 mg, 91%).
  • Step 1 C028-0 (1.36 g, 0.01 mol), SM-2 (378 g, 0.012 mol), triethylsilyl hydride (1.36 g, 0.012 mol) were dissolved in acetonitrile (20 ml), TFA (1.34 g, 0.012 mol) was added under nitrogen protection, and the reaction was stirred at 80°C for 3 h.
  • Step 2 C028-1 (700 mg, 2.43 mmol) was dissolved in a mixed solution of 10 mL of THF and MeOH. 8 mL of LiOH (2 M) was added to the reaction under nitrogen protection. The reaction was carried out at 25°C for 2 hours. After the reaction was completed, the pH was adjusted to 4 with dilute hydrochloric acid, and then extracted three times with ethyl acetate (15 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried to obtain C028-2 (500 mg, 75%).
  • Step 3 C028-2 (200 mg, 0.73 mmol) and INT-2 (240 mg, 0.88 mmol) were dissolved in 8 mL of DMSO.
  • DPPA (0.19 mL, 0.88 mmol)
  • TEA 0.3 mL, 2.19 mmol
  • the reaction was carried out at 90 ° C for 1 hour.
  • the organic phase was washed three times with saturated NaHCO 3 , extracted three times with ethyl acetate (8 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried.
  • the residue was prepared by Prep-HPLC to obtain C028 (26.6 mg, 7%).
  • Step 1 C029-0 (300 mg, 1.76 mmol) was dissolved in 5 mL of acetonitrile, followed by the addition of m-fluorobenzaldehyde (218 mg, 1.76 mmol), triethylsilyl (1.03 g, 8.82 mmol) and TEA (1.03 g, 8.82 mmol), and the reaction solution was heated to 80 ° C and stirred for 3 hours.
  • Step 2 C029-1 (380 mg, 1.37 mmol) and lithium hydroxide (114.8 mg, 2.73 mmol) were dissolved in a mixed solvent of tetrahydrofuran (4 mL) and methanol (2 mL), and the reaction solution was stirred at room temperature for 2 hours under nitrogen protection. After the reaction, dilute hydrochloric acid was added to adjust the pH to 3-4, and then water (10 mL) and ethyl acetate (10 mL*3) were added for extraction, and the organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried to obtain the target compound C029-2 (200 mg, 55.4%).
  • Step 3 C029-2 (100 mg, 0.38 mmol) was dissolved in 2 mL DMSO, followed by SM2 (104 mg, 0.46 mmol). DPPA (125 mg, 0.46 mmol) and TEA (115 mg, 1.14 mmol) were added to the reaction solution, and the reaction solution was heated to 90°C under nitrogen protection and stirred for 1 hour. After the reaction was completed, the reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL*3), the organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by spin drying. The residue was purified by reverse phase column chromatography to obtain the target compound C029 (50.2 mg, 26.4%).
  • Step 1 C030-0 (900 mg, 5.55 mmol) was dissolved in Dioxane (10 mL), (2-fluorophenyl)methylamine (700 mg, 5.55 mmol), cesium carbonate (125 mg, 0.55 mmol), BINAP (691 mg, 1.11 mmol), palladium acetate (359 mg, 0.55 mmol) were added, the gas was replaced three times under nitrogen, and the temperature was raised to 80 degrees for 3 hours.
  • Step 3 Dissolve C030-2 (360 mg, 1.518 mmol) in POCl 3 (12 mL), add two drops of DMF, stir at 80 degrees for 3 hours, and after the reaction is completed, concentrate the reaction solution by evaporation under reduced pressure. The residue is directly used in the next step C030-3 (400 mg)
  • Step 1 In a microwave tube, C031-0 (489 mg, 3.0 mmol) and t-BuONa (1.15 g, 12.0 mmol) were dissolved in 10 mL of anhydrous dioxane, nitrogen was bubbled for 5 minutes, RuPhos Pd G3 (250.8 mg, 0.3 mmol) was added, nitrogen was bubbled for 5 minutes, and trifluoroethylamine (2.0 mL) was added. The reaction solution was microwaved at 100°C for 2 hours.
  • Step 2 C031-1 and C031-1' (226 mg, 1.0 mmol) were dissolved in 4 mL of 6 M hydrochloric acid and stirred at 100°C overnight. The reaction solution was evaporated under reduced pressure and dried in vacuo to obtain DD217-165-3 (210 mg).
  • Step 4 C031-3 (230 mg, 1.0 mmol), TEA (303 mg, 3.0 mmol) and PdCl2dppf (73.5 mg, 0.1 mmol) were dissolved in 10 mL of methanol, and the reaction solution was reacted at 55°C for 18 hours under a CO atmosphere.
  • Step 5 C031-4 (110 mg, 0.43 mmol) was dissolved in a mixed solution of 3 mL of THF, 1.5 mL of MeOH, and 0.75 mL of H 2 O, and LiOH (20.6 mg, 0.86 mmol) was added, and the mixture was reacted at room temperature for 30 minutes. After the reaction, 1M HCl aqueous solution was used to quench the mixture until the pH value was 3-4, and the mixture was extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, filtered, and the obtained white solid was spin-dried to obtain the target product C031-5 (100 mg, 96%).
  • Step 2 C032-1 (1.2 g, 5.017 mmol) was dissolved in N, N-dimethylformamide (24 mL), 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.49 g, 15.051 mmol) and potassium carbonate (2.077 g, 15.051 mmol) were added, and the mixture was reacted at 50°C for 5 hours.
  • Step 3 C032-2 (1.297 g, 4.03 mmol) was dissolved in tetrahydrofuran (12 mL), 10% palladium/carbon was added, the mixture was evacuated three times under a hydrogen atmosphere, and the reaction was allowed to proceed overnight at room temperature. The reaction solution was filtered through diatomaceous earth to remove palladium/carbon. The filtrate was dried to obtain the product C032-3 (1.1 g, 93.2%).
  • Step 4 C032-3 (1.1 g, 3.767 mmol) was dissolved in 10 mL of hydrochloric acid/1,4-dioxane solution and reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain the product C032-4 (719.0 mg, 100%).
  • Step 5 C032-4 (36.0 mg, 0.188 mmol) and 3-(2-(2,6-dioxohesperidin-3-yl)-3-oxoisoindolin-5-yl)propanoic acid (50.0 mg, 0.158 mmol) were dissolved in pyridine (6.0 mL), and the mixture was vented three times to allow the reaction to proceed under nitrogen protection.
  • 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 39.1 mg, 0.206 mmol was added at 0°C.
  • reaction solution was poured into a saturated ammonium chloride solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried.
  • Step 1 C033-0 (500 mg, 3.6 mmol) was dissolved in 10 mL of acetonitrile, 4,4-difluorocyclohexanone (578.9 mg, 4.3 mmol), triethylsilyl (2.1 g, 18.0 mmol) and TFA (2.05 g, 18.0 mmol) were added, and the temperature was raised to 80°C for 2 hours. After the reaction was completed, a saturated ammonium chloride solution was added to quench, and the mixture was extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, spin-dried, and filtered to obtain compound C033-1 (760 mg, 82.2%).
  • Step 2 Dissolve C033-1 (760 mg, 3.0 mmol) in 10 mL of ethanol, add 76 mg of 10% palladium/carbon, and react at room temperature for 16 hours under hydrogen. The reaction mixture is filtered through diatomaceous earth, and the filtrate is dried to obtain a crude compound C033-2 (600 mg, 89%).
  • Step 1 Dissolve C034-0 (10.0 g, 55.802 mmol) in 90 mL of fuming nitric acid, add 24 mL of concentrated sulfuric acid, and stir at 45 degrees for 15 hours. After the reaction is complete, add the reaction solution dropwise to ice water (100 mL), extract with ethyl acetate (50 mL*3), combine the organic phases and wash with saturated sodium bicarbonate aqueous solution, dry over anhydrous sodium sulfate, and spin dry to obtain C034-1 (4.6 g, 37.1%)
  • Step 2 C034-1 (4.6 g, 20.534 mmol) was dissolved in acetic acid (10 mL), iron powder (16.0 g, 285.714 mmol) was added, and the reaction solution was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, the reaction solution was filtered, and water (50 mL) and ethyl acetate (50 mL*3) were added to the filtrate for extraction, and the organic phases were combined and washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and spin-dried to obtain C034-2 (2.1 g, 56.7%).
  • Step 4 C034-3 (3.1 g, 8.373 mmol) was dissolved in dichloromethane, triethylamine (6 mL) and copper trifluoromethanesulfonate (300 mg, 0.831 mg) were added, and stirred at room temperature for 1 hour. After the reaction was complete, water (20 mL) and ethyl acetate (20 mL*3) were added for extraction, and the organic phases were combined and dried over anhydrous sodium sulfate, and then spin-dried to obtain C034-4 (1.9 g, 82.6%).
  • Step 6 C034-5 (700 mg, 1.861 mmol) was dissolved in dioxane hydrochloride (10 mL) and stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated to obtain C034-6 (510 mg, 100%).
  • Step 9 Dissolve C034-8 (440 mg, 1.321 mmol) in trifluoroacetic acid (3 mL) and stir at room temperature for 1 hour. After the reaction is complete, concentrate the reaction solution, add water (5 mL) and ethyl acetate (5 mL*3) for extraction, combine the organic phases and use saturated sodium bicarbonate to obtain the mixture. The product was washed with aqueous solution, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to obtain C034-9 (210 mg, 68.4%).
  • Step 10 C034-9 (200 mg, 0.850 mmol) was dissolved in pyridine (2 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (250 mg, 1.310 mmol), 3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)propanoic acid (400 mg, 1.261 mmol) were added, and stirred at room temperature for 1 hour.
  • Step 1 C035-0 (15.0 g, 0.068 mol) was dissolved in 45 mL of methanol. At 0 ° C, under nitrogen protection, 80 mL of dichlorothionyl was added. The reaction was reacted at 60 ° C for 16 h. It was washed three times with saturated NaHCO 3 solution (30 mL), extracted three times with ethyl acetate (30 mL), and the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and spin-dried to obtain C035-1 (15.0 g, 94.0%).
  • Step 3 C035-2 (2.0 g, 0.010 mol), 1-ethoxy-2,2,2-trifluoroethane-1-ol (4.6 mL, 0.043 mol) and p-toluenesulfonic acid monohydrate (75 mg, 0.0004 mol) were dissolved in 15 mL of toluene.
  • the reaction was carried out at 120 ° C under nitrogen protection for 2 hours.
  • Step 5 C035-4 (180 mg, 0.632 mmol) was dissolved in 10 mL of a mixed solvent of tetrahydrofuran and methanol. At 0°C, under nitrogen protection, 5 mL of an aqueous lithium hydroxide solution (2 M) was added. The reaction was allowed to react at 25°C for 1 hour. The reaction solution was adjusted to a weak acid with an aqueous hydrochloric acid solution (6 M), and then extracted three times with ethyl acetate (8 mL). The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain the product C035-5 (150 mg, 87.7%), which was used directly in the next step.
  • Step 6 C035-5 (150 mg, 0.554 mol), diphenylphosphoryl azide (228 mg, 0.830 mmol) and triethylamine (167 mg, 1.660 mmol) were dissolved in potassium tert-butoxide (8 mL) and stirred at 90 ° C for 1 hour under a nitrogen atmosphere.
  • Step 7 Under nitrogen protection, C035-6 (130 mg, 0.380 mmol) was dissolved in hydrochloric acid/1,4-dioxane (5 mL) and reacted at 25° C. for 2 hours. The reaction solution was spin-dried to obtain C035-7 (50 mg, 54.4%), which was used directly in the next step.
  • Step 8 C035-7 (50 mg, 0.207 mmol) and 3-(2-(2,6-dioxohesperidin-3-yl)-3-oxoisoindolin-5-yl)propanoic acid (110 mg, 0.310 mmol) were dissolved in 5 mL of 1-methyl-2-pyrrolidone. 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride (130 mg, 0.413 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.69 mmol) were added at 0°C under nitrogen protection.
  • Step 1 Dissolve C036-0 (1.0 g, 6.1 mmol) in 10.0 mL of dichloromethane, then add di-tert-butyl dicarbonate (2.7 g, 12.2 mmol), 4-dimethylaminopyridine (748.9 mg, 6.1 mmol), triethylamine (620.3 mg, 6.13 mmol) to the reaction solution, and stir at room temperature for 12 hours.
  • Step 2 Dissolve C036-1 (1.5 g, 4.1 mmol) in 10.0 mL of dichloromethane, add 0.32 mL of trifluoroacetic acid, and stir at room temperature for 2 hours. After the reaction is completed, concentrate the reaction solution under reduced pressure to obtain the target compound C036-2 (1.0 g, 92%).
  • Step 4 C036-3 (350.0 mg, 1.0 mmol) was dissolved in 5.0 mL of ethanol and 5.0 mL of water, and then iron powder (170.0 mg, 3.0 mmol) and ammonium chloride (340.8 mg, 6.0 mmol) were added to the reaction solution, and the reaction was stirred at 80°C for 16 hours. After the reaction was completed, the reaction solution was filtered through a diatomaceous earth pad, and the ethanol was removed by rotary evaporation.
  • Step 5 C036-4 (120.0 mg, 0.38 mmol) was dissolved in 5.0 mL of dichloromethane solution, and then sodium carbonate (65.0 mg, 0.61 mmol) was dissolved in 1.0 mL of water, added to the reaction solution, and stirred at room temperature for 5 minutes. Then the temperature was lowered to 0°C, triphosgene (45.0 mg, 0.15 mmol) was added, and the reaction solution was stirred for half an hour under nitrogen protection.
  • the reaction mixture was extracted with water (10.0 mL) and ethyl acetate (10.0 mL*3), the organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target compound C036-5 (100.0 mg, 77.5%), which was directly used in the next step.
  • Step 1 C039-0 (5.0 g, 25.12 mmol) was dissolved in methanol (50 mL), 5.0 mL of concentrated sulfuric acid was added at 25°C, and the mixture was reacted at 75°C for 4 hours. The reaction solution was poured into a saturated sodium carbonate aqueous solution (100 mL), and ethyl acetate (100 mL) was added for extraction three times. The organic phases were combined and dried with sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain C039-1 (4.9 g, 91.6%).
  • Step 2 C039-1 (4.9 g, 23.00 mmol) was dissolved in N, N-dimethylformamide (30 mL), and then N, N-dimethylformamide dimethyl acetal (30 mL) was added, and stirred at 95 degrees for 12 hours under nitrogen protection.
  • the reaction solution was poured into a saturated sodium chloride aqueous solution (200 mL), and ethyl acetate (150 mL) was added to extract three times, the organic phases were combined and dried with sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain a crude product C039-2 (4.82 g, 78.2%).
  • Step 4 C039-3 (2.6 g, 13.47 mmol) was dissolved in acetone (100 mL), potassium carbonate (5.577 g, 40.41 mmol) and p-toluenesulfonyl chloride (3.07 g, 16.16 mmol) were added in sequence at 25 degrees, and the mixture was reacted at 70 degrees for 16 hours.
  • Step 5 C039-4 (300 mg, 1.6 mmol), lithium hydroxide (3.1 mL, 3.1 mmol), tetrahydrofuran (4 mL) and methanol (2 mL) were mixed and reacted at room temperature for 3 hours.
  • the reaction solution was concentrated under reduced pressure to remove tetrahydrofuran and methanol, and ethyl acetate (10 mL x 3) was added for extraction.
  • the aqueous phase was adjusted to pH 2-3 with 1M dilute hydrochloric acid, and ethyl acetate (15.0 mL x 3) was added for extraction.
  • the organic phase was treated with anhydrous sulfuric acid.
  • the residue was dried over sodium bicarbonate and concentrated under reduced pressure to give C039-5 (180 mg, 35%).
  • Step 6 C039-5 (180 mg, 0.54 mmol) and potassium tert-butoxide (321 mg, 2.9 mmol) were added to tetrahydrofuran (2 mL) and reacted at room temperature overnight. The reaction solution was quenched, and ethyl acetate (10 mL x 3) was added for extraction. The aqueous phase was adjusted to pH 2-3 with 1M dilute hydrochloric acid, and ethyl acetate (15 mL x 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain C039-6 (90 mg, 93%).
  • Step 1 C040-0 (300 mg, 1.55 mmol) and lithium hydroxide (189 mg, 4.50 mmol) were dissolved in a mixed solution of 10 mL of water and tetrahydrofuran. The reaction solution was reacted at room temperature for two hours. The tetrahydrofuran in the reaction solution was dried and diluted hydrochloric acid was added to adjust the pH to acidic. At this time, solids precipitated. The solids were filtered and washed with water, and the product C040-1 (270 mg, 97%) was obtained after drying.
  • Step 2 C040-1 (130 mg, 0.72 mmol), INT-2 (238 mg, 0.87 mmol), diphenylphosphoryl azide (239 mg, 0.87 mmol), and triethylamine (239 mg, 0.87 mmol) were dissolved in 3 mL of dimethyl sulfoxide and stirred at 90° C. for one hour.
  • Step 3 C041-2 (200 mg, 0.9 mmol), INT-2 (304 mg, 1.1 mmol), triethylamine (281 mg, 2.9 mmol) and diphenylphosphoryl azide (305 mg, 1.1 mmol) were dissolved in anhydrous dimethyl sulfoxide (4 mL). The reaction solution was stirred at 90 ° C for 1.5 hours. The reaction solution was diluted with a small amount of acetonitrile to obtain C041 (3.36 mg, 0.7%).
  • Step 2 C042-1 (180 mg, 0.73 mmol) was dissolved in 2 mL of dimethyl sulfoxide, followed by the addition of 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (216 mg, 0.88 mmol), diphenylphosphoryl azide (216 mmol, 0.88 mmol) and triethylamine (202 mg, 2.19 mmol), followed by replacement of the gas three times under nitrogen atmosphere, and the temperature was raised to 90°C for reaction for 2 hours.
  • Step 1 C043-0 (5.0 g, 21.9 mmol), hydroxylamine hydrochloride (7.6 g, 109.3 mmol), sodium acetate (9.0 g, 109.3 mmol) were dissolved in 50.0 mL of methanol solution, and the reaction solution was heated to 70 ° C under nitrogen protection and stirred overnight. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was added with water (50.0 mL) and ethyl acetate (60.0 mL) and extracted three times, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried to obtain the product C043-1 (5.0 g, 94.3%).
  • Step 3 C043-2 (1.5 g, 6.6 mmol) was dissolved in 30.0 mL of tetrahydrofuran, replaced with nitrogen, and then lithium tert-butoxide (576 mg, .26 mmol), 1,3-dimethyl-2-pyrimidone (419.0 mg, 3.3 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.6 g, 19.8 mmol) were added.
  • the reaction solution was heated to 70 ° C under nitrogen protection and stirred overnight.
  • Step 1 C044-0 (202 mg, 1.787 mmol) and methyl 5-bromo-2-fluorobenzoate (500 mg, 2.144 mmol), Brettphos-Pd-G3 (162 mg, 0.179 mmol), Ruphos (167 mg, 0.357 mmol) and cesium carbonate (1.7 g, 5.360 mmol) were dissolved in 10 mL of toluene and reacted at 70 ° C for 16 hours under nitrogen protection.
  • Step 2 C044-1 (180 mg, 0.679 mmol) was dissolved in 5 mL of a mixed solvent of tetrahydrofuran and methanol. 5 mL of lithium hydroxide aqueous solution (2.0 M) was added to the reaction under nitrogen protection. After reacting at 25°C for 1 hour, the reaction solution was adjusted to weak acidity with hydrochloric acid aqueous solution (6 M), extracted with ethyl acetate (10 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic matter was concentrated under reduced pressure to obtain the product C044-2 (140 mg, 82.4%), which was directly used in the next step.
  • cesium carbonate 1.0 g, 3.076 mmol
  • palladium acetate 50 mg, 0.221 mmol
  • 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) 70 mg,
  • Step 1 C046-0 (3.0 g, 18.52 mmol), 2-(trifluoromethyl)aniline (3.58 g, 22.2 mmol, palladium acetate (418 mg, 1.85 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (1.15 g, 1.85 mmol) and cesium carbonate (18.1 g, 55.56 mmol) were dissolved in 30 mL of anhydrous toluene, and the reaction solution was heated to 110°C and stirred overnight under nitrogen protection.
  • Step 5 C046-4 (380.0 mg, 1.21 mmol) and lithium hydroxide (152 mg, 3.62 mmol) were dissolved in a mixed solution of 10 mL of water and tetrahydrofuran. The reaction solution was reacted at room temperature for two hours. The tetrahydrofuran in the reaction solution was dried, and then dilute hydrochloric acid was added to adjust the pH to acidic, at which time solids precipitated. The solids were filtered and washed with water, and dried to obtain the product C046-5 (380.0 mg, 99.8%).
  • Step 1 C047-0 (2.0 g, 8.621 mmol) was dissolved in anhydrous toluene (20 mL), cesium carbonate (4.0 g, 12.307 mmol), 2-(trifluoromethyl)aniline (1.67 g, 10.372 mmol), S-(-)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (540 mg, 0.868 mmol), palladium acetate (200 mg, 0.868 mmol), and stirred at 120 degrees for 15 hours.
  • Step 3 C047-2 (340 mg, 0.821 mmol) was dissolved in a tetrahydrofuran/methanol (5 mL) mixed solution (4/1), and a 2M lithium hydroxide aqueous solution (2 mL) was added, and stirred at room temperature for 12 hours. After the reaction was complete, a 1M hydrochloric acid solution was added to adjust the pH to a weak acid, and ethyl acetate (10 mL*3) was added to extract the product, which was dried and concentrated to obtain C047-3 (328 mg, 100%).
  • Step 1 C046-3 (1.0 g, 3.440 mmol), triethylamine (1.04 g, 10.320 mmol), di-tert-butyl dicarbonate (1.12 g, 5.160 mmol) and 4-dimethylaminopyridine (42 mg, 0.340 mmol) were dissolved in 15.0 mL of N, N-dimethylformamide solution. The reaction solution was reacted at room temperature for one hour. Water (30.0 mL) was added to the reaction solution, extracted three times with ethyl acetate (30.0 mL), the organic phases were combined and dried with anhydrous sodium sulfate, and concentrated to obtain compound C048-1 (1.3 g, 96.8%).
  • Step 3 C048-2 (100 mg, 0.271 mmol) and 3-(2,6-dioxohesperidin-3-yl)3-oxoisoindolin-5-yl) propionic acid (125 mg, 0.401 mmol) were dissolved in a mixed solution of 2.0 mL of pyridine and 2.0 mL of dichloromethane, 0.5 mL of phosphorus oxychloride was added dropwise to the reaction solution, and then the reaction was continued at room temperature overnight.
  • Step 1 C049-0 (350.0 mg, 1.0 mmol), tert-butyl acrylate (154.0 mg, 1.2 mmol), palladium acetate (22.0 mg, 0.1 mmol) and potassium acetate (190.0 mg, 2.0 mmol) were dissolved in 10.0 mL of N,N-dimethylformamide, and the reaction solution was heated to 110°C under nitrogen protection and stirred overnight. After the reaction was completed, it was cooled to room temperature, 10.0 mL of water was added, and a precipitate was precipitated. The solid was then collected and washed with petroleum ether to obtain C049-1 (300.0 mg, 75.0%).
  • Step 2 C049-1 (300.0 mg, 0.75 mmol) and 10% palladium/carbon (30.0 mg) were dissolved in 10.0 mL of tetrahydrofuran, and the reaction solution was stirred at room temperature overnight under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered and washed with diatomaceous earth and dried to obtain the target compound C049-2 (250.0 mg, 83.1%).
  • Step 3 C049-2 (100.0 mg, 0.25 mmol) was dissolved in 3.0 mL of 1,4-dioxane, and then 3.0 mL of hydrochloric acid/1,4-dioxane was added and stirred overnight under nitrogen protection. After the reaction was completed, the product C049-3 (60.0 mg, 70%) was obtained by concentration under reduced pressure.
  • Step 4 C049-3 (60.0 mg, 0.17 mmol) and N1-(4,4-difluorocyclohexyl)-4-fluorobenzene-1,3-diamine (51.0 mg, 0.17 mmol) were dissolved in 5.0 mL of pyridine, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (37.0 mg, 0.20 mmol) was added under nitrogen protection at 0°C. The reaction was stirred at 25°C for 14 hours.
  • Step 1 Dissolve C050-0 (5.0 g, 20.30 mmol), N-bromosuccinimide (3.6 g, 20.30 mmol), and azobisisobutyronitrile (164 mg, 1.0 mmol) in 50 mL of carbon tetrachloride solution.
  • the reaction solution was reacted at 80 degrees for two hours under nitrogen protection.
  • Step 2 C050-1 (5.5 g, 16.87 mmol), N,N-diisopropylethylamine (6.53 g, 50.6 mmol), 3-amino-2,6-piperidindione (3.24 g, 25.3 mmol) were dissolved in 50 mL of N,N-dimethylformamide solution, and the reaction solution was reacted at 100 degrees for two hours under nitrogen protection. The reaction solution was cooled to room temperature, and solids precipitated. The solids were collected by filtration and dried to obtain compound C050-2 (5.3 g, 92.2%).
  • Step 3 C050-2 (1.0 g, 2.93 mmol) and tert-butyl acrylate (563.0 mg, 4.40 mmol), palladium acetate (68 mg, 0.29 mmol), potassium acetate (862 mg, 8.80 mmol) were dissolved in 15 mL of dimethyl sulfoxide solution, and stirred at 100°C for overnight reaction.
  • Step 4 C050-3 (440 mg, 1.13 mmol) and 10% palladium/carbon (100 mg) were dissolved in 10 mL of methanol, and stirred at room temperature overnight. The reaction solution was filtered and the filtrate was collected and concentrated under reduced pressure to obtain compound C050-4 (300 mg, 68.2%).
  • Step 5 Dissolve C050-4 (280 mg, 0.72 mmol) in 10 mL of hydrochloric acid in dioxane, stir and react at room temperature overnight. Concentrate the reaction solution under reduced pressure to obtain compound C050-5 (230 mg, 100%).
  • Step 2 C052-1 (50 mg, 0.13 mmol) was dissolved in a mixed solvent of 2 mL of tetrahydrofuran and 1.0 mL of methanol, and then 0.5 mL of lithium hydroxide aqueous solution (2M) was added, and the reaction was stirred at room temperature for 6 hours. After the reaction was completed, dilute hydrochloric acid was added to the reaction solution to adjust the pH to weak acidity, and then extracted with water (10 mL) and ethyl acetate (10 mL*3), and the organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried to obtain the target compound C052-2 (38 mg, 84.5%).
  • Step 1 C053-0 (5.0 g, 39.683 mmol) was dissolved in 50 mL of diethylene glycol dimethyl ether solvent, and the temperature was raised to 180°C under nitrogen protection. Then sodium difluorochloroacetate (48.2 g, 317.460 mmol) was dissolved in 50 mL of diethylene glycol dimethyl ether, and then added to the reaction solution in batches, and the temperature was kept at 180°C for 4 hours. After the reaction was completed, the reaction mixture was filtered to remove the residue, and the filtrate was extracted with water (100 mL) and petroleum ether (100 mL*3).
  • Step 2 C053-1 (2.2 g, 12.493 mmol) was dissolved in a mixed solution of tetrahydrofuran (12 mL) and methanol (3 mL), and after vacuuming and nitrogen filling, 3 mL of lithium hydroxide aqueous solution (2 M) was added, and the reaction was stirred overnight at room temperature.
  • Step 4 C053-3 (1.2 g, 5.150 mmol) was dissolved in 10 mL of hydrogen chloride-dioxane solution. The reaction solution was reacted at room temperature overnight under nitrogen protection. After the reaction was completed, the reaction solution was directly spin-dried to obtain compound C053-4 (600 mg, 87.7%).
  • Step 5 C053-4 (200 mg, 1.504 mmol) was dissolved in 10 mL of toluene, and then methyl 2-fluoro-5-iodobenzoate (512 mg, 1.805 mmol), palladium acetate (35 mg, 0.150 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (95 mg, 0.150 mmol) and cesium carbonate (1.49 g, 4.512 mmol) were added. The reaction solution was heated to 110°C under nitrogen protection and stirred overnight.
  • reaction solution was extracted with water (10 mL) and ethyl acetate (10 mL*3), the organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by spin drying.
  • Step 6 C053-5 (100 mg, 0.351 mmol) was dissolved in a mixed solvent of 2 mL tetrahydrofuran and 1 mL methanol, and then an aqueous lithium hydroxide solution (2 M) was added, and the reaction was stirred at room temperature for 6 hours. After the reaction was completed, dilute hydrochloric acid was added to the reaction solution to adjust the pH to acidic, and then extracted with water (10 mL) and ethyl acetate (10 mL*3), and the organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried to obtain the target compound C053-6 (90 mg, 94.7%).
  • Step 7 C053-6 (480 mg, 1.771 mmol) was dissolved in 5 mL potassium tert-butoxide, and then diphenylphosphoryl azide (585 mg, 2.125 mmol) and triethylamine (540 mg, 5.314 mmol) were added.
  • the reaction solution was heated to 90° C. under nitrogen protection and stirred for one hour.
  • the reaction solution was extracted with water (10 mL) and ethyl acetate (10 mL*3), the organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by spin drying.
  • Step 8 C053-7 (200 mg, 0.585 mmol) was dissolved in 2 mL of hydrogen chloride-dioxane solution and stirred at room temperature overnight. After the reaction was completed, the reaction solution was directly spin-dried to obtain the target compound C053-8 (90 mg, 94.7%).
  • Step 9 3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)propionic acid (125 mg, 0.412 mmol)) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (82 mg, 0.431 mmol) were added to 2 mL of pyridine, and then C053-8 (80 mg, 0.330 mmol) was added. The reaction solution was stirred at room temperature for 2 hours under nitrogen protection.
  • Step 1 C054-0 (1.0 g, 3.6 mmol), iodoethane (854.0 mg, 5.4 mmol), potassium acetate (840.0 mg, 5.4 mmol) were dissolved in 10.0 mL of N, N-dimethylformamide, and the reaction solution was heated to 80 ° C under nitrogen protection and stirred overnight.
  • Step 2 C054-1 (280.0 mg, 0.92 mmol) and 10% palladium/carbon (30.0 mg) were dissolved in 10.0 mL tetrahydrofuran, and the reaction solution was stirred at room temperature overnight under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered and washed with diatomaceous earth to obtain the target compound C054-2 (220.0 mg, 87.3%).
  • Step 2 Dissolve C055-1 (6.8 g, 28.661 mmol) and 10% palladium/carbon (5.0 g) in 500.0 mL of methanol solution. Keep the reaction solution at room temperature overnight under hydrogen protection. Filter the reaction solution with celite and concentrate to obtain compound C055-2 (5.8 g, 97.6%).
  • Step 4 C055-3 (5.3 g, 15.899 mmol) and 2-methylpyridine borane (5.1 g, 47.697 mmol) were dissolved in 50.0 mL of acetic acid solution. The reaction solution was reacted at room temperature for four hours, and then the temperature was raised to 90 degrees and the reaction was continued for four hours.
  • Step 5 C055-4 (3.5 g, 12.098 mmol) and lithium hydroxide (869 mg, 36.294 mmol) were dissolved in 40.0 mL of a mixture of methanol and water (1/1), and the reaction solution was reacted at 50 degrees overnight. The methanol in the reaction solution was dried by rotary evaporation, and diluted hydrochloric acid was added to adjust the acidity. At this time, solids precipitated, and the solids were filtered and collected to obtain compound C055-5 (3.0 g, 90.1%).
  • Step 8 C055-7 (200 mg, 0.81 mmol) and pyridine (200 mg, 0.81 mmol) were dissolved in 5.0 mL of tetrahydrofuran, the reaction solution was cooled to 0°C, phenyl chloroformate (254 mg, 1.63 mmol) was then added, the mixture was returned to room temperature, and stirring was continued for 1 hour.
  • Step 9 3-(6-bromo-1-oxoisoindol-2-yl)piperidine-2,6-dione (200 mg, 0.621 mmol), tributyl(1-ethoxyethylene)tin (269 mg, 0.745 mmol) and bistriphenylphosphine palladium dichloride (44 mg, 0.062 mmol) were dissolved in N,N-dimethylformamide (10.0 mL). The reaction solution was reacted at 90 degrees overnight. Dilute hydrochloric acid (1N, 5.0 mL) was added to the reaction solution, and solids precipitated. The solids were filtered and washed with ethyl acetate to obtain compound D C055-Int 2-1 (177 mg, 99.9%).
  • Step 2 C058-2 (160 mg, 0.465 mmol), (4-fluoro-3-(methoxycarbonyl)phenyl)boric acid (110 mg, 0.558 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (34 mg, 0.046 mmol) and potassium carbonate (128 mg, 0.930 mmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL).
  • Step 2 C058-3 (90 mg, 0.215 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and methanol (0.5 mL). At 0 ° C, under nitrogen protection, 3 mL of lithium hydroxide aqueous solution (2 M) was added. The reaction was reacted at 25 ° C for 1 hour. After the reaction solution was adjusted to a weak acid with hydrochloric acid aqueous solution (6 M), it was extracted with ethyl acetate (5 mL) three times, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain the product C058-4 (70 mg, 80.4%), which was directly used in the next step.
  • Step 4 C058-5 (80 mg, 0.118 mmol) was dissolved in 5 mL of dichloromethane. Under nitrogen protection, 2 mL of trifluoroacetic acid was added. After reacting at 25°C for 16 hours, the reaction solution was spin-dried and C058 (5.27 mg, 8.2%) was prepared by Prep-HPLC.
  • Step 1 C058-2 (1.0 g, 3.509 mmol) and N,N-dimethylformamide dimethyl acetal (1.5 mL) were dissolved in toluene (20.0 mL). The reaction solution was reacted at 60 degrees overnight. The reaction solution was concentrated to obtain a crude product C059-1 (1.0 g, 83.8%) which was directly used in the next step.
  • Step 2 C059-1 (1 g, 2.941 mmol) and ethylhydrazine sulfate (353 mg, 5.882 mmol) were dissolved in ethanol (20.0 mL). The reaction solution was reacted at 90 degrees overnight. The reaction solution was concentrated and the residue was purified by Prep-HPLC to obtain compound C059-2 (280 mg, 28.3%).
  • Step 4 C059-3 (80 mg, 0.253 mmol) and lithium hydroxide monohydrate (42 mg, 1.001 mmol) were dissolved in a solution of methanol (5.0 mL) and water (5.0 mL), and the reaction was allowed to react at room temperature for two hours. The reaction solution was adjusted to a weakly acidic pH, extracted three times with ethyl acetate (10.0 mL), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound C059-4 (75 mg, 97.8%).
  • Step 1 C065-0 (3 g, 15.306 mmol), ruthenium trichloride (86 mg, 0.383 mmol) and sodium periodate (10.6 g, 49.438 mmol) were dissolved in a mixed solvent of acetonitrile (10.0 mL), carbon tetrachloride (10.0 mL) and water (20.0 mL), and the reaction solution was reacted at room temperature overnight.
  • Step 3 C065-2 (2.2 g, 8.059 mmol) and 10% palladium/carbon (1.0 g) were placed in methanol (150.0 mL), and the reaction solution was reacted overnight under hydrogen protection at room temperature. The reaction solution was filtered through a diatomaceous earth pad, and the filtrate was concentrated to obtain compound C065-3 (1.9 g, 97.0%)
  • Step 4 C065-3 (50 mg, 0.206 mmol) and 3-(2-(2,6-dioxohesperidin-3-yl)-3-oxoisoindolin-5-yl) propionic acid (65 mg, 0.206 mmol) were dissolved in dichloromethane (2.0 mL) and pyridine (2.0 mL) solution, phosphorus oxychloride (0.5 mL) was added dropwise, and the reaction solution was reacted at room temperature for ten minutes.
  • Step 1 Dissolve C065-3 (100 mg, 0.412 mmol) in dichloromethane (5.0 mL), add sodium carbonate aqueous solution (70 mg dissolved in 2.0 mL water), and add triphosgene (49 mg, 0.165 mmol). The reaction solution was reacted at room temperature for half an hour. The reaction solution was extracted twice with dichloromethane (5.0 mL). The organic phases were combined and concentrated, and the crude product C066-1 was directly put into the next step.
  • Step 1 C084-0 (10 g, 53.401 mmol), di-tert-butyl dicarbonate (14 g, 64.212 mmol), 4-dimethylaminopyridine (6.6 g, 53.401 mmol), triethylamine (16.2 g, 160.404 mmol) were dissolved in tetrahydrofuran (100.0 mL).
  • Step 2 C084-1 (12.5 g, 43.554 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (19.4 g, 83.621 mmol), tert-butyl lithium (5.0 g, 62.722 mmol), N,N-dimethylpropylene urea (2.7 g, 20.911 mmol) were dissolved in tetrahydrofuran (100.0 mL). The reaction solution was reacted at room temperature overnight.
  • Step 3 C084-2 (10.1 g, 27.371 mmol) and sodium hydroxide (3.3 g, 82.506 mmol) were dissolved in 60.0 mL of a mixed solution of methanol and water (1/1), and the reaction solution was reacted at room temperature for three hours. The reaction solution was neutralized and extracted with ethyl acetate (50.0 mL*3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain compound C084-3 (9.0 g, 92.8%).
  • Step 1 C068-0 (600 mg, 2.381 mmol) was dissolved in anhydrous N, N-dimethylformamide (10.0 mL), sodium hydrogen (240 mg, 6.012 mmol, 60% in mineral oil) was added under ice bath, stirring was maintained at zero degree for 40 minutes, iodoethane (1.6 g, 10.256 mmol) was added, and stirring was gradually restored to room temperature for 4 hours.
  • Step 3 Dissolve the raw material C068-2 (200 mg, 0.751 mmol) in anhydrous dimethyl sulfoxide, add triethylamine (0.3 mL), diphenylphosphoryl azide (250 mg, 0.912 mmol), INT-2 (250 mg, 0.912 mmol), and react at 90 degrees for 2 hours.
  • Step 1 Dissolve C069-0 (4.7 g, 27.6 mmol) and 4,4-difluorocyclohexane-1-one (4.46 g, 33.1 mmol) in acetonitrile (30 mL). Add triethylsilyl (22.0 mL, 138.1 mmol) and trifluoroacetic acid (10.6 mL, 138.1 mmol) under nitrogen protection. After stirring at 80 ° C for 2 hours, the reaction solution was poured into a saturated aqueous ammonium chloride solution (15 mL) to quench and extracted with ethyl acetate.
  • Step 3 C069-2 (100 mg, 0.33 mmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL) and methanol (1 mL). At 0°C, under nitrogen protection, 5 mL of aqueous lithium hydroxide solution (2 M) was added. After the reaction was allowed to react at 25°C for 1 hour, the reaction solution was adjusted to weak acidity with aqueous hydrochloric acid solution (6 M). The mixture was extracted with ethyl acetate (8 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the product C069-3 (85 mg, 89.5%), which was used directly in the next step.
  • Step 4 C069-3 (85 mg, 0.29 mmol) and INT-2 (97 mg, 0.35 mmol) were dissolved in dimethyl sulfoxide (5 mL). Diphenylphosphoryl azide (0.07 mL, 0.35 mmol) and triethylamine (0.12 mL, 0.89 mmol) were added at 0°C under nitrogen protection. After the reaction was reacted at 90°C for 1 hour, it was quenched with saturated sodium bicarbonate aqueous solution (15 mL), extracted with ethyl acetate (8 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was prepared by Prep-HPLC to obtain the product C069 (24.86 mg, 15.1%).
  • Step 2 C070-1 (1.0 g, 3.27 mmol) was dissolved in 10.0 mL of dimethyl sulfoxide solvent, potassium carbonate (2.32 g, 9.83 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.56 g, 9.83 mmol) were added to the reaction solution, and stirred at 60°C for 3 hours. After the reaction was completed, the reaction mixture was extracted with water (10.0 mL) and ethyl acetate (10.0 mL*3), the organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried to obtain the target compound C070-2 (1.1 g, 89.5%).
  • Step 3 C070-2 (1.1 g, 2.84 mmol) was dissolved in 10.0 mL of methanol solvent, and then 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (0.43 g, 0.57 mmol) and triethylamine (0.88 g, 8.52 mmol) were added, and the mixture was ventilated with a carbon monoxide balloon three times. The reaction solution was stirred at 60°C overnight under a carbon monoxide atmosphere.
  • Step 4 Dissolve C070-3 (700.0 mg, 1.91 mmol) in 5.0 mL of dichloromethane solution, then add 5.0 mL of trifluoroacetic acid, stir at room temperature for 2 hours. After the reaction is completed, the reaction solution is dried to obtain the target compound C070-4 (325.0 mg, 63.8%)
  • Step 5 C070-4 (150.0 mg, 0.56 mmol) was dissolved in 2.0 mL of methanol and 8.0 mL of tetrahydrofuran solution, and then 2.0 mL of lithium hydroxide aqueous solution (2M) was added. After the reaction was complete, the reaction solution was adjusted to pH 5.0 with dilute hydrochloric acid, and then ethyl acetate (20.0 mL) was added and extracted three times. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain the target compound C070-5 (130.0 mg, 92.2%).

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Abstract

La présente divulgation concerne un nouveau modulateur de protéine GSPT1. Le nouveau modulateur de GSPT1 de la présente invention présente une affinité élevée, peut dégrader GSPT1, et a donc le potentiel de prévenir et de traiter des maladies, des troubles ou des états pathologiques associés à GSPT1.
PCT/CN2024/107819 2023-07-28 2024-07-26 Composé arylamine ayant un effet de dégradation de protéine Pending WO2025026218A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN120441535A (zh) * 2025-07-08 2025-08-08 苏州国匡医药科技有限公司 一种含炔基的gspt1降解剂及其应用

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111285850A (zh) * 2018-12-06 2020-06-16 中国科学院上海药物研究所 一类异吲哚啉类化合物、其制备方法、药物组合物及其应用
CN114650868A (zh) * 2019-10-30 2022-06-21 达纳-法伯癌症研究公司 Helios的小分子降解剂及其使用方法
WO2022152821A1 (fr) * 2021-01-13 2022-07-21 Monte Rosa Therapeutics Ag Composés d'isoindolinone
WO2022200857A1 (fr) * 2021-03-22 2022-09-29 Monte Rosa Therapeutics Ag Compositions pharmaceutiques destinées à être utilisées pour prévenir ou traiter une maladie ou un trouble provoqué par ou associé à un ou plusieurs codons de terminaison prématurés
WO2023069720A1 (fr) * 2021-10-22 2023-04-27 Monte Rosa Therapeutics, Inc. Composés qui assurent la médiation de la dégradation de protéines et leurs procédés d'utilisation
WO2024015855A1 (fr) * 2022-07-13 2024-01-18 Monte Rosa Therapeutics, Inc. Polythérapie comprenant des agents de dégradation de colle moléculaire ciblant le gspt1 et des inhibiteurs de la voie pi3k/akt/mtor
CN117917402A (zh) * 2022-10-21 2024-04-23 暨南大学 异吲哚酰胺类化合物及其药物组合物和应用
WO2024109918A1 (fr) * 2022-11-24 2024-05-30 西藏海思科制药有限公司 Agent de dégradation de gspt1 et son utilisation en médecine
WO2024125437A1 (fr) * 2022-12-13 2024-06-20 南京圣和药业股份有限公司 Agent de dégradation de gspt1 et son utilisation

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111285850A (zh) * 2018-12-06 2020-06-16 中国科学院上海药物研究所 一类异吲哚啉类化合物、其制备方法、药物组合物及其应用
CN114650868A (zh) * 2019-10-30 2022-06-21 达纳-法伯癌症研究公司 Helios的小分子降解剂及其使用方法
WO2022152821A1 (fr) * 2021-01-13 2022-07-21 Monte Rosa Therapeutics Ag Composés d'isoindolinone
WO2022200857A1 (fr) * 2021-03-22 2022-09-29 Monte Rosa Therapeutics Ag Compositions pharmaceutiques destinées à être utilisées pour prévenir ou traiter une maladie ou un trouble provoqué par ou associé à un ou plusieurs codons de terminaison prématurés
WO2023069720A1 (fr) * 2021-10-22 2023-04-27 Monte Rosa Therapeutics, Inc. Composés qui assurent la médiation de la dégradation de protéines et leurs procédés d'utilisation
WO2024015855A1 (fr) * 2022-07-13 2024-01-18 Monte Rosa Therapeutics, Inc. Polythérapie comprenant des agents de dégradation de colle moléculaire ciblant le gspt1 et des inhibiteurs de la voie pi3k/akt/mtor
CN117917402A (zh) * 2022-10-21 2024-04-23 暨南大学 异吲哚酰胺类化合物及其药物组合物和应用
WO2024109918A1 (fr) * 2022-11-24 2024-05-30 西藏海思科制药有限公司 Agent de dégradation de gspt1 et son utilisation en médecine
WO2024125437A1 (fr) * 2022-12-13 2024-06-20 南京圣和药业股份有限公司 Agent de dégradation de gspt1 et son utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 22 June 2022 (2022-06-22), XP093272149, Database accession no. 2776091-07-5 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN120441535A (zh) * 2025-07-08 2025-08-08 苏州国匡医药科技有限公司 一种含炔基的gspt1降解剂及其应用

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