WO2019170150A1 - 蛋白降解靶向bcr-abl化合物及其抗肿瘤应用 - Google Patents

蛋白降解靶向bcr-abl化合物及其抗肿瘤应用 Download PDF

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WO2019170150A1
WO2019170150A1 PCT/CN2019/077535 CN2019077535W WO2019170150A1 WO 2019170150 A1 WO2019170150 A1 WO 2019170150A1 CN 2019077535 W CN2019077535 W CN 2019077535W WO 2019170150 A1 WO2019170150 A1 WO 2019170150A1
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amino
piperazin
dioxopiperidin
carboxamide
benzyl
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PCT/CN2019/077535
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English (en)
French (fr)
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杨小宝
姜标
阴倩倩
陈金聚
赵全菊
任超伟
孙仁红
孙宁
仇星
孔莹
李岩
刘林义
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上海科技大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
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    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
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    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present disclosure relates to compounds for protein degradation targeting BCR-ABL fusion proteins and their anti-tumor applications.
  • T(9;22)(q34;q11) chromosomal ectopic also known as Philadelphia philosomal translocation or Philadelphia chromosome (Ph), which shows that the long arm of chromosome 9 and the long arm of chromosome 22 interact with each other.
  • Translocation translocation of the Abelson leukemia virus (ABL) 1 gene located on chromosome 9 to the breakpoint cluster region (Bcr) gene, forming a Bcr-Abl fusion gene [1] ,2].
  • ABL Abelson leukemia virus
  • Bcr breakpoint cluster region
  • This characteristic ectopic ectopic is present in most chronic myeloid leukemia (CML), part of acute lymphoblastic leukemia (ALL) and a few acute myeloid leukemia (AML).
  • CML chronic myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • tyrosine protein kinases Under normal conditions, the activity of tyrosine protein kinases is strictly regulated. Compared with normal tyrosine protein kinases, BCR-ABL fusion proteins have sustained activation of tyrosine kinase (TK) and activate downstream signaling pathways, including RAS, Janus kinase (JAK)/signal transcripts.
  • TK tyrosine kinase
  • JK Janus kinase
  • TKIs tyrosine kinase inhibitors
  • Gleevec is the first molecularly targeted drug for the treatment of tumors. It was approved for marketing in the United States in 2001. As the first TKI inhibitor against BCR-ABL protein, it became the first-line drug for the treatment of CML [7] ]. Its mechanism of action is to replace the ATP of the BCR-ABL fusion protein structure, so that the tyrosine kinase catalytic central site can not bind to ATP, competitively inhibit BCR-ABL autophosphorylation and substrate phosphorylation. In order to inhibit the proliferation of BCR-ABL-positive leukemia cells and promote their apoptosis. It has good curative effect and safety.
  • the number of point mutations has been confirmed to increase gradually, which can occur in the ATP-binding loop (P-loop), the imatinib binding site, the activation loop (A-loop), and the catalytic region (C-loop). These point mutations are directly Blocking or indirectly interfering with the binding of the drug to the Bcr-Abl protein, thus reducing the patient's sensitivity to treatment.
  • BCR-ABL TKI inhibitors In order to overcome the resistance of imatinib, the second generation of BCR-ABL TKI inhibitors emerged, including dasatinib-dsatinib (Sprycel) [9] [10] and bosutinib (Bosulif) [11] can inhibit imatinib resistance caused by most BCR-ABL mutations other than T315I.
  • Dasatinib is a dual kinase inhibitor of the Bcr-Abl tyrosine kinase and the Src family kinase. Studies have shown that the occurrence of Ph + leukemia is dependent on the dual activation of Src kinase and BCR-ABL kinase [12], dasatinib inhibits both tyrosine kinase and Src kinase, and can penetrate the blood-brain barrier, in 2006 6 On the 28th of the month, the US FDA was used to treat CML and Ph + ALL.
  • dasatinib Unlike imatinib, the inhibitory effect of dasatinib is independent of conformation and binds to both activated and non-activated forms of Bcr-Abl kinase, thus overcoming resistance caused by point mutations in many ABL kinase regions (T3151) Except for mutants).
  • dasatinib can also inhibit the autophosphorylation of Src kinase protein in a variety of human tumor cells, and is also effective for some solid tumors [13].
  • Bosutinib is a potent dual inhibitor of protein kinase Src-ABL that potently inhibits wild-type BCR-ABL and most Imatinib-resistant BCR-ABL mutations (except V299L and T315I), September 2012
  • the FDA approved the treatment of patients with CML who were intolerant or resistant to imatinib in the chronic phase, accelerated phase or blast phase, and clinical studies have shown that it is also effective for some solid tumors [14].
  • TKI can not eliminate CML leukemia stem cells
  • this group of leukemia stem cells is the root cause of disease recurrence, so CML patients need long-term medication.
  • a theoretical hypothesis is that although TKI can inhibit the kinase activity of BCR-ABL in leukemia stem cells, BCR-ABL can play a non-kinase activity function and act as a scaffold protein "protein scaffold”. Signal pathways help leukemia stem cell survival [17]. Therefore, the therapeutic strategy of targeting degradation of BCR-ABL may be effective in clearing CML leukemia stem cells, solving the problem of patients needing long-term medication and the resulting secondary resistance.
  • Target proteins can be used to treat tumors by degrading protein expression.
  • the ubiquitin-mediated protein degradation pathway controls the selective degradation of most proteins in eukaryotic cells.
  • proteins are first labeled with ubiquitin and then recognized and degraded by the proteasome.
  • Ubiquitin-protein ligase (E3) binds directly to proteins, which determines the specificity of degradation [18].
  • Designing a Proteolysis Targeting Drug (PROTAD) using an in vivo ubiquitination process is a new model for drug development.
  • PROTAD small molecule drugs use the cell's inherent ubiquitin-proteasome system to regulate targeted protein degradation [19].
  • PROTAD can simultaneously bind to the target protein and E3 ubiquitin ligase, ubiquitinating the target protein that could not bind to E3, and then being recognized and degraded by the proteasome.
  • PROTAD's target proteins can be proteins with no significant active sites, such as transcription factors and scaffold proteins, which are often difficult to design by small molecules.
  • Agent [20] Therefore, PROTAD has a very broad application prospect, and the application research of PROTAD technology has been successfully reported, including estrogen-related receptor ⁇ [21], cell retinoic acid binding protein (CRABP-II) [22] and BRD4 [20]. ].
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present disclosure also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament:
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof, of the present disclosure for use in the prevention and/or treatment of cancer.
  • the present disclosure also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention and/or treatment of cancer.
  • the present disclosure also provides a method of treating or preventing cancer comprising administering to a subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof .
  • FIG. 1 shows the detection of a series of PROTAD compounds ((1)-(27) and (30)-(35) in FIG. 1) compared to the comparative example compounds according to an embodiment of the present disclosure by Western-blot method.
  • FIG. 2 shows the degradation activity of a Dasa-Lin-VHL system compound (SIAIS 151178) against a BCR-ABL resistant mutant according to an embodiment of the present disclosure.
  • FIG. 3 shows the effect of a Dasa-Lin-VHL system PROTAD compound (SIAIS 151178) on a BCR-ABL + K562 cell xenograft mouse model in accordance with an embodiment of the present disclosure.
  • FIG. 4 shows the degradation activity of the Dasa-Lin-VHL system PROTAD compound (SIAIS 151178) on BCR-ABL protein at an in vivo level according to an embodiment of the present disclosure.
  • an aspect of the present disclosure provides a compound of formula (I):
  • Bcr-abl-TKIs is covalently linked to LIN via a group A, and wherein the ULM is covalently linked to LIN;
  • Bcr-abl-TKIs is a Bcr-abl tyrosine kinase inhibitor or an analog thereof having the same function
  • LIN is a linking group which is a linear or branched alkylene chain, wherein the linear or branched alkylene chain is optionally one or more -O-, -CONH-, -NHCO -, -NH-, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof interrupted one or more times, wherein the linear or branched
  • the alkylene chain of the chain is optionally substituted with one or more substituents;
  • ULM is a small molecule ligand of VHL or CRBN protease with ubiquitination
  • Group A is -CO-
  • the Bcr-abl-TKIs represents a portion of a compound represented by the following structural formula:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 each independently represent an alkyl group or H.
  • the R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 are independently Represents a linear or branched C 1-10 alkyl group or H.
  • the C 1-10 alkyl group is preferably a C 1-9 alkyl group, more preferably a C 1-8 alkyl group, still more preferably a C 2-8 alkyl group, more preferably It is a C 1-7 alkyl group, even more preferably a C 1-6 alkyl group, a C 1-5 alkyl group, or a C 1-4 alkyl group, or a C 1-3 alkyl group.
  • Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and Tepentyl.
  • the ULM represents a structure of the following formula (II):
  • X represents -CH 2 - or -CO-
  • Y represents -CH 2 -, -NH- or -O-
  • Z 1 represents a carbonyl group or Z 1 is absent.
  • the ULM represents a structure of the following formula (III):
  • Z 2 represents a carbonyl group or is absent.
  • the LIN is a methylene group or a linear or branched C 2 -C 30 alkylene chain (preferably a C 2 -C 29 alkylene chain, C 2 -C 28 Alkyl chain, C 2 -C 27 alkylene chain, C 2 -C 26 alkylene chain, C 2 -C 25 alkylene chain, C 2 -C 24 alkylene chain, C 2 -C 23 Alkyl chain, C 2 -C 22 alkylene chain, C 2 -C 21 alkylene chain, C 2 -C 20 alkylene chain, C 2 -C 19 alkylene chain, C 2 -C 18 Alkyl chain, C 2 -C 17 alkylene chain, C 2 -C 16 alkylene chain, C 2 -C 15 alkylene chain, C 2 -C 14 alkylene chain, C 2 -C 13 Alkyl chain, C 2 -C 12 alkylene chain, C 2 -C 11 alkylene chain, C 2 -C 10
  • the LIN represents: a linear or branched C 1 -C 20 alkylene chain, -(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -, -( CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -O-(CH 2 ) n3 -, -(CR 13 R 14 ) n1 -(O(CR 15 R 16 ) n2 ) m1 -, -(CR 17 R 18 ) n1 -(O(CR 19 R 20 ) n2 ) m1 -O-(CR 21 R 22 ) n3 -, -(CH 2 ) n1 -(CONH-(CH 2 ) n2 ) m1 -, -(CH 2 ) n1 -(CONH-(CH 2 ) n2 ) m1 -O-(CH 2 )
  • N1, n2, n3, n4, n5, n6, m1, m2 independently represent 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 An integer of 17, 18, 19 or 20.
  • the LIN represents -(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -O- (CH 2 ) n3 -, wherein n1, n2, n3, m1 independently represent 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 An integer of 17, 18, 19 or 20; wherein said LIN is optionally substituted by one or more substituents selected from the group consisting of hydroxyl, amino, thiol and halogen.
  • the LIN represents:
  • the LIN represents a linear or branched C 1 -C 20 alkylene chain optionally substituted with one or more substituents, wherein the substituent is selected from a hydroxyl group, Amino group, mercapto group and halogen.
  • the LIN represents:
  • the LIN is a linear or branched alkylene chain substituted by one or more substituents one or more times, wherein the substituent is selected from the group consisting of a hydroxyl group, an amino group, a thiol group, and halogen.
  • the LIN is a linear or branched C 1 -C 30 alkylene chain substituted with one or more substituents selected from a hydroxyl group, an amino group, a thiol group, a halogen or a combination thereof.
  • the substituent may be, for example, 1-30, 1-25, 1-20, or 1-15, 1-10, 1-9, 1-8, 1 -7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 8, 8, 7, 6, 5, 4, 3, 2, 1.
  • the LIN represents a straight or branched alkylene chain interrupted by one or more heterocyclic or heteroarylene groups or any combination thereof, or a -(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - whose carbon chain is interrupted one or more times by one or more arylene or heterocyclylene or heteroarylene or any combination thereof, Wherein n1, n2, and m1 independently represent 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 An integer; wherein the LIN is optionally substituted with one or more substituents selected from the group consisting of a hydroxyl group, an amino group, a thiol group, and a halogen.
  • the LIN represents:
  • N1, n2, n3, n4, n5, n6, m1, m2 independently represent 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 An integer of 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30.
  • the LIN represents:
  • the LIN represents -(CH 2 ) n1 -(CONH-(CH 2 ) n2 ) m1 -, -(CH 2 ) n1 -(CONH-(CH 2 ) n2 ) m1 - O-(CH 2 ) n3 -, or -(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -O-(CH 2 ) n3 -CONH-(CH 2 ) n4 -(O(CH 2 ) n5 M2 -O-(CH 2 ) n6 -; wherein n1, n2, n3, n4, n5, n6, m1, m2 independently represent 1, 2, 3, 4, 5, 6, 7, 8, 9, An integer of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; wherein said LIN is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, Sul
  • the LIN represents -(CH 2 ) n1 -NHCO-(CH 2 ) n2 -, wherein n1, n2 independently represent 1, 2, 3, 4, 5, 6, 7 An integer of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30;
  • the LIN is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, sulfhydryl and halogen.
  • the LIN is -(CH 2 ) n1 -NHCO-(CH 2 ) n2 -, wherein n1, n2 independently represent 1, 2, 3, 4, 5, 6, 7 An integer of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30.
  • the LIN is -CH 2 NHCOCH 2 -, -(CH 2 ) 2 NHCO(CH 2 ) 2 -, -(CH 2 ) 3 NHCO(CH 2 ) 3 -, -( CH 2 ) 4 NHCO(CH 2 ) 4 -, -(CH 2 ) 5 NHCO(CH 2 ) 5 -, -(CH 2 ) 6 NHCO(CH 2 ) 6 -, -(CH 2 ) 6 NHCO(CH 2 6 -, -(CH 2 ) 7 NHCO(CH 2 ) 7 -, -(CH 2 ) 8 NHCO(CH 2 ) 8 -, -(CH 2 ) 9 NHCO(CH 2 ) 9 -, -(CH 2 10 NHCO(CH 2 ) 10 -, -(CH 2 ) 11 NHCO(CH 2 ) 11 -, -(CH 2 ) 12 NHCO(CH 2 )
  • the LIN represents a linear or branched alkylene chain interrupted by one or more alkenylene groups one or more times; wherein the LIN is optionally one or more Substituted by a substituent selected from the group consisting of a hydroxyl group, an amino group, a fluorenyl group, and a halogen.
  • the LIN represents a linear or branched alkylene chain interrupted one or more times by one or more alkynylene groups; wherein the LIN is optionally one or more Substituted by a substituent selected from the group consisting of a hydroxyl group, an amino group, a fluorenyl group, and a halogen.
  • the LIN is -(CH 2 ) n1 -C ⁇ C-(CH 2 ) n2 - or -(CH 2 ) n1 -C ⁇ CC ⁇ C-(CH 2 ) n2 -
  • n1, n2 independently represent 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21
  • the compound of formula (I) may also be a compound of formula (IV):
  • the compound of formula (I) may also be a compound of formula (V):
  • the compound of formula (I) may also be a compound of formula (VI):
  • the compound of formula (I) may also be a compound of formula (VII):
  • the compound of formula (I) may also be a compound of formula (VIII):
  • the compound of formula (I) may also be a compound of formula (IX):
  • the compounds of formula (I) of the present disclosure may have a stereo configuration and thus may exist in more than one stereoisomeric form.
  • the present disclosure also relates to compounds having a substantially pure isomeric form having a stereo configuration, such as greater than about 90% ee, such as about 95% ee or 97% ee, or greater than 99% ee, and mixtures thereof, including racemic mixtures.
  • These isomers can be prepared using asymmetric syntheses (e.g., chiral intermediates) or by chiral resolution.
  • Another aspect of the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as described in the present disclosure, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present disclosure further includes at least one additional drug for treating or preventing cancer.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof, of the present disclosure is for use as a medicament.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof, of the present disclosure for use in the prevention and/or treatment of cancer.
  • the cancer is selected from the group consisting of: Ph + chronic myeloid leukemia (CML): including chronic phase (CP) in chronic phase, accelerated phase (AP) in accelerated phase, and blast crisis in blast crisis (BC); Ph + acute lymphoblastic leukemia (ALL); PDGFR (platelet-derived growth factor receptor) gene rearrangement related myelodysplastic syndrome / myeloproliferative diseases (MDS) /MPD); invasive systemic mastocytosis (ASM); Hypereosinophilic Syndrome (HES); Chronic Eosinophilic Leukemia (CEL); Dermatofibrosarcoma protuberans (DFSP); and Kit + gastrointestinal stromal tumor (GIST).
  • CML chronic myeloid leukemia
  • ALL chronic lymphoblastic leukemia
  • ALL Ph + acute lymphoblastic leukemia
  • PDGFR platelet-derived growth factor receptor gene rearrangement related myelodysplastic syndrome / myeloproliferative diseases (MDS) /MP
  • the Ph + chronic myeloid leukemia is in a chronic phase, an accelerated phase, or a blast phase.
  • the compounds of formula I of the present disclosure, and pharmaceutically acceptable salts thereof, are useful, for example, as agents for pharmaceutical compositions for parenteral or parenteral administration.
  • the pharmaceutical composition can be prepared according to any means known to those of ordinary skill in the art by combining the compound of formula I or a pharmaceutically acceptable salt thereof, optionally with other medically valuable substances, together with suitable, none This is accomplished by toxic, inert, therapeutically compatible solid or liquid carrier materials and, where appropriate, conventional pharmaceutical adjuvants, together with suitable forms of administration of the desired formulation.
  • the amount of active ingredient compound is sufficient to produce the desired effect on the course or condition of the disease.
  • the pharmaceutical compositions can be prepared in a variety of different dosage forms after sterilization according to methods known in the pharmaceutical art.
  • the pharmaceutical compositions of the present disclosure may be formulated into powders, troches, tablets (for example, conventional tablets, dispersible tablets, orally disintegrating tablets), granules, suitable for oral administration, depending on the desired route of administration.
  • a solution for example, a sterile injectable solution prepared by using water, Ringer's solution or isotonic sodium chloride solution or the like as a carrier or solvent according to methods known in the art
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof, of the present disclosure is for use in the preparation of a medicament for preventing and/or treating cancer.
  • the cancer is selected from the group consisting of: Ph + chronic myeloid leukemia (CML): including chronic phase (CP) in chronic phase, accelerated phase (AP) in accelerated phase, and blast in blast phase Crisis (BC); Ph + acute lymphoblastic leukemia (ALL); PDGFR (platelet-derived growth factor receptor) gene rearrangement related myelodysplastic syndrome / myeloproliferative diseases (myelodysplastic / myeloproliferative diseases, MDS/MPD); aggressive systemic mastocytosis (ASM); Hypereosinophilic Syndrome (HES); Chronic Eosinophilic Leukemia (CEL); Dermatofibrosarcoma protuberans (DFSP); and Kit + gastrointestinal stromal tumor (GIST).
  • CML chronic myeloid leukemia
  • ALL chronic lymphoblastic leuk
  • the cancer is selected from the group consisting of: Ph + chronic myeloid leukemia (CML): including chronic phase (CP) in chronic phase, accelerated phase (AP) in accelerated phase, and blast crisis in blast crisis (BC); Ph + acute lymphoblastic leukemia (ALL); PDGFR (platelet-derived growth factor receptor) gene rearrangement related myelodysplastic syndrome / myeloproliferative diseases (MDS) /MPD); invasive systemic mastocytosis (ASM); Hypereosinophilic Syndrome (HES); Chronic Eosinophilic Leukemia (CEL); Dermatofibrosarcoma protuberans (DFSP); and Kit + gastrointestinal stromal tumor (GIST).
  • CML chronic myeloid leukemia
  • ALL chronic lymphoblastic leukemia
  • ALL PDGFR (platelet-derived growth factor receptor) gene rearrangement related myelodysplastic syndrome / myeloproliferative diseases (MDS) /MPD
  • ASM invasive systemic mast
  • the compound of the formula (I), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the present disclosure may be administered by any suitable method. , for example, by at least one selected from the group consisting of nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, pleural administration, peritoneal administration, vaginal administration, intramuscular administration Administration to subcutaneous administration, transdermal administration, epidural administration, intrathecal administration, and intravenous administration is administered to the subject.
  • the bond broken by the wavy line shows the point at which the depicted group is attached to other portions of the molecule.
  • the ULM represents the following structure of the formula (II)
  • X represents -CH 2 - or -CO-
  • Y represents -CH 2 -, -NH- or -O-
  • Z 1 represents a carbonyl group or Z 1 is absent. It is a derivative of CRBN ubiquitin ligase small molecule ligands Thalidomide, Lenalidomide, or Pomalidomide.
  • the ULM represents the following structure of the formula (III)
  • Z 2 represents a carbonyl group or is absent. It is VHL-1 (chemical name is (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl) a derivative of benzyl)pyrrolidine-2-carboxamide).
  • the compounds of formula (I) of the present disclosure are also referred to as PROTAD compounds, PROTAD small molecules, or degradation agents, and are used interchangeably.
  • LIN and “linker” are used interchangeably and each denote a linking group LIN in a compound of formula I.
  • halogen atom or halogen, used alone or in combination, means fluorine, chlorine, bromine or iodine, and is preferably F, Cl or Br.
  • alkyl used alone or in combination, refers to a straight or branched alkyl group.
  • C x -C y alkyl (x and y each being an integer) refers to a straight or branched alkyl group containing from x to y carbon atoms.
  • C 1-10 alkyl as used in the present disclosure, alone or in combination, means a straight or branched alkyl group having 1 to 10 carbon atoms.
  • the C 1-10 alkyl group of the present disclosure is preferably a C 1-9 alkyl group, more preferably a C 1-8 alkyl group, still more preferably a C 2-8 alkyl group, more preferably a C 1-7 alkyl group, or even More preferably, it is a C 1-6 alkyl group, a C 1-5 alkyl group, or a C 1-4 alkyl group.
  • C 1-3 alkyl refers to an alkyl group having 1 to 3 carbon atoms, and illustrative examples thereof include a methyl group, an ethyl group, a n-propyl group, and an isopropyl group.
  • alkylene (which is used interchangeably with “alkylene chain”), alone or in combination, refers to a straight or branched divalent saturated hydrocarbon group consisting of carbon and hydrogen atoms.
  • Cx- Cy alkylene (x and y each being an integer) refers to a straight or branched alkylene group containing from x to y carbon atoms.
  • the C 1 -C 30 alkylene group of the present disclosure is preferably a C 1 -C 29 alkylene group, a C 1 -C 28 alkylene group, a C 1 -C 27 alkylene group, a C 1 -C 26 alkylene group, C 1 -C 25 alkylene, C 1 -C 24 alkylene, C 1 -C 23 alkylene, C 1 -C 22 alkylene, C 1 -C 21 alkylene, C 1 -C 20 Alkyl, C 1 -C 19 alkylene, C 1 -C 18 alkylene, C 1 -C 17 alkylene, C 1 -C 16 alkylene, C 1 -C 15 alkylene, C 1 -C 14 alkylene, C 1 -C 13 alkylene, C 1 -C 12 alkylene, C 1 -C 11 alkylene, C 1 -C 10 alkylene, C 1 -C 9 alkylene , C 1 -C 8 alkylene, C 1
  • Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylidene, butylene, isobutylene, sec-butyl, tert-butyl, pentylene, isoamyl , nalopentyl, atpentylene, hexylene, heptylene, octylene, fluorenylene, fluorenylene, undecylene, dodecylene, decylene, ya Tetraalkyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, undecylene, decylene, arsenyl, sub-twenty Dialkyl, tetracosyl, tetracosyl, halopentadecyl, dihexadecyl, heptacosyl, septylene, sub-nine Alkyl, and tridecy
  • arylene refers to a divalent aromatic hydrocarbon group containing from 5 to 14 carbon atoms and optionally one or more fused rings, such as phenylene or sub. Naphthyl or anthracenylene.
  • the "arylene” is an optionally substituted arylene.
  • the substituted arylene group means an arylene group substituted by a substituent 1-3 times, wherein the substituent is selected from a C 1-3 alkyl group, a C 1-3 alkoxy group, a halogen, an amino group or a hydroxyl group.
  • C 1-3 alkoxy used alone or in combination means a straight or branched alkoxy group having 1 to 3 carbon atoms.
  • Representative examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy. Preferred are methoxy and ethoxy.
  • cycloalkyl used alone or in combination, refers to a single ring having from 3 to 12 carbon atoms saturated and partially unsaturated (ie having one or more double bonds, but not fully conjugated). Or a bicyclic cyclic hydrocarbon group.
  • C 3 -C 10 cycloalkyl means a monocyclic saturated and partially unsaturated having 3 to 10 carbon atoms (i.e., having one or more double bonds, but not fully conjugated) cyclic or bicyclic hydrocarbon.
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decahydronaphthalene, octahydrogen And cyclopentadiene, octahydro-1H-indole, spiro group.
  • cycloalkylene used alone or in combination, refers to a single having from 3 to 12 carbon atoms saturated and partially unsaturated (ie having one or more double bonds, but not fully conjugated).
  • a cyclic or bicyclic cyclic hydrocarbon divalent group used alone or in combination, refers to a single having from 3 to 12 carbon atoms saturated and partially unsaturated (ie having one or more double bonds, but not fully conjugated).
  • cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexylene, cycloheptylene, and subring Octyl, dedecalinyl, octahydrocyclopentadienyl subunit, octahydro-1H-fluorene subunit, sirocyclo.
  • a cycloalkylene group can be unsubstituted or substituted according to well-defined definitions.
  • heteroarylene used alone or in combination means having one or more (for example, 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3).
  • heteroarylene groups include, but are not limited to, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienylene, thiazolyl, isoisothiazolyl, A thiadiazole group, a pyridostylene group, an imidazolyl group, a pyrazolyl group, a tributazolyl group, a pyridylene group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, an anthranylene group, a pyridinium group Sulfhydryl, benzofuranyl, isophthalonitrile, benzothiophenyl, carbazolyl, benzimidazolyl, benzoxazolyl, benzoxisoxazolyl, phenylene Thiazolyl, benzotrithiazolyl, benzotriazolyl, benzo[2,1,3]
  • heterocyclylene used alone or in combination, refers to a 4- to 6-membered saturated divalent monocyclic group comprising one or more independently selected from the group consisting of sulfur, oxygen and nitrogen. Hetero atom.
  • heterocyclylene examples include, but are not limited to, sulfabutyl, oxetylene, pyrrolidinyl, imidazolidinyl, pyridazolidinyl, arazolyl, arylene Tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidine, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and Dioxolyl.
  • the heterocyclylene group can be unsubstituted or substituted as defined.
  • alkynylene used alone or in combination, means having from 2 to 10 (preferably from 2 to 6, more preferably from 2 to 4) carbon atoms having one or more carbon-carbon triple bonds.
  • preferred alkynylene groups include, but are not limited to, ethynylene, 1-propynylene, 1-butynylene, and 1,3-diacetylene.
  • alkenylene used alone or in combination, means 2 to 10 (preferably 2 to 6, more preferably 2 to 4) carbon atoms having one or more carbon-carbon double bonds.
  • alkenylene groups include, but are not limited to, vinylidene, 1-propene subunit, 1-butene subunit.
  • Salts or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs of the compounds of formula I described herein are also encompassed within the scope of the disclosure.
  • the salt or pharmaceutically acceptable salt of the compound of Formula I refers to a non-toxic inorganic or organic acid and/or base addition salt.
  • examples include: sulfates, hydrochlorides, citrates, maleates, sulfonates, or p-toluenesulfonates, and the like.
  • “Pharmaceutically acceptable carrier” means a pharmaceutically acceptable material such as a filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, A useful compound is carried or transported into a patient or administered to a patient such that it can perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another organ or part of the body.
  • the carrier is compatible with the other ingredients of the formulation, including the compounds useful in the present disclosure, and is not deleterious to the patient, and the carrier must be "acceptable.”
  • materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, B Cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil And soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide And aluminum hydroxide;
  • the "therapeutically effective amount" of a compound of the present disclosure depends on the age, sex and weight of the patient, the current medical condition of the patient, and the cancer progression of the patient being treated. Those skilled in the art will be able to determine appropriate dosages based on these and other factors.
  • room temperature refers to ambient temperature, such as a temperature of 20-30 °C.
  • the compound developed by the present disclosure belongs to a protein degradation targeting small molecule compound, which is mainly composed of four parts.
  • the first part of BCR-ABL-TKIs is a compound having BCR-ABL tyrosine kinase inhibitory activity; the second part is LIN Linking unit; the third part of ULM is a small molecule ligand of VHL or CRBN protease with ubiquitination function; and the fourth part of group A is a carbonyl group, which covalently binds BCR-ABL-TKIs and LIN, and LIN and ULM is covalently combined.
  • the specific recognition of the target protein by Bcr-abl-TKIs inhibits the tyrosine kinase activity of Bcr-abl, while the E3 ligase specifically ubiquitinates the Bcr-abl protein to be degraded by the proteasome system, targeting BCR-ABL.
  • the PROTAD small molecule of the present disclosure eliminates the pathogenic BCR-ABL fusion protein by degradation, and on the one hand can obtain genetic or molecular biological remission in Ph + leukemia patients, and on the other hand, to overcome the resistance of targeted drugs. Great significance.
  • PROTAD small molecule designed and developed by the present disclosure can also degrade other tyrosine kinase receptors, such as KIT, SRC protein kinase and PDGFR, and has potential value for the treatment of these target-related tumors.
  • the CO 2 C-LIN-ULM linking group is formed by covalently linking with ULM (Ubiquitin Ligase binding Moiety)
  • the product was subjected to column chromatography (silica gel: 200-300 mesh), and a C18 reverse phase column (100 g) was used for separation. All reactions were carried out in an air atmosphere without special explanation; the reaction was followed by TLC or LC-MS.
  • Solvents and reagents are processed as follows:
  • N-(2-Chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide (1.0 g, 2.54 mmol)
  • Anhydrous piperazine (1.31 g, 15.21 mmol)
  • N,N-diisopropylethylamine (4.9 g, 38.0 mmol)
  • anhydrous n-BuOH 8 mL
  • reaction mixture was cooled to room temperature, the reaction solvent was distilled off under reduced pressure, followed by addition of 20mL saturated sodium bicarbonate solution, extracted with ethyl acetate (4x 50mL), the combined organic phases were washed with brine (20mL), dried over anhydrous Na 2 SO 4
  • the reaction mixture was cooled to room temperature, poured into a 90% saline solution, extracted with ethyl acetate (4x 50mL), the combined organic phases were washed with water (2x 30mL), brine, water and dried (50mL) dried over anhydrous Na 2 SO 4, under reduced pressure
  • the reaction solvent was evaporated under reduced pressure and lyophilized with water to give the title compound HO 2 C-LIN-ULM.
  • the reaction mixture was cooled to room temperature, poured into a 90% saline solution, extracted with ethyl acetate (4x 50mL), the combined organic phases were washed with water (2x 30mL), brine, water and dried (50mL) dried over anhydrous Na 2 SO 4, under reduced pressure
  • the reaction solvent was evaporated under reduced pressure and lyophilized with water to give the title compound HO 2 C-LIN-ULM.
  • the corresponding diacid (5.0 mmol, 2.5 equiv) was added to a 250 mL three-necked flask, followed by anhydrous DMF (10 mL) and anhydrous dichloromethane (150 mL), and NMM (10.0 mmol, 5 equi) Lenalidomide (2 mmol, 1 equiv), HOAT (2.4 mmol, 1.2 equiv) and EDCI (2.4 mmol, 1.2 equiv) were added and then stirred at room temperature overnight.
  • the corresponding diacid (5.0 mmol, 2.5 equiv) was added to a 250 mL three-necked flask, followed by anhydrous DMF (10 mL) and anhydrous dichloromethane (150 mL), and NMM (10.0 mmol, 5 equi) , VHL-1 (2 mmol, 1 equiv), HOAT (2.4 mmol, 1.2 equiv) and EDCI (2.4 mmol, 1.2 equiv), and the mixture was stirred under ice-water bath for 5 h, then warmed to room temperature overnight.
  • Step 1 Preparation of 6,6'-((oxybis(ethane-2,1-diyl))bis(oxy))dihexanoic acid according to Scheme 8 (SIAIS 171082B)
  • Step 2 Preparation of 6,6'-((oxybis(ethane-2,1-diyl))bis(oxy))dihexanoyl chloride according to Scheme 8 (SIAIS 171104A)
  • the compound (SIAIS171082B) (100 mg, 0.30 mmol) was added to a 50 mL egg-shaped flask, anhydrous THF (10 mL) was added, and thionyl chloride (0.2 mL) was slowly added dropwise at room temperature, and the mixture was heated to reflux and stirred. 2h. After the completion of the reaction, the reaction solvent was evaporated under reduced pressure to give the title product (SIAIS 171104A) as a red brown oil, 150 mg. This product was used in the next step without further purification.
  • Step 3 Preparation of 6-(2-(2-((6-(2-(2-(2)6-dioxopiperidin-3-yl)-1,3-dioxoisoporphyrin) according to Scheme 8 4-yl)amino)-6-oxohexyl)oxy)ethoxy)ethoxy)hexanoic acid (SIAIS 171104B):
  • Step 1 Preparation of 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione according to Scheme 9 (SIAIS 151103 ):
  • Step 1 Preparation of 4-((2-(2-aminoethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 according to Scheme 9. , 3-dione (SIAIS151012B):
  • the compound succinic acid (325 mg, 2.75 mmol) was added to a 100 mL three-necked flask, followed by anhydrous DMF (5 mL) and anhydrous dichloromethane (50 mL), and NMM (1.
  • the compound succinic acid (325 mg, 2.75 mmol) was added to a 100 mL three-necked flask, followed by anhydrous DMF (5 mL) and anhydrous dichloromethane (50 mL), and NMM (1.
  • the compound pemamoamine (273.2 mg, 1 mmol, 1 equiv) and anhydrous THF (15 mL) were added to a 100 mL egg-shaped flask, and glutaryl chloride (0.64 mL, 5 mmol, 5.0 equiv) was slowly added dropwise with stirring at room temperature. After the addition was completed, the temperature was slowly raised to 80 ° C and stirred for 3 h.
  • the compound lenalidomide (259.3 mg, 1 mmol) was added to a 25 mL egg-shaped flask followed by anhydrous NMP (5 mL), N,N-diisopropylethylamine (387.7 mg, 3 mmol) and 5-bromo Tert-butyl valerate (284.6 mg, 1.2 mmol) was added, slowly warmed to 100 ° C and stirred overnight.
  • VHL-1 (934 mg, 2 mmol, 1 equiv), 4-azidobutyric acid (258.2 mg, 2 mmol, 1 equiv), HOAt (54.4 mg, 0.4 mmol, 0.2 equiv), EDCI (in order) were added to the reaction flask at room temperature. 766.8 mg, 4 mmol, 2 equiv), DMF (5 mL), DCM (20 mL), NMM (2.02 g, 20 mmol, 10 equiv). After the completion of the reaction by LC-MS, the DCM was vortexed, poured into 90% brine, and extracted with ethyl acetate (4 ⁇ 50 mL).
  • tert-Butyl 6-(2-(2-((6-iodohexyl)oxy)ethoxy)ethoxy)hexanoate 500 mg, 1.03 mmol was added to a 25 mL three-neck bottle, followed by the addition of TFA ( 3 mL) and dry DCM (3 mL) were stirred at room temperature overnight.
  • Step 1 Preparation of 2-(2-((6-chlorohexyl)oxy)ethoxy)-1-ethanol (SIAIS 180112) according to Scheme 16:
  • Step 2 Preparation of 6-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethoxy)hexanoic acid (SIAIS 171094B) according to Scheme 16:
  • SIAIS 180112 700 mg, 3.11 mmol
  • tert-butyl 6-bromohexanoate 784 mg, 3.11 mmol
  • anhydrous DMF 15 mL
  • Step 3 Preparation of (2S,4R)-1-((S)-2-(tert-butyl)-22-chloro-4-oxo-10,13,16-trioxa-3-nitrogen according to Scheme 16. Heterodocosacarbonyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (SIAIS180114):
  • the substrate 4-bromoisobenzofuran-1,3-dione (500 mg, 2.20 mmol), 3-aminopiperidine-2,6-dione (400 mg, 2.42 mmol) and anhydrous sodium acetate (220 mg, 2.64 mmol) was added together to a 100 mL egg-shaped flask followed by glacial acetic acid (10 mL). The reaction was then slowly warmed to 140 ° C and stirred for 12 h.
  • reaction solution was cooled to room temperature, and a large amount of white solid was precipitated; then filtered, and the filter cake, water (10 mL) and methanol (2 mL) were added together in an egg-shaped bottle, stirred well for 0.5 h, and then filtered. The filter cake is washed with water. The compound was dried under reduced pressure (SIAIS 172136).
  • reaction product SIAIS172145 250 mg, 0.65 mmol was added to a 100 mL egg-shaped bottle, followed by dioxane (20 mL) and 10% wet Pd/C, respectively, and the reaction system was replaced with H 2 (25 psi) three times. Stir at room temperature overnight. After the completion of the reaction, the mixture was filtered with EtOAc EtOAcjjjjjjjjj Water dichloromethane (5 mL) was added together to a 50 mL egg-shaped bottle, followed by stirring at room temperature for 2 h.
  • Step 1 Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione according to Scheme 18 (SIAIS 180151):
  • the substrate 4-hydroxyisobenzofuran-1,3-dione (500 mg, 3.05 mmol), 3-aminopiperidine-2,6-dione (502 mg, 3.05 mmol) and triethylamine (340 mg, 3.36) Ment) was added together to a 100 mL egg-shaped flask followed by anhydrous toluene (20 mL). The reaction was then slowly warmed to 110 ° C and stirred for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, and a large amount of brown solid was precipitated.
  • the filter cake was added to an egg-shaped bottle containing 10 mL of a 30% ethyl acetate/petroleum ether solution, and stirred well for 0.2 h. It was then suction filtered and the filter cake was washed with petroleum ether.
  • the compound (SIAIS 180151) was obtained after drying under reduced pressure.
  • Step 2 Preparation of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetate according to Scheme 18 Butyl ester (SIAIS180152):
  • Step 3 Preparation of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetic acid according to Scheme 18 SIAIS172101B):
  • Example 1 N-(2-chloro-6-methylphenyl)-2-((6-(4-(3-(2-(2-(2,6-dioxopiperidine-3) -yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propionyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole
  • SIAIS 151063 N-(2-chloro-6-methylphenyl)-2-((6-(4-(3-(2-(2-(2,6-dioxopiperidine-3) -yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propionyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole
  • the compound (SIAIS 151064) was prepared as a yellow solid, 13.7 mg according to the general procedure described in Scheme 19 using the Dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 151004 under suitable conditions as understood in the art.
  • the compound (SIAIS 151067) was prepared as a yellow solid, 15.7 mg according to the general procedure described in Scheme 19 under the appropriate conditions understood in the art using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 151005.
  • Example 5 N-(2-chloro-6-methylphenyl)-2-((6-(4-(1-((2-(2,6-dioxopiperidin-3-yl))) -1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecane-18-acyl)piperazin-1-yl)-2 Of -methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (SIAIS 151069)
  • the compound (SIAIS 151069) was prepared as a yellow solid, 35 mg, using the general procedure of Scheme 19, under the appropriate conditions understood in the art, using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 151007.
  • Example 6 N-(2-chloro-6-methylphenyl)-2-((6-(4-((2-(2,6-dioxopiperidin-3-yl))-1, Preparation of 3-dioxoisoindol-4-yl)aminoacetyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (SIAIS 151072)
  • the compound (SIAIS 151072) was prepared using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 151025 according to the general procedure described in Scheme 19 under suitable conditions as understood in the art, as a yellow solid, 19.1 mg.
  • Example 7 N-(2-chloro-6-methylphenyl)-2-((6-(4-(3-((2-(2,6-dioxopiperidin-3-yl))) -1,3-dioxoisoindolin-4-yl)amino)propionyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (SIAIS151074 Preparation
  • the compound (SIAIS 151074) was prepared as a yellow solid, 24.4 mg according to the general procedure described in Scheme 19 using the Dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS151026 under suitable conditions as understood in the art.
  • Example 8 N-(2-chloro-6-methylphenyl)-2-((6-(4-(4-((2-(2,6-dioxopiperidin-3-yl))) -1,3-dioxoisoindolin-4-yl)amino)butyryl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (SIAIS151070 Preparation
  • the compound (SIAIS 151070) was prepared as a yellow solid, 31.2 mg, according to the general procedure described in Scheme 19, under the appropriate conditions understood in the art, using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 151019.
  • the compound (SIAIS 151071) was prepared as a yellow solid, 10 mg, using the general procedure of Scheme 19, under the appropriate conditions understood in the art, using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 1512020.
  • the compound (SIAIS 151075) was prepared as a yellow solid, 26.7 mg according to the general procedure described in Scheme 19 under the appropriate conditions understood in the art using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 151027.
  • the compound (SIAIS 151181) was prepared as a yellow solid, 22.3 mg, using the general procedure described in Scheme 19 under appropriate conditions as understood in the art, using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 151086.
  • the compound (SIAIS 164108) was prepared as a white solid, 12.6 mg according to the general procedure described in Scheme 19, under appropriate conditions as understood in the art, using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 171004.
  • the compound (SIAIS 164109) was prepared as a white solid, 12.7 mg, according to the general procedure described in Scheme 19, under the appropriate conditions understood in the art, using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 164084.
  • the compound (SIAIS 164110) was prepared as a white solid, 13.1 mg, using the general procedure described in Scheme 19 under appropriate conditions as understood in the art, using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 171005.
  • the compound (SIAIS 164181) was prepared as a white solid, 7 mg, according to the general procedure described in Scheme 19, under the appropriate conditions understood in the art, using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 164101.
  • the compound (SIAIS 164182) was prepared as a white solid, 9.7 mg according to the general procedure described in Scheme 19 under the appropriate conditions understood in the art using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 164102.
  • Example 16 N-(2-Chloro-6-methylphenyl)-2-((6-(4-(2-(2-(2-(2-((()))) -4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxo But-2-yl)amino)-2-oxoethoxy)ethoxy)acetyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide Preparation of (SIAIS 151080)
  • the compound (SIAIS 151080) was prepared as a white solid, 23 mg, using the general procedure described in Scheme 19 under the appropriate conditions understood in the art, using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 151010. The yield was 45%.
  • Example 17 N-(2-chloro-6-methylphenyl)-2-((6-(4-(3-(2-(3-((())))) -4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxo But-2-yl)amino)-3-oxopropoxy)ethoxy)propionyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide Preparation of (SIAIS 151076)
  • the compound (SIAIS 151076) was prepared as a white solid, 26.7 mg according to the general procedure described in Scheme 19 under the appropriate conditions understood in the art using the dasatinib derivative SIAIS151055 and the HO 2 C-LIN-ULM intermediate SIAIS151002. The yield was 73%.
  • Example 18 N-(2-chloro-6-methylphenyl)-2-((6-(4-((S)-15-((2S,4R)-4-hydroxy-2-(( 4-(4-Methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-16,16-dimethyl-13-oxo-4,7,10-trioxa
  • -14-azaheptadecanoyl piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide
  • the compound (SIAIS 151077) was prepared as a white solid, 41.5 mg, according to the general procedure described in Scheme 19, under the appropriate conditions understood in the art, using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 151003. The yield was 84%.
  • Example 19 N-(2-chloro-6-methylphenyl)-2-((6-(4-((S)-18-((2S,4R)-4-hydroxy-2-(( 4-(4-Methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-19,19-dimethyl-16-oxo-4,7,10,13-tetra Preparation of oxa-17-azaicosanoyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (SIAIS 151078)
  • the compound (SIAIS 151078) was prepared as a white solid, 23 mg, using the general procedure of Scheme 19, under the appropriate conditions understood in the art, using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 151008. Yield 45%.
  • Example 20 N-(2-chloro-6-methylphenyl)-2-((6-(4-((S)-21-((2S,4R)-4-hydroxy-2-(( 4-(4-Methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-22,22-dimethyl-19-oxo-4,7,10,13,16 -Preparation of pentaoxa-20-azadocosyloxy)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (SIAIS 151079)
  • the compound (SIAIS 151079) was prepared as a white solid, 27.5 mg according to the general procedure described in Scheme 19 using the Dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 151009 under suitable conditions as understood in the art. , yield 53%.
  • Example 21 N-(2-chloro-6-methylphenyl)-2-((6-(4-(4-((S)-1-((2S,4R)-4-hydroxy-) 2-((4-(4-Methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl) Preparation of amino)-4-oxobutyryl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (SIAIS 151174)
  • the compound (SIAIS 151174) was prepared as a white solid, 8.5 mg according to the general procedure described in Scheme 19 under the appropriate conditions understood in the art using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 074011. , yield 26%.
  • Example 22 N-(2-chloro-6-methylphenyl)-2-((6-(4-(5-((S)-1-((2S,4R)-4-hydroxy-) 2-((4-(4-Methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl) Preparation of amino)-5-oxopentanoyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (SIAIS 151175)
  • the compound (SIAIS 151175) was prepared as a white solid, 7.6 mg according to the general procedure described in Scheme 19 under the appropriate conditions understood in the art using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 074012. , yield 24%.
  • the compound (SIAIS 151176) was prepared as a white solid, 7.8 mg according to the general procedure described in Scheme 19 under the appropriate conditions understood in the art using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 074013. , yield 23%.
  • Example 24 N-(2-chloro-6-methylphenyl)-2-((6-(4-(7-((S)-1-((2S,4R)-4-hydroxy-) 2-((4-(4-Methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl) Preparation of amino)-7-oxoheptanoyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (SIAIS 151177)
  • the compound (SIAIS 151177) was prepared as a white solid, 8.3 mg according to the general procedure described in Scheme 19 under the appropriate conditions understood in the art using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 074014. , yield 25%.
  • Example 25 N-(2-chloro-6-methylphenyl)-2-((6-(4-(8-((S)-1-((2S,4R)-4-hydroxy-) 2-((4-(4-Methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl) Preparation of amino)-8-oxooctanoyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (SIAIS 151178)
  • the compound (SIAIS 151178) was prepared as a white solid, 12.1 mg according to the general procedure described in Scheme 19 under the appropriate conditions understood in the art using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 074015. , yield 36%.
  • Example 26 N-(2-chloro-6-methylphenyl)-2-((6-(4-(9-((S)-1-((2S,4R)-4-hydroxy-) 2-((4-(4-Methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl) Preparation of amino)-9-oxodecanoyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (SIAIS 151179)
  • the compound (SIAIS 151179) was prepared as a white solid, 9.3 mg according to the general procedure described in Scheme 19 under the appropriate conditions understood in the art using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 074016. , yield 27%.
  • Example 27 N-(2-chloro-6-methylphenyl)-2-((6-(4-(10-((S)-1-((2S,4R)-4-hydroxy-) 2-((4-(4-Methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl) Preparation of amino)-10-oxodecanoyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (SIAIS 151180)
  • the compound (SIAIS 151180) was prepared as a white solid, 8.4 mg, using the general procedure described in Scheme 19 under appropriate conditions as understood in the art, using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 074019. , yield 24%.
  • Example 28 N-(2-chloro-6-methylphenyl)-2-((6-(4-(14-((S)-1-((2S,4R)-4-hydroxy-) 2-((4-(4-Methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl) Preparation of amino)-14-oxotetradecanoyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (SIAIS 164193)
  • the compound (SIAIS 164193) was prepared as a white solid, 6.2 mg according to the general procedure described in Scheme 19 under the appropriate conditions understood in the art using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 164185. The yield is 25%.
  • Example 29 N-(2-chloro-6-methylphenyl)-2-((6-(4-(16-((S)-1-((2S,4R)-4-hydroxy-) 2-((4-(4-Methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl) Preparation of amino)-16-oxohexadecanoyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (SIAIS 164194)
  • the compound (SIAIS 164194) was prepared as a white solid, 6.8 mg according to the general procedure described in Scheme 19 under the appropriate conditions understood in the art using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 164189.
  • Example 30 N-(2-chloro-6-methylphenyl)-2-((6-(4-(6-(2-(2-(6-(2-) Dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)-6-oxohexyl)oxy)ethoxy)ethoxy)hexanoyl) Preparation of piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (SIAIS 171114)
  • the compound (SIAIS 171114) was prepared as a yellow solid, 3.0 mg according to the general procedure described in Scheme 19 under the appropriate conditions understood in the art using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 171104B.
  • the compound (SIAIS 164133) was prepared as a yellow solid, 11.4 mg, according to the general procedure described in Scheme 19, under the appropriate conditions understood in the art, using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 164119. , yield 60%.
  • the compound (SIAIS 164132) was prepared as a yellow solid, 7.9 mg according to the general procedure described in Scheme 19 under the appropriate conditions understood in the art using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 164118.
  • Example 33 N-(2-chloro-6-methylphenyl)-2-((6-(4-(5-((2-(2,6-dioxopiperidin-3-yl))) -1,3-dioxoisoindol-4-yl)amino)-5-oxopentanoyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5
  • Formamide (SIAIS 184053)
  • the compound (SIAIS 184053) was prepared as a yellow solid, 10 mg, using the general procedure of Scheme 19, under the appropriate conditions understood in the art, using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 184044.
  • Example 34 N-(2-chloro-6-methylphenyl)-2-((6-(4-(5-((2-(2,6-dioxopiperidin-3-yl))) Preparation of 1-oxoisoindoline-4-yl)amino)pentanoyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (SIAIS 184052)
  • the compound (SIAIS 184052) was prepared as a white solid, 10.9 mg according to the general procedure described in Scheme 19 under the appropriate conditions understood in the art using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 184047. The yield was 41%.
  • Example 36 N1-(5-(4-(6-(6-(6-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidine 4-yl)piperazin-1-yl)-5-oxopentyl)-N10-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-) Preparation of methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carboxamide (SIAIS 184032)
  • the compound (SIAIS 184032) was prepared as a white solid, 10.2 mg, according to the general procedure described in Scheme 19, under the appropriate conditions understood in the art, using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 164178B. , yield 45%.
  • Example 37 N-(2-chloro-6-methylphenyl)-2-((6-(4-(4-(1-(4-(4-((()))) -4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxo But-2-yl)amino)-4-oxobutyl)-1H-1,2,3-triazol-4-yl)butyryl)piperazin-1-yl)-2-methylpyrimidine-4 Of -amino)amino)thiazole-5-carboxamide (SIAIS 164134)
  • the compound (SIAIS 164134) was prepared as a white solid, 9.1 mg according to the general procedure described in Scheme 19 under the appropriate conditions understood in the art using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 164128. , yield 37%.
  • Example 38 N-(2-Chloro-6-methylphenyl)-2-((6-(4-(3-(2-(2,6-dioxopiperidin-3-yl))- Preparation of 1,3-dioxoisoindolin-4-yl)propionyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (SIAIS 172150)
  • the compound (SIAIS 172150) was prepared as a white solid, 24.2 mg, using the general procedure described in Scheme 19 under the appropriate conditions understood in the art using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 172147. , yield 47%.
  • Example 39 N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-((2-(2,6-dioxopiperidin-3-yl))) -1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide ( Preparation of SIAIS184128)
  • the compound (SIAIS 184128) was prepared as a white solid, 18.5 mg according to the general procedure described in Scheme 19 under the appropriate conditions understood in the art using the dasatinib derivative SIAIS 151055 and the HO 2 C-LIN-ULM intermediate SIAIS 172101B. , yield 52%.
  • Example 40 4-((2,4-Dichloro-5-methoxyphenyl)amino)-7-(3-(4-(3-(2-(2-(2,6-)) Oxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propionyl)piperazin-1-yl)propoxy)-6-A
  • SIAIS 151157 Preparation of oxyquinoline-3-carbonitrile
  • the compound (SIAIS 151157) was prepared as a yellow solid, 12.3 mg, according to the general procedure described in Scheme 19, under suitable conditions understood in the art, using the Bersutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 151001.
  • Example 41 4-((2,4-Dichloro-5-methoxyphenyl)amino)-7-(3-(4-(3-(2-(2-((2-(2) 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propionyl)piperazin-1-yl)propane
  • SIAIS 151158 Preparation of oxy)-6-methoxyquinoline-3-carbonitrile
  • the compound (SIAIS 151158) was prepared as a yellow solid, 14 mg, according to the general procedure described in Scheme 19, under the appropriate conditions understood in the art, using the besutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 151004.
  • Example 42 4-((2,4-Dichloro-5-methoxyphenyl)amino)-7-(3-(4-(3-(2-(2-(2-(2-) (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propionyl)per Preparation of pyrazin-1-yl)propoxy)-6-methoxyquinoline-3-carbonitrile (SIAIS 151159)
  • the compound (SIAIS 151159) was prepared as a yellow solid, 13.2 mg, using the general method described in Scheme 19 under appropriate conditions as understood in the art, using the Bersutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 151005.
  • Example 43 4-((2,4-Dichloro-5-methoxyphenyl)amino)-7-(3-(4-(1-((2-(2,6-dioxo)) Pyridin-3-yl)-1,3-dioxoisoindol-4-yl)amino)-3,6,9,12-tetraoxapentadecane-15-yl)piperazine-1- Preparation of propyloxy)-6-methoxyquinoline-3-carbonitrile (SIAIS 151160)
  • the compound (SIAIS 151160) was prepared as a yellow solid, 9.8 mg according to the general procedure described in Scheme 19, under suitable conditions understood in the art, using the Bosutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 151006.
  • Example 44 4-((2,4-Dichloro-5-methoxyphenyl)amino)-7-(3-(4-(1-((2-(2,6-dioxo)) Pyridin-3-yl)-1,3-dioxoisoindol-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecane-18-yl)piperazine- Preparation of 1-yl)propoxy)-6-methoxyquinoline-3-carbonitrile (SIAIS 151161)
  • the compound (SIAIS 151161) was prepared as a yellow solid, 13.2 mg, using the general method described in Scheme 19 under appropriate conditions as understood in the art, using the besutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 151007.
  • Example 45 4-((2,4-Dichloro-5-methoxyphenyl)amino)-7-(3-(4-((2-(2,6-dioxopiperidine-3) -yl)-1,3-dioxoisoindol-4-yl)aminoacetyl)piperazin-1-yl)propoxy)-6-methoxyquinoline-3-carbonitrile (SIAIS151164 Preparation
  • the compound (SIAIS 151164) was prepared as a yellow solid, 8.6 mg according to the general procedure described in Scheme 19, under suitable conditions understood in the art, using the Bersutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 151525.
  • Example 46 4-((2,4-Dichloro-5-methoxyphenyl)amino)-7-(3-(4-(3-((2-(2,6-dioxo)) Pyridin-3-yl)-1,3-dioxoisoindol-4-yl)amino)propionyl)piperazin-1-yl)propoxy)-6-methoxyquinoline-3- Preparation of carbonitrile (SIAIS151165)
  • the compound (SIAIS 151165) was prepared as a yellow solid, 9.2 mg according to the general procedure described in Scheme 19, under suitable conditions understood in the art, using the Bersutinib derivative SIAIS151151 and the HO 2 C-LIN-ULM intermediate SIAIS151026.
  • Example 47 4-((2,4-Dichloro-5-methoxyphenyl)amino)-7-(3-(4-(4-((2-(2,6-dioxo)) Pyridin-3-yl)-1,3-dioxoisoindol-4-yl)amino)butyryl)piperazin-1-yl)propoxy)-6-methoxyquinoline-3- Preparation of carbonitrile (SIAIS 151162)
  • the compound (SIAIS 151162) was prepared as a yellow solid, 11.3 mg, according to the general procedure described in Scheme 19, under appropriate conditions as understood in the art, using the Bersutinib derivative SIAIS151151 and the HO 2 C-LIN-ULM intermediate SIAIS151019.
  • Example 48 4-((2,4-Dichloro-5-methoxyphenyl)amino)-7-(3-(4-(5-((2-(2,6-dioxo)) Pyridin-3-yl)-1,3-dioxoisoindol-4-yl)amino)pentanoyl)piperazin-1-yl)propoxy)-6-methoxyquinoline-3- Preparation of carbonitrile (SIAIS151163)
  • the compound (SIAIS 151163) was prepared as a yellow solid, 12 mg, using the general procedure of Scheme 19, under the appropriate conditions understood in the art, using the Bersutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 1512020.
  • Example 49 4-((2,4-Dichloro-5-methoxyphenyl)amino)-7-(3-(4-(6-((2-(2,6-dioxo)) Pyridin-3-yl)-1,3-dioxoisoindol-4-yl)amino)hexanoyl)piperazin-1-yl)propoxy)-6-methoxyquinoline-3- Preparation of carbonitrile (SIAIS151166)
  • the compound (SIAIS 151166) was prepared as a yellow solid, 12.8 mg according to the general procedure described in Scheme 19, under suitable conditions understood in the art, using the Bersutinib derivative SIAIS151151 and the HO 2 C-LIN-ULM intermediate SIAIS151027.
  • Example 50 4-((2,4-Dichloro-5-methoxyphenyl)amino)-7-(3-(4-(7-((2-(2,6-dioxo)) Pyridin-3-yl)-1,3-dioxoisoindol-4-yl)amino)heptanoylpiperazin-1-yl)propoxy)-6-methoxyquinoline-3- Preparation of carbonitrile (SIAIS 151167)
  • the compound (SIAIS 164104) was prepared as a yellow solid, 13.2 mg, using the general method described in Scheme 19 under appropriate conditions as understood in the art, using the Bersutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 171004.
  • Example 52 4-(4-(3-((3-Cyano-4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxyquinolin-7) -yl)oxy)propyl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl
  • 4-oxobutyramide (SIAIS164105)
  • the compound (SIAIS 164105) was prepared as a yellow solid, 11.8 mg, according to the general procedure described in Scheme 19, under appropriate conditions as understood in the art, using the besutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 164084.
  • the compound (SIAIS 164106) was prepared as a yellow solid, 14.1 mg, using the general method described in Scheme 19 under appropriate conditions as understood in the art, using the Bersutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 171005.
  • Example 54 (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(3-((3-cyano-4-((2,4-dichloro))) 5-5-methoxyphenyl)amino)-6-methoxyquinolin-7-yl)oxy)propyl)piperazin-1-yl)-4,16-dioxo-7,10, 13-Trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (SIAIS172082) preparation
  • the compound (SIAIS 172082) was prepared as a white solid, 6.2 mg according to the general procedure described in Scheme 19, under suitable conditions understood in the art, using the Bersutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 151003.
  • the compound (SIAIS 172083) was prepared as a white solid, 5.0 mg, using the general method described in Scheme 19 under appropriate conditions as understood in the art using the Bosutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 151008.
  • the compound (SIAIS 172084) was prepared as a white solid, 6.0 mg, using the general method described in Scheme 19 under appropriate conditions as understood in the art, using the besutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 151009.
  • the compound (SIAIS 172072) was prepared as a white solid, 10 mg, according to the general procedure described in Scheme 19, under the appropriate conditions understood in the art, using the Bersutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 074011.
  • the compound (SIAIS 172073) was prepared as a white solid, 10.7 mg, using the general method described in Scheme 19 under appropriate conditions as understood in the art, using the Bersutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 074012.
  • the compound (SIAIS 172074) was prepared as a white solid, 9.0 mg, using the general method described in Scheme 19 under appropriate conditions as understood in the art, using the Bersutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 074013.
  • the compound (SIAIS 172075) was prepared as a white solid, 9.6 mg according to the general procedure described in Scheme 19, under suitable conditions understood in the art, using the Bersutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 074014.
  • the compound (SIAIS 172076) was prepared according to the general procedure described in Scheme 19 under suitable conditions as understood in the art using the Bersutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 074015.
  • the compound (SIAIS 172077) was prepared as a white solid, 6.4 mg, using the general method described in Scheme 19 under appropriate conditions as understood in the art, using the Bersutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 074016.
  • the compound (SIAIS 172078) was prepared as a white solid, 7.3 mg according to the general procedure described in Scheme 19, under suitable conditions understood in the art, using the Bersutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 074019.
  • the compound (SIAIS 172079) was prepared as a white solid, 6.6 mg according to the general procedure described in Scheme 19, under suitable conditions understood in the art, using the Bersutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 074020.
  • Example 65 4-(4-(3-((3-Cyano-4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxyquinolin-7) -yl)oxy)propyl)piperazin-1-yl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo) Preparation of Porphyrin-4-yl)amino)ethyl)-4-oxobutanamide (SIAIS164136)
  • the compound (SIAIS 164136) was prepared as a yellow solid, 12.4 mg according to the general procedure described in Scheme 19, under suitable conditions understood in the art, using the Bersutinib derivative SIAIS 151151 and the HO 2 C-LIN-ULM intermediate SIAIS 164119. , yield 71%.
  • Example 66 4-((4-(3-(2-((2-(2)6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4- Ethyl)amino)ethoxy)propionyl)piperazin-1-yl)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino Preparation of phenyl)benzamide (SIAIS1197001)
  • Example 67 4-((4-(3-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoporphyrin) 4-yl)amino)ethoxy)ethoxy)propionyl)piperazin-1-yl)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)) Preparation of pyrimidin-2-yl)amino)phenyl)benzamide (SIAIS 1197015)
  • Example 68 4-((4-(3-(2-(2-(2-(2-(2-(2-(2)6-dioxopiperidin-3-yl)-1,3-dioxo) Porphyrin-4-yl)amino)ethoxy)ethoxy)propionyl)piperazin-1-yl)methyl)-N-(4-methyl-3-((4- Preparation of (pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide (SIAIS 1197017)
  • Example 69 4-((4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino) -3,6,9,12-tetraoxapentadecane-15-yl)piperazin-1-yl)methyl)-N-(4-methyl-3-((4-(pyridine-3) Of -pyrimidin-2-yl)amino)phenyl)benzamide (SIAIS 1197019)
  • Example 70 4-((4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino) )-3,6,9,12,15-pentaoxaoctadecane-18-acyl)piperazin-1-yl)methyl)-N-(4-methyl-3-((4-(pyridine) Preparation of -3-yl)pyrimidin-2-yl)amino)phenyl)benzamide (SIAIS1197021)
  • Example 71 4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)aminoacetyl) Piperazin-1-yl)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide (SIAIS1197003) preparation
  • the compound (SIAIS1197003) was prepared in yellow according to the general method described in Scheme 19 under appropriate conditions as understood in the art using the corresponding substrate demethylimatinib and HO 2 C-LIN-ULM intermediate SIAIS151025. Solid, 11.1 mg, yield 33%.
  • Example 72 4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino) Propionyl) piperazin-1-yl)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide
  • (SIAIS1197005) 4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino) Propionyl) piperazin-1-yl)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide
  • Example 73 4-((4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxaisoindolin-4-yl)amino) Butyryl)piperazin-1-yl)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide Preparation of (SIAIS1197007)
  • the compound (SIAIS1197007) was prepared in yellow according to the general method described in Scheme 19 under appropriate conditions as understood in the art using the corresponding substrate demethylimatinib and HO 2 C-LIN-ULM intermediate SIAIS151019. Solid, 14.0 mg, yield 40%.
  • Example 74 4-((4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxaisoindolin-4-yl)amino) Valentyl) piperazin-1-yl)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide Preparation of (SIAIS1197009)
  • Example 75 4-((4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino) Hexanoyl)piperazin-1-yl)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide
  • Example 76 4-((4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino) Heptanoyl)piperazin-1-yl)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide
  • the compound (SIAIS1197043) was prepared in white according to the general method described in Scheme 19 under appropriate conditions as understood in the art using the corresponding substrate demethylimatinib and HO 2 C-LIN-ULM intermediate SIAIS 1511010. Solid, 15.2 mg, yield 33%.
  • the compound (SIAIS 1197029) was prepared in white according to the general procedure described in Scheme 19 using the corresponding substrate demethylimatinib and HO 2 C-LIN-ULM intermediate SIAIS151002 under suitable conditions as understood in the art. Solid, 13.2 mg, yield 29%.
  • Example 80 (2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(4-((4-methyl-3-((4-(pyridine)-3) -yl)pyrimidin-2-yl)amino)phenyl)carbamoyl)benzyl)piperazin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3 -Aza-nonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (SIAIS 1197039)
  • the compound (SIAIS1197041) was prepared using the corresponding substrate demethylimatinib and HO 2 C-LIN-ULM intermediate SIAIS 151009 according to the general procedure described in Scheme 19, under suitable conditions as understood in the art. Solid, 16.4 mg, yield 33%.
  • the compound (SIAIS 074027) was prepared in white according to the general procedure described in Scheme 19 using the corresponding substrate demethylimatinib and HO 2 C-LIN-ULM intermediate SIAIS074011 under suitable conditions as understood in the art. Solid, 42.2 mg, yield 68%.
  • Example 84 (2S,4R)-1-((S)-3,3-dimethyl-2-(6-(4-(4-(4-methyl-3-((4-) Pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)carbamoyl)benzyl)piperazin-1-yl)-6-oxohexanoylamino)butyryl)-4-hydroxy-N- Preparation of (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (SIAIS074029)
  • the dasatinib derivative SIAIS151055 (0.45 mmol, 1 equiv) was added to a 25 mL egg-shaped flask followed by anhydrous DMF (2 mL), N,N-diisopropylethylamine (2.25 mmol, 5 equiv) And NaI (0.90 mmol, 2 equiv), the corresponding chloro substrate (SIAIS 180114) (0.90 mmol, 2 equiv) was added with stirring at room temperature, and the temperature was slowly raised to 80 ° C and stirred overnight.
  • the dasatinib derivative SIAIS 151055 (9.7 mg, 0.022 mmol) was added to a 25 mL egg-shaped bottle followed by anhydrous DMF (1.5 mL), N,N-diisopropylethylamine (18.8) Mg, 0.15 mmol), iodine substrate (SIAIS 171116) (10 mg, 0.015 mmol) was added with stirring at room temperature, slowly warmed to 80 ° C and stirred overnight.
  • BCR-ABL positive cells-K562 cells human chronic myeloid leukemia cells
  • ATCC American Type Culture Collection
  • U937 cell human monocytic leukemia cell line was purchased from American Type Culture Collection (ATCC);
  • HEK293 cells human embryonic kidney cells
  • ATCC American Type Culture Collection
  • the cells used were cultured in a 37 ° C incubator containing 5% CO 2 .
  • the cell complete medium was supplemented with 10% fetal bovine serum in RPMI l640 medium, and the final concentration of penicillin and streptomycin was 100 U/mL. All cells were tested for mycoplasma negative by the Mycoplasma Test Kit before the experiment.
  • the cells were seeded in an amount of 2000-5000 cells/well in 100 ⁇ L of RPMI1640 complete medium.
  • the test chemicals were subjected to 3-fold gradient dilution from the highest concentration of 10 ⁇ M, and 10 concentrations were set from high to low.
  • 100 ⁇ L of the diluted PROTAD compound of the present disclosure was added to the inoculated 100 ⁇ L cells, and the cells were treated for 48 hours. Thereafter, the cell viability assay was performed according to the reagent operating instructions of CCK-8, the negative control was DMSO, and the positive control was a commercial inhibitor. After 2 hours of CCK-8 treatment, the value of OD450 was measured using a microplate reader.
  • All the IC 50 of compounds of the examples are below 100nM. It is worth mentioning that inhibitors Dasatinib IC 50 of 0.4nM, IC 50 is the lowest we designed and synthesized compounds PROTAD reached 1.47nM, tumor cell growth inhibition effect achieved with the drug Dasatinib very close parental level.
  • Table 2 CCK-8 assay according to the present disclosure for example compounds of tumor cell proliferation inhibition activity IC 50 values.
  • NA No significant inhibition of proliferation was observed when the highest concentration was 10 ⁇ M.
  • Cell seed plate K562 cells were added to a 24-well plate at a cell density of 3 ⁇ 10 5 /mL, and the total volume was 1.5 mL; the PROTAD series compound of the present disclosure and the comparative example compound (Dasa-6-2-2) -6-VHL, Dasa-6-2-2-6-CRBN) Set 5 concentration gradients of 1nM, 10nM, 100nM, 1 ⁇ M, 10 ⁇ M, respectively, and add DMSO and commercial parent inhibitor group (Dasatinib (Dasa) As a negative control and a positive control, the cells were collected in a 1.5 mL EP tube and centrifuged at 3000 rpm for 3 minutes.
  • Electrophoresis At the beginning of the Bio Rad electrophoresis apparatus, the voltage is 80V electrophoresis, and when the dye enters the separation gel, the voltage is adjusted to 120V;
  • Table 3 shows the degradation results of BCR-ABL protein and c-ABL protein by the PROTAD compound of the present disclosure.
  • NA No significant degradation was observed when the highest concentration was 10 ⁇ M.
  • BCR-ABL mutant stable strain establishment The BCR-ABL target fragment was cloned into the retroviral vector PMIGR1, and then utilized.
  • the Site-Directed Mutagenesis Kit obtained mutant forms such as PMIGR1-BCR-ABL-G250E/E255K/V299L/F317L/F317V/T315I/T315A, and established a stable expression of BCR-ABL wild type and mutation on U937 cells using a retroviral infection system.
  • (2) Cell seed plate The above-mentioned cells were added to a 24-well plate at a cell density of 3 ⁇ 10 5 /mL, and the total volume was 1.5 mL; the PROTAD compound SIAIS151178 of the present disclosure was set to 10 nM, 100 nM, 1 ⁇ M, and 10 ⁇ M, respectively. At the same concentration gradient, the small molecule inhibitor treatment group Dasatinib (dasatinib) was set as the control. After 24 hours of treatment, the cells were collected in 1.5 mL EP tube, centrifuged at 3000 rpm for 3 minutes, and the cell pellet was collected and 30 ⁇ L PBS suspension cells were added. Then add 30ul of 2 ⁇ SDS lysate, the metal bath is 100°C, and the collected sample is followed by western blotting to detect the effect of the compound SIAIS151178 on BCR-ABL resistance mutation.
  • the small molecule inhibitor treatment group Dasatinib dasatinib
  • K562-Luc cells The luciferase luciferase fragment was cloned into the lentiviral vector Plenti-IRES-ZSGREEN vector, and a K562-Luc cell line stably expressing the reporter gene luciferase was established on K562 cells using a lentivirus infection system. .
  • BCR-ABL+K562 cell transplanted tumor model 5*106K562-Luc cells were inoculated subcutaneously into immunodeficient NOD-SCID mice. After 2 weeks, the tumor volume of the mice was close to 200 mm 3 , and the mice were randomly divided into groups. The experimental design was divided into 5 groups. Vehicle (solvent) treatment group, the present disclosure designed the synthetic Dasa-Lin-VHL system compound SIAIS151178 three dose treatment group (5, 15, 45mg / kg), inhibitor Dasatinib treatment group, administration for 2 weeks, periodic measurement small The size and weight of the tumor were changed. Two weeks after the administration, the mouse tumor-bearing condition was observed by in vivo imaging of the mouse. The administration was then stopped and the tumor recurrence was observed.
  • Vehicle (solvent) treatment group the present disclosure designed the synthetic Dasa-Lin-VHL system compound SIAIS151178 three dose treatment group (5, 15, 45mg / kg), inhibitor Dasatinib treatment group, administration for 2 weeks, periodic measurement small The size and weight
  • the PROTRAD series of compounds of the present disclosure were initially screened using K562 cell lines. The results showed that: (1) The PROTAD series of compounds of the present invention can significantly inhibit the proliferation of BCR-ABL-positive cell lines, and have no significant inhibitory activity on non-BCR-ABL-driven cell lines, and exhibits good proliferation inhibition activity and selectivity. (2) The Dasa-Lin-VHL system compound synthesized by the present disclosure is reported for the first time, and can effectively degrade BCR-ABL and c-ABL protein, and compare the Dasa-6-2-2-6-VHL compound of Example 1 and The BCR-ABL protein cannot be degraded; and the Dasa-Lin-VHL system compound SIAIS151178 synthesized in the present disclosure is taken as an example.
  • the in vitro cell level of SIAIS151178 can degrade wild-type BCR-ABL and some clinically relevant mutant proteins, in vivo mouse xenografts.
  • the model can degrade BCR-ABL, inhibit the BCR-ABL signaling pathway, and significantly inhibit tumor growth.
  • the Dasa-Lin-CRBN system compound synthesized by the present disclosure designed to degrade BCR-ABL activity better than the reported comparative example compound Dasa-6-2-2-6-CRBN.
  • SIAIS151178 can also degrade other tyrosine kinase receptors, such as SRC protein kinase, KIT, and PDGFR, for these target-related tumors.
  • the treatment also has potential value.
  • BCR-ABL inhibitors Although the clinical application of BCR-ABL inhibitors has greatly improved the prognosis of patients with Ph + CML, they still face two major problems: patients need long-term medication, which brings a large economic burden and also faces the problem of acquired resistance. . Although TKI can induce apoptosis of CML leukemia cells, it can not kill CML leukemia initiating cells. Studies have shown that in addition to its kinase function, BCR-ABL can also act as scaffold protein to recruit protein complexes to function as scaffold proteins, thereby knock-down The BCR-ABL protein has therapeutic significance.
  • the disclosed PROTAD compound can degrade the BCR-ABL protein, which may remove leukemia stem cells to some extent, delay the occurrence of drug resistance, and also degrade the drug-associated mutant forms to solve the clinical existence of TKI arrest. Drug recurrence and drug resistance issues are of great significance.
  • the study provides a new treatment strategy for Philadelphia chromosome-positive leukemia and other solid tumor patients.
  • Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and into lerance.Blood, 2007.110 (10): p.3540-6.

Abstract

本公开提供式(I)的蛋白降解靶向BCR-ABL化合物及其抗肿瘤应用。式(I)化合物对BCR-ABL靶蛋白具有降解和抑制作用，其主要由四部分组成，第一部分BCR-ABL-TKIs是具有BCR-ABL酪氨酸激酶抑制活性的化合物；第二部分LIN是链接单元；第三部分ULM是具有泛素化功能的VHL或者CRBN蛋白酶的小分子配体；以及第四部分基团A为羰基，其将BCR-ABL-TKIs和LIN共价结合，且LIN与ULM共价结合。本公开设计合成的一系列化合物具有广泛的药理活性，有降解BCR-ABL蛋白和抑制BCR-ABL活性的功能，可用于相关的肿瘤治疗。

Description

蛋白降解靶向BCR-ABL化合物及其抗肿瘤应用 技术领域
本公开涉及用于蛋白降解靶向BCR-ABL融合蛋白的化合物及其抗肿瘤应用。
背景技术
T(9；22)(q34；q11)染色体异位，又称费城染色体易位(Philadelphia translocation)或费城染色体(Philadelphia chromosome,Ph)，表现为9号染色体长臂与22号染色体长臂进行相互易位，使位于9号染色体的Abelson白血病病毒(abelson leukemia virus，ABL)1基因易位至22号染色体上的断裂从集区(breakpoint cluster region，Bcr)基因，形成Bcr-Abl融合基因[1,2]。该特征性染色体异位存在在大部分慢性粒细胞白血病(chronic myeloid leukemia,CML)，部分急性淋巴细胞性白血病(acute lymphoblastic leukemia,ALL)及少数急性髓细胞白血病(acute myeloid leukemia,AML)中。在正常状况下，酪氨酸蛋白激酶的活性受到严格的调控。与正常酪氨酸蛋白激酶比较，BCR-ABL融合蛋白具有持续激活的酪氨酸激酶活性(tyrosine kinase，TK)，激活下游信号通路，包括RAS,Janus激酶(Janus kinase，JAK)/信号转录子和转录激活蛋白(signal transducers and activators of transcription,STAT)和磷脂酰肌醇-3激酶(phosphatidylinositol-3-kinase,PI-3K)等，从而促进细胞增殖、生长因子依赖性减弱、凋亡受抑等，从而引起细胞的恶性转化,是Ph +白血病(费城染色体阳性白血病)发病的根本原因[3]。
过去以干扰素或者化疗为主的传统治疗方案疗效差、副作用大，且不能从根本上消除致病的Bcr-Abl基因，因而无法使患者获得遗传学或分子生物学缓解。异基因造血干细胞移植受到年龄与合适供体的限制，且移植相关并发症发生率高、死亡风险大，因而只有小部分患者能做异基因造血干细胞移植。目前酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)使Ph +白血病的治疗获得重大突破,目前已成为CML的一线治疗方法[4,5]；同时诱导化疗中加入TKI抑制剂已经成为Ph +ALL患者诱导化疗的金标准[6]，从而整体上提高了患者无病生存率(DFS)和总生存率(OS)。随着对TKI的进一步研究，现在已有一代药物(伊马替尼)、二代药物(如达沙替尼、伯舒替尼)用于Ph +白血病的临床治疗。
伊马替尼(Gleevec)是第一个用于***的分子靶向药物，于2001年在美国获准上市，作为首个针对BCR-ABL蛋白的TKI抑制剂，成为治疗CML的一线药物[7]。 其作用机理是通过取代BCR-ABL融合蛋白结构中的磷酸腺苷(ATP)，使酪氨酸激酶催化中心位点不能与ATP相结合，竞争性抑制BCR-ABL自身磷酸化和底物磷酸化，从而达到抑制BCR-ABL阳性白血病细胞的增殖并促进其凋亡的作用。具有较好的疗效及安全性，作为一线药物能诱导绝大部分CML慢性期患者获得长期持续的临床缓解，但对于加速期、急变期患者远期疗效不甚理想，而且一旦治疗中止，疾病常常会复发，因此病人需要长期服药，由此带来的继发耐药问题以及患者的经济负担都是无法回避的严峻问题。随着对耐药机制的深入研究，Bcr-Abl激酶区基因点突变或基因表达增加导致的酪氨酸激酶活性增强是引起耐药的主要原因[8]。目前已证实的点突变类型逐渐增多，可发生在ATP结合环(P-环)、伊马替尼结合位点、激活环(A-环)、催化区(C-环)，这些点突变直接阻断或间接干扰药物与Bcr-Abl蛋白的结合，因而降低了患者对治疗的敏感性。为了克服伊马替尼的耐药问题，第2代BCR-ABL的TKI抑制剂应运而生，包括达沙替尼-dasatinib(Sprycel)[9][10]和伯舒替尼bosutinib(Bosulif)[11]可抑制除T315I以外的绝大部分BCR-ABL突变导致的伊马替尼耐药。
达沙替尼是一个Bcr-Abl酪氨酸激酶和Src家族激酶的双重激酶抑制剂。研究表明Ph +白血病的发生同时依赖于Src激酶和BCR-ABL激酶的双活化[12]，达沙替尼同时抑制酪氨酸激酶和Src激酶，以及能透过血脑屏障，于2006年6月28日通过美国FDA用于治疗CML和Ph +ALL。与伊马替尼不同的是，达沙替尼的抑制作用不依赖构象，与活化和非活化形式的Bcr-Abl激酶均能结合，因此能够克服许多ABL激酶区点突变导致的耐药(T3151突变体除外)。另外达沙替尼亦能抑制多种人肿瘤细胞中Src激酶蛋白的自主磷酸化，对一些实体瘤也有效[13]。
伯舒替尼是一种强效的蛋白激酶Src-ABL双重抑制剂,可以有效抑制野生型BCR-ABL和大多数Imatinib耐药的BCR-ABL突变(除V299L和T315I外)，2012年9月4日FDA批准主要用于治疗慢性期、加速期或急变期对伊马替尼等治疗不耐受或有耐药的CML患者，同时临床研究表明其对一些实体瘤也有效[14]。
尽管新一代的TKIs可以克服耐药问题，但TKI单独使用并不能清除CML白血病干细胞[16]，这群白血病干细胞是疾病复发的根源，因此CML病人需要终生长期服药。研究表明TKI无法清除CML白血病干细胞的一种理论假设是：TKI虽然可以抑制白血病干细胞内BCR-ABL的激酶活性，但BCR-ABL可以发挥非激酶活性功能，作为脚手架蛋白“protein scaffold”启动代偿信号通路，帮助白血病干细胞存活[17]。因此靶向降解BCR-ABL的治疗策略或许能够有效清除CML白血病干细胞，解决病人需要长期服药的问题以及由此带来的继发耐药。
恶性肿瘤极大地威胁着人类健康，针对靶蛋白，可以通过降解蛋白表达以达到***的目的。泛素介导的蛋白降解通路控制着真核细胞内绝大多数蛋白质的选择性降解，在此降解途径中，蛋白质先被泛素标记，然后被蛋白酶体识别和降解。其中泛素连 接酶(Ubiquitin-protein ligase，E3)直接与蛋白质结合，决定了降解的特异性[18]。利用生物体内泛素化过程设计具有蛋白降解靶向药物(Proteolysis Targeting Drug,PROTAD)是药物开发的新模式。PROTAD小分子药物就是利用细胞固有的泛素-蛋白酶体***调控靶向蛋白质降解[19]。PROTAD可以同时与靶蛋白和E3泛素连接酶结合，使本来不能与E3结合的靶蛋白泛素化，进而被蛋白酶体识别并降解。与传统的针对蛋白激酶活性位点的小分子不同，PROTAD的靶蛋白可以是没有明显活性位点的蛋白质，如转录因子和支架蛋白等，而这类蛋白质往往很难通过传统方式设计小分子抑制剂[20]。因此PROTAD具有非常广泛的应用前景，目前对PROTAD技术的应用研究已有成功的报导，包括***相关受体α[21]，细胞维甲酸结合蛋白(CRABP-II)[22]和BRD4[20]。
目前为止，未见到有报道采用招募Von Hippel Lindau(VHL)E3连接酶对BCR-ABL蛋白有降解作用的PROTAD化合物。本公开首次设计合成的PROTAD系列化合物通过招募VHL E3连接酶可以有效降解BCR-ABL和c-ABL蛋白；另外虽然采用招募Cereblon(CRBN)E3连接酶对BCR-ABL蛋白有降解作用的PROTAD化合物已有报道[23]，但本公开设计全新的PROTAD对BCR-ABL蛋白降解作用优于现有的文献报道[23]。
发明概述
本公开提供一种式(I)化合物：
Figure PCTCN2019077535-appb-000001
或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中BCR-ABL-TKIs、LIN、ULM、A部分以及所有取代基如发明详述中所定义。
本公开还提供一种医药组合物，其包含所述的式(I)化合物或其医药学上可接受的盐，及至少一种医药学上可接受的载体。
本公开还提供一种所述的式(I)化合物，或其医药学上可接受的盐，其是用作药剂：
Figure PCTCN2019077535-appb-000002
本公开所述的式(I)化合物，或其医药学上可接受的盐，其用于预防及/或治疗癌症。
本公开还提供一种所述的式(I)化合物或其医药学上可接受的盐的用途，其是用于制备用以预防及/或治疗癌症的药剂。
本公开还提供一种治疗或预防癌症的方法，其包括向受试者施用治疗有效量的所述的式(I)化合物，或其医药学上可接受的盐，或所述的药物组合物。
附图说明
图1显示了采用Western-blot法检测根据本公开一实施方式的PROTAD一系列化合物(图1中的(1)-(27)和(30)-(35))相比于比较实施例化合物(图1中的(28)和(29))对BCR-ABL和c-ABL蛋白的降解活性的结果。
图2显示了根据本公开一实施方式的Dasa-Lin-VHL体系化合物(SIAIS151178)对BCR-ABL耐药突变体的降解活性。
图3显示了根据本公开一实施方式的Dasa-Lin-VHL体系PROTAD化合物(SIAIS151178)对BCR-ABL +K562细胞移植瘤小鼠模型的影响。
图4显示了根据本公开一实施方式的Dasa-Lin-VHL体系PROTAD化合物(SIAIS151178)在体内水平对BCR-ABL蛋白的降解活性。
具体实施方式
目前为止，未见到有报道采用招募Von Hippel Lindau(VHL)E3连接酶对BCR-ABL蛋白有降解作用的PROTAD化合物。本公开首次设计合成的PROTAD系列化合物通过招募VHL可以有效降解BCR-ABL和c-ABL蛋白。另外本公开设计合成的另一系列全新的PROTAD系列化合物通过招募Cereblon(CRBN)E3连接酶可以高效降解BCR-ABL蛋白。虽然采用招募Cereblon(CRBN)E3连接酶的PROTAD化合物已有报道[23]，但本公开的PROTAD系列化合物对BCR-ABL蛋白降解作用优于现有的文献报道[23]。
因此，本公开的一方面提供一种式(I)化合物：
Figure PCTCN2019077535-appb-000003
其中Bcr-abl-TKIs通过基团A共价连接LIN，以及其中ULM共价连接LIN；
其中Bcr-abl-TKIs是Bcr-abl酪氨酸激酶抑制剂或者其具有相同功能的类似物；
LIN是连接基团，其是直链或支链的亚烷基链，其中所述直链或支链的亚烷基链可选地被一或多个-O-、-CONH-、-NHCO-、-NH-、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，其中所述直链或支链的亚烷基链可选地被一或多个取代基取代；
ULM是具有泛素化功能的VHL或CRBN蛋白酶小分子配体；以及
基团A为-CO-；
或其盐、对映异构体、立体异构体、溶剂化物、多晶型物。
在本公开的一实施方式中，所述Bcr-abl-TKIs表示由以下结构通式所表示的化合物部分：
Figure PCTCN2019077535-appb-000004
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12分别独立地表示烷基或H。
在本公开的一子实施方式中，所述R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12分别独立地表示直链或支链C 1-10烷基或H。在本公开的一子实施方式中，所述C 1-10烷基优选为C 1-9烷基，较优选为C 1-8烷基，还较优选为C 2-8烷基，更优选为C 1-7烷基，甚至更优选为C 1-6烷基，C 1-5烷基，或C 1-4烷基，或C 1-3烷基。代表性实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、和特戊基。
在本公开的一实施方式中，所述ULM表示以下式(II)结构：
Figure PCTCN2019077535-appb-000005
其中X表示-CH 2-或-CO-，Y表示-CH 2-、-NH-或-O-，以及Z 1表示羰基或Z 1不存在。
在本公开的一实施方式中，所述ULM表示以下式(III)结构：
Figure PCTCN2019077535-appb-000006
其中Z 2表示羰基或不存在。
在本公开的一实施方式中，所述LIN是亚甲基或直链或支链的C 2-C 30亚烷基链(优选C 2-C 29亚烷基链，C 2-C 28亚烷基链，C 2-C 27亚烷基链，C 2-C 26亚烷基链，C 2-C 25亚烷基链，C 2-C 24亚烷基链，C 2-C 23亚烷基链，C 2-C 22亚烷基链，C 2-C 21亚烷基链，C 2-C 20亚烷基链，C 2-C 19亚烷基链，C 2-C 18亚烷基链，C 2-C 17亚烷基链，C 2-C 16亚烷基链，C 2-C 15亚烷基链，C 2-C 14亚烷基链，C 2-C 13亚烷基链，C 2-C 12亚烷基链，C 2-C 11亚烷基链，C 2-C 10亚烷基链，C 2-C 9亚烷基链，C 2-C 8亚烷基链，C 2-C 7亚烷基链，C 2-C 6亚烷基链，C 2-C 5亚烷基链，C 2-C 4亚烷基链，C 2-C 3亚烷基链)，其中所述LIN可选地被一或多个取代基取代；在所述LIN是直链或支链的C 2-C 30亚烷基链时，所述直链或支链的C 2-C 30亚烷基链可选地被一或多个-O-、-CONH-、-NHCO-、-NH-、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次。
在本公开的一实施方式中，所述LIN表示：直链或支链的C 1-C 20亚烷基链、-(CH 2) n1-(O(CH 2) n2) m1-、-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-、-(CR 13R 14) n1-(O(CR 15R 16) n2) m1-、-(CR 17R 18) n1-(O(CR 19R 20) n2) m1-O-(CR 21R 22) n3-、-(CH 2) n1-(CONH-(CH 2) n2) m1-、-(CH 2) n1-(CONH-(CH 2) n2) m1-O-(CH 2) n3-、-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-CONH-(CH 2) n4-(O(CH 2) n5) m2-O-(CH 2) n6-、-(CR 23R 24) n1-(O(CR 25R 26) n2) m1-O-(CR 27R 28) n3-CONH-(CR 29R 30) n4-(O(CR 31R 32) n5) m2-O-(CR 33R 34) n6-、-(CR 35R 36) n1-CONH-(O(CR 37R 38) n2) m1-、-(CH 2) n1-NHCO-(CH 2) n2-、-(CH 2) n1-(NHCO-(CH 2) n2) m1-、-(CH 2) n1-(NHCO-(CH 2) n2) m1-O-(CH 2) n3-、由一或多个亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次的直链或支链的亚烷基链、和其碳链被一或多个亚芳基或亚杂环基或亚杂芳基或它们的任意组合中断一或多次的-(CH 2) n1-(O(CH 2) n2) m1-；
R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30、R 31、R 32、R 33、R 34、R 35、R 36、R 37、R 38分别独立地表示H、直链或支链的C 1-C 10烷基或C 3-C 10环烷基，其中在相同的所述LIN中时，R 13、R 14、R 15、R 16，R 17、R 18、R 19、R 20、R 21、R 22，R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30、R 31、R 32、R 33、R 34，或R 35、R 36、R 37、R 38不同时为H；
n1、n2、n3、n4、n5、n6、m1、m2分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数。
在本公开的一实施方式中，所述LIN表示-(CH 2) n1-(O(CH 2) n2) m1-或-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-，其中n1、n2、n3、m1分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数；其中所述LIN可选地被一或多个取代基取代，所述取代基选自羟基、氨基、巯基和卤素。在本公开的一实施方式中，所述LIN表示：
-CH 2O(CH 2) 2OCH 2-；-CH 2O(CH 2) 2O(CH 2) 2-；-(CH 2) 3O(CH 2) 2-；
-(CH 2) 3O(CH 2) 2O(CH 2) 2-；-(CH 2) 3O(CH 2) 3-；-(CH 2) 2O(CH 2) 2-；
-(CH 2) 2O(CH 2) 2OCH 2-；-(CH 2) 2O(CH 2) 2O(CH 2) 2-；-(CH 2) 2O(CH 2) 2O(CH 2) 3-；
-(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2-；-(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 3-；
-(CH 2) 5O(CH 2) 2O(CH 2) 2O(CH 2) 5-；-(CH 2) 5O(CH 2) 2O(CH 2) 2O(CH 2) 6-；
-(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2-；
-(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 3-；
-(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2-；
-(CH 2) 3O(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2-；或
-(CH 2) 3O(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 3-。
在本公开的一实施方式中，所述LIN表示可选地被一或多个取代基取代的直链或支链的C 1-C 20亚烷基链，其中所述取代基选自羟基、氨基、巯基和卤素。在本公开的一实施方式中，所述LIN表示：
-CH 2-；-(CH 2) 2-；-(CH 2) 3-；-(CH 2) 4-；-(CH 2) 5-；-(CH 2) 6-；-(CH 2) 7-；-(CH 2) 8-；-(CH 2) 9-；-(CH 2) 10-；-(CH 2) 11-；-(CH 2) 12-；-(CH 2) 13-；-(CH 2) 14-；-(CH 2) 15-；-(CH 2) 16-；-(CH 2) 17-；-(CH 2) 18-；-(CH 2) 19-；或-(CH 2) 20-。
在本公开的一实施方式中，所述LIN是被一或多个取代基取代一或多次的直链或支链的亚烷基链，其中所述取代基选自羟基、氨基、巯基和卤素。
在本公开的一实施方式中，所述LIN是由一或多个选自羟基、氨基、巯基、卤素或其组合的取代基取代的直链或支链的C 1-C 30亚烷基链(优选C 1-C 29亚烷基链，C 1-C 28亚烷基链，C 1-C 27亚烷基链，C 1-C 26亚烷基链，C 1-C 25亚烷基链，C 1-C 24亚烷基链，C 1-C 23亚烷基链，C 1-C 22亚烷基链，C 1-C 21亚烷基链，C 1-C 20亚烷基链，C 1-C 19亚烷基链，C 1-C 18亚烷基链，C 1-C 17亚烷基链，C 1-C 16亚烷基链，C 1-C 15亚烷基链，C 1-C 14亚烷基链，C 1-C 13亚烷基链，C 1-C 12亚烷基链，C 1-C 11亚烷基链，C 1-C 10亚烷基链，C 1-C 9亚烷基链，C 1-C 8亚烷基链，C 1-C 7亚烷基链，C 1-C 6亚烷基链，C 1-C 5亚烷基链，C 1-C 4亚烷基链，C 1-C 3亚烷基链，或C 1-C 2亚烷基链)。在本公开的一子实施方式中，所述取代基可以是例如1-30个，1- 25个，1-20个，或者1-15，1-10，1-9，1-8，1-7，1-6，1-5，1-4，1-3，或1-2个，或是20、19、18、17、16、15、14、13、12、11、10、9、8、7、6、5、4、3、2、1个。
在本公开的一实施方式中，所述LIN表示由一或多个亚杂环基或亚杂芳基或它们的任意组合中断一或多次的直链或支链的亚烷基链、或者其碳链被一或多个亚芳基或亚杂环基或亚杂芳基或它们的任意组合中断一或多次的-(CH 2) n1-(O(CH 2) n2) m1-，其中n1、n2、m1分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数；其中所述LIN可选地被一或多个取代基取代，所述取代基选自羟基、氨基、巯基和卤素。在本公开的一实施方式中，所述LIN表示：
-(CH 2) n1-***基-(CH 2) n2-、-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-***基-(CH 2) n4-(O(CH 2) n5) m2-O-(CH 2) n6-、-(CH 2) n1-***基-(CH 2) n2-(O(CH 2) n3) m1-O-(CH 2) n4-或-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-***基-(CH 2) n4-；以及
n1、n2、n3、n4、n5、n6、m1、m2分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30的整数。
在本公开的一实施方式中，所述LIN表示：
Figure PCTCN2019077535-appb-000007
在本公开的一实施方式中，所述LIN表示-(CH 2) n1-(CONH-(CH 2) n2) m1-、-(CH 2) n1-(CONH-(CH 2) n2) m1-O-(CH 2) n3-、或-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-CONH-(CH 2) n4-(O(CH 2) n5) m2-O-(CH 2) n6-；其中n1、n2、n3、n4、n5、n6、m1、m2分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数；其中所述LIN可选地被一或多个取代基取代，所述取代基选自羟基、氨基、巯基和卤素。在本公开的一实施方式中，所述LIN表示：
-CH 2CONHCH 2-；-(CH 2) 2CONH(CH 2) 2-；-(CH 2) 3CONH(CH 2) 3-；-(CH 2) 4CONH(CH 2) 4-；-(CH 2) 3CONH(CH 2) 4-；-(CH 2) 5CONH(CH 2) 5-；-(CH 2) 6CONH(CH 2) 7-；-(CH 2) 6CONH(CH 2) 6-；-(CH 2) 7CONH(CH 2) 7-；-(CH 2) 8CONH(CH 2) 8-；-(CH 2) 9CONH(CH 2) 9-；-(CH 2) 10CONH(CH 2) 10-；或-(CH 2) 2CONH(CH 2) 2-O-(CH 2) 2-。
在本公开的一实施方式中，所述LIN表示-(CH 2) n1-NHCO-(CH 2) n2-，其中n1、n2分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30的整数；其中所述LIN可选地被 一或多个取代基取代，所述取代基选自羟基、氨基、巯基和卤素。在本公开的一实施方式中，所述LIN是-(CH 2) n1-NHCO-(CH 2) n2-，其中n1、n2分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30的整数。
在本公开的一实施方式中，所述LIN是-CH 2NHCOCH 2-、-(CH 2) 2NHCO(CH 2) 2-、-(CH 2) 3NHCO(CH 2) 3-、-(CH 2) 4NHCO(CH 2) 4-、-(CH 2) 5NHCO(CH 2) 5-、-(CH 2) 6NHCO(CH 2) 6-、-(CH 2) 6NHCO(CH 2) 6-、-(CH 2) 7NHCO(CH 2) 7-、-(CH 2) 8NHCO(CH 2) 8-、-(CH 2) 9NHCO(CH 2) 9-、-(CH 2) 10NHCO(CH 2) 10-、-(CH 2) 11NHCO(CH 2) 11-、-(CH 2) 12NHCO(CH 2) 12-、或-(CH 2) 4NHCO(CH 2) 8-。
在本公开的一实施方式中，所述LIN表示由一或多个亚烯基中断一或多次的直链或支链的亚烷基链；其中所述LIN可选地被一或多个取代基取代，所述取代基选自羟基、氨基、巯基和卤素。在本公开的一实施方式中，所述LIN是-(CH 2) n1-CH＝CH-(CH 2) n2-，其中n1、n2分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30的整数。
在本公开的一实施方式中，所述LIN表示由一或多个亚炔基中断一或多次的直链或支链的亚烷基链；其中所述LIN可选地被一或多个取代基取代，所述取代基选自羟基、氨基、巯基和卤素。在本公开的一实施方式中，所述LIN是-(CH 2) n1-C≡C-(CH 2) n2-或-(CH 2) n1-C≡C-C≡C-(CH 2) n2-，其中n1、n2分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30的整数。
在本公开的一实施方式中，所述式(I)化合物还可以是式(IV)化合物：
Figure PCTCN2019077535-appb-000008
其中，基团A、LIN、X、Y、Z 1、R 1、R 2、R 3、R 4如上文所定义，且包括其各实施方式中的定义。
在本公开的一实施方式中，所述式(I)化合物还可以是式(V)化合物：
Figure PCTCN2019077535-appb-000009
其中，基团A、LIN、Z 2、R 1、R 2、R 3、R 4如上文所定义，且包括其各实施方式中的定义。
在本公开的一实施方式中，所述式(I)化合物还可以是式(VI)化合物：
Figure PCTCN2019077535-appb-000010
其中，基团A、LIN、X、Y、Z 1、R 5、R 6、R 7、R 8如上文所定义，且包括其各实施方式中的定义。
在本公开的一实施方式中，所述式(I)化合物还可以是式(VII)化合物：
Figure PCTCN2019077535-appb-000011
其中，基团A、LIN、Z 2、R 5、R 6、R 7、R 8如上文所定义，且包括其各实施方式中的定义。
在本公开的一实施方式中，所述式(I)化合物还可以是式(VIII)化合物：
Figure PCTCN2019077535-appb-000012
其中，基团A、LIN、X、Y、Z 1、R 9、R 10、R 11、R 12如上文所定义，且包括其各实施方式中的定义。
在本公开的一实施方式中，所述式(I)化合物还可以是式(IX)化合物：
Figure PCTCN2019077535-appb-000013
其中，基团A、LIN、Z 2、R 9、R 10、R 11、R 12如上文所定义，且包括其各实施方式中的定义。
特别优选的是本公开表1中的以下式I化合物及其盐(尤其医药学上可接受的盐)：
表1化合物结构式及其名称
Figure PCTCN2019077535-appb-000014
Figure PCTCN2019077535-appb-000015
Figure PCTCN2019077535-appb-000016
Figure PCTCN2019077535-appb-000017
Figure PCTCN2019077535-appb-000018
Figure PCTCN2019077535-appb-000019
Figure PCTCN2019077535-appb-000020
Figure PCTCN2019077535-appb-000021
Figure PCTCN2019077535-appb-000022
Figure PCTCN2019077535-appb-000023
Figure PCTCN2019077535-appb-000024
Figure PCTCN2019077535-appb-000025
应认识到本公开的式(I)化合物可具有立体构型，因此能以一种以上的立体异构体形式存在。本公开还涉及具有立体构型的基本上纯异构体形式的化合物，如约大于90％ee，如约95％ee或97％ee，或大于99％ee，及其混合物，包括外消旋混合物。这些异构体可以采用不对称合成(例如用手性中间体)或通过手性拆分来制备。
本公开的另一方面还提供一种医药组合物，其包含如本公开所述的式(I)化合物或其医药学上可接受的盐，及医药学上可接受的载体。
本公开所述的医药组合物，进一步包括至少一种额外的治疗或预防癌症的药物。
在本公开的另一方面，本公开所述的式(I)化合物，或其医药学上可接受的盐，其是用作药剂。
在本公开的另一方面，本公开所述的式(I)化合物，或其医药学上可接受的盐，其用于预防及/或治疗癌症。
在一实施方式中，所述癌症选自：Ph +慢性粒细胞白血病(chronic myeloid leukemia,CML)：包括慢性期患者chronic phase(CP)，加速期患者accelerated phase(AP)以及急变期患者blast crisis(BC)；Ph +急性淋巴细胞性白血病(acute lymphoblastic leukemia,ALL)；PDGFR(platelet-derived growth factor receptor)基因重排相关的骨髓增生异常综合症/骨髓增殖性疾病(myelodysplastic/myeloproliferative diseases，MDS/MPD)；侵袭性***性肥大细胞增生症(aggressive systemic mastocytosis,ASM)；高嗜酸性细胞增多综合症(Hypereosinophilic Syndrome，HES)；慢性嗜酸性粒细胞白血病(Chronic Eosinophilic Leukemia,CEL)；隆突性皮肤纤维肉瘤(Dermatofibrosarcoma protuberans,DFSP)；和Kit +胃肠道间质瘤(gastrointestinal stromal tumor,GIST)。
在一子实施方式中，所述Ph +慢性粒细胞白血病处于慢性期、加速期或急变期。
本公开的式I化合物及其医药学上可接受的盐可用作例如用于经胃肠道或非经胃肠道给药的医药组合物形式的药剂。
医药组合物可根据任何本领域普通技术人员已知的方式制备，通过由将所述式I化合物或其医药学上可接受的盐可选地与其它具医疗价值的物质组合，连同合适、无毒、惰性、治疗上兼容的固体或液体载体物质及(必要时)常用医药佐剂一起生成合适的所需制剂给药形式来实现。在药物组合物中，活性成分化合物的含量足以对疾病的过程或病症产生所需的影响。
医药组合物可根据制药领域已知的方法除菌后制备成各种不同的剂型。根据所需的给药途径，可将本公开的医药组合物配制成适于口服给药的粉末剂、锭剂、片剂(例如常规片剂、分散片、口腔崩解片)、颗粒剂、丸剂、乳剂、水性或油性混悬剂、胶囊剂(例如软胶囊、硬胶囊、肠溶胶囊)；或者适合于静脉内、肌肉内、体腔内、组织内、皮内或者皮下给药的可注射的溶液剂(例如根据本领域已知方法采用水、林格氏溶液或等渗氯化钠溶液等作为载体或溶剂来配制的无菌注射溶液)等；或者适合于局部给药或通过皮肤或粘膜吸收给药的喷雾剂、含片或栓剂等。
在本公开的另一方面，本公开所述的式(I)化合物，或其医药学上可接受的盐，其是用于制备用以预防及/或治疗癌症的药剂。在一子实施方式中，所述癌症选自：Ph +慢性粒细胞白血病(chronic myeloid leukemia,CML)：包括慢性期患者chronic phase(CP)，加速期患者accelerated phase(AP)以及急变期患者blast crisis(BC)；Ph +急性淋巴细胞性白血病(acute lymphoblastic leukemia,ALL)；PDGFR(platelet-derived growth factor receptor)基因重排相关的骨髓增生异常综合症/骨髓增殖性疾病(myelodysplastic/myeloproliferative diseases，MDS/MPD)；侵袭性***性肥大细胞增生症(aggressive systemic mastocytosis,ASM)；高嗜酸性细胞增多综合症(Hypereosinophilic Syndrome，HES)；慢性嗜酸性粒细胞白血病(Chronic Eosinophilic Leukemia,CEL)；隆突性皮肤纤维肉瘤(Dermatofibrosarcoma protuberans,DFSP)；和Kit +胃肠道间质瘤(gastrointestinal stromal tumor,GIST)。在一实施方式中，所述Ph +慢性粒细胞白血病处于慢性期、加速期或急变期。
本公开的另一方面还提供治疗或预防癌症的方法，其包括向受试者施用治疗有效量的本公开所述的式(I)化合物，或其医药学上可接受的盐，或所述的药物组合物。在一实施方式中，所述癌症选自：Ph +慢性粒细胞白血病(chronic myeloid leukemia,CML)：包括慢性期患者chronic phase(CP)，加速期患者accelerated phase(AP)以及急变期患者blast crisis(BC)；Ph +急性淋巴细胞性白血病(acute lymphoblastic leukemia,ALL)；PDGFR(platelet-derived growth factor receptor)基因重排相关的骨髓增生异常综合症/骨髓增殖性疾病(myelodysplastic/myeloproliferative diseases，MDS/MPD)；侵袭性***性肥大细胞增生症(aggressive systemic mastocytosis,ASM)；高嗜酸性细胞增多综合症(Hypereosinophilic Syndrome，HES)；慢性嗜酸性粒细胞白血病(Chronic Eosinophilic Leukemia,CEL)；隆突性皮肤纤维肉瘤(Dermatofibrosarcoma protuberans,DFSP)；和Kit +胃肠道间质瘤(gastrointestinal stromal tumor,GIST)。在一子实施方式中，所述Ph +慢性粒细胞白血病处于慢性期、加速期或急变期。
在本公开所述的治疗或预防癌症的方法中，本公开所述的式(I)化合物，或其医药学上可接受的盐，或所述的药物组合物，可以通过任何合适方法给药，例如通过至少一种选自鼻腔给药、吸入给药、局部给药、口服给药、口腔粘膜给药、直肠给药、胸膜腔 给药、腹膜给药、***给药、肌内给药、皮下给药、经皮给药、硬膜外腔给药、鞘内给药和静脉给药的给药方式施用至所述受试者。
定义
在本文中，式(Ia)表示的化合物部分：
Figure PCTCN2019077535-appb-000026
是伊马替尼(Imatinib)的哌嗪去除氮上的甲基衍生得到的化合物部分，其中R 1、R 2、R 3、R 4如上文所定义。
Figure PCTCN2019077535-appb-000027
在本文中，式(Ib)表示的化合物部分：
Figure PCTCN2019077535-appb-000028
是达沙替尼(Dasatinib)的哌嗪去除氮上的羟乙基衍生得到的化合物部分，其中R 5、R 6、R 7、R 8如上文所定义。
Figure PCTCN2019077535-appb-000029
在本文中，式(Ic)表示的化合物部分：
Figure PCTCN2019077535-appb-000030
Figure PCTCN2019077535-appb-000031
是伯舒替尼(Bosutinib)的哌嗪去除氮上的甲基衍生得到的化合物部分，其中R 9、R 10、R 11、R 12如上文所定义。
Figure PCTCN2019077535-appb-000032
在本文中，由波形线断裂的键显示所绘示基团连接至分子的其他部分的点。例如，下文所绘示的基团
Figure PCTCN2019077535-appb-000033
表示所述式(Ia)的化合物部分是通过哌嗪的N原子连接至式(I)化合物的基团A。
在本文中，所述ULM表示以下的式(II)结构
Figure PCTCN2019077535-appb-000034
其中X表示-CH 2-或-CO-，Y表示-CH 2-、-NH-或-O-，以及Z 1表示羰基或Z 1不存在。其是CRBN泛素连接酶小分子配体沙利度胺(Thalidomide)、来那度胺(Lenalidomide)、或泊马度胺(Pomalidomide)的衍生物。
Figure PCTCN2019077535-appb-000035
在本文中，所述ULM表示以下的式(III)结构
Figure PCTCN2019077535-appb-000036
其中Z 2表示羰基或不存在。其是VHL-1(化学名称为(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)的衍生物。
Figure PCTCN2019077535-appb-000037
在本文中，本公开的式(I)化合物亦称为PROTAD化合物、PROTAD小分子、或降解剂，它们之间可互换使用。
在本文中，术语“LIN”和“linker”可交换使用，均表示式I化合物中的连接基团LIN。
在本公开中，单独或组合使用的术语“卤素原子”或“卤素”是指氟、氯、溴或碘，且优选为F、Cl或Br。
在本公开中，单独或组合使用的术语“烷基”是指直链或支链的烷基。术语“C x-C y烷基”(x及y各自为整数)是指含有x至y个碳原子的直链或支链烷基。本公开中单独或组合使用的术语“C 1-10烷基”是指含有1至10个碳原子的直链或支链烷基。本公开的C 1-10烷基优选为C 1-9烷基，较优选为C 1-8烷基，还较优选为C 2-8烷基，更优选为C 1-7烷基，甚至更优选为C 1-6烷基，C 1-5烷基，或C 1-4烷基。代表性实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、特戊基、己基、庚基、辛基、壬基及癸基。本公开的术语“C 1-3烷基”是指含有1至3个碳原子的烷基，其表示性实例包括甲基、乙基、正丙基及异丙基。
在本公开中，单独或组合使用的术语“亚烷基”(其与“亚烷基链”可互换使用)是指由碳和氢原子组成的直链或支链的二价饱和烃基团。术语“C x-C y亚烷基”(x及y各自为整数)是指含有x至y个碳原子的直链或支链的亚烷基。本公开的C 1-C 30亚烷基优选为 C 1-C 29亚烷基，C 1-C 28亚烷基，C 1-C 27亚烷基，C 1-C 26亚烷基，C 1-C 25亚烷基，C 1-C 24亚烷基，C 1-C 23亚烷基，C 1-C 22亚烷基，C 1-C 21亚烷基，C 1-C 20亚烷基，C 1-C 19亚烷基，C 1-C 18亚烷基，C 1-C 17亚烷基，C 1-C 16亚烷基，C 1-C 15亚烷基，C 1-C 14亚烷基，C 1-C 13亚烷基，C 1-C 12亚烷基，C 1-C 11亚烷基，C 1-C 10亚烷基，C 1-C 9亚烷基，C 1-C 8亚烷基，C 1-C 7亚烷基，C 1-C 6亚烷基，C 1-C 5亚烷基，C 1-C 4亚烷基，C 1-C 3亚烷基，或C 1-C 2亚烷基。代表性实例包括但不限于亚甲基、亚乙基、亚丙基、亚异丙基、亚丁基、亚异丁基、亚仲丁基、亚叔丁基、亚戊基、亚异戊基、亚新戊基、亚特戊基、亚己基、亚庚基、亚辛基、亚壬基、亚癸基、亚十一烷基、亚十二烷基、亚十三烷基、亚十四烷基、亚十五烷基、亚十六烷基、亚十七烷基、亚十八烷基、亚十九烷基、亚二十烷基、亚二十一烷基、亚二十二烷基、亚二十三烷基、亚二十四烷基、亚二十五烷基、亚二十六烷基、亚二十七烷基、亚二十八烷基、亚二十九烷基、和亚三十烷基。
在本公开中，单独或组合使用的术语“亚芳基”是指包含5至14个碳原子并且可选地包含一个或多个稠合环的二价芳香烃基团，例如亚苯基或亚萘基或亚芴基。在本公开中，所述“亚芳基”是可选地经取代的亚芳基。经取代的亚芳基是指经取代基取代1-3次的亚芳基，其中取代基选自C 1-3烷基、C 1-3烷氧基、卤素、氨基或羟基。
在本公开中，单独或组合使用的术语“C 1-3烷氧基”是指含有1至3个碳原子的直链或支链烷氧基。C 1-3烷氧基的代表性实例包括但不限于甲氧基、乙氧基、正丙氧基及异丙氧基。优选为甲氧基及乙氧基。
在本公开中，单独或组合使用的术语“环烷基”是指具有3至12个碳原子的饱和及部分不饱和(即具有一个或多个双键，但不是完全共轭)的单环或双环环烃基。术语“C 3-C 10环烷基”是指具有3至10个碳原子的饱和及部分不饱和(即具有一个或多个双键，但不是完全共轭)的单环或双环环烃基。环烷基的代表性实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环辛基、十氢萘、八氢并环戊二烯、八氢-1H-茚、螺环基。
在本公开中，单独或组合使用的术语“亚环烷基”是指具有3至12个碳原子的饱和及部分不饱和(即具有一个或多个双键，但不是完全共轭)的单环或双环环烃二价基团。亚环烷基的代表性实例包括但不限于亚环丙基、亚环丁基、亚环戊基、亚环戊烯基、亚环己基、亚环己烯基、亚环庚基、亚环辛基、亚十氢萘基、八氢并环戊二烯亚基、八氢-1H-茚亚基、亚螺环基。根据明确的定义，亚环烷基基团可未被取代或被取代。
在本公开中，单独或组合使用的术语“亚杂芳基”是指含有1个或多个(例如1至6个、或者1至5个、或者1至4个、或者1至3个)独立选自氧、氮和硫的杂原子的5-至10-元单环或二环的二价芳香环基团。该种亚杂芳基基团的代表性实例包括但不限于亚呋喃基、亚噁唑基、亚异噁唑基、亚噁二唑基、亚噻吩基、亚噻唑基、亚异噻唑基、亚噻二唑基、亚吡咯基、亚咪唑基、亚吡唑基、亚***基、亚吡啶基、亚嘧啶基、亚哒嗪基、亚吡嗪 基、亚吲哚基、亚异吲哚基、亚苯并呋喃基、亚异苯并呋喃基、亚苯并噻吩基、亚吲唑基、亚苯并咪唑基、亚苯并噁唑基、亚苯并异噁唑基、亚苯并噻唑基、亚苯并异噻唑基、亚苯并***基、亚苯并[2,1,3]噁二唑基、亚苯并[2,1,3]噻二唑基、亚苯并[1,2,3]噻二唑基、亚喹啉基、亚异喹啉基、亚萘啶基、亚噌啉基、亚喹唑啉基、亚喹喔啉基、亚酞嗪基、吡唑并[1,5-a]吡啶亚基、吡唑并[1,5-a]嘧啶亚基、咪唑并[1,2-a]吡啶亚基、1H-吡咯并[3,2-b]吡啶亚基、1H-吡咯并[2,3-b]吡啶亚基、4H-氟[3,2-b]吡咯亚基、吡咯并[2,1-b]噻唑亚基和咪唑并[2,1-b]噻唑亚基。根据明确的定义，亚杂芳基基团可未被取代或被取代。
在本公开中，单独或组合使用的术语“亚杂环基”是指4-至6-元饱和的二价单环基团，其包含有一个或多个独立地选自硫、氧和氮的杂原子。所述亚杂环基的代表性实例包括但不限于亚氮杂环丁基、亚氧杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚***基、亚四氢呋喃基、亚四氢噻吩基、亚四氢噻喃基、亚噁唑烷基、亚噻唑烷基、亚哌啶基、亚哌嗪基、亚吗啉基、亚硫代吗啉基和亚二氧杂环己基。所述亚杂环基可以是未取代的或如明确定义的取代的。
在本公开中，单独或组合使用的术语“亚炔基”是指具有一个或多个碳碳叁键的包含2至10个(优选2至6个、较优选2至4个)碳原子的直链或支链二价烃基。优选亚炔基的实例包括但不限于亚乙炔基、1-丙炔亚基、1-丁炔亚基和1,3-二炔亚基。
在本公开中，单独或组合使用的术语“亚烯基”是指具有一个或多个碳碳双键的包含2至10个(优选2至6个、较优选2至4个)碳原子的直链或支链二价烃基。优选亚烯基的实例包括但不限于亚乙烯基、1-丙烯亚基、1-丁烯亚基。
本公开所述式I化合物的盐或药学上可接受的盐、对映异构体、立体异构体、溶剂化物、多晶型物亦涵盖于本公开范围内。
在本公开的所有实施方式中，所述式I化合物的盐或药学上可接受的盐是指无毒无机的或有机的酸和/或碱加成盐。示例包括：硫酸盐、盐酸盐、枸橼酸盐、马来酸盐、磺酸盐、或对甲苯磺酸盐等。
“药学上可接受的载体”是指药学上可接受的材料，例如填充剂、稳定剂、分散剂、悬浮剂、稀释剂、赋形剂、增稠剂、溶剂或包封材料，将本公开中有用的化合物携带或运输到患者体内或给予患者，使得其可以执行其预期功能。通常，这样的构建体从一个器官或身体的一部分携带或运输到另一个器官或身体的一部分。载体与制剂的其他成分(包括本公开中有用的化合物)相容并且对患者无害，载体必须是“可接受的”。可用作药学上可接受的载体的材料的一些实例包括：糖，如乳糖，葡萄糖和蔗糖；淀粉，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，例如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；粉状黄蓍胶；麦芽；明胶；滑石；赋形剂，如可可脂和栓剂蜡；油，如花生油，棉籽油，红花油，芝麻油，橄榄油，玉米油和大豆油；二醇，如丙二醇；多元醇，如甘油，山 梨糖醇，甘露醇和聚乙二醇；酯类，如油酸乙酯和月桂酸乙酯；琼脂；缓冲剂，如氢氧化镁和氢氧化铝；表面活性剂磷酸盐缓冲溶液；和药物制剂中使用的其他无毒相容物质。
本公开的化合物的“治疗有效量”取决于患者的年龄，性别和体重，患者的当前医学状况以及所治疗患者的癌症进展情况。本领域技术人员能够根据这些和其它因素来确定合适的剂量。
本公开的术语“室温”是指周围环境温度，例如20-30℃的温度。
本公开研制开发的化合物属于一种蛋白降解靶向小分子化合物，其主要由四部分组成，第一部分BCR-ABL-TKIs是具有BCR-ABL酪氨酸激酶抑制活性的化合物；第二部分LIN是链接单元；第三部分ULM是具有泛素化功能的VHL或者CRBN蛋白酶的小分子配体；以及第四部分基团A为羰基，其将BCR-ABL-TKIs和LIN共价结合，且LIN与ULM共价结合。通过Bcr-abl-TKIs对靶蛋白的特异识别，抑制Bcr-abl的酪氨酸激酶活性，同时E3连接酶特异性使Bcr-abl蛋白泛素化从而被蛋白酶体***降解，靶向BCR-ABL的本公开的PROTAD小分子通过降解消除致病性的BCR-ABL融合蛋白，一方面可以使Ph +白血病患者获得遗传学或分子生物学缓解，另一方面对于克服靶向药物的耐药性也有重大意义。除此之外，本公开设计开发的PROTAD小分子还可以降解其他酪氨酸激酶受体，如KIT，SRC蛋白激酶以及PDGFR等，对于这些靶点相关的肿瘤的治疗也有潜在价值。
实施例
在下列说明中，为了提供对本公开的彻底了解而提出许多具体细节。本公开可在不具有部分或所有这些具体细节的情况下实施。在其他情况下，为了不对本公开造成不必要的混淆，不详述众所周知的过程操作。虽然本公开将结合具体实施例来进行说明，但应当理解的是，这并非旨在将本公开限制于这些实施例。
整个说明书及实例中使用下列缩写：
Boc              叔丁氧基羰基
n-BuOH           正丁醇
tBuOH            叔丁醇
Con.             浓度
DCM              二氯甲烷
DME              乙二醇二甲醚
DMF              N,N-二甲基甲酰胺
DMSO             二甲基亚砜
DIPEA            N,N-二异丙基乙胺
EDCI             碳化二亚胺
ESI              电喷雾离子化
equiv            当量
EtOH             乙醇
HATU             O-(7-氮杂苯并三氮唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸盐
HOAT             1-羟基-7-偶氮苯并三氮唑
HPLC             高效液相层析
HRMS             高分辨率质谱
LC-MS            液相色谱-质谱联用
LRMS             低分辨率质谱
LC               液相层析
Me               甲基
MeCN             乙腈
MeOH             甲醇
MS               质谱
MW               微波
NMM              N-甲基***啉
NMP              N-甲基吡咯烷酮
1H NMR           核磁共振氢谱
rt               室温
TFA              三氟乙酸
THF              四氢呋喃
TLC              薄层层析
TMS              三甲基硅烷基
HO 2C-LIN-ULM     连接基团与ULM(Ubiquitin Ligase binding Moiety)共价连接形成的
                中间体
PROTAD           蛋白降解靶向药物(Proteolysis Targeting Drug)
在本公开中， 1H NMR谱采用Bruker-500MHz型核磁共振仪测定，用含0.1％TMS的CD 3OD做溶剂，其中 1H NMR谱以CD 3OD(δ＝3.31ppm)作为内标；或用含0.1％TMS的CDCl 3做溶剂，其中 1H NMR谱以CDCl 3(δ＝7.26ppm)作为内标；或使用含0.03％TMS的DMSO-d 6做溶剂，其中 1H NMR谱以DMSO-d 6(δ＝2.50ppm)作为内标；LRMS谱在AB Triple 4600型质谱仪上测定，HPLC制备在SHIMADZU LC-20AP型仪器上测定，HPLC纯度在SHIMADZU LC-30AP或Waters 1525型仪器上测定；产品经柱层析(硅胶:200-300目),C18反相柱(100g)制备分离。所有反应未作特别说明均在空气氛围下进行；反应用TLC或LC-MS跟踪。
溶剂及试剂处理如下：
反应所用溶剂DCM、DMF、NMP、无水EtOH、无水MeOH等均购自国药集团；
HPLC制备所用的是制备级CH 3CN及去离子水；
中间体去甲基伊马替尼，达沙替尼中间体(N-(2-氯-6-甲基苯基)-2-[(6-氯-2-甲基-4-嘧啶基)氨基]-5-噻唑甲酰胺)，伯舒替尼中间体(7-(3-氯丙氧基)-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-3-氰基喹啉)，以及各种不同长度碳链链接单元linker(本公开式I化合物的连接基团LIN)均可直接购买得到。
其它试剂和药品未经特别说明均从商业途径买来直接使用。
合成中间体
中间体制备例1：达沙替尼衍生物的制备
Figure PCTCN2019077535-appb-000038
根据方案1制备N-(2-氯-6-甲基苯基)-2-((2-甲基-6-(哌嗪-1-基)嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151055)：
将N-(2-氯-6-甲基苯基)-2-[(6-氯-2-甲基-4-嘧啶基)氨基]-5-噻唑甲酰胺(1.0g,2.54mmol)，无水哌嗪(1.31g,15.21mmol)，N,N-二异丙基乙胺(4.9g,38.0mmol)和无水n-BuOH(8mL)一起加入30mL的微波反应管中,室温下搅拌10分钟，然后缓慢向微波管中鼓入氩气，密封后，将反应管放入微波反应器中，缓慢升温至120℃，并搅拌1h。将反应液降至室温，放置过夜，有大量白色固体析出，抽滤，滤饼用无水正丁醇洗涤2次，减压除去溶剂得化合物SIAIS151055，为白色固体,0.9g，收率80％。 1H NMR(500MHz,DMSO)δ9.88(s,1H),8.23(s,1H),7.43–7.38(m,1H),7.31–7.24(m,2H),6.04(s,1H),3.45(d,J＝4.6Hz,4H),2.79–2.71(m,4H),2.44–2.37(m,3H),2.25(s,3H).HRMS(ESI)C 20H 23ClN 7OS +[M+H] +,计算值444.1368；实测值,444.1301.
中间体制备例2：伯舒替尼衍生物的制备
Figure PCTCN2019077535-appb-000039
根据方案2制备4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基-7-(3-(哌嗪-1-基)丙氧基)喹啉-3-甲腈(SIAIS151151)：
将7-(3-氯丙氧基)-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-3-氰基喹啉(1.0g,2.14mmol)，无水哌嗪(0.93g,10.7mmol)，碘化钠(0.4g,2.14mmol)和乙二醇二甲醚(8mL)一起加入30mL的微波反应管中,室温下搅拌10min，然后缓慢向微波管中鼓入氩气，将反应管放入微波反应器上，升至95℃并搅拌1h。将反应液降至室温，减压蒸去反应溶剂，随后加入20mL的饱和碳酸氢钠溶液，乙酸乙酯萃取(4x 50mL),合并有机相，饱和食盐水洗(20mL),无水Na 2SO 4干燥，减压蒸去溶剂，粗品经柱层析(洗脱剂(v/v)：二氯甲烷/甲醇＝10:1)纯化得化合物SIAIS151151，为浅棕色固体，0.55g，收率50％。 1H NMR(500MHz,DMSO)δ8.39(s,1H),7.82(s,1H),7.72(s,1H),7.30(s,1H),7.28(s,1H),5.75(s,1H),4.19(t,J＝6.4Hz,2H),3.94(s,3H),3.85(s,3H),2.76(t,J＝4.8Hz,4H),2.43(t,J＝7.1Hz,2H),2.39–2.32(m,4H),1.99–1.91(m,2H).HRMS(ESI)：计算值C 25H 28Cl 2N 5O 3 +[M+H] +,516.1564；实测值,516.1699.
制备泊马度胺聚乙二醇(PEG)系列HO 2C-LIN-ULM中间体的通用方法：
Figure PCTCN2019077535-appb-000040
将2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉--1,3-二酮(5mmol,1equiv)，相应的胺(6mmol,1.2equiv)和N,N-二异丙基乙胺(25mmol,5equiv)一起加入30mL的微波反应管中，随后加入NMP(8mL),室温下搅拌10分钟，然后缓慢向微波管中鼓入氩气，将反应管放入微波反应器上，升至110℃，并搅拌2h。将反应液降至室温，倾入90％食盐水中，乙酸乙酯萃取(4x 50mL),合并有机相，水洗(2x 30mL),饱和食盐水洗(50mL),无水Na 2SO 4干燥，减压蒸去溶剂，粗品经柱层析(洗脱剂(v/v)：石油醚/乙酸乙酯＝1:1)纯化得到中间体；随后将该化合物加入50mL单口瓶中，加入88％的20mL甲酸,室温搅拌12h。减压蒸去反应溶剂，加水冻干得最终的目标化合物HO 2C-LIN-ULM。
中间体制备例3：3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)丙酸(SIAIS151001)的制备
根据方案3的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的胺是3-(2-氨基乙氧基)丙酸叔丁酯。得到化合物(SIAIS151001)为黄色固体，1.0g,收率48％。 1H NMR(500MHz,DMSO)δ12.17(s,1H),11.09(s,1H),7.57(dd,J＝8.5,7.5Hz,1H),7.13(d,J＝8.6Hz,1H),7.04(d,J＝7.0Hz,1H),6.59(t,J＝5.7Hz,1H),5.05(dd,J＝12.8,5.4 Hz,1H),3.65(t,J＝6.3Hz,2H),3.59(t,J＝5.5Hz,2H),3.46(q,J＝5.5Hz,2H),2.91–2.83(m,1H),2.61–2.52(m,2H),2.46(t,J＝6.3Hz,2H),2.05–2.00(m,1H)；HRMS(ESI)m/z:计算值C 18H 20N 3O 7 +[M+H] +,390.1301；实测值,390.1261.
中间体制备例4：3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酸(SIAIS151004)的制备
根据方案3的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的胺是3-(2-(2-氨基乙氧基)乙氧基)丙酸叔丁酯。得到化合物(SIAIS151004)为黄色固体,0.95g,收率51％。 1H NMR(500MHz,DMSO)δ11.09(s,1H),7.58(dd,J＝8.0,7.5Hz,1H),7.14(d,J＝8.6Hz,1H),7.04(d,J＝7.0Hz,1H),6.60(t,J＝5.7Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),3.62–3.58(m,4H),3.56–3.54(m,2H),3.52–3.49(m,2H),3.46(dd,J＝11.1,5.5Hz,2H),2.92–2.84(m,1H),2.66–2.51(m,2H),2.42(t,J＝6.4Hz,2H),2.06–1.98(m,1H)；HRMS(ESI)m/z:计算值C 20H 24N 3O 8 +[M+H] +,434.1558；实测值,434.1445.
中间体制备例5：(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)丙酸(SIAIS151005)的制备
根据方案3的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的胺是3-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)丙酸叔丁酯。得到化合物(SIAIS151005)为黄色固体,0.95g,收率61％。 1H NMR(500MHz,DMSO)δ11.09(s,1H),7.58(dd,J＝8.0,7.0Hz,1H),7.15(d,J＝8.6Hz,1H),7.04(d,J＝7.0Hz,1H),6.61(t,J＝5.8Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),3.63–3.48(m,14H),2.92–2.83(m,1H),2.64–2.52(m,2H),2.18(t,J＝8.1Hz,2H),2.07–1.99(m,1H).HRMS(ESI)m/z:计算值C 22H 28N 3O 9 +[M+H] +,478.1820；实测值,478.1159.
中间体制备例6：1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十五烷-15-酸(SIAIS151006)的制备
根据方案3的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的胺是1-氨基-3,6,9,12-四氧杂十五烷-15-酸叔丁酯。得到化合物(SIAIS151006)为黄色固体,0.87g,收率53％。 1H NMR(500MHz,DMSO)δ11.09(s,1H),7.58(dd,J＝8.5,7.5Hz,1H),7.15(d,J＝8.6Hz,1H),7.04(d,J＝7.0Hz,1H),6.60(t,J＝5.7Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),3.63–3.48(m,18H),2.92–2.84(m,1H),2.63–2.52(m,2H),2.41(t,J＝6.4Hz,2H),2.07–1.98(m,1H).HRMS(ESI)m/z:计算值C 24H 32N 3O 10 +[M+H] +,522.2082；实测值,522.2178.
中间体制备例7：1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12,15-五氧杂十八烷-18-酸(SIAIS151007)的制备
根据方案3的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的胺是基1-氨基-3,6,9,12,15-五氧杂十八烷-18-酸叔丁酯。得到化合物(SIAIS151007)为 黄色固体,0.8g,收率51％。 1H NMR(500MHz,DMSO)δ11.09(s,1H),7.58(t,J＝8.0Hz,1H),7.14(d,J＝8.6Hz,1H),7.04(d,J＝7.0Hz,1H),6.60(t,J＝5.7Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),3.63–3.54(m,8H),3.54–3.48(m,12H),3.30(dd,J＝7.0Hz,4H),2.92–2.84(m,1H),2.63–2.52(m,2H),2.06–1.99(m,1H).HRMS(ESI)m/z:计算值C 26H 36N 3O 11 +[M+H] +,566.2344；实测值,566.2679.
制备泊马度胺烷基碳链系列HO 2C-LIN-ULM中间体的通用方法：
Figure PCTCN2019077535-appb-000041
将2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮(7mmol,1equiv)，相应的胺(8.4mmol,1.2equiv)和N,N-二异丙基乙胺(35mmol,5equiv)一起加入30mL的微波反应管中，随后加入NMP(8mL),室温下搅拌10分钟，然后缓慢向微波管中鼓入氩气，将反应管放入微波反应器上，升至110℃，并搅拌2h。将反应液降至室温，倾入90％食盐水中，乙酸乙酯萃取(4x 50mL),合并有机相，水洗(2x 30mL),饱和食盐水洗(50mL),无水Na 2SO 4干燥，减压蒸去溶剂，粗品经柱层析(洗脱剂(v/v)：石油醚/乙酸乙酯＝1:1)纯化得到中间体；随后将该系列化合物加入50mL单口瓶中，加入88％的20mL甲酸,室温搅拌12h。减压蒸去反应溶剂，加水冻干得最终的目标化合物HO 2C-LIN-ULM。
中间体制备例8：(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基乙酸(SIAIS151025)的制备
根据方案4的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的胺是氨基乙酸叔丁酯。得到化合物(SIAIS151025)为黄色固体,1.2g,收率48％。 1H NMR(500MHz,DMSO)δ11.10(s,1H),7.59(dd,J＝15.9,8.5Hz,1H),7.07(d,J＝7.0Hz,1H),6.99(d,J＝8.6Hz,1H),6.86(t,J＝5.7Hz,1H),5.06(dt,J＝15.1,7.6Hz,1H),4.08(d,J＝5.7Hz,2H),2.92–2.84(m,1H),2.63–2.52(m,2H),2.07–2.02(m,1H).HRMS(ESI)m/z:计算值C 18H 20N 3O 6 +[M+H] +,332.0877；实测值,332.0720.
中间体制备例9：3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙酸(SIAIS151026)的制备
根据方案4的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的胺是3-氨基丙酸叔丁酯。得到化合物(SIAIS151026)为黄色固体,0.93g,收率39％。 1H NMR(500MHz,DMSO)δ11.09(s,1H),7.59(dd,J＝8.0,7.5Hz,1H),7.15(d,J＝8.6Hz,1H),7.04(d,J＝7.0Hz,1H),6.67(t,J＝6.0Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),3.53(dd,J ＝12.6,6.3Hz,2H),2.92–2.84(m,1H),2.65–2.53(m,4H),2.08–1.98(m,1H).HRMS(ESI)m/z:计算值C 16H 16N 3O 6 +[M+H] +,346.1034；实测值,346.0868.
中间体制备例10：4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁酸(SIAIS151019)的制备
根据方案4的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的胺是4-氨基丁酸叔丁酯。得到化合物(SIAIS151019)为黄色固体,0.8g,收率61％。 1H NMR(500MHz,DMSO)δ12.14(s,1H),11.09(s,1H),7.58(dd,J＝8.4,7.3Hz,1H),7.13(d,J＝8.6Hz,1H),7.02(d,J＝7.0Hz,1H),6.65(t,J＝6.0Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),3.32(dd,J＝13.7,6.7Hz,2H),2.94–2.82(m,1H),2.66–2.51(m,2H),2.30(t,J＝7.2Hz,2H),2.05–2.00(m,1H),1.82–1.75(m,2H).HRMS(ESI)m/z:计算值C 17H 18N 3O 6 +[M+H] +,360.1190；实测值,360.1223.
中间体制备例11：5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酸(SIAIS151020)的制备
根据方案4的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的胺是5-氨基戊酸叔丁酯。得到化合物(SIAIS151020)为黄色固体,0.9g,收率50％。 1H NMR(500MHz,DMSO)δ12.05(s,1H),11.11(s,1H),7.57(dd,J＝8.3,7.4Hz,1H),7.09(d,J＝8.6Hz,1H),7.02(d,J＝7.0Hz,1H),6.56(t,J＝5.9Hz,1H),5.05(dd,J＝12.7,5.4Hz,1H),3.32–3.28(m,2H),2.94–2.82(m,1H),2.62–2.51(m,2H),2.27–2.25(m,2H),2.06–1.99(m,1H),1.62–1.53(m,4H).HRMS(ESI)m/z:计算值C 18H 20N 3O 6 +[M+H] +,374.1347；实测值,374.1384.
中间体制备例12：6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)己酸(SIAIS151027)的制备
根据方案4的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的胺是6-氨基己酸叔丁酯。得到化合物(SIAIS151027)为黄色固体,1.26g,收率61％。 1H NMR(500MHz,DMSO)δ12.00(s,1H),11.09(s,1H),7.58(dd,J＝8.3,7.4Hz,1H),7.09(d,J＝8.6Hz,1H),7.02(d,J＝7.0Hz,1H),6.54(t,J＝5.9Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),3.30–3.27(m,2H),2.92–2.84(m,1H),2.63–2.51(m,2H),2.21(t,J＝7.5Hz,2H),2.08–1.98(m,1H),1.60–1.50(m,4H),1.38–1.31(m,2H).HRMS(ESI)m/z:计算值C 19H 22N 3O 6 +[M+H] +,388.1503；实测值,388.1119.
中间体制备例13：7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酸(SIAIS151086)的制备
根据方案4的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的胺是7-氨基庚酸叔丁酯。得到化合物(SIAIS151086)为黄色固体,1.3g,收率64％。 1H NMR(500MHz,DMSO)δ12.04(s,1H),11.09(s,1H),7.58(dd,J＝8.3,7.3Hz,1H),7.09 (d,J＝8.6Hz,1H),7.02(d,J＝7.0Hz,1H),6.53(t,J＝5.9Hz,1H),5.05(dd,J＝12.7,5.4Hz,1H),3.28(dd,J＝13.4,6.7Hz,2H),2.94–2.82(m,1H),2.65–2.51(m,2H),2.19(t,J＝7.3Hz,2H),2.05–2.00(m,1H),1.60–1.53(m,2H),1.53–1.46(m,2H),1.37–1.28(m,4H).HRMS(ESI)m/z:计算值C 20H 24N 3O 6 +[M+H] +,402.1660；实测值,402.1643.
制备来那度胺烷基碳链系列HO 2C-LIN-ULM中间体的通用方法：
Figure PCTCN2019077535-appb-000042
将相应的二酸(5.0mmol,2.5equiv)加入250mL的三口瓶中,随后加入无水DMF(10mL)和无水二氯甲烷(150mL)，冰水浴搅拌下分别加入NMM(10.0mmol,5equiv),来那度胺(2mmol,1equiv)，HOAT(2.4mmol,1.2equiv)和EDCI(2.4mmol,1.2equiv)，加完随后升至室温搅拌过夜。反应完全后加入1mL的去离子水淬灭，减压蒸去二氯甲烷，随后利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到目标化合物HO 2C-LIN-ULM。
中间体制备例14：3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3-氧代丙酸(SIAIS171004)的制备
根据方案5的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是丙二酸。得到化合物(SIAIS171004)为白色固体,0.32g,收率24％。 1H NMR(500MHz,DMSO)δ11.02(s,1H),10.03(s,1H),7.86(d,J＝7.1Hz,1H),7.62–7.43(m,2H),5.15(dd,J＝13.4,4.9Hz,1H),4.36(dd,J＝35.5,17.5Hz,2H),3.42(s,2H),2.95–2.87(m,1H),2.63–2.59(m,1H),2.38–2.28(m,1H),2.07–2.01(m,1H).HRMS(ESI)m/z:计算值C 16H 16N 3O 6 +[M+H] +,346.1034；实测值,346.1015.
中间体制备例15：4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-4-氧代丁酸(SIAIS164084)的制备
根据方案5的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是琥珀酸。得到化合物(SIAIS164084)为白色固体,0.11g,收率44％。 1H NMR(500MHz,DMSO)δ12.16(s,1H),11.02(s,1H),9.86(s,1H),7.81(dd,J＝7.1,1.7Hz,1H),7.57–7.40(m,2H),5.15(dd,J＝13.3,5.1Hz,1H),4.35(dd,J＝35.5,17.5Hz,2H),2.96–2.87(m,1H),2.65–2.58(m,3H),2.55–2.53(m,2H),2.37–2.29(m,1H),2.06–2.00(m,1H).HRMS(ESI)m/z:计算值C 17H 18N 3O 6 +[M+H] +,360.1190；实测值,360.1198.
中间体制备例16：5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-5-氧代戊酸(SIAIS171005)的制备
根据方案5的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是戊二酸。得到化合物(SIAIS171005)为白色固体,0.52g,收率35％。 1H NMR(500MHz,DMSO)δ11.01(s,1H),9.80(s,1H),7.81(d,J＝5.8Hz,1H),7.54–7.46(m,2H),5.15(dd,J＝13.3,5.1Hz,1H),4.36(dd,J＝35.5,17.5Hz,2H),2.97–2.85(m,1H),2.77–2.75(m,2H),2.66–2.57(m,1H),2.42–2.39(m,1H),2.35(dd,J＝13.1,4.4Hz,1H),2.30–2.27(m,1H),2.03–1.97(m,1H),1.85–1.79(m,2H).HRMS(ESI)m/z:计算值C 18H 20N 3O 6 +[M+H] +,374.1347；实测值,374.1526.
中间体制备例17：6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-6-氧代己酸(SIAIS164101)的制备
根据方案5的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是己二酸。得到化合物(SIAIS164101)为白色固体,0.4g,收率27％。 1H NMR(500MHz,MeOD)δ7.70(d,J＝7.9Hz,1H),7.66(d,J＝7.4Hz,1H),7.52(t,J＝7.7Hz,1H),5.16(dd,J＝13.4,5.2Hz,1H),4.53–4.43(m,2H),2.95–2.87(m,1H),2.81–2.76(m,1H),2.55–2.48(m,1H),2.46(t,J＝7.2Hz,2H),2.36(t,J＝7.0Hz,2H),2.22–2.16(m,1H),1.79–1.66(m,4H).HRMS(ESI)m/z:计算值C 19H 22N 3O 6 +[M+H] +,388.1503；实测值,388.1714.
中间体制备例18：7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-7-氧代庚酸(SIAIS164102)的制备
根据方案5的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是庚二酸。得到化合物(SIAIS164102)为白色固体,0.45g,收率28％。 1H NMR(500MHz,MeOD)δ7.70(d,J＝7.9Hz,1H),7.65(d,J＝7.4Hz,1H),7.52(t,J＝7.7Hz,1H),5.16(dd,J＝13.4,5.2Hz,1H),4.49(t,J＝10.1Hz,2H),2.94–2.87(m,1H),2.81–2.76(m,1H),2.54–2.48(m,1H),2.45(t,J＝7.5Hz,2H),2.32(t,J＝7.0Hz,2H),2.22–2.16(m,1H),1.77–1.72(m,2H),1.70–1.63(m,2H),1.48-1.42(m,2H).HRMS(ESI)m/z:计算值C 20H 24N 3O 6 +[M+H] +,402.1660；实测值,402.1890.
制备VHL-1系列聚乙二醇(PEG)系列HO 2C-LIN-ULM中间体的通用方法：
Figure PCTCN2019077535-appb-000043
将相应的二酸(5.0mmol,2.5equiv)加入250mL的三口瓶中,随后加入无水DMF(10mL)和无水二氯甲烷(150mL)，冰水浴搅拌下分别加入NMM(10.0mmol,5equiv),VHL-1(2mmol,1equiv)，HOAT(2.4mmol,1.2equiv)和EDCI(2.4mmol,1.2equiv)，加完在冰水浴下搅拌5h，随后升至室温搅拌过夜。反应完全后加入1mL的去离子水淬灭，减压蒸去二氯甲烷，随后利用C18反相柱制备，(洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％)，减压蒸去乙腈，冻干后得到目标化合物HO 2C-LIN-ULM。
中间体制备例19：2-(2-(2-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-2-氧代乙氧基)乙氧基)乙酸(SIAIS151010)的制备
根据方案6的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是2,2'-(乙烷-1,2-二基二(氧基))二乙酸。得到化合物(SIAIS151010)为白色固体,0.2g,收率23％。 1H NMR(500MHz,DMSO)δ8.98(s,1H),8.60(t,J＝5.9Hz,1H),7.48(d,J＝9.5Hz,1H),7.40(s,4H),4.57(d,J＝9.6Hz,1H),4.47–4.37(m,2H),4.35(s,1H),4.29–4.22(m,1H),4.07(d,J＝12.5Hz,1H),3.97(s,2H),3.69–3.59(m,8H),2.44(s,3H),2.07–2.03(m,1H),1.93–1.87(m,1H),0.94(s,9H).HRMS(ESI)m/z:计算值C 28H 39N 4O 8S +[M+H] +,591.2483；实测值,591.2365.
中间体制备例20：3-(2-(3-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-3-氧代丙氧基)乙氧基)丙酸(SIAIS151002)的制备
根据方案6的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是3,3'-(乙烷-1,2-二基二(氧基))二丙酸。得到化合物(SIAIS151002)为白色固体,0.53g,收率44％。 1H NMR(500MHz,DMSO)δ12.17(s,1H),8.99(s,1H),8.57(t,J＝6.0Hz,1H),7.92(d,J＝9.3Hz,1H),7.41(dd,J＝18.5,8.2Hz,4H),4.55(d,J＝9.5Hz,1H),4.46–4.40(m,2H),4.36(s,1H),4.23(dd,J＝15.8,5.4Hz,1H),3.69–3.56(m,7H),3.49–3.46(m,4H),2.58–2.53(m,1H),2.47–2.42(m,2H),2.45(s,3H),2.39–2.32(m,1H),2.06–2.01(m,1H),1.95–1.88(m,1H),0.94(s,9H).HRMS(ESI)m/z:计算值C 30H 43N 4O 8S +[M+H] +,619.2796；实测值,619.2973.
中间体制备例21：(S)-15-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-羰基)-16,16-二甲基-13-氧代-4,7,10-三氧杂-14-氮杂十七烷酸(SIAIS151003)的制备
根据方案6的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是3,3'-((氧基双(乙烷-2,1-二基))二(氧基))二丙酸。得到化合物(SIAIS151003)为白色固体,0.63g,收率59％。 1H NMR(500MHz,DMSO)δ8.99(s,1H),8.57(t,J＝6.0Hz,1H),7.92(d,J＝9.4Hz,1H),7.41(dd,J＝18.5,8.2Hz,4H),4.56(d,J＝9.4Hz,1H),4.47– 4.41(m,2H),4.36(s,1H),4.23(dd,J＝15.9,5.5Hz,1H),3.70–3.57(m,8H),3.51–3.47(m,7H),2.58–2.52(m,1H),2.47–2.42(m,2H),2.45(s,3H),2.39–2.32(m,1H),2.08–2.00(m,1H),1.94–1.88(m,1H),0.94(s,9H).HRMS(ESI)m/z:计算值C 32H 47N 4O 9S +[M+H] +,663.3058；实测值,663.3008.
中间体制备例22：(S)-18-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-羰基)-19,19-二甲基-16-氧代-4,7,10,13-四氧杂-17-氮杂二十烷酸(SIAIS151008)的制备
根据方案6的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是4,7,10,13-四氧杂十六烷二酸。得到化合物(SIAIS151008)为白色固体,0.53g,收率51％。 1H NMR(500MHz,DMSO)δ8.98(s,1H),8.56(t,J＝6.0Hz,1H),7.91(d,J＝9.4Hz,1H),7.40(dd,J＝18.8,8.3Hz,4H),4.55(d,J＝9.4Hz,1H),4.45–4.40(m,2H),4.35(s,1H),4.22(dd,J＝15.8,5.5Hz,1H),3.69–3.54(m,10H),3.48(d,J＝2.7Hz,9H),2.56–2.52(m,1H),2.45–2.41(m,2H),2.45(s,3H),2.38–2.32(m,1H),2.06–2.00(m,1H),1.94–1.88(m,1H),0.93(s,9H).HRMS(ESI)m/z:计算值C 34H 51N 4O 10S +[M+H] +,707.3320；实测值,707.2945.
中间体制备例23：(S)-21-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-羰基)-22,22-二甲基-19-氧代-4,7,10,13,16-五氧杂-20-氮杂二十三烷酸(SIAIS151009)的制备
根据方案6的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是4,7,10,13,16-五氧杂十九烷二酸。得到化合物(SIAIS151009)为白色固体,0.82g,收率85％。 1H NMR(500MHz,DMSO)δ8.98(s,1H),8.56(d,J＝5.7Hz,1H),7.91(d,J＝9.3Hz,1H),7.40(dd,J＝18.6,7.9Hz,4H),4.55(d,J＝9.3Hz,1H),4.47–4.40(m,2H),4.35(s,1H),4.22(dd,J＝15.7,5.2Hz,1H),3.68–3.56(m,11H),3.51-3.49(s,9H),2.56–2.53(m,1H),2.45–2.41(m,5H),2.44(s,3H),2.36(dd,J＝13.4,7.0Hz,1H),2.08–2.00(m,1H),1.94–1.86(m,1H),0.93(s,9H).HRMS(ESI)m/z:计算值C 36H 55N 4O 11S +[M+H] +,751.3583；实测值,751.3199.
VHL-1系列聚烷基碳链系列HO 2C-LIN-ULM中间体的制备方法：
Figure PCTCN2019077535-appb-000044
将相应的二酸(5.0mmol,2.5equiv)加入250mL的三口瓶中,随后加入无水DMF(10mL)和无水二氯甲烷(150mL)，冰水浴搅拌下分别加入NMM(10.0mmol,5 equiv),VHL-1(2mmol,1equiv)，HOAT(2.4mmol,1.2equiv)和EDCI(2.4mmol,1.2equiv)，加完冰水浴下搅拌5h，随后升至室温搅拌过夜。反应完全后加入1mL的去离子水淬灭，减压蒸去二氯甲烷，随后利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到目标化合物。
中间体制备例24：4-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-4-氧代丁酸(SIAIS074011)的制备
根据方案7的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是琥珀酸。得到化合物(SIAIS074011)为白色固体,0.82g,收率65％。 1H NMR(500MHz,CDCl 3)δ11.88(s,1H),8.85(s,J＝11.2Hz,1H),7.69(s,1H),7.37–7.29(m,4H),6.09(br,1H),4.67–4.54(m,3H),4.49(s,1H),4.29(dd,J＝15.0,5.0Hz,1H),4.05(d,J＝11.3Hz,1H),3.73–3.63(m,1H),2.73–2.58(m,1H),2.57–2.41(m,3H),2.50(s,3H),2.31–2.14(m,2H),0.96(s,9H).HRMS(ESI)m/z:计算值C 26H 35N 4O 6S +[M+H] +,531.2272；实测值,531.2275.
中间体制备例25：5-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-5-氧代戊酸(SIAIS074012)的制备
根据方案7的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是戊二酸。得到化合物(SIAIS074012)为白色固体,0.85g,收率67％。 1H NMR(500MHz,CDCl 3)δ9.08(s,1H),8.65(br,1H),8.10(s,1H),7.38–7.29(m,4H),4.72–4.64(m,3H),4.52(s,1H),4.25(dd,J＝15.4,5.0Hz,1H),4.09(d,J＝10.5Hz,1H),3.73(d,J＝10.0Hz,1H),2.48(s,3H),2.39–2.13(m,6H),1.92–1.74(m,2H),0.96(s,9H).HRMS(ESI)m/z:计算值C 27H 37N 4O 6S +[M+H] +,545.2428；实测值,545.2428.
中间体制备例26：6-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-6-氧代己酸(SIAIS074013)的制备
根据方案7的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是己二酸。得到化合物(SIAIS074013)为白色固体,0.79g,收率55％。 1H NMR(500MHz,CDCl 3)δ8.99(s,1H),7.66(s,1H),7.39–7.33(m,4H),7.30(d,J＝7.5Hz,1H).7.14(br,1H),4.67–4.61(m,3H),4.52(s,1H).4.28(dd,J＝15.4,5.0Hz,1H),4.09(d,J＝11.4Hz,1H),3.74–3.63(m,1H),2.52(s,3H),2.31–2.17(m,6H),1.65–1.53(m,4H),0.96(s,9H).HRMS(ESI)m/z:计算值C 28H 40N 4O 6S +[M+H] +,559.2585；实测值,559.3632.
中间体制备例27：7-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-7-氧代庚酸(SIAIS074014)的制备
根据方案7的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是庚二酸。得到化合物(SIAIS074014)为白色固体,0.8g,收率57％。 1H NMR(500MHz,CDCl 3)δ8.90(s,1H),7.42–7.38(m,1H),7.41–7.33(m,4H),7.31(d,J＝9.0Hz, 1H),6.38(br,1H),4.79–4.46(m,3H),4.55(s,1H),4.28(dd,J＝15.2,5.1Hz,1H),4.12(d,J＝11.3Hz,1H),3.72–3.63(m,1H),2.51(s,3H),2.38–2.33(m,1H),2.28–2.21(m,4H),2.18–2.12(m,1H),1.62–1.52(m,3H),1.33–1.23(m,3H),0.96(s,9H).HRMS(ESI)m/z:计算值C 29H 41N 4O 6S +[M+H] +,573.2741；实测值,573.3804.
中间体制备例28：8-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-8-氧代辛酸(SIAIS074015)的制备
根据方案7的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是辛二酸。产物(SIAIS074015)为白色固体,0.95g,收率68％。 1H NMR(500MHz,CDCl 3)δ8.82(s,1H),7.43(t,J＝6.0Hz,1H),7.34(s,4H),6.98(d,J＝8.5Hz,1H),6.10(s,1H),4.69–4.65(m,1H),4.63–4.51(m,2H),4.55–4.50(m,1H),4.38–4.27(m,1H),4.11(d,J＝16.7Hz,1H),3.72–3.62(m,1H),2.51(s,3H),2.39–2.13(m,6H),1.58–1.54(m,4H),1.33–1.21(m,4H),0.95(s,9H).HRMS(ESI)m/z:计算值C 30H 43N 4O 6S +[M+H] +,587.2898；实测值,587.2917.
中间体制备例29：9-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-9-氧代壬酸(SIAIS074016)的制备
根据方案7的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是壬二酸。产物(SIAIS074016)为白色固体,0.92g,收率64％。 1H NMR(500MHz,CDCl 3)δ8.82(s,1H),7.35(s,4H),7.02(t,J＝14.3Hz,1H),5.99(s,1H),4.74–4.49(m,4H),4.30(dd,J＝15.2,5.1Hz,1H),4.13(d,J＝11.3Hz,1H),3.67(dd,J＝11.5,3.5Hz,1H),2.51(s,3H),2.42–2.36(m,1H),2.28(t,J＝7.5Hz,2H),2.24–2.12(m,3H),1.67–1.48(m,4H),1.35–1.22(m,6H),0.95(s,9H).HRMS(ESI)m/z:计算值C 31H 45N 4O 6S +[M+H] +,601.3054；实测值,601.3150.
中间体制备例30：10-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-10-氧代癸酸(SIAIS074019)的制备
根据方案7的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是癸二酸。产物(SIAIS074019)为白色固体,0.96g,收率66％。 1H NMR(500MHz,CDCl 3)δ8.79(s,1H),7.39–7.36(m,1H),7.35(s,4H),7.01(d,J＝9.0Hz,1H),5.80(s,1H),4.68–4.52(m,4H),4.29(dd,J＝15.2,5.0Hz,1H),4.12(d,J＝11.2Hz,1H),3.72–3.62(m,1H),2.51(s,3H),2.41–2.33(m,1H),2.32–2.23(m,2H),2.23–2.11(m,3H),1.65–1.48(m,4H),1.32–1.21(m,8H),0.95(s,9H).HRMS(ESI)m/z:计算值C 32H 47N 4O 6S +[M+H] +615.3211；实测值,615.4391.
中间体制备例31：11-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-11-氧代十一烷酸(SIAIS074020)的制备
根据方案7的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是十一烷二酸。产物(SIAIS074020)为白色固体,1g,收率67％。 1H NMR(500MHz,CDCl 3)δ8.77(s,1H),7.39–7.32(m,4H),7.30(m,1H),7.01(d,J＝8.8Hz,1H),5.52(br,1H),4.69–4.59(m,3H),4.53(s,1H),4.29(dd,J＝15.2,5.0Hz,1H),4.14(d,J＝11.3Hz,1H),3.68–3.64(m,1H),2.51(s,3H),2.44–2.40(m,1H),2.29(t,J＝7.1Hz,2H),2.26–2.12(m,3H),1.68–1.48(m,4H),1.30–1.20(m,10H),0.95(s,9H).HRMS(ESI)m/z:计算值C 33H 49N 4O 6S +[M+H] +,629.3367；实测值,629.4540.
中间体制备例32：14-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-14-氧代十四烷酸(SIAIS164185)的制备
根据方案7的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是十四烷二酸。产物(SIAIS164185)为白色固体,523mg,收率70％。 1H NMR(500MHz,MeOD)δ8.95(s,1H),7.48(d,J＝8.4Hz,2H),7.44–7.41(m,2H),4.64(s,1H),4.58–4.49(m,3H),4.36(d,J＝15.4Hz,1H),3.91(d,J＝11.0Hz,1H),3.81(dd,J＝10.9,3.9Hz,1H),2.48(s,3H),2.32–2.22(m,11H),2.12–2.05(m,1H),1.63–1.56(m,10H),1.29–1.28(m,8H),1.04(s,9H).HRMS(ESI)m/z:计算值C 36H 55N 4O 6S +[M+H] +,671.3837；实测值,671.0892.
中间体制备例33：16-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-16-氧代十六烷酸(SIAIS164189)的制备
根据方案7的方法、在本领域可理解的适当条件下制备得到，不同之处在于采用的二酸是十六烷二酸。产物(SIAIS164189)为白色固体,488mg,收率68％。 1H NMR(500MHz,MeOD)δ8.90(s,1H),7.49–7.44(m,2H),7.44–7.40(m,2H),4.64(s,1H),4.59–4.48(m,3H),4.40–4.31(m,1H),3.90(d,J＝11.1Hz,1H),3.80(dd,J＝10.9,3.9Hz,1H),2.48(s,3H),2.30–2.25(m,8H),2.23–2.19(m,1H),2.11–2.06(m,1H),1.62–1.59(m,10H),1.30–1.29(m,6H),1.04(s,9H).HRMS(ESI)m/z:计算值C 38H 59N 4O 6S +[M+H] +,699.4150；实测值,699.0566.
其它HO 2C-LIN-ULM中间体的通用制备方法：
中间体制备例34：6-(2-(2-((6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-6-氧代己基)氧基)乙氧基)乙氧基)己酸(SIAIS171104B)的制备
Figure PCTCN2019077535-appb-000045
步骤1：根据方案8制备6,6'-((氧基双(乙烷-2,1-二基))二(氧基))二己酸(SIAIS171082B)
将二乙二醇(500mg,4.71mmol)，6-溴己酸叔丁酯(2370mg,9.42mmol)和无水DMF(15mL)一起加入干燥的100mL的三口瓶中，随后鼓入氮气，冰水浴下缓慢加入NaH(566mg,14.13mmol,60％in oil)，加毕，冰水浴下搅拌10min，随后升至室温并搅拌过夜。反应结束后，冰水浴下加水缓慢淬灭反应，乙酸乙酯萃取(50mL x1)，随后水相用2N的稀盐酸水溶液调至溶液pH＝2-3，乙酸乙酯萃取(50mL x3)，合并有机相，水洗(50mL x 3)，饱和食盐水洗(500mL)，无水Na 2SO 4干燥，过滤，浓缩得目标化合物(SIAIS171082B)，为淡黄色油状物，620mg,收率39％, 1H NMR(500MHz,CDCl 3)δ3.67–3.62(m,4H),3.60–3.54(m,4H),3.49–3.45(m,4H),2.38–2.35(m,4H),1.68–1.57(m,8H),1.46–1.40(m,4H).HRMS(ESI)m/z:计算值C 16H 31O 7 +[M+H] +,335.2064；实测值,334.9111.粗品未进行进一步纯化，直接用于下一步反应。
步骤2：根据方案8制备6,6'-((氧基双(乙烷-2,1-二基))二(氧基))二己酰氯(SIAIS171104A)
将化合物(SIAIS171082B)(100mg,0.30mmol)加入50mL的蛋形瓶中，加入无水THF(10mL)，室温下缓慢滴加二氯亚砜(0.2mL)，滴毕，升温至回流状态并搅拌2h。反应完全后，随后减压蒸去反应溶剂，得目标产物(SIAIS171104A)为红棕色油状物，150mg。该产物未被进一步纯化，直接用于下一步反应。
步骤3：根据方案8制备6-(2-(2-((6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-6-氧代己基)氧基)乙氧基)乙氧基)己酸(SIAIS171104B)：
将泊马度胺(40mg,0.15mmol)和无水THF(3mL)加入一个25mL的蛋形瓶中，室温搅拌下缓慢滴加(SIAIS171104A)(150mg,粗品)，滴毕,缓慢升温至回流状态，并搅拌4h。原料反应完后，将反应液冷却至室温，加入1mL的水淬灭并搅拌30min,减压除去反应溶剂，得固体粗品；随后利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到目标化合物(SIAIS171104B)，为淡 黄色固体,20mg,收率23％；HRMS(ESI)m/z:计算值C 29H 40N 3O 10 +[M+H] +,590.2708；实测值,590.2694.
其它HO 2C-LIN-ULM中间体的通用制备方法：
Figure PCTCN2019077535-appb-000046
中间体制备例35：4-((2-氨基乙基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS151103)的制备
步骤1：根据方案9制备4-((2-氨基乙基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS151103):
将2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮(2.0g,7.24mmol)，叔丁基(2-氨基乙基)氨基甲酸酯(1.28g,7.96mmol)和N,N-二异丙基乙胺(4.68g,36.2mmol)一起加入30mL的微波反应管中，随后加入NMP(10mL),室温下搅拌10分钟，然后缓慢向微波管中鼓入氩气，将反应管放入微波反应器上，升至110℃，并搅拌2h。反应结束后，将反应液降至室温，倾入90％食盐水中，乙酸乙酯萃取(4x 50mL),合并有机相，水洗(2x 30mL),饱和食盐水洗(50mL),无水Na 2SO 4干燥，减压蒸去溶剂，粗品经柱层析(洗脱剂(v/v)：石油醚/乙酸乙酯＝1:1)纯化得到中间体；随后将该化合物加入50mL单口瓶中，加入甲酸(20mL),室温搅拌12h。减压蒸去反应溶剂，加水冻干得目标化合物(SIAIS151103)。产物为黄色固体,1.6g,两步收率70％。 1H NMR(500MHz,DMSO)δ8.36(s,2H),7.64–7.58(m,1H),7.18(t,J＝6.2Hz,1H),7.07(d,J＝7.1Hz,1H),6.84(t,J＝6.2Hz,1H),5.06(dd,J＝12.7,5.4Hz,1H),3.56(dd,J＝12.2,6.0Hz,2H),2.96(t,J＝6.1Hz,2H),2.93–2.85(m,1H),2.61–2.51(m,2H),2.06–2.00(m,1H).HRMS(ESI)m/z:计算值C 15H 17N 4O 4 +[M+H] +,317.1244；实测值,317.1236.
中间体制备例36：4-((2-(2-氨基乙氧基)乙基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS151012B)的制备
步骤1：根据方案9制备4-((2-(2-氨基乙氧基)乙基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS151012B):
将2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮(1.35g,4.90mmol)，叔丁基(2-(2-氨基乙氧基)乙基)氨基甲酸酯(1.5g,5.39mmol)和N,N-二异丙基乙胺(3.16g,24.5mmol)一起加入30mL的微波反应管中，随后加入NMP(10mL),室温下搅拌10分钟，然后缓慢向微波管中鼓入氩气，将反应管放入微波反应器上，升至110℃，并搅拌2h。反应结 束后，将反应液降至室温，倾入90％食盐水中，乙酸乙酯萃取(4x 50mL),合并有机相，水洗(2x 30mL),饱和食盐水洗(50mL),无水Na 2SO 4干燥，减压蒸去溶剂，粗品经柱层析(洗脱剂(v/v)：石油醚/乙酸乙酯＝1:1)纯化得到中间体；随后将该化合物加入50mL单口瓶中，加入甲酸(20mL),室温搅拌12h。减压蒸去反应溶剂，加水冻干得目标化合物(SIAIS151012B)。产物为淡黄色固体,856.6mg,两步收率49％, 1H NMR(500MHz,DMSO)δ8.33(s,1H),7.61–7.57(m,1H),7.16(dd,J＝8.5,6.4Hz,1H),7.05(dd,J＝7.0,4.3Hz,1H),6.67–6.57(m,1H),5.05(dd,J＝12.8,5.4Hz,1H),3.64–3.60(m,3H),3.58–3.55(m,2H),3.51–3.46(m,3H),2.90–2.88(m,1H),2.63–2.51(m,2H),2.06–2.00(m,1H).HRMS(ESI)m/z:计算值C 17H 21N 4O 5 +[M+H] +,361.1506；实测值,361.1685.
中间体制备例37：4-((2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙基)氨基)-4-氧代丁酸(SIAIS164119)的制备
根据方案9制备4-((2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙基)氨基)-4-氧代丁酸(SIAIS164119):
将化合物丁二酸(325mg,2.75mmol)加入100mL的三口瓶中,随后加入无水DMF(5mL)和无水二氯甲烷(50mL)，冰水浴搅拌下分别加入NMM(1.12g,11mmol),化合物(SIAIS151103)(350mg,1.10mmol)，HOAt(180mg,1.32mmol)和EDCI(252mg,1.32mmol)，加完冰水浴下搅拌5h，随后升至室温搅拌过夜。反应完全后加入1mL的去离子水淬灭，减压蒸去二氯甲烷，随后利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到目标化合物(SIAIS164119)。产物为黄色固体,170mg,收率41％。 1H NMR(500MHz,MeOD)δ7.55–7.50(m,1H),7.10(d,J＝8.6Hz,1H),7.04(t,J＝6.3Hz,1H),5.05(dd,J＝12.4,5.5Hz,1H),3.47-3.39(m,4H),2.89-2.82(m,1H),2.79–2.65(m,2H),2.58(t,J＝7.0Hz,2H),2.45(t,J＝7.0Hz,2H),2.16–2.05(m,1H).HRMS(ESI)m/z:计算值C 19H 21N 4O 7 +[M+H] +,417.1405；实测值,417.0916。
中间体制备例38：4-((2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙基)氨基)-4-氧代丁酸(SIAIS164118)的制备
根据方案9制备4-((2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙基)氨基)-4-氧代丁酸(SIAIS164118):
将化合物丁二酸(325mg,2.75mmol)加入100mL的三口瓶中,随后加入无水DMF(5mL)和无水二氯甲烷(50mL)，冰水浴搅拌下分别加入NMM(1.12g,11mmol),化合物(SIAIS151012B)(390mg,1.10mmol)，HOAt(180mg,1.32mmol)和EDCI(252mg,1.32mmol)，加完冰水浴下搅拌5h，随后升至室温搅拌过夜。反应完全后加入1mL的去离子水淬灭，减压蒸去二氯甲烷，随后利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到目标化合物(SIAIS164118)。为淡黄色固体,280mg,收率61％。 1H NMR(500MHz,MeOD)δ7.59–7.53(m,1H),7.12–7.04(m, 2H),5.11–5.03(m,1H),3.71(t,J＝5.2Hz,2H),3.58(dd,J＝11.4,5.6Hz,2H),3.50(dd,J＝10.8,5.4Hz,2H),3.45–3.37(m,2H),3.32–3.31(m,2H),2.92–2.82(m,1H),2.79–2.65(m,2H),2.63–2.56(m,1H),2.55–2.48(m,1H),2.15–2.07(m,1H).HRMS(ESI)m/z:计算值C 21H 25N 4O 8 +[M+H] +,461.1667；实测值,461.1672。
中间体制备例39：5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-5-氧代戊酸(SIAIS184044)的制备
Figure PCTCN2019077535-appb-000047
根据方案10制备5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-5-氧代戊酸(SIAIS184044)：
将化合物泊马度胺(273.2mg,1mmol,1equiv)和无水THF(15mL)加入一个100mL的蛋形瓶中，室温搅拌下缓慢滴加戊二酰氯(0.64mL,5mmol,5.0equiv)，滴加完成之后，缓慢升温至80℃，并搅拌3h。随后将反应液冷却至室温，加入0.5mL的水淬灭,减压除去反应溶剂；随后粗品利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得淡黄色固体化合物SIAIS184044,193.7mg,收率50％. 1H NMR(500MHz,DMSO)δ11.14(s,1H),9.73(s,1H),8.44(d,J＝8.4Hz,1H),7.83(dd,J＝8.3,7.5Hz,1H),7.62(d,J＝7.3Hz,1H),5.14(dd,J＝12.9,5.4Hz,1H),2.93–2.86(m,1H),2.65–2.51(m,4H),2.37–2.26(m,2H),2.12–2.02(m,1H),1.91–1.78(m,2H).HRMS(ESI)m/z:计算值C 18H 18N 3O 7 +[M+H] +,388.1139；实测值,388.1149.
其它HO 2C-LIN-ULM中间体的通用制备方法：
Figure PCTCN2019077535-appb-000048
中间体制备例40：叔丁基5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊酸酯(SIAIS184046)的制备
根据方案11制备叔丁基5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊酸酯(SIAIS184046)：
将化合物来那度胺(259.3mg,1mmol)加入一个25mL的蛋形瓶中，随后加入无水NMP(5mL),N,N-二异丙基乙胺(387.7mg,3mmol)和5-溴戊酸叔丁酯(284.6mg,1.2mmol)，加毕，缓慢升温至100℃，并搅拌过夜。反应结束后，随后利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到目标化合物(SIAIS184046),为淡黄色固体,260mg,收率63％. 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.28(t,J＝7.7Hz,1H),6.92(d,J＝7.2Hz,1H),6.74(d,J＝8.0Hz,1H),5.58(s,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.22(d,J＝17.1Hz,1H),4.12(d,J＝17.1Hz,1H),3.12(t,J＝6.1Hz,2H),2.95–2.89(m,1H),2.62(d,J＝16.7Hz,1H),2.36–2.19(m,3H),2.08–1.96(m,1H),1.59(dd,J＝8.4,5.1Hz,4H),1.39(d,J＝6.1Hz,9H).HRMS(ESI)m/z:计算值C 22H 30N 3O 5 +[M+H] +,416.2180；实测值,416.1274.
中间体制备例41：5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊酸(SIAIS184047)的制备
根据方案11制备5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊酸(SIAIS184047)：
将化合物(SIAIS184046)(260mg,0.63mmol)加入25mL的蛋形瓶中，随后加入DCM(5mL),TFA(15mL),室温下搅拌1h。反应结束后，减压蒸去溶剂，加水冻干得目标产物(SIAIS184047)，为淡黄色固体,210mg,收率93％。 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.28(t,J＝7.7Hz,1H),6.92(t,J＝10.9Hz,1H),6.76(d,J＝8.0Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),5.07–4.83(m,3H),4.23(d,J＝17.2Hz,1H),4.13(d,J＝17.1Hz,1H),3.13(d,J＝6.4Hz,2H),2.97–2.87(m,1H),2.61(d,J＝16.7Hz,1H),2.38–2.21(m,3H),2.06–1.98(m,1H),1.67–1.55(m,4H)；HRMS(ESI)m/z:计算值C 18H 22N 3O 5 +[M+H] +,360.1554；实测值,360.0739.
中间体制备例42：(S)-3-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-羰基)-2,2-二甲基-5-氧代-11,14,17-三氧杂-4-二十三烷-23-酸(SIAIS180127)的制备
Figure PCTCN2019077535-appb-000049
根据方案12制备(S)-3-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-羰基)-2,2-二甲基-5-氧代-11,14,17-三氧杂-4-二十三烷-23-酸(SIAIS180127)：
室温下，将化合物SIAIS171082B(46mg,0.14mmol)，VHL-1(32mg,0.07mmol),HOAt(14mg,0.10mmol),EDCI(20mg,0.10mmol),无水DMF(0.3mL)和DCM(1.2mL)，NMM(35mg,0.34mmol)加入10mL的蛋形瓶中，随后室温搅拌过夜。LC-MS检测反应结束后，HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)，旋去乙腈，冻干得目标产物(SIAIS180127),为白色固体,33mg,收率64％。 1H NMR(500MHz,MeOD)δ9.05(s,1H),7.49(d,J＝8.1Hz,2H),7.43(d,J＝8.2Hz,2H),4.64(s,1H),4.59–4.49(m,3H),4.36(d,J＝15.5Hz,1H),3.91(d,J＝11.2Hz,1H),3.80(dd,J＝11.0,3.8Hz,1H),3.63–3.61(m,4H),3.58–3.56(m,4H),3.50–3.44(m,4H),2.50(s,3H),2.36–2.19(m,5H),2.11–2.05(m,1H),1.66–1.55(m,8H),1.44–1.36(m,4H),1.04(s,9H).HRMS(ESI)m/z:计算值C 38H 59N 4O 9S +[M+H] +,747.3997；实测值,746.6856.
中间体制备例43：5-(10-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-10-氧代癸酰氨基)戊酸(SIAIS164178B)的制备
Figure PCTCN2019077535-appb-000050
根据方案13制备5-(10-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-10-氧代癸酰氨基)戊酸(SIAIS164178B)：
室温下，在反应瓶中，依次加入化合物SIAIS074019(40mg,0.07mmol)，5-氨基戊酸叔丁酯(11.3mg,0.07mmol),HOAt(17.7mg,0.14mmol),EDCI(24.9mg,0.14mmol),无水DMF(2mL)和NMM(32.9mg,0.35mmol)，室温下搅拌反应过夜。LC-MS检测反应结束后，HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)，旋去乙腈，冻干后得目标化合物；将得到的该化合物加入25mL的蛋形瓶中，随后加入无水二氯甲烷(1mL)和TFA(3mL),室温搅拌2h。反应完全后，减压蒸去溶剂，加水冻干得目标化合物(SIAIS164178B)，为白色固体,24mg,收率92％, 1H NMR(500MHz,DMSO)δ8.99(s,1H),8.58–8.51(m,1H),7.83(d,J＝9.4Hz,1H),7.73(t,J＝5.6Hz,1H),7.40(q,J＝8.4Hz,4H),4.54(d,J＝9.4Hz,1H),4.45–4.40(m,2H),4.35(s,1H),4.24–4.20(m,2H),3.69–3.63(m,3H),3.03–2.97(m,2H),2.45(s,3H),2.22–2.17(m,2H),2.13–2.07 (m,1H),2.05–1.99(m,2H),1.94–1.86(m,1H),1.49–1.44(m,6H),1.41–1.34(m,2H),1.23(d,J＝6.7Hz,8H),0.92(s,9H).HRMS(ESI)m/z:计算值C 37H 56N 5O 7S +[M+H] +,714.3895；实测值,714.1117.
其它HO 2C-LIN-ULM中间体的通用制备方法：
Figure PCTCN2019077535-appb-000051
中间体制备例44：(2S,4R)-1-((S)-2-(4-叠氮基丁酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS164050)的制备
根据方案14制备(2S,4R)-1-((S)-2-(4-叠氮基丁酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS164050)：
室温下，在反应瓶中，依次加入VHL-1(934mg,2mmol,1equiv)，4-叠氮丁酸(258.2mg,2mmol,1equiv),HOAt(54.4mg,0.4mmol,0.2equiv),EDCI(766.8mg,4mmol,2equiv),DMF(5mL),DCM(20mL)，NMM(2.02g,20mmol,10equiv)，室温反应过夜。LC-MS检测反应结束后，旋去DCM，倾入90％食盐水中，乙酸乙酯萃取(4x 50mL),合并有机相，水洗(2x 30mL),饱和食盐水洗(50mL),无水Na 2SO 4干燥，减压蒸去溶剂，粗品经柱层析(洗脱剂(v/v)：二氯甲烷/甲醇＝40:1)纯化得到化合物(SIAIS164050)，为淡黄色液体，734mg,收率68％。 1H NMR(500MHz,MeOD)δ8.87(s,1H),7.48–7.41(m,4H),4.62(s,1H),4.58–4.50(m,3H),4.38–4.33(m,1H),3.91(d,J＝11.0Hz,1H),3.80(dd,J＝10.9,3.9Hz,1H),3.33(t,J＝5.0Hz,2H),2.48(d,J＝5.3Hz,3H),2.41–2.32(m,2H),2.22(dd,J＝13.1,7.6Hz,1H),2.11–2.06(m,1H),1.90–1.82(m,2H),1.04(s,9H).HRMS(ESI)m/z:计算值C 26H 36N 7O 4S +[M+H] +,542.2544；实测值,542.2256.
中间体制备例45：4-(1-(4-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-4-氧代丁基)-1H-1,2,3-***-4-基)丁酸(SIAIS164128)的制备
根据方案14制备4-(1-(4-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-4-氧代丁基)-1H-1,2,3-***-4-基)丁酸(SIAIS164128)：
室温下，在反应瓶中，依次加入5-乙炔酸(22.4mg,0.2mmol,1equiv)，化合物(SIAIS164050)(108.3mg,0.2mmol,1equiv),CuSO 4(31.9mg,0.2mmol,1equiv),抗坏血 酸钠(39.6mg,0.2mmol,1equiv),DMF(1mL), tBuOH(1mL)，H 2O(1mL)，室温反应2h。LC-MS检测反应结束后，随后利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到目标化合物SIAIS164128，白色固体，100mg,收率76％。 1H NMR(500MHz,MeOD)δ9.19(d,J＝3.4Hz,1H),7.87(s,1H),7.51–7.42(m,4H),4.60(s,1H),4.59–4.54(m,2H),4.51(s,1H),4.43(t,J＝6.8Hz,2H),4.36(d,J＝15.3Hz,1H),3.93(d,J＝11.1Hz,1H),3.80(dd,J＝11.0,3.8Hz,1H),2.77(t,J＝7.6Hz,2H),2.51(d,J＝3.8Hz,3H),2.36(t,J＝7.3Hz,2H),2.32-2.28(m,2H),2.25–2.15(m,3H),2.11–2.06(m,1H),2.00–1.94(m,2H),1.04(s,9H).HRMS(ESI)m/z:计算值C 32H 44N 7O 6S +[M+H] +,654.3068；实测值,654.2990.
中间体制备例46：N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)-6-(2-(2-(6-碘己基氧基)乙氧基)乙氧基)己酰胺(SIAIS171116)的制备
Figure PCTCN2019077535-appb-000052
将叔丁基6-(2-(2-((6-碘己基)氧基)乙氧基)乙氧基)己酸酯(500mg,1.03mmol)加入25mL的三口瓶中，随后加入TFA(3mL)和无水DCM(3mL)，室温下搅拌过夜。反应完全后，减压除去溶剂，加水冻干得目标产物6-(2-(2-((6-碘己基)氧基)乙氧基)乙氧基)己酰氯(SIAIS171115)(淡黄色固体,440mg，粗品)；随后将化合物SIAIS171115(100mg,粗品)加入25mL的蛋形瓶中，加入无水THF(3mL)，室温下缓慢滴加氯化亚砜(0.2mL)，滴毕，升温至回流状态并搅拌2h，减压蒸去反应溶剂，得粗品酰氯，随后向蛋形瓶中加入无水THF(3mL)和泊马度胺(40mg,0.15mmol)，加毕缓慢升温至回流状态，并搅拌4h。原料反应完后，将反应液冷却至室温，加入1mL的水淬灭并搅拌30min,减压除去反应溶剂，得固体粗品；随后利用C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到目标化合物(SIAIS171116)为淡黄色固体,50mg,收率50％, 1H NMR(500MHz,CDCl 3)δ9.42(s,1H),8.83(d,J＝8.3Hz,1H),8.18(s,1H),7.72(dd,J＝8.4,7.5Hz,1H),7.53(dd,J＝36.0,18.0Hz,1H),4.96(dd,J＝12.4,5.4Hz,1H),3.68–3.62(m,4H),3.61–3.54(m,4H),3.47(dt,J＝13.1,6.6Hz,4H),3.18(t,J＝7.0Hz,2H),2.96–2.88(m,1H),2.85–2.72(m,2H),2.47(t,J＝7.6Hz,2H),2.23–2.13(m, 1H),1.87–1.74(m,4H),1.67–1.56(m,4H),1.49–1.33(m,6H).HRMS(ESI)m/z:计算值C 29H 40IN 3O 8 +[M+H] +,686.1933；实测值,686.1941.
中间体制备例47：(2S,4R)-1-((S)-2-(叔丁基)-22-氯-4-氧代-10,13,16-三氧杂-3-氮杂二十二碳酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS180114)的制备
Figure PCTCN2019077535-appb-000053
步骤1：根据方案16制备2-(2-((6-氯己基)氧基)乙氧基)-1-乙醇(SIAIS180112)：
将二乙二醇(5.3g,50.12mmol)，1-溴-6-氯己烷(10g,50.12mmol)和DMSO(100mL)一起加入250mL的蛋形瓶中，冰水浴下缓慢滴加15％的KOH水溶液(50mL)，滴毕，升至室温并搅拌过夜。乙酸乙酯萃取(150mL x3)，合并有机相，水洗(100mL x 3)，饱和食盐水洗(100mL)，无水Na 2SO 4干燥、过滤和浓缩，粗品经柱层析分离(洗脱剂(v/v)：石油醚/乙酸乙酯＝3:1)，旋去溶剂得目标产物(SIAIS180112)，为淡黄色油状物，1.7g,收率15％. 1H NMR(500MHz,CDCl 3)δ3.76–3.71(m,2H),3.69–3.67(m,2H),3.64–3.61(m,2H),3.59(dd,J＝5.7,3.6Hz,2H),3.53(t,J＝6.7Hz,2H),3.47(t,J＝6.6Hz,2H),2.49(s,1H),1.84–1.73(m,2H),1.71–1.53(m,4H),1.49–1.43(m,2H),1.41–1.35(m,2H).HRMS(ESI)m/z:计算值C 10H 22ClO 3 +[M+H] +,225.1252；实测值,225.0804.
步骤2：根据方案16制备6-(2-(2-((6-氯己基)氧基)乙氧基)乙氧基)己酸(SIAIS171094B)：
将SIAIS180112(700mg,3.11mmol)，6-溴己酸叔丁酯(784mg,3.11mmol)和无水DMF(15mL)一起加入干燥的100mL的三口瓶中，随后鼓入氮气，冰水浴下缓慢加入NaH(375mg,9.30mmol,60％in oil)，加毕，冰水浴下搅拌10min，随后升至室温并搅拌过夜。反应结束后，冰水浴下加水缓慢淬灭反应，乙酸乙酯萃取(50mL x1)，随后水相用2N的稀盐酸水溶液调至溶液pH＝2-3，乙酸乙酯萃取(50mL x3)，合并有机相，水洗(50mL x 3)，饱和食盐水洗(500mL)，无水Na 2SO 4干燥，过滤，浓缩得目标化合物(SIAIS171094B)，为淡黄色油状物，600mg,收率57％, 1H NMR(500MHz, CDCl 3)δ3.65–3.63(m,4H),3.60–3.57(m,4H),3.53(t,J＝6.7Hz,2H),3.47(td,J＝6.6,1.6Hz,4H),2.37–2.33(m,2H),1.79–1.73(m,2H),1.68–1.57(m,6H),1.46–1.33(m,6H).HRMS(ESI)m/z:计算值C 16H 32ClO 5 +[M+H] +,339.1933；实测值,338.8928；粗品未进行进一步纯化，直接用于下一步反应。
步骤3：根据方案16制备(2S,4R)-1-((S)-2-(叔丁基)-22-氯-4-氧代-10,13,16-三氧杂-3-氮杂二十二碳酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS180114)：
将(SIAIS171094B)(210mg,0.62mmol)，VHL-1(289.4mg,0.62mmol)，HATU(471.3mg,1.24mmol)和无水DMF(10mL)一起加入50mL的蛋形瓶中，随后加入N,N-二异丙基乙胺(400.5mg,3.10mmol),室温搅拌过夜。反应结束后，反应液经反相C18柱分离，洗脱剂(v/v)：乙腈/(水+0.05％TFA)＝10％–100％，旋去乙腈，冻干得目标产物(SIAIS180114).(白色固体，270mg,收率58％). 1H NMR(500MHz,MeOD)δ8.89(s,1H),7.52–7.45(m,2H),7.43–7.41(m,2H),4.64(s,1H),4.60–4.52(m,2H),4.50(m,1H),4.39–4.32(m,1H),3.90(d,J＝11.0Hz,1H),3.80(dd,J＝11.0,3.9Hz,1H),3.62–3.55(m,10H),3.49–3.46(m,4H),2.49–2.48(m,3H),2.34–2.18(m,3H),2.10–2.08(m,1H),1.80–1.72(m,2H),1.63–1.56(m,6H),1.49–1.36(m,6H),1.03(m,9H).HRMS(ESI)m/z:计算值C 38H 60ClN 4O 7S +[M+H] +,751.3866；实测值,750.6442.
其它HO 2C-LIN-ULM中间体的通用制备方法：
Figure PCTCN2019077535-appb-000054
中间体制备例48：4-溴-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS172136)的制备
根据方案17制备4-溴-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS172136):
将底物4-溴异苯并呋喃-1,3-二酮(500mg,2.20mmol)，3-氨基哌啶-2,6-二酮(400mg,2.42mmol)和无水醋酸钠(220mg,2.64mmol)一起加入到100mL的蛋形瓶中，随 后加入冰乙酸(10mL)。随后将反应液缓慢升至140℃，并搅拌12h。反应结束后，将反应液降至室温，有大量白色固体析出；随后抽滤，将滤饼，水(10mL)和甲醇(2mL)一起加入到蛋形瓶中，充分搅拌0.5h，随后抽滤，滤饼用水洗涤。减压干燥得化合物(SIAIS172136),产物为白色固体,700mg,收率94％。 1H NMR(500MHz,DMSO)δ11.14(s,1H),8.14(d,J＝1.4Hz,1H),8.09(dd,J＝7.9,1.7Hz,1H),7.86(d,J＝7.9Hz,1H),5.16(dd,J＝12.9,5.4Hz,1H),2.93–2.85(m,1H),2.65–2.50(m,2H),2.08–2.04(m,1H).HRMS(ESI)m/z:计算值C 13H 10BrN 2O 4 +[M+H] +,336.9818；实测值,336.9810.
中间体制备例49：(E)-3-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-4-基)丙烯酸叔丁酯(SIAIS172145)的制备
根据方案17制备(E)-3-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-4-基)丙烯酸叔丁酯(SIAIS172145):
将配体三叔丁基膦四氟硼酸(110mg,0.38mmol),N-甲基二环己基胺(250mg,1.28mmol)，Pd 2(dba) 3(163mg,0.64mmol)和无水二氧六环(6mL)一起加入50mL的蛋形瓶中，室温下搅拌30min。随后加入化合物(SIAIS172136)(300mg,0.89mmol)和丙烯酸叔丁酯(228mg,1.98mmol)。加毕后，将反应液在氮气保护下缓慢升至55℃，并搅拌12h。反应结束后，减压蒸去反应溶剂，硅胶拌样，粗品经柱层析(洗脱剂：40％EA/PE)纯化得化合物(SIAIS172145),产物为淡黄色固体,270mg,收率79％。 1H NMR(500MHz,CDCl 3)δ8.11(s,1H),8.02(s,1H),7.89(d,J＝7.7Hz,1H),7.84(dd,J＝7.8,1.2Hz,1H),7.65(d,J＝16.0Hz,1H),6.54(d,J＝16.0Hz,1H),5.00(dd,J＝12.5,5.3Hz,1H),2.94–2.72(m,3H),2.20–2.13(m,1H),1.54(s,9H).HRMS(ESI)m/z:计算值C 20H 21N 2O 6 +[M+H] +,385.1394；实测值,385.1389.
中间体制备例50：3-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-4-基)丙酸(SIAIS172147)的制备
根据方案17制备3-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-4-基)丙酸(SIAIS172147):
将反应物SIAIS172145(250mg,0.65mmol)加入100mL的蛋形瓶中，随后分别加入二氧六环(20mL)和10％湿Pd/C，反应体系用H 2(25psi)置换三次，将反应液室温搅拌过夜。反应完毕后，抽滤，二氧六环洗涤，滤液在减压下浓缩得淡黄色油状物，粗品未进行进一步纯化，直接用于下步反应；将上述所得的粗品,TFA(1mL)和无水二氯甲烷(5mL)一起加入50mL的蛋形瓶中，随后室温下搅拌2h。反应完全后，减压除去反应溶剂，将所得的粗品进行C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到目标化合物(SIAIS172147)，产物为白色固体,180mg,两步收率84％。 1H NMR(500MHz,DMSO)δ12.22(s,1H),11.12(s,1H),7.86–7.79(m,2H),7.77–7.70(m,1H),5.13(dd,J＝12.8,5.4Hz,1H),3.01(t,J＝7.4Hz,2H),2.93–2.85(m,1H),2.64 (t,J＝7.4Hz,2H),2.62–2.50(m,2H),2.08–2.02(m,1H).HRMS(ESI)m/z:计算值C 16H 15N 2O 6 +[M+H] +,331.0925；实测值,331.0919.
中间体制备例51：2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙酸(SIAIS172101B)的制备
Figure PCTCN2019077535-appb-000055
步骤1:根据方案18制备2-(2,6-二氧代哌啶-3-基)-4-羟基异吲哚啉-1,3-二酮(SIAIS180151)：
将底物4-羟基异苯并呋喃-1,3-二酮(500mg,3.05mmol)，3-氨基哌啶-2,6-二酮(502mg,3.05mmol)和三乙胺(340mg,3.36mmol)一起加入到100mL的蛋形瓶中，随后加入无水甲苯(20mL)。随后将反应液缓慢升至110℃，并搅拌12h。反应结束后，将反应液降至室温，有大量棕色固体析出；随后抽滤，将滤饼加入到装有10mL的30％乙酸乙酯/石油醚溶液的蛋形瓶中，充分搅拌0.2h，随后抽滤，滤饼用石油醚洗涤。减压干燥得化合物(SIAIS180151),产物为白色固体,770mg,收率92％。 1H NMR(500MHz,DMSO)δ11.17(s,1H),11.08(s,1H),7.65(dd,J＝8.3,7.3Hz,1H),7.32(d,J＝7.1Hz,1H),7.25(d,J＝8.3Hz,1H),5.07(dd,J＝12.8,5.4Hz,1H),2.92–2.85(m,1H),2.62–2.51(m,2H),2.07–1.96(m,1H).HRMS(ESI)m/z:计算值C 13H 11N 2O 5 +[M+H] +,275.0662；实测值,275.0666.
步骤2：根据方案18制备2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙酸叔丁酯(SIAIS180152):
将化合物SIAIS180151(412mg,1.50mmol),溴乙酸叔丁酯(350mg,1.80mmol)，无水碳酸氢钠(190mg,2.25mmol)，碘化钾(25mg,0.15mmol)和无水DMF(10mL)一起加入50mL的蛋形瓶中，缓慢升温至60℃并搅拌12h。反应结束后，向反应瓶中加入水，乙酸乙酯萃取，合并有机相，水洗，饱和食盐水，无水硫酸钠干燥，减压蒸去反应溶剂，硅胶拌样，粗品经柱层析(洗脱剂：40％EA/PE)纯化得化合物(SIAIS180152),产物为淡黄色固体,520mg,收率89％。 1H NMR(500MHz,DMSO)δ11.11(s,1H),7.82–7.78(m,1H),7.48(d,J＝7.1Hz,1H),7.38(d,J＝8.5Hz,1H),5.10(dd,J＝12.8,5.4Hz,1H), 4.97(s,2H),2.95–2.83(m,1H),2.62–2.52(m,2H),2.08–1.98(m,1H),1.44-1.43(m,9H).HRMS(ESI)m/z:计算值C 19H 21N 2O 7 +[M+H] +,389.1343；实测值,389.1339.
步骤3：根据方案18制备2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙酸(SIAIS172101B):
将上述所得化合物SIAIS180152(500mg,1.29mmol),TFA(2mL)和无水二氯甲烷(10mL)一起加入50mL的蛋形瓶中，随后室温下搅拌2h。反应完全后，减压除去反应溶剂，将所得的粗品进行C18反相柱制备，洗脱剂(v/v)：乙腈/(水+0.1％TFA)＝10％–100％，减压蒸去乙腈，冻干后得到目标化合物(SIAIS172101B)，产物为白色固体,400mg,收率92％。 1H NMR(500MHz,DMSO)δ13.25(s,1H),11.11(s,1H),7.79(dd,J＝8.5,7.3Hz,1H),7.47(d,J＝7.2Hz,1H),7.39(d,J＝8.6Hz,1H),5.10(dd,J＝12.8,5.4Hz,1H),4.98(s,2H),2.93–2.85(m,1H),2.63–2.51(m,2H),2.08–2.00(m,1H).HRMS(ESI)m/z:计算值C 15H 13N 2O 7 +[M+H] +,333.0717；实测值,333.0719.
本公开蛋白降解靶向BCR-ABL蛋白PROTAD化合物的通用合成方法:
Figure PCTCN2019077535-appb-000056
根据方案19，室温下，在反应瓶中，依次加入相应的抑制剂(1equiv)，相应的HO 2C-LIN-ULM中间体(1equiv),HOAt(2equiv),EDCI(2equiv),无水DMF(2mL)，NMM(5equiv)，室温下搅拌反应过夜。LC-MS检测反应结束后，HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)，旋去乙腈，冻干后得目标化合物。
制备实例
实施例1：N-(2-氯-6-甲基苯基)-2-((6-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151063)的制备
Figure PCTCN2019077535-appb-000057
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS151001制备得到化合物(SIAIS151063)，为黄色固体,30.2mg,收率82％, 1H NMR(500MHz,MeOD)δ8.21(s,1H),7.55–7.47(m,1H),7.37(dd,J＝7.5,1.5Hz,1H),7.30–7.21(m,2H),7.04(d,J＝8.5Hz,1H),6.95(d,J＝7.1Hz,1H),6.13(s,1H),5.02(dd,J＝12.8,5.4Hz,1H),3.84(t,J＝5.8Hz,2H),3.79–3.62(m,10H),3.52–3.45(m,2H),2.87–2.79(m,1H),2.77–2.61(m,4H),2.54(s,3H),2.33(s,3H),2.13–2.05(m,1H).HRMS(ESI)m/z:计算值C 38H 40ClN 10O 7S +[M+H] +,815.2485；实测值,815.3241.
实施例2：N-(2-氯-6-甲基苯基)-2-((6-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151064)的制备
Figure PCTCN2019077535-appb-000058
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS151004制备得到化合物(SIAIS151064)，为黄色固体,13.7mg,收率35％, 1H NMR(500MHz,MeOD)δ8.18(s,1H),7.49–7.43(m,1H),7.38–7.34(m,1H),7.29–7.21(m,2H),6.97(d,J＝8.6Hz,1H),6.92(d,J＝7.1Hz,1H),6.09(s,1H),5.05(dd,J＝12.7,5.5Hz,1H),3.79(t,J＝5.8Hz,4H),3.70(dd,J＝11.6,6.3Hz,6H),3.64(t,J＝3.8Hz,6H),3.42(t,J＝5.2Hz,2H),2.89–2.79(m,1H),2.78–2.65(m,4H),2.50(s,3H),2.33(s,3H),2.15–2.09(m,1H).HRMS(ESI)m/z:计算值C 40H 44ClN 10O 8S +[M+H] +,859.2747；实测值,859.3538.
实施例3：N-(2-氯-6-甲基苯基)-2-((6-(4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151067)的制备
Figure PCTCN2019077535-appb-000059
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS151005制备得到化合物(SIAIS151067)，为黄色固体,15.7mg,收率38％, 1H NMR(500MHz,MeOD)δ8.17(s,1H),7.54–7.46(m,1H),7.37(d,J＝6.0Hz,1H),7.29–7.22(m,2H),6.99(dd,J＝14.0,7.8Hz,2H),6.17(s,1H),5.05(dd,J＝12.8,5.5Hz,1H),3.84–3.72(m,10H),3.68(t,J＝5.2Hz,2H),3.65–3.62(m,6H),3.61–3.59(m,2H),3.43(t,J＝5.2Hz,2H),2.92–2.81(m,1H),2.77–2.66(m,4H),2.54(s,3H),2.33(s,3H),2.15–2.09(m,1H).HRMS(ESI)m/z:计算值C 42H 48ClN 10O 9S +[M+H] +,903.3009；实测值,903.2500.
实施例4：N-(2-氯-6-甲基苯基)-2-((6-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十五烷-15-酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151068)的制备
Figure PCTCN2019077535-appb-000060
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS151006制备得到化合物(SIAIS151068)，为黄色固体,18.6mg,收率43％, 1H NMR(500MHz,MeOD)δ8.17(s,1H),7.50(t,J＝7.8Hz,1H),7.36(d,J＝7.2Hz,1H),7.31–7.21(m,2H),7.06–6.95(m,2H),6.19(s,1H),5.05(dd,J＝12.8,5.5Hz,1H),3.85–3.71(m,10H),3.70(t,J＝5.2Hz,2H),3.66–3.57(m,12H),3.44(t,J＝5.0Hz,2H),2.90–2.82(m,1H),2.76–2.65(m,4H),2.55(s,3H),2.33(s,3H),2.16–2.07(m,1H).HRMS(ESI)m/z:计算值C 44H 52ClN 10O 10S +[M+H] +,947.3272；实测值,947.2704.
实施例5：N-(2-氯-6-甲基苯基)-2-((6-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12,15-五氧杂十八烷-18-酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151069)的制备
Figure PCTCN2019077535-appb-000061
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS151007制备得到化合物(SIAIS151069)，为黄色固体,35mg,收率78％, 1H NMR(500MHz,MeOD)δ8.18(s,1H),7.54–7.48(m,1H),7.36(d,J＝7.4Hz,1H),7.28–7.22(m,2H),7.03(dd,J＝16.0,7.8Hz,2H),6.23(s,1H),5.04(dd,J＝12.8,5.4Hz,1H),3.86–3.73(m,10H),3.71(t,J＝5.1Hz,2H),3.78–3.68(m,10H),3.65–3.60(m,7H),3.59–3.57(m,9H),3.46(t,J＝5.1Hz,2H),2.89–2.81(m,1H),2.76–2.65(m,4H),2.57(s,3H),2.32(s,3H),2.15–2.08(m,1H).HRMS(ESI)m/z:计算值C 46H 56ClN 10O 11S +[M+H] +,991.3534；实测值,991.2469.
实施例6：N-(2-氯-6-甲基苯基)-2-((6-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基乙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151072)的制备
Figure PCTCN2019077535-appb-000062
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS151025制备得到化合物(SIAIS151072)，为黄色固体,19.1mg,收率56％, 1H NMR(500MHz,MeOD)δ8.11(s,1H),7.51–7.46(m,1H),7.27(d,J＝7.9Hz,1H),7.19–7.12(m,2H),7.01(d,J＝7.0Hz,1H),6.94(d,J＝8.5Hz,1H),6.19(s,1H),4.98(dd,J＝12.6,5.3Hz,1H),4.19(s,2H),3.83–3.63(m,8H),2.82–2.73(m,1H),2.69–2.61(m,2H),2.50(s,3H),2.22(s,3H),2.06–1.99(m,1H).HRMS(ESI)m/z:计算值C 35H 34ClN 10O 6S +[M+H] +,757.2067；实测值,757.1286.
实施例7：N-(2-氯-6-甲基苯基)-2-((6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151074)的制备
Figure PCTCN2019077535-appb-000063
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS151026制备得到化合物(SIAIS151074)，为黄色固体,24.4mg,收率70％, 1H NMR(500MHz,MeOD)δ8.20(s,1H),7.60–7.53(m,1H),7.36(d,J＝7.4Hz,1H),7.28–7.22(m,2H),7.13(d,J＝8.6Hz,1H),7.05(d,J＝7.1Hz,1H),6.22(s,1H),5.03(dd,J＝12.7,5.5Hz,1H),3.78–3.66(m,10H),2.90–2.82(m,1H),2.79(t,J＝6.2Hz,2H),2.75–2.63(m,2H),2.57(s,3H),2.32(s,3H),2.10–2.03(m,1H).HRMS(ESI)m/z:计算值C 36H 36ClN 10O 6S +[M+H] +,771.2223；实测值,771.1824.
实施例8：N-(2-氯-6-甲基苯基)-2-((6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151070)的制备
Figure PCTCN2019077535-appb-000064
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS151019制备得到化合物(SIAIS151070)，为黄色固体,31.2mg,收率88％, 1H NMR(500MHz,DMSO)δ11.53(s,1H),11.09(s,1H),9.89(s,1H),8.22(s,1H),7.59(dd,J＝8.5,7.1Hz,1H),7.40(d,J＝7.7Hz,1H),7.31–7.23(m,2H),7.19(d,J＝8.7Hz,1H),7.02(d,J＝7.0Hz,1H),6.68(s,1H),6.07(s,1H),5.05(dd,J＝12.7,5.4Hz,1H),3.51–3.48(m,8H),3.34(t,J＝7.1Hz,2H),2.92–2.84(m,1H),2.64–2.52(m,2H),2.45(t,J＝7.1Hz,2H),2.43(s,3H),2.24(s,3H),2.04–2.00(m,1H),1.86–1.79(m,2H).HRMS(ESI)m/z:计算值C 37H 38ClN 10O 6S +[M+H] +,785.2380；实测值,785.1578.
实施例9：N-(2-氯-6-甲基苯基)-2-((6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151071)的制备
Figure PCTCN2019077535-appb-000065
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS151020制备得到化合物(SIAIS151071)，为黄色固体,10mg,收率28％, 1H NMR(500MHz,MeOD)δ8.21(s,1H),7.56(dd,J＝8.5,7.2Hz,1H),7.37(d,J＝7.1Hz,1H),7.26(t,J＝7.7Hz,2H),7.08(d,J＝8.6Hz,1H),7.04(d,J＝7.1Hz,1H),6.30(s,1H),5.04(dd,J＝12.6,5.5Hz,1H),3.83–3.69(m,8H),3.40(t,J＝6.1Hz,2H),2.89–2.80(m,1H),2.76–2.67(m,2H),2.61(s,3H),2.53(d,J＝6.4Hz,2H),2.32(s,3H),2.13–2.07(m,1H),1.80–1.72(m,4H).HRMS(ESI)m/z:计算值C 38H 40ClN 10O 6S +[M+H] +,799.2536；实测值,799.1711.
实施例10：N-(2-氯-6-甲基苯基)-2-((6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151075)的制备
Figure PCTCN2019077535-appb-000066
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS151027制备得到化合物(SIAIS151075)，为黄色固体,26.7mg,收率73％, 1H NMR(500MHz,MeOD)δ8.19(s,1H),7.53(t,J＝7.0Hz,1H),7.36(d,J＝7.6Hz,1H),7.28–7.22(m,2H),7.05(d,J＝8.6Hz,1H),7.00(d,J＝7.1Hz,1H),6.17(s,1H),5.04(dd,J＝12.4,5.5Hz,1H),3.81–3.64(m,8H),3.35(t,J＝6.8Hz,2H),2.88–2.80(m,1H),2.76–2.65(m,2H),2.56(s,3H),2.48(t,J＝7.4Hz,2H),2.32(s,3H),2.13–2.07(m,1H),1.74–1.67(m,4H),1.53–1.47(m,2H).HRMS(ESI)m/z:计算值C 39H 42ClN 10O 6S +[M+H] +,813.2693；实测值,813.2278.
实施例11：N-(2-氯-6-甲基苯基)-2-((6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151181)的制备
Figure PCTCN2019077535-appb-000067
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS151086制备得到化合物(SIAIS151181)，为黄色固体,22.3mg,收率60％, 1H NMR(500MHz,MeOD)δ7.54(dd,J＝8.5,7.1Hz,1H),7.36(d,J＝6.1Hz,1H),7.28–7.22(m,3H),7.03(dd,J＝10.7,7.8Hz,2H),6.15(s,1H),5.04(dd,J＝12.6,5.5Hz,1H),3.89–3.62(m,8H),3.34(t,J＝7.5Hz,2H),2.87–2.80(m,1H),2.77–2.68(m,2H),2.56(s,3H),2.45(t,J＝7.5Hz,2H),2.32(s,3H),2.13–2.08(m,1H),1.72–1.64(m,4H),1.53–1.39(m,4H).HRMS(ESI)m/z:计算值C 40H 44ClN 10O 6S +[M+H] +,827.2849；实测值,827.3884.
实施例12：N-(2-氯-6-甲基苯基)-2-((6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3-氧代丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS164108)的制备
Figure PCTCN2019077535-appb-000068
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS171004制备得到化合物(SIAIS164108)，为白色固体,12.6mg,收率49％, 1H NMR(500MHz,MeOD)δ8.22(s,1H),7.81(d,J＝7.7Hz,1H),7.67(d,J＝7.5Hz,1H),7.54(t,J＝7.8Hz,1H),7.37(d,J＝7.2Hz,1H),7.29–7.23(m,2H),6.32(s,1H),5.15(dd,J＝13.0,5.0Hz,1H),4.51(dd,J＝22.0,17.5Hz,2H),3.83(s,8H),2.96–2.88(m,1H),2.81–2.75(m,1H),2.70(s,1H),2.62(s,3H),2.53–2.43(m,2H),2.32(s,3H),2.23–2.17(m,1H).HRMS(ESI)m/z:计算值C 36H 36ClN 10O 6S +[M+H] +,771.2223；实测值,771.3122.
实施例13：N-(2-氯-6-甲基苯基)-2-((6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-4-氧代丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS164109)的制备
Figure PCTCN2019077535-appb-000069
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS164084制备得到化合物(SIAIS164109)，为白色固体,12.7mg,收率48％, 1H NMR(500MHz,MeOD)δ8.23(s,1H),7.74(d,J＝7.5Hz,1H),7.64(d,J＝7.4Hz,1H),7.51(t,J＝7.8Hz,1H),7.37(dd,J＝7.2,1.9Hz,1H),7.29–7.22(m,2H),6.32(s,1H),5.18(dd,J＝13.3,5.2Hz,1H),4.48(dd,J＝20.0,17.5Hz,2H),4.04–3.65(m,8H),2.96–2.88(m,1H),2.86–2.76(m,5H),2.63(s,3H),2.50–2.42(m,1H),2.31(s,3H),2.23–2.16(m,1H).HRMS(ESI)m/z:计算值C 37H 38ClN 10O 6S +[M+H] +,785.2380；实测值,785.3319.
实施例14：N-(2-氯-6-甲基苯基)-2-((6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-5-氧代戊酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS164110)的制备
Figure PCTCN2019077535-appb-000070
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS171005制备得到化合物(SIAIS164110)，为白色固体,13.1mg,收率49％, 1H NMR(500MHz,DMSO)δ11.65(s,1H),11.01(s,1H),9.94(s,1H),9.85(s,1H),8.26(s,1H),7.83(dd,J＝7.1,1.6Hz,1H),7.54–7.46(m,2H),7.40(d,J＝6.4Hz,1H),7.34–7.21(m,2H),6.13(s,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.38(dd,J＝22.0,17.5Hz,2H),3.62–3.51(m,8H),2.97–2.86(m,1H),2.63–2.58(m,1H),2.45(s,3H),2.47–2.40(m,4H),2.39–2.30(m,1H),2.24(s,3H),2.06–1.99(m,1H),1.91–1.82(m,2H).HRMS(ESI)m/z:计算值C 38H 40ClN 10O 6S +[M+H] +,799.2536；实测值.799.3481.
实施例14：N-(2-氯-6-甲基苯基)-2-((6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-6-氧代己酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS164181)的制备
Figure PCTCN2019077535-appb-000071
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS164101制备得到化合物(SIAIS164181)，为白色固体,7mg,收率38％， 1H NMR(500MHz,MeOD)δ8.23(s,1H),7.71(d,J＝7.3Hz,1H),7.64(d,J＝7.0Hz,1H),7.52(t,J＝7.8Hz,1H),7.37(dd,J＝7.1,2.0Hz,1H),7.30–7.22(m,2H),6.34(s,1H),5.18(dd,J＝13.3,5.2Hz,1H),4.55–4.44(m,2H),3.76(s,8H),2.91(dd,J＝22.3,9.1Hz,1H),2.78(d,J＝15.5Hz,1H),2.65(s,3H),2.57–2.44(m,5H),2.32(s,3H),2.22–2.14(m,1H),1.84–1.69(m,4H).HRMS(ESI)m/z:计算值C 39H 42ClN 10O 6S +[M+H] +,813.2693；实测值.813.2683.
实施例15：N-(2-氯-6-甲基苯基)-2-((6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-7-氧代庚酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS164182)的制备
Figure PCTCN2019077535-appb-000072
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS164102制备得到化合物(SIAIS164182)，为白色固体,9.7mg,收率52％， 1H NMR(500MHz,MeOD)δ8.24(s,1H),7.70(d,J＝7.9Hz,1H),7.64(d,J＝7.0Hz,1H),7.51(dd,J＝9.0,5.9Hz,1H),7.37(dd,J＝7.2,2.1Hz,1H),7.30–7.22(m,2H),6.33(s,1H),5.17(dd,J＝13.3,5.2Hz,1H),4.48(t,J＝9.6Hz,3H),3.75(s,8H),2.91(ddd,J＝18.7,13.5,5.4Hz,1H),2.81–2.75(m,1H),2.65(s,3H),2.49(dt,J＝15.8,6.0Hz,6H),2.32(s,3H),2.23–2.16(m,1H),1.80–1.66(m,5H).HRMS(ESI)m/z:计算值C 39H 42ClN 10O 6S +[M+H] +,827.2849；实测值.826.8941.
实施例16：N-(2-氯-6-甲基苯基)-2-((6-(4-(2-(2-(2-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-2-氧 代乙氧基)乙氧基)乙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151080)的制备
Figure PCTCN2019077535-appb-000073
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS151010制备得到化合物(SIAIS151080)，为白色固体,23mg,收率45％。 1H NMR(500MHz,MeOD)δ8.92(s,1H),8.19(s,1H),7.44–7.35(m,5H),7.28–7.22(m,2H),6.20(s,1H),4.73(s,1H),4.58(t,J＝8.5Hz,1H),4.53–4.46(m,2H),4.44–4.35(m,3H),4.07(dd,J＝21.0,16.0Hz,2H),3.88–3.66(m,14H),2.55(s,3H),2.46(s,3H),2.32(s,3H),2.29–2.24(m,1H),2.14–2.06(m,1H),1.04(s,9H).HRMS(ESI)m/z:计算值C 48H 59ClN 11O 8S 2 +[M+H] +,1016.3673；实测值,1016.3214.
实施例17：N-(2-氯-6-甲基苯基)-2-((6-(4-(3-(2-(3-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-3-氧代丙氧基)乙氧基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151076)的制备
Figure PCTCN2019077535-appb-000074
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS151002制备得到化合物(SIAIS151076)，为白色固体,26.7mg,收率73％。 1H NMR(500MHz,MeOD)δ8.93(s,1H),8.21(s,1H),7.47(d,J＝8.2Hz,2H),7.44–7.39(m,2H),7.37(dd,J＝7.2,1.4Hz,1H),7.28–7.23(m,2H),6.27(s,1H),4.66(s,1H),4.59–4.49(m,3H),4.36(d,J＝15.5Hz,1H),3.89(d,J＝11.0Hz,1H),3.86–3.69(m,13H),3.64–3.60(m,4H),2.71(t,J＝6.1Hz,2H),2.58(s,3H),2.56–2.52(m,1H),2.50(d,J＝6.1Hz,1H),2.48(s,3H),2.32(s,3H),2.25–2.20(m,1H),2.11–2.06(m,1H),1.04(s,9H).HRMS(ESI)m/z:计算值C 50H 63ClN 11O 8S 2 +[M+H] +,1044.3986；实测值,1044.3367.
实施例18：N-(2-氯-6-甲基苯基)-2-((6-(4-((S)-15-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-羰基)-16,16-二甲基-13-氧代-4,7,10-三氧杂-14-氮杂十七烷酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151077)的制备
Figure PCTCN2019077535-appb-000075
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS151003制备得到化合物(SIAIS151077)，为白色固体,41.5mg,收率84％。 1H NMR(500MHz,MeOD)δ8.85(s,1H),8.11(s,1H),7.36(d,J＝8.2Hz,2H),7.34–7.30(m,2H),7.28–7.24(m,1H),7.18–7.12(m,2H),6.20(s,1H),4.54(s,1H),4.49–4.37(m,3H),4.25(d,J＝15.5Hz,1H),3.78–3.65(m,12H),3.62–3.57(m,2H),3.54–3.46(m,8H),2.61(t,J＝6.1Hz,2H),2.49(s,3H),2.47–2.43(m,1H),2.39–2.34(m,4H),2.22(s,3H),2.15–2.09(m,1H),2.01–1.95(m,1H),0.93(s,9H).HRMS(ESI)m/z:计算值C 52H 67ClN 11O 9S 2 +[M+H] +,1088.4248；实测值,1088.3640.
实施例19：N-(2-氯-6-甲基苯基)-2-((6-(4-((S)-18-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-羰基)-19,19-二甲基-16-氧代-4,7,10,13-四氧杂-17-氮杂二十烷酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151078)的制备
Figure PCTCN2019077535-appb-000076
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS151008制备得到化合物(SIAIS151078)，为白色固体,23mg,收率45％. 1H NMR(500MHz,MeOD)δ8.95(s,1H),8.20(s,1H),7.46(d,J＝8.1Hz,2H),7.44–7.39(m,2H),7.36(d,J＝7.2Hz,1H),7.28–7.22(m,2H),6.29(s,1H),4.64(s,1H),4.59–4.47(m,3H),4.35(d,J＝15.5Hz,1H),3.91–3.82(m,3H),3.81–3.75(m,9H),3.73–3.67(m,2H),3.62–3.57(m,12H),2.71(t,J＝6.0Hz,2H),2.59(s,3H),2.57–2.53(m,1H),2.49–2.44(m,4H),2.32(s,3H),2.27–2.18(m,1H),2.11–2.05(m,1H),1.03(s,9H).HRMS(ESI)m/z:计算值C 54H 71ClN 11O 10S 2 +[M+H] +,1132.4510；实测值,1132.3996.
实施例20：N-(2-氯-6-甲基苯基)-2-((6-(4-((S)-21-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-羰基)-22,22-二甲基-19-氧代-4,7,10,13,16-五氧杂-20-氮杂二十三烷酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151079)的制备
Figure PCTCN2019077535-appb-000077
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS151009制备得到化合物(SIAIS151079)，为白色固体,27.5mg,收率53％. 1H NMR(500MHz,MeOD)δ8.86(s,1H),8.11(s,1H),7.37(d,J＝8.1Hz,2H),7.34–7.29(m,2H),7.26(d,J＝7.2Hz,1H),7.19–7.12(m,2H),6.22(s,1H),4.54(s,1H),4.53–4.38(m,3H),4.35(d,J＝15.5Hz,1H),3.80–3.73(m,3H),3.71–3.65(m,9H),3.63–3.57(m,2H),3.52–3.48(m,16H),2.62(t,J＝6.0Hz,2H),2.49(s,3H),2.47–2.43(m,1H),2.39–2.34(m,1H),2.38(s,3H),2.22(s,3H),2.15–2.09(m,1H),2.00–1.95(m,1H),1.03(s,9H).HRMS(ESI)m/z:计算值C 56H 75ClN 11O 11S 2 +[M+H] +,1176.4772；实测值,1176.4277.
实施例21：N-(2-氯-6-甲基苯基)-2-((6-(4-(4-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-4-氧代丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151174)的制备
Figure PCTCN2019077535-appb-000078
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS074011制备得到化合物(SIAIS151174)，为白色固体,8.5mg,收率26％. 1H NMR(500MHz,MeOD)δ9.40(s,1H),8.24(s,1H),7.52–7.46(m,4H),7.37(d,J＝6.8Hz,1H),7.30–7.22(m,2H),6.39(s,1H),4.61(s,1H),4.58–4.47(m,3H),4.40–4.36(m,1H),4.08–3.67(m,10H),2.79–2.57(m,4H),2.65(s,3H),2.53(s,3H),2.32(s,3H),2.25–2.18(m,1H),2.10–2.04(m,1H),1.03(s,9H).HRMS(ESI)m/z:计算值C 46H 55ClN 11O 6S 2 +[M+H] +,956.3461；实测值,956.2902.
实施例22：N-(2-氯-6-甲基苯基)-2-((6-(4-(5-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-5-氧代戊酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151175)的制备
Figure PCTCN2019077535-appb-000079
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS074012制备得到化合物(SIAIS151175)，为白色固体,7.6mg,收率24％. 1H NMR(500MHz,MeOD)δ9.44(s,1H),8.23(s,1H),7.53–7.49(m,2H),7.48–7.45(m,2H),7.39–7.35(m,1H),7.30–7.22(m,2H),6.39(s,1H),4.62(s,1H),4.59–4.49(m,3H),4.41–4.36(m,1H),3.98–3.66(m,10H),2.64(s,3H),2.53(s,3H),2.48(t,J＝7.5Hz,2H),2.40–2.34(m,2H),2.32(s,3H),2.25–2.21(m,1H),2.13–2.05(m,1H),2.10–2.05(m,2H),1.09–1.03(m,9H).HRMS(ESI)m/z:计算值C 47H 57ClN 11O 6S 2 +[M+H] +,970.3618；实测值,970.3060.
实施例23：N-(2-氯-6-甲基苯基)-2-((6-(4-(6-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-6-氧代己酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151176)的制备
Figure PCTCN2019077535-appb-000080
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS074013制备得到化合物(SIAIS151176)，为白色固体,7.8mg,收率23％. 1H NMR(500MHz,MeOD)δ9.49(s,1H),8.23(s,1H),7.53–7.51(m,2H),7.48–7.46(m,2H),7.38–7.35(m,1H),7.30–7.23(m,2H),6.39(s,1H),4.63(s,1H),4.58–4.48(m,3H),4.41-4.37(m,1H),3.96–3.74(m,10H),2.65(s,3H),2.55(s,3H),2.48(t,J＝6.4Hz,2H),2.35–2.29(m,5H),2.25–2.19(m,1H),2.10–2.05(m,1H),1.70–1.62(m,4H),1.04(s,9H).HRMS(ESI)m/z:计算值C 48H 59ClN 11O 6S 2 +[M+H] +,984.3774；实测值,984.3125.
实施例24：N-(2-氯-6-甲基苯基)-2-((6-(4-(7-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-7-氧代庚酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151177)的制备
Figure PCTCN2019077535-appb-000081
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS074014制备得到化合物(SIAIS151177)，为白色固体,8.3mg,收率25％. 1H NMR(500MHz,MeOD)δ9.45(s,1H),8.24(s,1H),7.52(d,J＝8.1Hz,2H),7.49–7.46(m,2H),7.37(d,J＝7.0Hz,1H),7.28–7.23(m,2H),6.39(s,1H),4.64(s,1H),4.60–4.48(m,3H),4.41–4.37(m,1H),4.05–3.65(m,10H),2.65(s,3H),2.54(s,3H),2.46(t,J＝7.5Hz,2H),2.36–2.19(m,3H),2.32(s,3H),2.10–2.05(m,1H),1.68–1.62(m,4H),1.43–1.37(m,2H),1.02(s,9H).HRMS(ESI)m/z:计算值C 49H 61ClN 11O 6S 2 +[M+H] +,998.3931；实测值,998.3324.
实施例25：N-(2-氯-6-甲基苯基)-2-((6-(4-(8-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-8-氧代辛酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151178)的制备
Figure PCTCN2019077535-appb-000082
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS074015制备得到化合物(SIAIS151178)，为白色固体,12.1mg,收率36％. 1H NMR(500MHz,MeOD)δ9.34(s,1H),8.23(s,1H),7.53–7.49(m,2H),7.48–7.45(m,2H),7.37(d,J＝7.0Hz,1H),7.30–7.22(m,2H),6.38(s,1H),4.64(s,1H),4.59–4.49(m,3H),4.40–4.36(m,1H),4.03–3.68(m,10H),2.65(s,3H),2.53(s,3H),2.46(t,J＝7.5Hz,2H),2.32(s,3H),2.30–2.19(m,3H),2.11–2.04(m,1H),1.67–1.60(m,4H),1.42–1.35(m,4H),1.03(s,9H).HRMS(ESI)m/z:计算值C 50H 63ClN 11O 6S 2 +[M+H] +,1012.4087；实测值,1012.3439.
实施例26：N-(2-氯-6-甲基苯基)-2-((6-(4-(9-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-9-氧代壬酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151179)的制备
Figure PCTCN2019077535-appb-000083
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS074016制备得到化合物(SIAIS151179)，为白色固体,9.3mg,收率27％. 1H NMR(500MHz,MeOD)δ9.43(s,1H),8.23(s,1H),7.54–7.51(m,2H),7.49–7.46(m,2H),7.41–7.33(m,1H),7.30–7.23(m,2H),6.39(s,1H),4.64(s,1H),4.59–4.49(m,3H),4.40–4.36(m,1H),4.09–3.69(m,10H),2.65(s,3H),2.54(s,3H),2.45(t,J＝7.6Hz,2H),2.32(s,3H),2.30–2.19(m,3H),2.10–2.04(m,1H),1.66–1.59(m,4H),1.40–1.32(m,6H),1.03(s,9H).HRMS(ESI)m/z:计算值C 51H 65ClN 11O 6S 2 +[M+H] +,1026.4244；实测值,1026.5215.
实施例27：N-(2-氯-6-甲基苯基)-2-((6-(4-(10-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-10-氧代癸酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151180)的制备
Figure PCTCN2019077535-appb-000084
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS074019制备得到化合物(SIAIS151180)，为白色固体,8.4mg,收率24％. 1H NMR(500MHz,MeOD)δ9.33(s,1H),8.23(s,1H),7.53–7.49(m,2H),7.47–7.45(m,2H),7.38–7.35(m,1H),7.28–7.23(m,2H),6.38(s,1H),4.63(s,1H),4.59–4.48(m,3H),4.41–4.35(m,1H),3.96–3.72(m,10H),2.64(s,3H),2.52(s,3H),2.45(t,J＝7.5Hz,2H),2.31(s,3H),2.29–2.19(m,3H),2.10–2.04(m,1H),1.64–1.58(m,4H),1.40–1.30(m,8H),1.03(s,9H).HRMS(ESI)m/z:计算值C 52H 67ClN 11O 6S 2 +[M+H] +,1040.4400；实测值,1040.3784.
实施例28：N-(2-氯-6-甲基苯基)-2-((6-(4-(14-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-14-氧代十四烷酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS164193)的制备
Figure PCTCN2019077535-appb-000085
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS164185制备得到化合物(SIAIS164193)，为白色固体,6.2mg,收率25％。 1H NMR(500MHz,DMSO)δ11.56(s,1H),9.90(s,1H),9.00(s,1H),8.56(t,J＝5.8Hz,1H),8.24(s,1H),7.83(d,J＝9.4Hz,1H),7.40(q,J＝8.1Hz,5H),7.31–7.23(m,3H),6.09(s,1H),4.54(d,J＝9.4Hz,1H),4.44–4.41(m,2H),4.34(s,1H),4.21(dd,J＝15.7,5.4Hz,1H),3.50–3.45(m,8H),3.43–3.40(m,2H),2.46–2.41(m,8H),2.33(t,J＝7.6Hz,3H),2.28–2.23(m,6H),2.13–2.08(m,1H),2.07–1.99(m,1H),1.50(s,6H),1.24–1.22(m,10H),0.93(s,9H).HRMS(ESI)m/z:计算值C 56H 74ClN 11O 6S 2 +[M+H] +,1096.5026；实测值,1096.6575.
实施例29：N-(2-氯-6-甲基苯基)-2-((6-(4-(16-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-16-氧代十六烷酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS164194)的制备
Figure PCTCN2019077535-appb-000086
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS164189制备得到化合物(SIAIS164194)，为白色固体,6.8mg,收率27％, 1H NMR(500MHz,DMSO)δ11.56(s,1H),9.91(s,1H),9.00(s,1H),8.57(t,J＝6.1Hz,1H),8.24(s,1H),7.84(d,J＝9.3Hz,1H),7.40(t,J＝8.7Hz,5H),7.31–7.25(m,3H),6.09(s,1H),4.55(d,J＝9.4Hz,1H),4.48–4.41(m,2H),4.35(s,1H),4.22(dd,J＝16.0,5.5Hz,1H),3.48–3.45(m,8H),3.43–3.38(m,2H),2.45(t,J＝5.0Hz,8H),2.34(t,J＝6.5Hz,3H),2.27–2.24(m,6H),2.14–2.08(m,1H),2.04–2.00(m,1H),1.50(d,J ＝6.2Hz,6H),1.24–1.23(m,14H),0.94(s,9H).HRMS(ESI)m/z:计算值C 58H 78ClN 11O 6S 2 +[M+H] +,1124.5339；实测值,1123.6957.
实施例30：N-(2-氯-6-甲基苯基)-2-((6-(4-(6-(2-(2-((6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-6-氧代己基)氧基)乙氧基)乙氧基)己酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS171114)的制备
Figure PCTCN2019077535-appb-000087
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS171104B制备得到化合物(SIAIS171114)，为黄色固体,3.0mg,收率17％, 1H NMR(500MHz,MeOD)δ8.63(d,J＝8.4Hz,1H),8.22(s,1H),7.81–7.71(m,1H),7.57(t,J＝9.4Hz,1H),7.37(d,J＝7.0Hz,1H),7.27–7.24(m,2H),6.36(s,1H),5.13(dd,J＝12.5,5.5Hz,1H),4.00–3.75(m,8H),3.66–3.53(m,8H),3.50–3.42(m,4H),2.94–2.82(m,1H),2.80–2.70(m,2H),2.66(s,3H),2.51(t,J＝7.5Hz,2H),2.48–2.42(m,2H),2.31(s,3H),2.20–2.11(m,1H),1.77–1.74(m,2H),1.70–1.55(m,6H),1.52–1.35(m,4H).HRMS(ESI)m/z:计算值C 49H 60ClN 10O 10S +[M+H] +,1015.3898；实测值,1015.3921.
实施例31：N-(2-氯-6-甲基苯基)-2-((6-(4-(4-((2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙基)氨基)-4-氧代丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS164133)的制备
Figure PCTCN2019077535-appb-000088
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS164119制备得到化合物(SIAIS164133)，为黄色固体,11.4mg,收率60％. 1H NMR(500MHz,MeOD)δ8.23(s,1H),7.55(dd,J＝8.5,7.2Hz,1H),7.37(dd,J＝7.2,2.0Hz,1H),7.30–7.22(m,2H),7.13(d,J＝8.5Hz,1H),7.04(d,J＝7.1Hz,1H),6.33(s,1H),5.05(dd,J＝12.6,5.5Hz,1H),3.75(s,8H),3.50–3.41(m,4H), 2.88–2.81(m,1H),2.76–2.65(ddd,J＝20.8,15.5,5.6Hz,7H),2.52(t,J＝6.6Hz,2H),2.32(s,3H),2.15–2.05(m,1H).HRMS(ESI)m/z:计算值C 39H 41ClN 11O 7S +[M+H] +,842.2594；实测值,842.0407.
实施例32：N-(2-氯-6-甲基苯基)-2-((6-(4-(4-((2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙基)氨基)-4-氧代丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS164132)的制备
Figure PCTCN2019077535-appb-000089
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS164118制备得到化合物(SIAIS164132)，为黄色固体,7.9mg,收率40％, 1H NMR(500MHz,MeOD)δ8.23(s,1H),7.57(dd,J＝8.5,7.2Hz,1H),7.38–7.34(m,1H),7.30–7.22(m,2H),7.07(dd,J＝17.6,7.8Hz,2H),6.36(s,1H),5.10(dd,J＝12.5,5.4Hz,1H),3.97–3.69(m,10H),3.59(t,J＝5.2Hz,2H),3.49(t,J＝5.1Hz,2H),3.42(t,J＝4.9Hz,2H),2.92–2.84(m,1H),2.77–2.55(m,9H),2.32(s,3H),2.13–2.09(m,1H).HRMS(ESI)m/z:计算值C 41H 45ClN 11O 8S +[M+H] +,886.2856；实测值,886.0532.
实施例33：N-(2-氯-6-甲基苯基)-2-((6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-5-氧代戊酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS184053)的制备
Figure PCTCN2019077535-appb-000090
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS184044制备得到化合物(SIAIS184053)，为黄色固体,10mg,收率55％, 1H NMR(500MHz,DMSO)δ11.59(s,1H),11.14(s,1H),9.92(s,1H),9.73(s,1H),8.45(d,J＝8.4Hz,1H),8.24(s,1H),7.93–7.76(m,1H),7.62(d,J＝7.0Hz,1H),7.40(d,J＝7.7Hz,1H),7.35–7.20(m,2H),6.11(s,1H),5.14(dd,J＝12.8,5.4Hz, 1H),3.76–3.68(m,8H),2.96–2.82(m,1H),2.60(dd,J＝26.0,6.5Hz,2H),2.53(d,J＝4.4Hz,2H),2.47(d,J＝7.4Hz,2H),2.44(s,3H),2.24(s,3H),2.10–2.01(m,1H),1.94–1.81(m,2H).HRMS(ESI)m/z:计算值C 38H 38ClN 10O 7S +[M+H] +,813.2329；实测值,813.2346.
实施例34：N-(2-氯-6-甲基苯基)-2-((6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS184052)的制备
Figure PCTCN2019077535-appb-000091
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS184047制备得到化合物(SIAIS184052)，为白色固体,10.9mg,收率41％。 1H NMR(500MHz,DMSO)δ11.63(s,1H),11.00(s,1H),9.93(s,1H),8.25(s,1H),7.40(d,J＝7.9Hz,1H),7.28(td,J＝15.2,7.4Hz,3H),6.96(d,J＝7.4Hz,1H),6.80(d,J＝8.1Hz,1H),6.12(s,1H),5.11(dd,J＝13.2,5.3Hz,1H),4.25(d,J＝16.7Hz,1H),4.15(d,J＝17.3Hz,1H),3.59(s,8H),3.16(s,2H),2.92(t,J＝12.8Hz,1H),2.61(d,J＝16.9Hz,1H),2.45(s,3H),2.41(s,2H),2.30(d,J＝8.6Hz,1H),2.24(s,3H),2.04(s,1H),1.63(s,4H).HRMS(ESI)m/z:计算值C 38H 42ClN 10O 5S +[M+H] +,785.2743；实测值.785.2776.
实施例35：N-(2-氯-6-甲基苯基)-2-((6-(4-((S)-3-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-羰基)-2,2-二甲基-5-氧代-11,14,17-三氧杂-4-氮杂二十三烷-23-酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS180147)的制备
Figure PCTCN2019077535-appb-000092
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS180127制备得到化合物(SIAIS180147)，为白色固体,2.9mg,收率8％. 1H NMR(500MHz,MeOD)δ9.54(d,J＝5.5Hz,1H),8.24(s,1H),7.53(d,J＝8.1Hz,2H),7.48(d,J＝8.3Hz,2H),7.39–7.35(m,1H), 7.29–7.23(m,2H),6.40(s,1H),4.63(s,1H),4.58–4.53(m,2H),4.49(s,1H),4.38(d,J＝15.7Hz,1H),3.95–3.73(m,10H),3.63–3.61(m,4H),3.59–3.55(m,4H),3.50–3.45(m,4H),2.65(s,3H),2.55(s,3H),2.47(t,J＝7.5Hz,2H),2.31(s,3H),2.30–2.19(m,3H),2.10–2.05(m,1H),1.67–1.57(m,8H),1.46–1.37(m,4H),1.03(s,9H).HRMS(ESI)m/z:计算值C 58H 79ClN 11O 9S 2 +[M+H] +,1172.5187；实测值,1172.3144.
实施例36：N1-(5-(4-(6-((5-((2-氯-6-甲基苯基)氨基甲酰基)噻唑-2-基)氨基)-2-甲基嘧啶-4-基)哌嗪-1-基)-5-氧代戊基)-N10-((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)癸二酰胺(SIAIS184032)的制备
Figure PCTCN2019077535-appb-000093
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS164178B制备得到化合物(SIAIS184032)，为白色固体,10.2mg,收率45％. 1H NMR(500MHz,MeOD)δ9.88(s,1H),8.24(s,1H),7.56(d,J＝8.3Hz,2H),7.51(d,J＝8.3Hz,2H),7.38–7.35(m,1H),7.27–7.22(m,2H),4.63(s,1H),4.56(dd,J＝16.1,8.0Hz,2H),4.49(s,1H),4.40(d,J＝15.8Hz,1H),3.95–3.87(m,4H),3.82–3.75(m,6H),3.20(t,J＝6.7Hz,2H),2.66(s,2H),2.58(s,3H),2.49(t,J＝7.3Hz,2H),2.31(s,3H),2.30–2.26(m,1H),2.25–2.21(m,2H),2.18(t,J＝7.5Hz,3H),2.12–2.02(m,1H),1.65–1.56(m,8H),1.32(s,8H),1.03(s,9H).HRMS(ESI)m/z:计算值C 57H 76ClN 12O 7S 2 +[M+H] +,1139.5084；实测值,1139.4847.
实施例37：N-(2-氯-6-甲基苯基)-2-((6-(4-(4-(1-(4-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-4-氧代丁基)-1H-1,2,3-***-4-基)丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS164134)的制备
Figure PCTCN2019077535-appb-000094
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS164128制备得到化合物(SIAIS164134)，为白色固体,9.1mg,收率37％. 1H NMR(500MHz,MeOD)δ9.73(s,1H),8.24(s,1H),8.11(s,1H),7.54(d,J＝8.2Hz,2H),7.50(d,J＝8.2Hz,2H),7.38–7.36(m,1H),7.29–7.24(m,2H),6.40(s,1H),4.62–4.55(m,3H),4.53–4.50(m,3H),4.43–4.39(m,1H),3.94–3.75(m,10H),2.86(t,J＝7.7Hz,2H),2.65(s,3H),2.58–2.54(m,5H),2.38–2.31(m,5H),2.26–2.22(m,3H),2.10–2.02(m,3H),1.04(s,9H).HRMS(ESI)m/z:计算值C 52H 64ClN 14O 6S 2 +[M+H] +,1079.4258；实测值,1079.1240.
实施例38：N-(2-氯-6-甲基苯基)-2-((6-(4-(3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS172150)的制备
Figure PCTCN2019077535-appb-000095
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS172147制备得到化合物(SIAIS172150)，为白色固体,24.2mg,收率47％. 1H NMR(500MHz,DMSO)δ11.12(s,1H),9.94(s,1H),8.25(s,1H),7.88–7.82(m,2H),7.78(dd,J＝7.8,1.1Hz,1H),7.40(d,J＝7.7Hz,1H),7.31–7.23(m,2H),6.12(s,1H),5.14(dd,J＝12.8,5.4Hz,1H),3.59(s,6H),3.49(dd,J＝7.8,3.0Hz,1H),3.41(dd,J＝7.8,3.0Hz,1H),3.04(t,J＝7.5Hz,2H),2.93–2.85(m,1H),2.80(t,J＝7.5Hz,2H),2.64–2.52(m,2H),2.45(s,3H),2.24(s,3H),2.06–2.02(m,1H).HRMS(ESI)m/z:计算值C 36H 35ClN 9O 6S +[M+H] +,756.2114；实测值,756.2140.
实施例39：N-(2-氯-6-甲基苯基)-2-((6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS184128)的制备
Figure PCTCN2019077535-appb-000096
根据方案19所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物SIAIS151055和HO 2C-LIN-ULM中间体SIAIS172101B制备得到化合物(SIAIS184128)，为白色固体,18.5mg,收率52％. 1H NMR(500MHz,MeOD)δ8.21(s,1H),7.77(dd,J＝8.5,7.3Hz,1H),7.51(d,J＝7.1Hz,1H),7.42(d,J＝8.5Hz,1H),7.36(dd,J＝7.2,1.9Hz,1H),7.28–7.22(m,2H),6.30(s,1H),5.17(d,J＝2.3Hz,2H),5.14–5.08(m,1H),3.80(d,J＝29.3Hz,8H),2.90–2.80(m,1H),2.78–2.68(m,2H),2.61(s,3H),2.31(s,3H),2.16–2.10(m,1H).HRMS(ESI)m/z:计算值C 35H 33ClN 9O 7S +[M+H] +,758.1907；实测值,758.1913.
实施例40：4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈(SIAIS151157)的制备
Figure PCTCN2019077535-appb-000097
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS151001制备得到化合物(SIAIS151157)，为黄色固体，12.3mg,收率48％, 1H NMR(500MHz,MeOD)δ8.86(s,1H),8.00(s,1H),7.66(s,1H),7.55(dd,J＝8.4,7.2Hz,1H),7.42(s,1H),7.38(s,1H),7.08(d,J＝8.6Hz,1H),6.99(d,J＝7.0Hz,1H),5.05(dd,J＝12.6,5.4Hz,1H),4.77–4.69(m,1H),4.38(t,J＝4.9Hz,3H),4.06(s,3H),3.94(s,3H),3.88–3.80(m,2H),3.78–3.68(s,4H),3.53–3.49(m,2H),3.36(t,J＝7.2Hz,2H),3.23–2.94(m,3H),2.90–2.81(m,2H),2.74–2.66(m,2H),2.43–2.35(m,2H),2.14–2.08(m,1H).HRMS(ESI)m/z:计算值C 43H 45Cl 2N 8O 9 +[M+H] +,887.2681；实测值,887.2507。
实施例41：4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈(SIAIS151158)的制备
Figure PCTCN2019077535-appb-000098
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS151004制备得到化合物(SIAIS151158)，为黄色固体，14mg,收率52％, 1H NMR(500MHz,MeOD)δ8.83(s,1H),7.96(s,1H),7.66(s, 1H),7.51–7.45(m,1H),7.41(s,1H),7.36(s,1H),7.04(d,J＝8.6Hz,1H),6.94(d,J＝7.1Hz,1H),5.07(dd,J＝12.6,5.5Hz,1H),4.78–4.65(m,1H),4.38(t,J＝5.5Hz,2H),4.36–4.24(m,1H),4.06(s,3H),3.95(s,3H),3.81–3.60(m,12H),3.48(t,J＝5.1Hz,2H),3.46–3.40(m,2H),3.28–3.12(m,2H),3.10–2.95(m,1H),2.92–2.83(m,2H),2.76–2.66(m,2H),2.46–2.39(m,2H),2.14–2.09(m,1H).HRMS(ESI)m/z:计算值C 45H 49Cl 2N 8O 10 +[M+H] +,931.2943；实测值,931.2866.
实施例42：4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈(SIAIS151159)的制备
Figure PCTCN2019077535-appb-000099
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS151005制备得到化合物(SIAIS151159)，为黄色固体，13.2mg,收率46％, 1H NMR(500MHz,MeOD)δ8.83(s,1H),7.94(s,1H),7.66(s,1H),7.47(dd,J＝8.0,7.0Hz,1H),7.41(s,1H),7.36(s,1H),7.00(d,J＝8.5Hz,1H),6.96(d,J＝7.1Hz,1H),5.07(dd,J＝12.6,5.5Hz,1H),4.78–4.70(m,1H),4.46–4.32(m,3H),4.05(s,3H),3.95(s,3H),3.81–3.58(m,16H),3.50–3.43(m,4H),3.27–3.00(m,3H),2.95–2.83(m,2H),2.78–2.65(m,2H),2.48–2.39(m,2H),2.15–2.08(m,1H).HRMS(ESI)m/z:计算值C 47H 53Cl 2N 8O 11 +[M+H] +,975.3205；实测值,975.3144.
实施例43：4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十五烷-15-酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈(SIAIS151160)的制备
Figure PCTCN2019077535-appb-000100
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS151006制备得到化合物(SIAIS151160)，为黄色固体，9.8mg,收率33％, 1H NMR(500MHz,MeOD)δ8.83(s,1H),7.96(s,1H),7.66(s,1H),7.48(dd,J＝8.4,7.2Hz,1H),7.41(s,1H),7.37(s,1H),7.01(d,J＝8.6Hz,1H),6.96(d,J＝7.1Hz,1H),5.06(dd,J＝12.6,5.5Hz,1H),4.76(s,1H),4.45–4.34(m,3H),4.07(s,3H), 3.95(s,3H),3.76–3.72(m,6H),3.65–3.55(m,14H),3.49–3.44(m,4H),3.24–3.04(m,3H),2.90–2.83(m,2H),2.77–2.67(m,2H),2.53–2.43(m,2H),2.13–2.08(m,1H).HRMS(ESI)m/z:计算值C 49H 57Cl 2N 8O 12 +[M+H] +,1019.3468；实测值,1019.3348.
实施例44：4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12,15-五氧杂十八烷-18-酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈(SIAIS151161)的制备
Figure PCTCN2019077535-appb-000101
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS151007制备得到化合物(SIAIS151161)，为黄色固体，13.2mg,收率43％, 1H NMR(500MHz,MeOD)δ8.84(s,1H),7.98(s,1H),7.65(d,J＝4.0Hz,1H),7.49(dd,J＝8.3,7.3Hz,1H),7.41(t,J＝9.8Hz,2H),7.00(dd,J＝18.1,7.8Hz,2H),5.05(dd,J＝12.7,5.4Hz,1H),4.73(s,1H),4.44(t,J＝5.3Hz,2H),4.39–4.30(m,1H),4.07(s,3H),3.95(s,3H),3.80–3.70(m,6H),3.67–3.58(m,18H),3.50–3.44(m,4H),3.28–3.00(m,3H),2.91–2.82(m,2H),2.76–2.63(m,2H),2.52–2.4(m,2H),2.16–2.07(m,1H).HRMS(ESI)m/z:计算值C 51H 61Cl 2N 8O 13 +[M+H] +,1063.3730；实测值,1063.3582.
实施例45：4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基乙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈(SIAIS151164)的制备
Figure PCTCN2019077535-appb-000102
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS151025制备得到化合物(SIAIS151164)，为黄色固体，8.6mg,收率36％, 1H NMR(500MHz,MeOD)δ8.85(s,1H),8.00(s,1H),7.66(s,1H),7.57–7.51(m,1H),7.40(d,J＝4.4Hz,2H),7.07(d,J＝7.1Hz,1H),7.00(d,J＝8.4Hz,1H),5.08(dd,J＝12.5,5.5Hz,1H),4.76–4.58(m,1H),4.50–4.42(m,2H),4.26(s,3H),4.09(s,3H),4.40–4.14(m,3H),3.81–3.61(s,3H),3.57–3.47(m,2H),3.30–2.97(m,3H),2.91–2.82(m,1H),2.77–2.69(m,2H),2.52–2.45(m,2H),2.18–2.10(m,1H).HRMS(ESI)m/z:计算值C 40H 39Cl 2N 8O 8 +[M+H] +,829.2262；实测值,829.2137.
实施例46：4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈(SIAIS151165)的制备
Figure PCTCN2019077535-appb-000103
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS151026制备得到化合物(SIAIS151165)，为黄色固体，9.2mg,收率38％, 1H NMR(500MHz,MeOD)δ8.85(s,1H),8.00(s,1H),7.66(s,1H),7.58(dd,J＝8.4,7.2Hz,1H),7.40(s,2H),7.14(d,J＝8.6Hz,1H),7.06(d,J＝7.1Hz,1H),5.04(dd,J＝12.5,5.5Hz,1H),4.79–4.64(m,1H),4.44(t,J＝5.3Hz,2H),4.33–4.13(m,1H),4.08(s,3H),3.94(s,3H),3.82–3.52(m,5H),3.47–3.42(m,2H),3.26–2.92(m,3H),2.90–2.79(m,2H),2.79–2.63(m,3H),2.47–2.43(m,2H),2.13–2.08(m,1H).HRMS(ESI)m/z:计算值C 41H 41Cl 2N 8O 8 +[M+H] +,843.2419；实测值,843.1989.
实施例47：4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈(SIAIS151162)的制备
Figure PCTCN2019077535-appb-000104
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS151019制备得到化合物(SIAIS151162)，为黄色固体，11.3mg,收率45％, 1H NMR(500MHz,MeOD)δ8.84(s,1H),8.00(s,1H),7.66(s,1H),7.57(dd,J＝8.5,7.2Hz,1H),7.40(d,J＝3.8Hz,2H),7.13(d,J＝8.6Hz,1H),7.05(d,J＝7.0Hz,1H),5.06(dd,J＝12.6,5.5Hz,1H),4.78–4.62(m,1H),4.44(t,J＝5.5Hz,2H),4.34–4.14(m,1H),4.08(s,3H),3.94(s,3H),3.79–3.52(m,3H),3.49–3.40(m,4H),3.25–2.95(m,3H),2.91–2.78(m,1H),2.76–2.68(m,2H),2.59(s,2H),2.49–2.43(m,2H),2.13–2.08(m,1H),2.03–1.98(m,2H).HRMS(ESI)m/z:计算值C 42H 43Cl 2N 8O 8 +[M+H] +,857.2575；实测值,857.2471.
实施例48：4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈(SIAIS151163)的制备
Figure PCTCN2019077535-appb-000105
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS151020制备得到化合物(SIAIS151163)，为黄色固体，12mg,收率47％, 1H NMR(500MHz,MeOD)δ8.86(s,1H),8.01(s,1H),7.67(s,1H),7.56(dd,J＝8.4,7.2Hz,1H),7.41(s,2H),7.07(d,J＝8.5Hz,1H),7.04(d,J＝7.0Hz,1H),5.05(dd,J＝12.6,5.4Hz,1H),4.77–4.62(m,1H),4.45(t,J＝5.3Hz,2H),4.32–4.15(s,1H),4.08(s,3H),3.94(s,3H),3.82–3.56(m,3H),3.50–3.43(m,2H),3.42–3.36(m,2H),3.22–2.94(m,3H),2.87–2.80(m,1H),2.75–2.67(m,2H),2.55(s,2H),2.49–2.43(m,2H),2.12–2.06(m,1H),1.80–1.71(m,4H).HRMS(ESI)m/z:计算值C 43H 45Cl 2N 8O 8 +[M+H] +,871.2732；实测值,871.2615.
实施例49：4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈(SIAIS151166)的制备
Figure PCTCN2019077535-appb-000106
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS151027制备得到化合物(SIAIS151166)，为黄色固体，12.8mg,收率50％, 1H NMR(500MHz,MeOD)δ8.85(s,1H),8.00(s,1H),7.66(s,1H),7.55(dd,,J＝8.0,7.0Hz,1H),7.40(d,J＝3.9Hz,2H),7.04(dd,J＝12.2,7.8Hz,2H),5.05(dd,J＝12.4,5.5Hz,1H),4.79–4.64(m,1H),4.45(t,J＝5.5Hz,2H),4.35–4.18(m,1H),4.08(s,3H),3.93(s,3H),3.84–3.54(m,3H),3.48(t,J＝7.2Hz,2H),3.36(t,J＝6.8Hz,2H),3.27–2.95(m,3H),2.89–2.82(m,1H),112.78–2.65(m,2H),2.54–2.43(m,4H),2.13–2.08(m,1H),1.76–1.65(m,4H),1.53–1.47(m,2H).HRMS(ESI)m/z:计算值C 44H 47Cl 2N 8O 8 +[M+H] +,885.2888；实测值,885.2423.
实施例50：4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈(SIAIS151167)的制备
Figure PCTCN2019077535-appb-000107
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS151086制备得到4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈(SIAIS151167)，为黄色固体，14.1mg,收率54％, 1H NMR(500MHz,MeOD)δ8.82(s,1H),7.97(s,1H),7.66(s,1H),7.55(dd,,J＝8.5,7.5Hz,1H),7.39(d,J＝6.1Hz,2H),7.05(t,J＝8.3Hz,2H),5.05(dd,J＝12.4,5.5Hz,1H),4.79–4.63(m,1H),4.44(t,J＝5.5Hz,2H),4.32–4.14(m,1H),4.08(s,3H),3.93(s,3H),3.80–3.54(m,3H),3.48(t,J＝7.2Hz,2H),3.35(t,J＝6.8Hz,2H),3.25–3.00(m,3H),2.89–2.81(m,1H),2.78–2.65(m,2H),2.54–2.43(m,4H),2.14–2.07(m,1H),1.72–1.62(m,4H),1.52–1.43(m,4H).HRMS(ESI)m/z:计算值C 45H 49Cl 2N 8O 8 +[M+H] +,899.3045；实测值,899.2559.
实施例51：3-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-3-氧代丙酰胺(SIAIS164104)的制备
Figure PCTCN2019077535-appb-000108
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS171004制备得到化合物(SIAIS164104)，为黄色固体,13.2mg,收率54％, 1H NMR(500MHz,DMSO)δ11.32(s,1H),11.03(s,1H),10.22(s,1H),8.95(s,1H),8.23(s,1H),7.88(dd,J＝7.4,1.3Hz,1H),7.84(s,1H),7.57–7.47(m,4H),5.16(dd,J＝13.3,5.1Hz,1H),4.51–4.42(m,2H),4.38–4.30(m,3H),4.14(d,J＝15.1Hz,1H),4.02(s,3H),3.88(s,3H),3.72(s,2H),3.65–3.59(m,2H),3.34–3.28(m,2H),3.25–3.08(m,3H),3.03–2.88(m,2H),2.64–2.60(m,1H),2.41–2.28(m,3H),2.09–2.02(m,1H).HRMS(ESI)m/z:计算值C 41H 41Cl 2N 8O 8 +[M+H] +,843.2419；实测值,843.3409.
实施例52：4-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-4-氧代丁酰胺(SIAIS164105)的制备
Figure PCTCN2019077535-appb-000109
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS164084制备得到化合物(SIAIS164105)，为黄色固体,11.8mg,收率48％, 1H NMR(500MHz,MeOD)δ8.87(s,1H),8.01(s,1H),7.72(d,J＝7.9Hz,1H),7.67(s,1H),7.63(d,J＝7.4Hz,1H),7.51(t,J＝7.7Hz,1H),7.41(d,J＝6.2Hz,2H),5.18(dd,J＝13.3,5.1Hz,1H),4.77–4.66(m,1H),4.48(s,2H),4.45(t,J＝5.6Hz,2H),4.40–4.32(m,1H),4.07(s,3H),3.94(s,3H),3.80–3.72(m,2H),3.71–3.61(m,1H),3.51–3.45(m,2H),3.25–3.15(m,1H),3.12–3.03(s,1H),3.00–2.55(m,7H),2.50–2.43(m,3H),2.22–2.16(m,1H).HRMS(ESI)m/z:计算值C 42H 43Cl 2N 8O 8 +[M+H] +,857.2575；实测值,857.3555.
实施例53：5-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-5-氧代戊酰胺(SIAIS164106)的制备
Figure PCTCN2019077535-appb-000110
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS171005制备得到化合物(SIAIS164106)，为黄色固体,14.1mg,收率56％, 1H NMR(500MHz,DMSO)δ11.18(s,1H),11.02(s,1H),9.92(s,1H),8.92(s,1H),8.21(s,1H),7.84–7.81(m,2H),7.56–7.45(m,4H),5.15(dd,J＝13.3,5.1Hz,1H),4.51–4.44(m,1H),4.42–4.30(m,4H),4.09(d,J＝13.8Hz,1H),4.01(s,3H),3.88(s,3H),3.57–3.54(m,3H),3.31–3.24(m,2H),3.16–3.05(m,3H),2.98–2.87(m,2H),2.63–2.59(m,1H),2.47–2.42(m,3H),2.38–2.30(m,3H),2.08–1.99(m,1H),1.88–1.82(m,2H).HRMS(ESI)m/z:计算值C 43H 45Cl 2N 8O 8 +[M+H] +,871.2732；实测值,871.3725.
实施例54：(2S,4R)-1-((S)-2-(叔丁基)-16-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-4,16-二氧代-7,10,13-三氧杂-3-氮杂十六烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS172082)的制备
Figure PCTCN2019077535-appb-000111
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS151003制备得到化合物(SIAIS172082)，为白色固体,6.2mg,收率46％, 1H NMR(500MHz,MeOD)δ9.95(s,1H),8.88(s,1H),8.04(s,1H),7.67(s,1H),7.57(d,J＝7.7Hz,2H),7.52(d,J＝8.1Hz,2H),7.42(d,J＝6.1Hz,2H),4.64(s,1H),4.60–4.56(m,2H),4.50–4.47(m,3H),4.42(d,J＝15.9Hz,1H),4.09(s,3H),3.94(s,3H),3.90(d,J＝11.1Hz,1H),3.82–3.76(m,4H),3.74–3.70(m,3H),3.67–3.59(m,10H),3.53–3.47(m,2H),3.27–3.17(m,2H),3.11–3.05(m,1H),2.88–2.80(m,1H),2.69–2.55(m,6H),2.51–2.45(m,3H),2.26–2.22(m,1H),2.11–2.03(m,1H),1.04(s,9H).HRMS(ESI)m/z:计算值C 57H 72Cl 2N 9O 11S +[M+H] +,1160.4444；实测值,1160.4225.
实施例55：(2S,4R)-1-((S)-2-(叔丁基)-19-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-4,19-二氧代-7,10,13,16-四氧杂-3-氮杂十九烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS172083)的制备
Figure PCTCN2019077535-appb-000112
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS151008制备得到化合物(SIAIS172083)，为白色固体,5.0mg,收率36％, 1H NMR(500MHz,MeOD)δ9.90(s,1H),8.88(s,1H),8.03(s,1H),7.67(s,1H),7.56(d,J＝8.4Hz,2H),7.52(d,J＝8.3Hz,2H),7.42(d,J＝5.0Hz,2H),4.64(s,1H),4.59–4.52(m,2H),4.50–4.46(m,3H),4.42(d,J＝15.7Hz,1H),4.09(s,3H),3.94(s,3H),3.90(d,J＝10.9Hz,1H),3.82–3.71(m,7H),3.64–3.60(m,14H),3.53–3.47(m,2H),3.26–3.15(m,2H),3.12–3.05(m,1H),2.92–2.84(m,1H),2.63–2.55(m,5H),2.51– 2.46(m,3H),2.28–2.21(m,1H),2.10–2.04(m,1H),1.04(s,9H).HRMS(ESI)m/z:计算值C 63H 84Cl 2N 9O 8S +[M+H] +,1204.4706；实测值,1204.4476.
实施例56：(2S,4R)-1-((S)-2-(叔丁基)-22-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-4,22-二氧代-7,10,13,16,19-五氧杂-3-氮杂二十二碳酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS172084)的制备
Figure PCTCN2019077535-appb-000113
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS151009制备得到化合物(SIAIS172084)，为白色固体,6.0mg,收率42％, 1H NMR(500MHz,MeOD)δ9.57(d,J＝4.9Hz,1H),8.88(d,J＝3.7Hz,1H),8.02(s,1H),7.67(s,1H),7.53(d,J＝8.3Hz,2H),7.48(d,J＝8.3Hz,2H),7.41(d,J＝4.4Hz,2H),4.63(s,1H),4.58–4.52(m,2H),4.49–4.45(m,3H),4.41–4.37(m,1H),4.08(s,3H),3.93(s,3H),3.89(d,J＝11.1Hz,1H),3.81–3.68(m,9H),3.62–3.60(m,20H),3.50–3.46(m,2H),2.63–2.53(m,3H),2.55(s,3H),2.51–2.45(m,3H),2.25–2.21(m,1H),2.10–2.04(m,1H),1.03(s,9H),HRMS(ESI)m/z:计算值C 61H 80Cl 2N 9O 13S +[M+H] +,1248.4968；实测值,1248.4678。
实施例57：(2S,4R)-1-((S)-2-(4-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-4-氧代丁酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS172072)的制备
Figure PCTCN2019077535-appb-000114
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS074011制备得到化合物(SIAIS172072)，为白色固体,10mg,收率83％, 1H NMR(500MHz,MeOD)δ8.97(s,1H),8.86(s,1H),7.99(s,1H),7.67(s,1H),7.47(d,J＝8.3Hz,2H),7.43–7.39(m,4H),4.62–4.48(m,4H),4.44(t,J＝5.4Hz,2H),4.37(d,J＝15.5Hz,1H),4.08(s,3H),3.93(s,3H),3.89(d,J＝11.0Hz,1H),3.80 (dd,J＝11.0,4.0Hz,1H),3.49(t,J＝7.3Hz,2H),3.33–3.31(m,6H),2.78–2.58(m,4H),2.48(s,3H),2.48–2.43(m,2H),2.24–2.20(m,1H),2.11–2.06(m,1H),1.05(s,9H).HRMS(ESI)m/z:计算值C 51H 60Cl 2N 9O 8S +[M+H] +,1028.3657；实测值,1028.3466.
实施例58：(2S,4R)-1-((S)-2-(5-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-5-氧代戊酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS172073)的制备
Figure PCTCN2019077535-appb-000115
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS074012制备得到化合物(SIAIS172073)，为白色固体,10.7mg,收率87％, 1H NMR(500MHz,MeOD)δ9.61(s,1H),8.88(s,1H),8.01(s,1H),7.67(s,1H),7.55–7.51(m,2H),7.49–7.47(m,2H),7.41(d,J＝2.7Hz,2H),4.63–4.49(m,4H),4.46(t,J＝5.4Hz,2H),4.40(d,J＝15.7Hz,1H),4.08(s,3H),3.93(s,3H),3.82–3.59(m,4H),3.51–3.45(m,2H),3.34–3.31(m,2H),3.30–3.00(m,4H),2.55(s,3H),2.47(s,4H),2.37(t,J＝7.1Hz,2H),2.28–2.21(m,1H),2.11–2.04(m,1H),1.97–1.89(m,2H),1.05(s,9H).HRMS(ESI)m/z:计算值C 52H 62Cl 2N 9O 8S +[M+H] +,1042.3814；实测值,1042.3593.
实施例59：(2S,4R)-1-((S)-2-(6-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-6-氧代己酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS172074)的制备
Figure PCTCN2019077535-appb-000116
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS074013制备得到化合物(SIAIS172074)，为白色固体,9.0mg,收率73％, 1H NMR(500MHz,MeOD)δ9.93(s,1H),8.88(s,1H),8.03(s,1H),7.67(s,1H),7.58–7.56(m,2H),7.53–7.51(m,2H),7.42(d,J＝4.2Hz,2H),4.64–4.45(m,6H),4.41(d,J＝15.7Hz,1H),4.09(s,3H),3.94(s,3H),3.91(d,J＝11.2Hz,1H),3.83–3.73(m,3H),3.70–3.46(m,4H),3.30–3.06(m,4H),2.60(s,3H),2.53–2.44(m,4H),2.38– 2.28(m,2H),2.27–2.20(m,1H),2.10–2.02(m,1H),1.72–1.62(m,4H),1.04(s,9H).HRMS(ESI)m/z:计算值C 53H 64Cl 2N 9O 8S +[M+H] +,1056.3970；实测值,1056.3754.
实施例60：(2S,4R)-1-((S)-2-(7-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-7-氧代庚酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS172075)的制备
Figure PCTCN2019077535-appb-000117
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS074014制备得到化合物(SIAIS172075)，为白色固体,9.6mg,收率77％, 1H NMR(500MHz,MeOD)δ9.99(s,1H),8.88(s,1H),8.04(s,1H),7.66(s,1H),7.58–7.56(m,2H),7.53–7.51(m,2H),7.42(d,J＝5.5Hz,2H),4.64–4.45(m,6H),4.41(d,J＝15.8Hz,1H),4.09(s,3H),3.94(s,3H),3.90(d,J＝11.1Hz,1H),3.83–3.73(m,3H),3.72–3.43(m,4H),3.30–3.04(m,4H),2.60(s,3H),2.52–2.44(m,4H),2.34–2.21(m,3H),2.11–2.04(m,1H),1.68–1.61(m,4H),1.42–1.36(m,2H),1.03(s,9H).HRMS(ESI)m/z:计算值C 54H 66Cl 2N 9O 8S +[M+H] +,1070.4127；实测值,1070.3939.
实施例61：(2S,4R)-1-((S)-2-(8-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-8-氧代辛酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS172076)的制备
Figure PCTCN2019077535-appb-000118
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS074015制备得到化合物(SIAIS172076).为白色固体,6.0mg,收率48％, 1H NMR(500MHz,MeOD)δ9.99(s,1H),8.88(s,1H),8.04(s,1H),7.67(s,1H),7.59–7.57(m,2H),7.54–7.52(m,2H),7.43(d,J＝4.2Hz,2H),4.64(s,1H),4.59–4.54(m,2H),4.50–4.46(m,3H),4.41(d,J＝15.7Hz,1H),4.09(s,3H),3.94(s,3H),3.91(d,J＝11.1Hz,1H),3.83–3.73(m,3H),3.70–3.46(m,4H),3.30–3.04(m,4H),2.61(s,3H),2.51–2.45(m,4H),2.33–2.22(m,3H),2.10–2.04(m,1H),1.66–1.60(m,4H),1.42– 1.36(m,4H),1.04(s,9H).HRMS(ESI)m/z:计算值C 55H 68Cl 2N 9O 8S +[M+H] +,1084.4238；实测值,1084.4072.
实施例62：(2S,4R)-1-((S)-2-(9-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-9-氧代壬酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS172077)的制备
Figure PCTCN2019077535-appb-000119
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS074016制备得到化合物(SIAIS172077)，为白色固体,6.4mg,收率48％, 1H NMR(500MHz,MeOD)δ9.93(s,1H),8.88(s,1H),8.03(s,1H),7.67(s,1H),7.57(d,J＝8.3Hz,2H),7.53–7.51(m,2H),7.42(d,J＝2.6Hz,2H),4.64(s,1H),4.60–4.53(m,2H),4.50–4.46(m,3H),4.41(d,J＝15.7Hz,1H),4.09(s,3H),3.94(s,3H),3.91(d,J＝11.1Hz,1H),3.83–3.73(m,3H),3.68–3.46(m,4H),3.30–3.08(m,4H),2.60(s,3H),2.51–2.44(m,4H),2.34–2.20(m,3H),2.10–2.04(m,1H),1.66–1.60(m,4H),1.38–1.34(m,6H),1.03(s,9H).HRMS(ESI)m/z:计算值C 56H 70Cl 2N 9O 8S +[M+H] +,1098.4440；实测值,1098.4216.
实施例63：(2S,4R)-1-((S)-2-(10-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-10-氧代癸酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS172078)的制备
Figure PCTCN2019077535-appb-000120
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS074019制备得到化合物(SIAIS172078)，为白色固体,7.3mg,收率56％, 1H NMR(500MHz,MeOD)δ9.80(d,J＝2.7Hz,1H),8.88(s,1H),8.03(s,1H),7.67(s,1H),7.56(d,J＝8.3Hz,2H),7.51(d,J＝8.3Hz,2H),7.42(d,J＝1.8Hz,2H),4.64(s,1H),4.56(dd,J＝11.8,6.1Hz,2H),4.50–4.46(m,3H),4.40(d,J＝15.7Hz,1H),4.09(s,3H),3.94(s,3H),3.91(d,J＝11.0Hz,1H),3.83–3.72(m,3H),3.70–3.46(m, 4H),3.30–3.06(m,4H),2.59(s,3H),2.51–2.44(m,4H),2.33–2.20(m,3H),2.10–2.05(m,1H),1.66–1.58(m,4H),1.38–1.32(,8H),1.03(s,9H).HRMS(ESI)m/z:计算值C 57H 72Cl 2N 9O 8S +[M+H] +,1112.4596；实测值,1112.4366.
实施例64：(2S,4R)-1-((S)-2-(11-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-11-氧代十一烷酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS172079)的制备
Figure PCTCN2019077535-appb-000121
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS074020制备得到化合物(SIAIS172079)，为白色固体,6.6mg,收率50％, 1H NMR(500MHz,MeOD)δ9.86(s,1H),8.88(s,1H),8.03(s,1H),7.67(s,1H),7.56(d,J＝8.4Hz,2H),7.52(d,J＝8.4Hz,2H),7.42(d,J＝1.5Hz,2H),4.64(s,1H),4.56(dd,J＝16.5,9.5Hz,2H),4.50–4.46(m,3H),4.41(d,J＝15.7Hz,1H),4.09(s,3H),3.94(s,3H),3.91(d,J＝11.0Hz,1H),3.83–3.73(m,3H),3.66–3.46(m,4H),3.30–3.04(m,4H),2.59(s,3H),2.50–2.44(m,4H),2.33–2.21(m,3H),2.10–2.04(m,1H),1.64–1.58(m,4H),1.38–1.32(m,10H),1.03(s,9H).HRMS(ESI)m/z:计算值C 58H 74Cl 2N 9O 8S +[M+H] +,1126.4753；实测值,1126.4546.
实施例65：4-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-N-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙基)-4-氧代丁酰胺(SIAIS164136)的制备
Figure PCTCN2019077535-appb-000122
根据方案19所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物SIAIS151151和HO 2C-LIN-ULM中间体SIAIS164119制备得到化合物(SIAIS164136)，为黄色固体，12.4mg,收率71％. 1H NMR(500MHz,MeOD)δ8.87(s,1H),8.00(s,1H),7.68(s,1H),7.56(dd,J＝8.4,7.2Hz,1H),7.40(d,J＝5.8Hz,2H),7.14(d,J＝8.6Hz,1H),7.05(d,J＝7.1Hz,1H),5.05(dd,J＝12.6,5.5Hz,1H),4.68(s,1H),4.45(t,J＝5.4Hz,2H),4.26(s,1H),4.08(s,3H),3.94(s,3H),3.73(s,2H),3.53(d,J＝59.0Hz,8H),3.10(s,2H),2.86(ddd,J＝19.1,13.9,5.2Hz,1H),2.78–2.67(m,3H),2.49(dd,J＝26.8,20.9Hz,5H),2.11(dd,J＝ 10.2,5.1Hz,1H).HRMS(ESI)m/z:计算值C 44H 46Cl 2N 9O 9 +[M+H] +,914.2790；实测值,914.0165.
实施例66：4-((4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺(SIAIS1197001)的制备
Figure PCTCN2019077535-appb-000123
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS151001制备得到化合物(SIAIS1197001)，为黄色固体,13.3mg,收率38％, 1H NMR(500MHz,MeOD)δ9.43(d,J＝1.7Hz,1H),8.86(d,J＝8.1Hz,1H),8.74(dd,J＝5.2,1.5Hz,1H),8.52(d,J＝5.3Hz,1H),8.24(d,J＝1.8Hz,1H),7.98(d,J＝8.3Hz,2H),7.77(dd,J＝7.9,5.3Hz,1H),7.60–7.51(m,3H),7.43(d,J＝5.2Hz,1H),7.36(dd,J＝8.3,2.1Hz,1H),7.28(d,J＝8.5Hz,1H),7.08(dd,J＝10.5,7.8Hz,2H),5.04(dd,J＝12.6,5.5Hz,1H),4.38(s,2H),3.79(t,J＝5.7Hz,2H),3.69(t,J＝5.2Hz,2H),3.48(t,J＝5.0Hz,2H),3.38–3.31(m,8H),2.91–2.84(m,2H),2.78–2.60(m,3H),2.33(s,3H),2.13–2.05(m,1H).HRMS(ESI)m/z:计算值C 46H 47N 10O 7 +[M+H] +,851.3624；实测值,851.3165.
实施例67：4-((4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺(SIAIS1197015)的制备
Figure PCTCN2019077535-appb-000124
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS151004制备得到化合物(SIAIS1197015)，为黄色固体,12.5mg,收率33％, 1H NMR(500MHz,MeOD)δ9.44(s,1H),8.89(d,J＝8.3Hz,1H),8.75(d,J＝4.7Hz,1H),8.52(d,J＝5.1Hz,1H),8.25(s,1H),8.02(d,J＝8.1Hz,2H),7.80(s,1H),7.60(t,J＝8.4Hz,2H),7.50(t,J＝7.5Hz,1H),7.44(d,J＝5.2Hz,1H),7.36(d,J＝8.2Hz,1H),7.28(d,J＝8.4Hz,1H),7.04(dd,J＝24.0,7.8Hz,2H),5.03(dd,J＝12.6,5.6Hz,1H),4.39(s,2H),3.78–3.69(m,8H),3.48(t,J＝5.0Hz,2H),3.30–3.16(m,8H),2.87–2.78(m,2H),2.76–2.66(m,3H),2.33(s,3H),2.12–2.04(m,1H).HRMS(ESI)m/z:计算值C 48H 51N 10O 7 +[M+H] +,895.3886；实测值,895.4430.
实施例68：4-((4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺(SIAIS1197017)的制备
Figure PCTCN2019077535-appb-000125
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS151005制备得到化合物(SIAIS1197017)，为黄色固体,16.6mg,收率43％, 1H NMR(500MHz,MeOD)δ9.38(s,1H),8.76(d,J＝8.2Hz,1H),8.69(d,J＝4.8Hz,1H),8.50(d,J＝5.1Hz,1H),8.24(s,1H),8.01(d,J＝7.9Hz,2H),7.69(dd,J＝7.4,5.9Hz,1H).7.61(d,J＝8.1Hz,1H),7.49(t,J＝7.6Hz,1H),7.40(d,J＝5.2Hz,1H),7.37(d,J＝8.8Hz,1H),7.28(d,J＝7.9Hz,1H),7.04–6.98(m,2H),5.06–5.02(m,1H),4.41(s,2H),3.78–3.61(m,19H),3.43(t,J＝5.0Hz,4H),2.90–2.79(m,1H),2.77–2.64(m,3H),2.52(t,J＝6.0Hz,1H),2.33(s,3H),2.13–2.05(m,1H).HRMS(ESI)m/z:计算值C 50H 55N 10O 7 +[M+H] +,939.4148；实测值,939.4696.
实施例69：4-((4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十五烷-15-酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺(SIAIS1197019)的制备
Figure PCTCN2019077535-appb-000126
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS151006制备得到化合物(SIAIS1197019)，为黄色固体,18.4mg,收率45％, 1H NMR(500MHz,MeOD)δ9.44(s,1H),8.90(d,J＝8.2Hz,1H),8.75(d,J＝5.0Hz,1H),8.52(d,J＝4.9Hz,1H),8.25(s,1H),8.03(d,J＝8.0Hz,2H),7.81(dd,J＝8.1,5.4Hz,1H),7.63(d,J＝8.1Hz,2H),7.48(t,J＝8.0Hz,1H),7.43(d,J＝5.2Hz,1H),7.35(dd,J＝8.0,1.7Hz,1H),7.28(d,J＝8.4Hz,1H),6.99(t,J＝8.1Hz,2H),5.03(dd,J＝12.9,5.5Hz,1H),4.43(s,2H),3.83–3.58(m,18H),3.41–3.35(m,9H),2.89–2.78(m,1H),2.78–2.59(m,3H),2.33(s,3H),2.12–2.04(m,1H).HRMS(ESI)m/z:计算值C 52H 59N 10O 7 +[M+H] +,983.4410；实测值,983.3912.
实施例70：4-((4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12,15-五氧杂十八烷-18-酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺(SIAIS1197021)的制备
Figure PCTCN2019077535-appb-000127
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS151007制备得到化合物(SIAIS1197021)，为黄色固体,9.5mg,收率21％, 1H NMR(500MHz,MeOD)δ9.44(s,1H),8.88(d,J＝8.3Hz,1H),8.75(d,J＝4.9Hz,1H),8.51(d,J＝5.4Hz,1H),8.26(s,1H),8.06(d,J＝8.1Hz,2H),7.80(dd,J＝8.0,5.3Hz,1H),7.65(d,J＝8.1Hz,2H),7.53–7.46(m,1H),7.42(d,J＝5.2Hz,1H),7.35(d,J＝7.7Hz,1H),7.27(d,J＝8.3Hz,1H),7.01(dd,J＝7.9,4.5Hz,2H),5.03(dd,J＝12.7,5.4Hz,2H),4.45(s,2H),3.77–3.58(m,20H),3.42(t,J＝5.1Hz,2H),3.34–3.31(m,8H),2.88–2.78(m,1H),2.75–2.64(m,3H),2.32(s,3H),2.12–2.04(m,1H).HRMS(ESI)m/z:计算值C 54H 63N 10O 7 +[M+H] +,1027.4672；实测值,1027.4310.
实施例71：4-((4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基乙酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺(SIAIS1197003)的制备
Figure PCTCN2019077535-appb-000128
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS151025制备得到化合物(SIAIS1197003)，为黄色固体,11.1mg,收率33％。 1H NMR(500MHz,MeOD)δ9.46(d,J＝2.0Hz,1H),8.90(d,J＝7.6Hz,1H),8.79–8.72(m,1H),8.52(d,J＝5.3Hz,1H),8.26(s,1H),8.08(d,J＝8.3Hz,2H),7.82(dd,J＝8.1,5.2Hz,1H),7.68(d,J＝8.3Hz,2H),7.58–7.52(m,1H),7.44(d,J＝5.3Hz,1H),7.36(dd,J＝8.2,2.1Hz,1H),7.29(d,J＝8.3Hz,1H),7.10(d,J＝7.1Hz,1H),6.99(d,J＝8.4Hz,1H),5.07(dd,J＝12.4,5.5Hz,1H),4.48(s,2H),4.26(s,2H),3.45–3.32(m,8H),2.92–2.80(m,1H),2.80–2.63(m,2H),2.33(s,3H),2.18–2.06(m,1H).HRMS(ESI)m/z:计算值C 43H 41N 10O 6 +[M+H] +,793.3205；实测值,793.2798.
实施例72：4-((4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺(SIAIS1197005)的制备
Figure PCTCN2019077535-appb-000129
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS151026制备得到化合物(SIAIS1197005)，为黄色固体,16.8mg,收率50％, 1H NMR(500MHz,MeOD)δ9.46(s,1H),8.91(d,J＝8.2Hz,1H),8.76(d,J＝4.5Hz,1H),8.52(d,J＝5.3Hz,1H),8.26(d,J＝1.9Hz,1H),8.06(d,J＝8.3Hz,2H),7.82(dd,J＝8.0,5.2Hz,1H),7.64(d,J＝8.4Hz,2H),7.57(dd,J＝8.6,7.1Hz,1H),7.44(d,J＝5.3Hz,1H),7.36(dd,J＝8.2,2.1Hz,1H),7.28(d,J＝8.3Hz,1H),7.12(d,J＝8.5Hz,1H),7.07(d,J＝6.8Hz,1H),5.06(dd,J＝12.5,5.5Hz,1H),4.42(s,2H),3.68(t,J＝6.1Hz,2H),3.30–3.15(m,8H),2.93–2.63(m,5H),2.33(s,3H),2.15–2.04(m,1H).HRMS(ESI)m/z:计算值C 44H 43N 10O 6 +[M+H] +,807.3362；实测值,807.2928.
实施例73：4-((4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺(SIAIS1197007)的制备
Figure PCTCN2019077535-appb-000130
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS151019制备得到化合物(SIAIS1197007)，为黄色固体,14.0mg,收率40％. 1H NMR(500MHz,MeOD)δ9.47(d,J＝1.7Hz,1H),8.91(d,J＝8.1Hz,1H),8.78(dd,J＝5.2,1.4Hz,1H),8.54(d,J＝5.3Hz,1H),8.28(d,J＝1.8Hz,1H),8.09(d,J＝8.2Hz,2H),7.82(dd,J＝7.9,5.4Hz,1H),7.66(d,J＝8.3Hz,2H),7.58(dd,J＝8.5,7.1Hz,1H),7.46(d,J＝5.3Hz,1H),7.39(dd,J＝8.2,2.1Hz,1H),7.31(d,J＝8.4Hz,1H),7.14(d,J＝8.6Hz,1H),7.09(d,J＝7.0Hz,1H),5.08(dd,J＝12.5,5.5Hz,1H),4.44(s,2H),3.44(t,J＝6.7Hz,2H),3.41–3.32(m,8H),2.96–2.64(m,3H),2.57(t,J＝6.9Hz,2H),2.35(s,3H),2.17–2.08(m,1H),2.07–1.95(m,2H).HRMS(ESI)m/z:计算值C 45H 45N 10O 6 +[M+H] +,821.3518；实测值,821.3642.
实施例74：4-((4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺(SIAIS1197009)的制备
Figure PCTCN2019077535-appb-000131
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS151020制备得到化合物(SIAIS1197009)，为黄色固体,14.8mg,收率43％, 1H NMR(500MHz,MeOD)δ9.43(d,J＝2.0Hz,1H),8.83(d,J＝8.4Hz,1H),8.75(d,J＝5.1Hz,1H),8.53(d,J＝5.2Hz,1H),8.27(s,1H),8.10(d,J＝8.2Hz,2H),7.76(dd,J＝8.1,5.1Hz,1H),7.67(d,J＝8.3Hz,2H),7.58(dd,J＝8.6,7.1Hz,1H),7.44(d,J＝5.3Hz,1H),7.40(d,J＝10.2Hz,1H),7.31(d,J＝8.3Hz,1H),7.08(t,J＝7.8Hz,2H),5.07(dd,J＝12.4,5.5Hz,1H),4.46(s,2H),3.45–3.36(m,10H),2.92–2.66(m,3H),2.53(s,2H),2.35(s,3H),2.17–2.07(m,1H),1.76(s,4H).HRMS(ESI)m/z:计算值C 46H 47N 10O 6 +[M+H] +,835.3675；实测值,835.3783.
实施例75：4-((4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺(SIAIS1197011)的制备
Figure PCTCN2019077535-appb-000132
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS151027制备得到化合物(SIAIS1197011)，为黄色固体,15.4mg,收率43％, 1H NMR(500MHz,MeOD)δ9.45(d,J＝1.8Hz,1H),8.88(d,J＝8.2Hz,1H),8.76(dd,J＝5.2,1.5Hz,1H),8.54(d,J＝5.3Hz,1H),8.27(s,1H),8.10(d,J＝8.3Hz,2H),7.80(dd,J＝8.0,5.2Hz,1H),7.68(d,J＝8.3Hz,2H),7.57(dd,J＝8.5,7.1Hz,1H),7.45(d,J＝5.3Hz,1H),7.39(dd,J＝8.1,2.1Hz,1H),7.31(d,J＝8.5Hz,1H),7.06(dd,J＝7.8,4.3Hz,2H),5.07(dd,J＝12.5,5.5Hz,1H),4.47(s,2H),3.43–3.35(m,10H),2.92–2.82(m,1H),2.79–2.66(m,2H),2.48(t,J＝7.5Hz,2H),2.35(s,3H),2.15–2.08(m,1H),1.77–1.65(m,4H),1.54–1.46(m,2H).HRMS(ESI)m/z:计算值C 47H 49N 10O 6 +[M+H] +,849.3831；实测值,849.3960.
实施例76：4-((4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺(SIAIS1197095)的制备
Figure PCTCN2019077535-appb-000133
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS151086制备得到化合物(SIAIS1197095)，为黄色固体,16.0mg,收率45％, 1H NMR(500MHz,MeOD)δ9.46(s,1H),8.91(s,1H),8.76(s,1H),8.52(d,J＝5.3Hz,1H),8.26(s,1H),8.08(d,J＝8.3Hz,2H),7.82(s,1H),7.66(d,J＝8.4Hz,2H),7.54(dd,J＝8.6,7.1Hz,1H),7.44(d,J＝5.2Hz,1H),7.36(d,J＝8.0Hz,1H),7.28(d,J＝8.4Hz,1H),7.03(dd,J＝7.8,4.0Hz,2H),5.04(dd,J＝12.4,5.5Hz,1H),4.45(s,2H),3.37–3.32(m,10H),2.89–2.80(m,1H),2.77–2.65(m,2H),2.43(t,J＝7.5Hz,2H),2.33(s,3H),2.13–2.06(m,1H),1.73–1.57(m,4H),1.51–1.37(m,4H).HRMS(ESI)m/z:计算值C 48H 51N 10O 6 +[M+H] +,863.3988；实测值,863.4003.
实施例77：(2S,4R)-1-((S)-3,3-二甲基-2-(2-(2-(2-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-2-氧代乙氧基)乙氧基)乙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS1197043)的制备
Figure PCTCN2019077535-appb-000134
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS151010制备得到化合物(SIAIS1197043)，为白色固体,15.2mg,收率33％。 1H NMR(500MHz,MeOD)δ9.46(d,J＝1.6Hz,1H),8.8(s,1H),8.76(dd,J＝5.3,1.5Hz,1H),8.52(t,J＝4.5Hz,1H),8.26(s,1H),8.06(d,J＝8.3Hz,2H),7.83(dd,J＝8.0,5.0Hz,1H),7.65(d,J＝8.4Hz,2H),7.50–7.37(m,5H),7.35(dd,J＝8.1,2.2Hz,1H),7.28(d,J＝8.1Hz,1H),4.69(s,1H),4.50(dd,J＝16.5,6.8Hz,1H),4.47–4.39(m,3H),4.30(d,J＝11.6Hz,2H),4.04(t,J＝6.0Hz,2H),3.80(dd,J＝10.9,3.7Hz,3H),3.77–3.70(m,4H),3.43–3.32(m,10H),2.49–2.42(m,3H),2.32(s,3H),2.28–2.21(m,1H),2.11– 2.03(m,1H),1.03(s,9H).HRMS(ESI)m/z:计算值C 56H 66N 11O 8S +[M+H] +,1052.4811；实测值,1052.4419.
实施例78：(2S,4R)-1-((S)-3,3-二甲基-2-(3-(2-(3-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-3-氧代丙氧基)乙氧基)丙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS1197029)的制备
Figure PCTCN2019077535-appb-000135
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS151002制备得到化合物(SIAIS1197029)，为白色固体,13.2mg,收率29％。 1H NMR(500MHz,MeOD)δ9.45(s,1H),8.88(s,1H),8.76(d,J＝5.2Hz,1H),8.52(d,J＝5.2Hz,1H),8.26(s,1H),8.08(d,J＝8.1Hz,2H),7.81(dd,J＝7.9,5.4Hz,1H),7.67(d,J＝8.1Hz,2H),7.50–7.37(m,6H),7.36(dd,J＝8.2,1.6Hz,1H),7.28(d,J＝8.3Hz,1H),4.63(s,1H),4.54(dd,J＝22.1,14.0Hz,2H),4.49–4.46(m,3H),4.35(d,J＝15.4Hz,1H),3.82–3.67(m,7H),3.59(s,4H),3.38–3.32(m,8H),2.56–2.51(m,1H),2.50–2.48(m,2H),2.45(s,3H),2.32(s,3H),2.20(s,1H),2.07(s,1H),1.03(s,9H).HRMS(ESI)m/z:计算值C 58H 70N 11O 8S +[M+H] +,1080.5124；实测值,1080.4665.
实施例79：(2S,4R)-1-((S)-2-(叔丁基)-16-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-4,16-二氧代-7,10,13-三氧杂-3-氮杂十六烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS1197031)的制备
Figure PCTCN2019077535-appb-000136
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS151003制备得到化合物(SIAIS1197031)，为白色固体,14.5mg,收率31％, 1H NMR(500MHz,MeOD)δ9.53(s,1H),8.91(s,1H),8.81(t,J＝5.7Hz,1H),8.54(d,J＝5.2Hz,1H),8.28(s,1H),8.08(d,J＝8.3Hz,2H),7.93(dd,J＝8.2,5.0Hz,1H),7.67(d,J＝8.3Hz,2H),7.50–7.36(m,6H),7.34(dd,J＝8.2,1.9Hz,1H),7.28(d,J＝8.4Hz,1H),4.63(s,1H),4.56(dd,J＝17.0,8.2Hz,1H),4.49–4.45(m,3H),4.35 (dd,J＝15.6,4.4Hz,1H),3.82–3.66(m,8H),3.64–3.57(m,10H),3.41–3.31(m,4H),2.66(t,J＝13.2Hz,2H),2.55–2.50(m,1H),2.48–2.45(m,3H),2.50–2.40(m,2H),2.32(s,3H),2.22–2.16(m,1H),2.10–2.04(m,1H),1.03(s,9H).HRMS(ESI)m/z:计算值C 60H 74N 11O 9S +[M+H] +,1124.5386；实测值,1124.4786.
实施例80：(2S,4R)-1-((S)-2-(叔丁基)-19-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-4,19-二氧代-7,10,13,16-四氧杂-3-氮杂十九烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS1197039)的制备
Figure PCTCN2019077535-appb-000137
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS151008制备得到化合物(SIAIS1197039)，为白色固体,16.0mg,收率36％, 1H NMR(500MHz,MeOD)δ9.47(d,J＝1.6Hz,1H),8.90(s,1H),8.78(dd,J＝5.3,1.5Hz,1H),8.52(d,J＝5.3Hz,1H),8.26(s,1H),8.09(d,J＝8.3Hz,2H),7.85(dd,J＝8.0,5.3Hz,1H),7.66(d,J＝8.3Hz,2H),7.49–7.37(m,6H),7.35(dd,J＝8.2,2.2Hz,1H),7.28(d,J＝8.3Hz,1H),4.60(s,1H),4.54(dd,J＝15.0,6.2Hz,2H),4.50–4.45(m,3H),4.34(dd,J＝15.5,7.6Hz,1H),3.79–3.66(m,7H),3.63–3.57(m,16H),3.35–3.32(m,4H),2.53(t,J＝6.3Hz,1H),2.49–2.42(m,2H),2.45(s,3H),2.32(s,3H),2.22–2.15(m,1H),2.10–2.03(m,1H),1.03(s,9H).HRMS(ESI)m/z:计算值C 62H 78N 11O 10S +[M+H] +,1168.5648；实测值,1168.5174.
实施例81：(2S,4R)-1-((S)-2-(叔丁基)-22-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-4,22-二氧代-7,10,13,16,19-五氧杂-3-氮杂二十二碳酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS1197041)的制备
Figure PCTCN2019077535-appb-000138
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS151009制备得到化合物(SIAIS1197041)，为白色固体,16.4mg,收率33％。 1H NMR(500MHz,MeOD)δ9.52(d,J＝1.6Hz,1H),8.91 (s,1H),8.81(dd,J＝5.4,1.3Hz,1H),8.54(d,J＝5.2Hz,1H),8.28(s,1H),8.08(d,J＝8.2Hz,2H),7.92(dd,J＝8.0,5.4Hz,1H),7.67(d,J＝8.3Hz,2H),7.50–7.37(m,6H),7.35(dd,J＝8.2,2.0Hz,1H),7.28(d,J＝8.4Hz,1H),4.61(s,1H),4.55(dd,J＝18.0,7.0Hz,2H),4.51–4.46(m,3H),4.35(dd,J＝15.7,7.4Hz,1H),3.82–3.66(m,7H),3.63–3.57(m,20H),3.40–3.34(m,4H),2.56–2.51(m,1H),2.50–2.43(m,1H),2.46(s,4H),2.32(s,3H),2.23–2.16(m,1H),2.09–2.03(m,1H),1.03(s,9H).HRMS(ESI)m/z:计算值C 64H 82N 11O 11S +[M+H] +,1212.5910；实测值,1212.5910.
实施例82：(2S,4R)-1-((S)-3,3-二甲基-2-(4-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-4-氧代丁酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS074027)的制备
Figure PCTCN2019077535-appb-000139
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS074011制备得到化合物(SIAIS074027)，为白色固体,42.2mg,收率68％。 1H NMR(500MHz,MeOD)δ9.57(d,J＝1.8Hz,1H),9.14–9.07(m,1H),8.96(s,1H),8.85(dd,J＝5.4,1.3Hz,1H),8.56(d,J＝5.3Hz,1H),8.28(s,1H),8.08(d,J＝8.2Hz,2H),7.99(dd,J＝8.2,5.2Hz,1H),7.67(d,J＝8.3Hz,2H),7.50–7.41(m,5H),7.35–7.28(m,2H),4.58–4.47(m,5H),4.36(d,J＝15.5Hz,1H),4.23–3.71(m,5H),3.73–3.46(m,2H),3.38(s,4H),2.76–2.52(m,4H),2.53–2.38(m,3H),2.33(s,3H),2.21–2.19(m,1H),2.10–2.05(m,1H),1.03(s,9H).HRMS(ESI)m/z:计算值C 54H 62N 11O 6S +[M+H] +,992.4600；实测值,992.2307.
实施例83：(2S,4R)-1-((S)-3,3-二甲基-2-(5-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-5-氧代戊酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS074028)的制备
Figure PCTCN2019077535-appb-000140
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS074012制备得到化合物(SIAIS074028)，为白色固体,40.3mg,收率64％, 1H NMR(500MHz,MeOD)δ9.59(s,1H),9.14(d,J＝8.1Hz,1H),9.04–8.91(m,1H),8.86(d,J＝4.7Hz,1H),8.56(d,J＝5.3Hz,1H),8.29(s,1H),8.13–7.94(m,3H),7.71–7.55(m,2H),7.56–7.36(m,5H),7.34–7.28(m,2H),4.70–4.40(m,6H),4.37(d,J＝15.5Hz,1H),4.02–3.72(m,4H),3.67–3.48(m,2H),3.48–3.32(m,4H),2.51–2.42(m,4H),2.42–2.27(m,5H),2.23–2.18(m,1H),2.15–1.95(m,2H),1.95–1.83(m,2H),1.04(d,J＝14.1Hz,9H).HRMS(ESI)m/z:计算值C 55H 64N 11O 6S +[M+H] +,1006.4756；实测值,1006.4807.
实施例84：(2S,4R)-1-((S)-3,3-二甲基-2-(6-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-6-氧代己酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS074029)的制备
Figure PCTCN2019077535-appb-000141
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS074013制备得到化合物(SIAIS074029)，为白色固体,38.4mg,收率60％, 1H NMR(500MHz,MeOD)δ9.58(d,J＝1.7Hz,1H),9.14(d,J＝8.3Hz,1H),9.04–8.93(m,1H),8.88–8.83(m,1H),8.56(d,J＝5.3Hz,1H),8.29(s,1H),8.09–7.99(m,3H),7.66(d,J＝9.1Hz,2H),7.52–7.37(m,5H),7.35–7.29(m,2H),4.68–4.29(m,8H),3.97–3.72(m,4H),3.68–3.51(m,2H),2.57–2.41(m,5H),2.39–2.24(m,5H),2.24–2.18(m,2H),2.11–2.01(m,2H),1.64–1.63(m,5H),1.02(s,9H).HRMS(ESI)m/z:计算值C 56H 66N 11O 6S +[M+H] +,1020.4913；实测值,1020.4922.
实施例85：(2S,4R)-1-((S)-3,3-二甲基-2-(7-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-7-氧代庚酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS074030)的制备
Figure PCTCN2019077535-appb-000142
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS074014制备得到化合物(SIAIS074030)，为白色固体,40.2mg,收率62％, 1H NMR(500MHz,MeOD)δ9.60(s,1H),9.16(d,J＝8.2Hz,1H),9.07–8.96(m,1H),8.87(d,J＝5.3Hz,1H),8.57(d,J＝5.3Hz,1H),8.30(s,1H),8.09–8.02(m,3H),7.67(d,J＝7.4Hz,2H),7.56–7.38(m,5H),7.34–7.29(m,2H),4.74–4.19(m,8H),4.01–3.73(m,4H),3.69–3.49(m,2H),2.54–2.36(m,5H),2.36–2.15(m,6H),2.13–1.98(m,2H),1.72–1.54(m,4H),1.46–1.31(m,4H),1.02(s,9H).HRMS(ESI)m/z:计算值C 57H 68N 11O 6S +[M+H] +,1034.5069；实测值,1034.5069.
实施例86：(2S,4R)-1-((S)-3,3-二甲基-2-(8-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-8-氧代辛酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS074031)的制备
Figure PCTCN2019077535-appb-000143
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS074015制备得到化合物(SIAIS074031)，为白色固体,33.3mg,收率61％, 1H NMR(500MHz,MeOD)δ9.59(s,1H),9.14(d,J＝8.2Hz,1H),9.05–8.94(m,1H),8.86(d,J＝5.3Hz,1H),8.55(d,6.9Hz,1H),8.29(s,1H),8.13–7.95(m,3H),7.67(d,J＝8.3Hz,2H),7.59–7.37(m,5H),7.35–7.29(m,2H),4.79–4.21(m,8H),3.99–3.70(m,4H),3.71–3.47(m,2H),2.53–2.36(m,5H),2.36–2.14(m,6H),2.14–1.96(m,2H),1.61(s,4H),1.43–1.30(m,6H),1.03(s,9H).HRMS(ESI)m/z:计算值C 58H 70N 11O 6S +[M+H] +,1048.5226；实测值,1048.5218.
实施例87：(2S,4R)-1-((S)-3,3-二甲基-2-(9-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-9-氧代壬酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS074032)的制备
Figure PCTCN2019077535-appb-000144
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS074016制备得到化合物(SIAIS074032)，为白色固体,32.1mg,收率58％, 1H NMR(500MHz,MeOD)δ9.62(s,1H),9.20(d,J＝8.2Hz,1H),9.06–8.98(m,1H),8.89(d,J＝5.3Hz,1H),8.58(d,J＝5.3Hz,1H),8.30(s,1H),8.09–8.04(m,3H),7.67(d,J＝8.3Hz,2H),7.60–7.39(m,5H),7.34–7.29(m,2H),4.79–4.25(m,8H),4.10–3.74(m,4H),3.44–3.39(m,2H),2.55–2.14(m,11H),2.14–1.95(m,2H),1.60(s,4H),1.35–1.30(m,8H),1.03(s,9H).HRMS(ESI)m/z:计算值C 59H 72N 11O 6S +[M+H] +,1062.5382；实测值,1062.5299.
实施例88：(2S,4R)-1-((S)-3,3-二甲基-2-(10-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-10-氧代癸酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS074033)的制备
Figure PCTCN2019077535-appb-000145
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS074019制备得到化合物(SIAIS074033)，为白色固体,33.6mg,收率60％, 1H NMR(500MHz,MeOD)δ9.57(s,1H),9.11(d,J＝8.1Hz,1H),8.99–8.93(m,1H),8.85(d,J＝5.4Hz,1H),8.56(d,J＝7.7Hz,1H),8.29(s,1H),8.09(d,J＝8.2Hz,2H),7.99(dd,J＝8.1,5.5Hz,1H),7.67(d,J＝8.3Hz,2H),7.53–7.38(m,5H),7.35–7.29(m,2H),4.70–4.30(m,8H),3.99–3.74(m,4H),3.71–3.52(m,2H),2.53–2.36(m,5H),2.35–2.17(m,6H),2.12–1.99(m,2H),1.60(s,4H),1.34–1.30(m,10H),1.03(s,9H).HRMS(ESI)m/z:计算值C 60H 74N 11O 6S +[M+H] +,1076.5539；实测值,1076.5445.
实施例89：(2S,4R)-1-((S)-3,3-二甲基-2-(11-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-11-氧代十一烷酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(SIAIS074034)的制备
Figure PCTCN2019077535-appb-000146
根据方案19所述通用方法，在本领域可理解的适当条件下，采用相应的底物去甲基伊马替尼和HO 2C-LIN-ULM中间体SIAIS074020制备得到化合物(SIAIS074034)，为白色固体,32.4mg,收率57％, 1H NMR(500MHz,MeOD)δ9.57(s,1H),9.11(d,J＝8.3Hz,1H),8.97(d,J＝6.7Hz,1H),8.85(d,J＝5.0Hz,1H),8.56(d,J＝4.8Hz,1H),8.29(s,1H),8.08(d,J＝8.2Hz,2H),7.99(dd,J＝8.0,5.5Hz,1H),7.67(d,J＝8.2Hz,2H),7.53–7.37(m,5H),7.37–7.27(m,2H),4.69–4.28(m,8H),4.02–3.76(m,4H),3.63–3.61(m,2H),2.52–2.37(m,5H),2.34–2.17(m,6H),2.13–1.99(m,2H),1.60(s,4H),1.32–1.30(m,12H),1.03(s,9H).HRMS(ESI)m/z:计算值C 61H 76N 11O 6S +[M+H] +,1090.5695；实测值,1090.5593.
比较实施例1：N-(2-氯-6-甲基苯基)-2-((6-(4-((S)-3-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-羰基)-2,2-二甲基-5-氧代-11,14,17-三氧杂-4-氮杂二十三烷-23-基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS180138；Dasa-6-2-2-6-VHL)的制备
Figure PCTCN2019077535-appb-000147
根据方案20，将达沙替尼衍生物SIAIS151055(0.45mmol,1equiv)加入25mL的蛋形瓶中，随后加入无水DMF(2mL),N,N-二异丙基乙胺(2.25mmol,5equiv)和NaI(0.90mmol,2equiv)，室温搅拌下加入相应的氯代底物(SIAIS180114)(0.90mmol,2equiv)，加毕缓慢升温至80℃，并搅拌过夜。LC-MS检测反应结束后，反应液过滤，滤液经HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)，旋去乙腈，冻干后得到化合物(SIAIS180138；Dasa-6-2-2-6-VHL)，为白色固体,2.7mg，收率9％。 1H NMR(500MHz,MeOD)δ9.93(s,1H),8.26(s,1H),7.57(d,J＝8.2Hz,2H),7.52(d,J＝8.2Hz,2H),7.37(dd,J＝7.1,2.2Hz,1H),7.30–7.22(m,2H),6.52(s,1H),4.63(s,1H),4.60–4.53(m,2H),4.52–4.48(m,1H),4.42–4.39(m,1H),3.91(d,J＝11.0Hz,1H),3.80(dd,J＝11.0,3.9Hz,1H),3.76(d,J＝11.5Hz,2H),3.68–3.60(m,6H),3.59–3.54(m,4H),3.51–3.46(m,4H),3.34–3.31(m,2H),3.30–3.18(m,4H),2.65(s,3H),2.60(s,3H),2.36–2.19(m,3H),2.32(s,3H),2.10–2.04(m,1H),1.88–1.80(m,2H),1.69–1.54(m,6H),1.47–1.37(m,6H),1.04(s,9H).HRMS(ESI)m/z:计算值C 58H 81ClN 11O 8S 2 +[M+H] +,1158.5394；实测值,1158.3389.
比较实施例2：N-(2-氯-6-甲基苯基)-2-((6-(4-(6-(2-(2-((6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-6-氧代己基)氧基)乙氧基)乙氧基)己基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS171119；Dasa-6-2-2-6-CRBN)的制备
Figure PCTCN2019077535-appb-000148
根据方案21，将达沙替尼衍生物SIAIS151055(9.7mg,0.022mmol)加入一个25mL的蛋形瓶中，随后加入无水DMF(1.5mL),N,N-二异丙基乙胺(18.8mg,0.15mmol)，室温搅拌下加入碘代底物(SIAIS171116)(10mg,0.015mmol)，加毕缓慢升温至80℃，并搅拌过夜。LC-MS检测反应结束后，反应液过滤，滤液经HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)，旋去乙腈，冻干后得最终化合物(SIAIS171119；Dasa-6-2-2-6-CRBN)，为黄色固体,2mg,收率14％. 1H NMR(500MHz,MeOD)δ8.64(d,J＝10.2Hz,1H),8.23(s,1H),7.77(dd,J＝8.4,7.4Hz,1H),7.57(d,J＝7.0Hz,1H),7.40–7.33(m,1H),7.30–7.20(m,2H),6.47(s,1H),5.13(dd,J＝12.6,5.5Hz,1H),3.74(d,J＝11.6Hz,2H),3.66–3.44(m,14H),3.31–3.29(m,4H),3.23–3.19(m,2H),2.92–2.83(m,1H),2.78–2.68(m,2H),2.62(s,3H),2.52(t,J＝7.4Hz,2H),2.31(s,3H),2.19–2.12(m,1H),1.90–1.73(m,4H),1.70–1.62(m,4H),1.52–1.36(m,6H).HRMS(ESI)m/z:计算值C 49H 62ClN 10O 9S +[M+H] +,1001.4105；实测值,1001.4128.
生物活性检测实验
实验试剂
Figure PCTCN2019077535-appb-000149
Figure PCTCN2019077535-appb-000150
实验细胞
BCR-ABL阳性细胞-K562细胞(人慢性髓系白血病细胞)购自美国模式培养物保藏所(American Type Culture Collection(ATCC))；
BCR-ABL阴性细胞：
U937细胞人单核细胞白血病细胞系购自美国模式培养物保藏所(American Type Culture Collection(ATCC))；
HEK293细胞(人胚肾细胞)购自美国模式培养物保藏所(American Type Culture Collection(ATCC))。
实验方法
细胞培养
使用的细胞培养在含5％CO 2的37℃培养箱中。细胞完全培养基为RPMI l640培养基中加入10％胎牛血清，青霉素、链霉素终浓度为100U/mL。所有细胞实验前用支原体检测试剂盒检测为支原体阴性。
一.PROTAD化合物肿瘤细胞半数抑制浓度(IC 50)测定
细胞以2000-5000个细胞/每孔的数量接种在含有100μL RPMI1640完全培养基中。将待测化学物从最高浓度10μM进行3倍梯度稀释，从高到低共设置10个浓度，然后取稀释好的本公开实施例PROTAD化合物100μL加入接种好的100μL细胞中，药物处理细 胞48小时后，按照CCK-8的试剂操作说明书进行细胞活性测定，阴性对照为DMSO，阳性对照为商品化的抑制剂。CCK-8处理2小时后，使用酶标仪测定O.D.450的值。本公开PROTAD化合物对细胞的生长抑制率计算公式为细胞抑制率％＝(对照组O.D.值-实验组O.D.值)/对照组O.D.值*100％，进一步通过Prism Graphpad软件进行绘制抑制曲线和统计本公开化合物的IC 50。
结果显示：本公开中的PROTAD系列化合物可以显著抑制BCR-ABL阳性K562细胞的增殖(如表2所示)，对其他非BCR-ABL驱动的细胞株，如U937细胞或HEK293细胞没有明显增殖抑制作用，说明本公开PROTAD化合物具有显著的增殖抑制活性和很好的选择性。所有的实施例化合物的IC 50都低于100nM。值得一提的是抑制剂Dasatinib的IC 50为0.4nM，我们设计合成的PROTAD化合物的IC 50最低达到了1.47nM，对肿瘤细胞生长抑制的效果达到了与母本药物Dasatinib极为接近的水平。
表2：CCK-8测定本公开实施例化合物对于肿瘤细胞增殖抑制活性的IC 50值。
Figure PCTCN2019077535-appb-000151
Figure PCTCN2019077535-appb-000152
注：NA：表示最高浓度10μM处理时未见有明显的增殖抑制作用。
二.PROTAD化合物对靶蛋白半数降解浓度(DC 50)测定
蛋白质免疫印迹Western-blot测定
(1)细胞种板：K562细胞加入24孔板中，细胞密度3×10 5/mL，总体积为1.5mL；本公开实施例PROTAD系列化合物和比较实施例化合物(Dasa-6-2-2-6-VHL,Dasa-6-2-2-6-CRBN)分别设置1nM、10nM、100nM、1μM、10μM 5个浓度梯度，同时设置加入DMSO和商品化母本抑制剂组(Dasatinib(达沙替尼)、(Bosutinib(伯舒替尼))、(Imatinib(伊马替尼)))作为阴性对照和阳性对照，药物处理16h后收集细胞于1.5mL EP管中，3000rpm离心3分钟，收集细胞沉淀后加入30μL PBS悬细胞后再加入30ul的2×SDS裂解液，金属浴100℃，加热5分钟，然后冰上放置5分钟，10000rpm离心5分钟，吸取上清为提取的细胞总蛋白。用Bradford法测定蛋白浓度，每个样品等浓度后，加入溴酚蓝作为上样指示剂；
(2)电泳：在Bio Rad电泳仪中开始时，电压80V电泳，当染料进入分离胶后，电压调成120V；
(3)转膜：裁剪相应大小的滤纸和硝酸纤维素膜(NC膜)；滤纸和NC膜均在转移电泳缓冲液中浸透。按“滤纸-凝胶-NC膜-滤纸”的顺序装置好放入电泳槽中转膜；恒压100V，1.5h；之后抗体孵育和显影等操作按照Cell Signaling Technology的抗体说明书进行。
结果如表3所示：采用Western-blot检测了本公开PROTAD系列化合物处理后的K562细胞16小时后的BCR-ABL以及c-ABL蛋白的表达，免疫蛋白印记实验表明：(1)本公开的PROTAD系列化合物(即所述降解剂)能够诱导BCR-ABL和c-ABL蛋白的降解, 并且这种降解作用呈剂量依赖性。而商品化母本抑制剂仅是抑制了BCR-ABL的酪氨酸激酶的活性，而不像本公开的降解剂那样可以将靶蛋白BCR-ABL降解。(2)本公开设计合成的Dasa-Lin-VHL体系化合物是首次报道可以有效降解BCR-ABL以及c-ABL蛋白，而比较实施例1的Dasa-6-2-2-6-VHL化合物并不能降解BCR-ABL蛋白；(3)本公开设计合成的Dasa-Lin-CRBN体系化合物降解活性优于报道的比较实施例化合物Dasa-6-2-2-6-CRBN。所有原始blotting结果见图1。
表3本公开实施例PROTAD化合物对BCR-ABL蛋白和c-ABL蛋白的降解结果.
化合物名称 BCR-ABL(DC 50,nM) c-ABL(DC 50,nM)
Dasatinib(达沙替尼) NA NA
Bosutinib(伯舒替尼) NA NA
Imatinib(伊马替尼) NA NA
SIAIS171114 10-100 10-100
SIAIS151063 1-10 1-10
SIAIS151064 1-10 10-100
SIAIS151067 1-10 10-100
SIAIS151068 1-10 10-100
SIAIS151069 1-10 10-100
SIAIS151072 <1 1-10
SIAIS172150 10-100 10-100
SIAIS184128 1-10 1-10
SIAIS151070 1-10 1-10
SIAIS151071 <1 1-10
SIAIS151075 1-10 1-10
SIAIS151181 1-10 1-10
SIAIS184053 10-100 10-100
SIAIS164108 10-100 10-100
SIAIS164109 100-1000 100-1000
SIAIS164110 10-100 10-100
SIAIS184052 1-10 10-100
SIAIS151078 100-1000 >1000
SIAIS151174 100-1000 100-1000
SIAIS151175 10-100 100-1000
SIAIS151176 10-100 100-1000
SIAIS151177 1-10 10-100
SIAIS151178 1-10 10-100
SIAIS151179 10-100 100-1000
SIAIS151180 1-10 10-100
SIAIS151158 10-100 10-100
SIAIS151159 10-100 10-100
SIAIS151160 10-100 10-100
SIAIS151161 100-1000 100-1000
SIAIS151164 10-100 10-100
SIAIS151162 10-100 10-100
SIAIS151163 10-100 10-100
SIAIS151166 10-100 10-100
SIAIS151167 10-100 10-100
SIAIS164136 1-10 1-10
SIAIS164105 10-100 10-100
SIAIS1197039 1000-1000 1000-1000
SIAIS074031 100-1000 100-1000
注：NA：表示最高浓度10μM处理时未见明显降解。
三.PROTAD化合物SIAIS151178对BCR-ABL耐药突变体的降解活性
临床Ph +CML患者在使用TKI抑制剂时常面临的问题是获得性耐药，BCR-ABL激酶区点突变是导致耐药的主要原因。基于此，我们研究本公开实施例PROTAD化合物对临床BCR-ABLTKI耐药相关的BCR-ABL突变体的降解情况。我们先以Dasa-Lin-VHL体系化合物SIAIS151178为代表性化合物，检测其对BCR-ABL系列突变体的降解活性。
(1)BCR-ABL突变体稳转株建立：将BCR-ABL目的片段克隆到逆转录病毒载体PMIGR1中，进而利用
Figure PCTCN2019077535-appb-000153
Site-Directed Mutagenesis Kit获得PMIGR1-BCR-ABL-G250E/E255K/V299L/F317L/F317V/T315I/T315A等突变体形式，利用逆转录病毒感染体系在U937细胞上建立稳定表达BCR-ABL野生型及突变体的细胞株
(2)细胞种板：将建立好的上述细胞加入24孔板中，细胞密度3×10 5/mL，总体积为1.5mL；本公开实施例PROTAD化合物SIAIS151178分别设置10nM、100nM、1μM、10μM等浓度梯度，同时设置小分子抑制剂处理组Dasatinib(达沙替尼)作为对照，药物的处理24h后收集细胞于1.5mL EP管中，3000rpm离心3分钟，收集细胞沉淀后加入30μL PBS悬细胞后再加入30ul的2×SDS裂解液，金属浴100℃，收集的样品接下来完成western blotting检测本公开化合物SIAIS151178对BCR-ABL耐药突变的影响
我们使用U937细胞外源检测Dasa-Lin-VHL体系PROTAD小分子SIAIS151178对各种临床耐药相关的BCR-ABL突变体的降解情况(图2)，结果表明本公开设计合成的Dasa-Lin-VHL体系化合物SIAIS151178可剂量依赖性显著降解BCR-ABL-G250E/V299L/F317L/F317V等突变体形式。
四.PROTAD化合物对BCR-ABL+K562细胞移植瘤小鼠模型的影响
除在体外使用K562细胞株对本公开PROTAD系列化合物进行了初步筛选外，我们同样在体内水平利用K562细胞移植瘤模型对本公开PROTAD化合物抑制肿瘤的活性进行研究。我们同样先以Dasa-Lin-VHL体系化合物SIAIS151178为代表性化合物开展体内抗BCR-ABL阳性白血病活性研究。
(1)K562-Luc细胞建立：将荧光素酶luciferase目的片段克隆到慢病毒载体Plenti-IRES-ZSGREEN载体中，利用慢病毒感染体系在K562细胞上建立稳定表达报告基因luciferase的K562-Luc细胞株。
(2)BCR-ABL+K562细胞小鼠移植瘤模型：将5*106K562-Luc细胞接种于免疫缺陷NOD-SCID小鼠皮下，2周后待小鼠肿瘤体积接近200mm 3，将小鼠随机分组,实验设计分为5组。Vehicle(溶媒)处理组，本公开设计合成的Dasa-Lin-VHL体系化合物SIAIS151178三个剂量处理组(5,15,45mg/kg)，抑制剂Dasatinib处理组，给药2周，期间定期测量小鼠荷瘤大小及体重改变。给药2周后同时利用小鼠活体成像观察小鼠荷瘤情况。随后停止给药，观察肿瘤复发情况。
体内实验(见图3)表明Dasa-Lin-VHL体系PROTAD小分子SIAIS151178可剂量依赖性的抑制K562细胞移植瘤的生长，且15mg/kg剂量浓度能够引起肿瘤消退。给药期间观察SIAIS151178对小鼠体重没有明显影响，也未发现明显的毒副作用，说明该PROTAD小分子体内呈现出很好的抗肿瘤活性和安全性。
五.PROTAD化合物体内水平对BCR-ABL蛋白的降解活性
我们进一步对本公开PROTAD化合物是否能在体内水平引起BCR-ABL蛋白降解进行研究。我们仍然以Dasa-Lin-VHL体系化合物SIAIS151178为代表性化合物，发现SIAIS151178在小鼠水平同样可以剂量依赖性降解BCR-ABL和C-ABL蛋白，并显著抑制BCR-ABL信号通路活性(结果见图4)。
综上所述，使用K562细胞株对本公开PROTAD系列化合物进行了初步筛选。结果显示：(1)本公开PROTAD系列化合物可以显著抑制BCR-ABL阳性细胞株的增殖，对非BCR-ABL驱动的细胞株无明显抑制活性，呈现很好的增殖抑制活性和选择性。(2)本公开设计合成的Dasa-Lin-VHL体系化合物是首次报道，可以有效降解BCR-ABL以及c-ABL蛋白，而比较实施例1的Dasa-6-2-2-6-VHL化合物并不能降解BCR-ABL蛋白；并且以本公开设计合成的Dasa-Lin-VHL体系化合物SIAIS151178为例，SIAIS151178体外细胞水平可以降解野生型BCR-ABL以及一些临床相关的突变体蛋白，体内小鼠移植瘤模型上可以降解BCR-ABL，抑制BCR-ABL信号通路，并显著抑制肿瘤生长。(3)本公开设计合成的Dasa-Lin-CRBN体系化合物降解BCR-ABL活性优于报道的比较实施例化合物Dasa-6-2-2-6-CRBN。(4)以本公开设计合成的Dasa-Lin-VHL体系化合物SIAIS151178为例，SIAIS151178还可以降解其他酪氨酸激酶受体，如SRC蛋白激酶，KIT，以及PDGFR等，对于这些靶点相关的肿瘤的治疗也有潜在价值。
虽然BCR-ABL抑制剂的临床应用极大改善了Ph +CML患者的预后，但依然面临两个主要问题：病人需要长期服药，带来很大的经济负担的同时也面临获得性耐药的问题。TKI虽然可以诱导CML白血病细胞凋亡，但并不能杀伤CML白血病起始细胞，研究表明BCR-ABL除发挥激酶功能外，还可以作为scaffold protein募集蛋白复合物发挥支架蛋白功能，由此knock-down BCR-ABL蛋白具有治疗学意义。理论上，本公开PROTAD化合物可以降解BCR-ABL蛋白，从某种程度上可能清除白血病干细胞，延缓耐药的发生，同时也可以降解与耐药相关的突变体形式，对解决临床存在的TKI停药复发和耐药性问题有着重大的意义。此项研究对费城染色体阳性的白血病以及其它实体瘤患者提供了一种新的治疗策略。
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Claims (37)

  1. 一种式(I)化合物：
    Figure PCTCN2019077535-appb-100001
    其中BCR-ABL-TKIs通过基团A共价连接LIN，以及ULM共价连接LIN；
    其中BCR-ABL-TKIs是BCR-ABL酪氨酸激酶抑制剂或者其具有相同功能的类似物；
    LIN是连接基团，其是直链或支链的亚烷基链，其中所述直链或支链的亚烷基链可选地被一或多个-O-、-CONH-、-NHCO-、-NH-、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，其中所述直链或支链的亚烷基链可选地被一或多个取代基取代；
    ULM是具有泛素化功能的VHL或CRBN蛋白酶小分子配体；以及
    基团A为-CO-；
    或其盐、对映异构体、立体异构体、溶剂化物、多晶型物。
  2. 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述BCR-ABL-TKIs表示由以下通式所表示的化合物部分：
    Figure PCTCN2019077535-appb-100002
    Figure PCTCN2019077535-appb-100003
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12分别独立地表示烷基或H。
  3. 如权利要求2所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12分别独立地表示直链或支链C 1-10烷基或H。
  4. 如权利要求1-3中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述ULM表示以下式(II)结构：
    Figure PCTCN2019077535-appb-100004
    其中X表示-CH 2-或-CO-，Y表示-CH 2-、-NH-或-O-，以及Z 1表示-CO-或Z 1不存在。
  5. 如权利要求1-3中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述ULM表示以下式(III)结构：
    Figure PCTCN2019077535-appb-100005
    其中Z 2表示-CO-或不存在。
  6. 如权利要求4所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(IV)化合物：
    Figure PCTCN2019077535-appb-100006
    Figure PCTCN2019077535-appb-100007
    其中，基团A、LIN、X、Y、Z 1、R 1、R 2、R 3、R 4如在权利要求4中所定义。
  7. 如权利要求5所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(V)化合物：
    Figure PCTCN2019077535-appb-100008
    其中，基团A、LIN、Z 2、R 1、R 2、R 3、R 4如在权利要求5中所定义。
  8. 如权利要求4所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(VI)化合物：
    Figure PCTCN2019077535-appb-100009
    其中，基团A、LIN、X、Y、Z 1、R 5、R 6、R 7、R 8如在权利要求4中所定义。
  9. 如权利要求5所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(VII)化合物：
    Figure PCTCN2019077535-appb-100010
    其中，基团A、LIN、Z 2、R 5、R 6、R 7、R 8如在权利要求5中所定义。
  10. 如权利要求4所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(VIII)化合物：
    Figure PCTCN2019077535-appb-100011
    其中，基团A、LIN、X、Y、Z 1、R 9、R 10、R 11、R 12如在权利要求4中所定义.
  11. 如权利要求5所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(IX)化合物：
    Figure PCTCN2019077535-appb-100012
    其中，基团A、LIN、Z 2、R 9、R 10、R 11、R 12如在权利要求5中所定义。
  12. 如权利要求1至11中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：直链或支链的C 1-C 30亚烷基链、-(CH 2) n1-(O(CH 2) n2) m1-、-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-、-(CR 13R 14) n1-(O(CR 15R 16) n2) m1-、-(CR 17R 18) n1-(O(CR 19R 20) n2) m1-O-(CR 21R 22) n3-、-(CH 2) n1-(CONH-(CH 2) n2) m1-、-(CH 2) n1-(CONH-(CH 2) n2) m1-O-(CH 2) n3-、-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-CONH-(CH 2) n4-(O(CH 2) n5) m2-O-(CH 2) n6-、-(CR 23R 24) n1-(O(CR 25R 26) n2) m1-O-(CR 27R 28) n3-CONH-(CR 29R 30) n4-(O(CR 31R 32) n5) m2-O-(CR 33R 34) n6-、-(CR 35R 36) n1-CONH-(O(CR 37R 38) n2) m1-、-(CH 2) n1-NHCO-(CH 2) n2-、-(CH 2) n1-(NHCO-(CH 2) n2) m1-、-(CH 2) n1-(NHCO-(CH 2) n2) m1-O-(CH 2) n3-、由一或多个亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次的直链或支链的亚烷基链、或其碳链被一或多个亚芳基或亚杂环基或亚杂芳基或它们的任意组合中断一或多次的-(CH 2) n1-(O(CH 2) n2) m1-；
    R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30、R 31、R 32、R 33、R 34、R 35、R 36、R 37、R 38分别独立地表示H、直链或支链 的C 1-C 10烷基或C 3-C 10环烷基，其中在相同的所述LIN中时，R 13、R 14、R 15、R 16，R 17、R 18、R 19、R 20、R 21、R 22，R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30、R 31、R 32、R 33、R 34，或R 35、R 36、R 37、R 38不同时为H；
    n1、n2、n3、n4、n5、n6、m1、m2分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数。
  13. 如权利要求12所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：
    -CH 2O(CH 2) 2OCH 2-；
    -CH 2O(CH 2) 2O(CH 2) 2-；
    -(CH 2) 3O(CH 2) 2-；
    -(CH 2) 3O(CH 2) 2O(CH 2) 2-；
    -(CH 2) 3O(CH 2) 3-；
    -(CH 2) 2O(CH 2) 2-；
    -(CH 2) 2O(CH 2) 2OCH 2-；
    -(CH 2) 2O(CH 2) 2O(CH 2) 2-；
    -(CH 2) 2O(CH 2) 2O(CH 2) 3-；
    -(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2-；
    -(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 3-；
    -(CH 2) 5O(CH 2) 2O(CH 2) 2O(CH 2) 5-；
    -(CH 2) 5O(CH 2) 2O(CH 2) 2O(CH 2) 6-；
    -(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2-；
    -(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 3-；
    -(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2-；
    -(CH 2) 3O(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2-；或
    -(CH 2) 3O(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 2O(CH 2) 3-。
  14. 如权利要求12所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：
    -CH 2-；-(CH 2) 2-；-(CH 2) 3-；-(CH 2) 4-；-(CH 2) 5-；-(CH 2) 6-；-(CH 2) 7-；-(CH 2) 8-；-(CH 2) 9-；-(CH 2) 10-；-(CH 2) 11-；-(CH 2) 12-；-(CH 2) 13-；-(CH 2) 14-；-(CH 2) 15-；-(CH 2) 16-；-(CH 2) 17-；-(CH 2) 18-；-(CH 2) 19-；或-(CH 2) 20-。
  15. 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述取代基选自羟基、氨基、巯基和卤素。
  16. 如权利要求15所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN是由一或多个选自羟基、氨基、巯基、卤素或其组合的取代基取代的直链或支链的C 1-C 20亚烷基链。
  17. 如权利要求12所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：-(CH 2) n1-***基-(CH 2) n2-、-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-***基-(CH 2) n4-(O(CH 2) n5) m2-O-(CH 2) n6-、-(CH 2) n1-***基-(CH 2) n2-(O(CH 2) n3) m1-O-(CH 2) n4-或-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-***基-(CH 2) n4-；以及
    n1、n2、n3、n4、n5、n6、m1、m2分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数。
  18. 如权利要求17所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：
    Figure PCTCN2019077535-appb-100013
  19. 如权利要求12所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：
    -CH 2CONHCH 2-；-(CH 2) 2CONH(CH 2) 2-；-(CH 2) 3CONH(CH 2) 3-；
    -(CH 2) 3CONH(CH 2) 4-；-(CH 2) 4CONH(CH 2) 4-；-(CH 2) 5CONH(CH 2) 5-；
    -(CH 2) 6CONH(CH 2) 7-；-(CH 2) 6CONH(CH 2) 6-；-(CH 2) 7CONH(CH 2) 7-；
    -(CH 2) 8CONH(CH 2) 8-；-(CH 2) 9CONH(CH 2) 9-；-(CH 2) 10CONH(CH 2) 10-；或
    -(CH 2) 2CONH(CH 2) 2-O-(CH 2) 2-。
  20. 如权利要求12所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN是-(CH 2) n1-NHCO-(CH 2) n2-，其中n1、n2分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数。
  21. 如权利要求20所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN是-(CH 2) 4NHCO(CH 2) 8-。
  22. 如权利要求12所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN是-(CH 2) n1-CH＝CH-(CH 2) n2-，其中n1、n2分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数。
  23. 如权利要求12所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN是-(CH 2) n1-C≡C-(CH 2) n2-或-(CH 2) n1-C≡C-C≡C-(CH 2) n2-，其中n1、n2分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数。
  24. 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其选自：
    N-(2-氯-6-甲基苯基)-2-((6-(4-(6-(2-(2-((6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-6-氧代己基)氧基)乙氧基)乙氧基)己酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(6-(2-(2-((6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)己基)氧基)乙氧基)乙氧基)己酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-(3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)丙氧基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙氧基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)丙氧基)乙氧基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十五烷-15-酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(16-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)-4,7,10,13-四氧杂十六烷酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)-3,6,9,12-四氧杂十五烷-15-酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12,15-五氧杂十八烷-18-酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基乙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)戊酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)庚酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)己酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)辛酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(9-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)壬酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)辛酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-5-氧代戊酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-6-氧代己酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-7-氧代庚酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-8-氧代辛酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(4-((2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙基)氨基)-4-氧代丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(4-((2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙基)氨基)-4-氧代丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3-氧代丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-4-氧代丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-5-氧代戊酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-6-氧代己酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-7-氧代庚酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-8-氧代辛酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(9-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-9-氧代壬酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(10-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-10-氧代癸酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(11-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-11-氧代十一烷酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)己酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)戊酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)庚酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-((S)-3-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-羰基)-2,2-二甲基-5-氧代-11,14,17-三氧杂-4-氮杂二十三烷-23-酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-((S)-3-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-羰基)-2,2-二甲基-11,14,17-三氧杂-4-氮杂二十三烷-23-酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(2-(2-(2-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-2-氧代乙氧基)乙氧基)乙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-(2-(3-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-3-氧代丙氧基)乙氧基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-((S)-15-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-羰基)-16,16-二甲基-13-氧代-4,7,10-三氧杂-14-十七烷酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-((S)-18-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-羰基)-19,19-二甲基-16-氧代-4,7,10,13-四氧杂-17-氮杂二十烷酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-((S)-21-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-羰基)-22,22-二甲基-19-氧代-4,7,10,13,16-五氧杂-20-氮杂二十三烷酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(2-(2-(2-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-(2-(3-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)丙氧基)乙氧基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-((S)-15-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-羰基)-16,16-二甲基-4,7,10-三氧杂-14-十七烷酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-((S)-18-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-羰基)-19,19-二甲基-4,7,10,13-四氧杂-17-氮杂二十烷酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(4-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-4-氧代丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(5-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-5-氧代戊酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(6-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-6-氧代己酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(6-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)己酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(7-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-7-氧代庚酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(7-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)庚酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(8-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-8-氧代辛酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(8-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)辛酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(9-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-9-氧代壬酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(9-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)壬酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(10-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-10-氧代癸酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(11-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-11-氧代十一烷酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(12-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-12-氧代十二烷酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(13-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-13-氧代十三烷酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(14-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-14-氧代十四烷酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(15-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-15-氧代十五烷酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(15-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)十五烷酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(16-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-16-氧代十六烷酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N1-(5-(4-(6-((5-((2-氯-6-甲基苯基)氨基甲酰基)噻唑-2-基)氨基)-2-甲基嘧啶-4-基)哌嗪-1-基)-5-氧代戊基)-N10-((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)癸二酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(4-(1-(4-(((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-4-氧代丁基)-1H-1,2,3-噻唑-4-基)丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    6-(2-(2-((6-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-6-氧代己基)氧基)乙氧基)乙氧基)-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己酰胺；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(6-(2-(2-((6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)己基)氧基)乙氧基)乙氧基)己酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙氧基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-(3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)丙氧基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)丙氧基)乙氧基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-(2-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)丙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十五烷-15-酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(16-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)-4,7,10,13-四氧杂十六烷酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)-3,6,9,12-四氧杂十五烷-15-酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12,15-五氧杂十八烷-18-酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基乙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)丁酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)戊酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)戊酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)辛酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(9-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)壬酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)辛酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-N-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙基)-4-氧代丁酰胺；
    3-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-3-氧代丙酰胺；
    4-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-4-氧代丁酰胺；
    5-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-5-氧代戊酰胺；
    6-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-6-氧代己酰胺；
    7-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-7-氧代庚酰胺；
    8-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-8-氧代辛酰胺；
    9-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-9-氧代壬酰胺；
    10-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-10-氧代癸酰胺；
    11-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-11-氧代十二烷酰胺；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)辛酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(9-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)壬酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)丁酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)戊酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)己酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)庚酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)辛酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(9-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)壬酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)辛酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(9-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)壬酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)丁酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(4-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丙氧基)丁酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(2-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丙氧基)乙氧基)乙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    (2S,4R)-1-((S)-2-(叔丁基)-22-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-4,22-二氧代-10,13,16-三氧杂-3-氮杂二十二烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(叔丁基)-22-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-22-氧代-10,13,16-三氧杂-3-氮杂二十二烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(2-(2-(2-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-2-氧代乙氧基)乙氧基)乙酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(3-(2-(3-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-3-氧代丙氧基)乙氧基)丙酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-((3-(2-(3-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-3-氧代丙氧基)乙氧基)丙基)氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(叔丁基)-16-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-4,16-二氧代-7,10,13-三氧杂-3-氮杂十六烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(叔丁基)-16-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-16-氧代-7,10,13-三氧杂-3-氮杂十六烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(叔丁基)-19-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-4,19-二氧代-7,10,13,16-四氧杂-3-氮杂十九烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(叔丁基)-22-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-4,22-二氧代-7,10,13,16,19-五氧杂-3-氮杂二十二烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(4-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-4-氧代丁酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(5-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-5-氧代戊酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(6-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-6-氧代己酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-((6-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-6-氧代己基)氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(7-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-7-氧代庚酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-((7-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-7-氧代庚基)氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(8-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-8-氧代辛酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-((8-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-8-氧代辛基)氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(9-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-9-氧代壬酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(10-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-10-氧代癸酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(11-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-11-氧代十一烷酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-((11-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-11-氧代十一烷基)氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(14-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-14-氧代十四烷酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(16-(4-(3-((3-氰基-4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基喹啉-7-基)氧基)丙基)哌嗪-1-基)-16-氧代十六烷酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    4-((4-(6-(2-(2-((6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-6-氧代己基)氧基)乙氧基)乙氧基)己酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(6-(2-(2-((6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)己基)氧基)乙氧基)乙氧基)己酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十五烷-15-酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12,15-五氧杂十八烷-18-酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(3-(3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)丙氧基)丙酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(3-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)丙氧基)乙氧基)丙酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(3-(2-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)丙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基乙酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)辛酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)戊酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)己酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)庚酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)辛酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(9-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)壬酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-4-氧代丁酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-5-氧代戊酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-6-氧代己酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-7-氧代庚酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-8-氧代辛酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(9-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-9-氧代壬酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(10-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-10-氧代癸酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    (2S,4R)-1-((S)-2-(叔丁基)-22-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-4,22-二氧代-10,13,16-三氧杂-3-氮杂二十二烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(叔丁基)-22-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-22-氧代-10,13,16-三氧杂-3-氮杂二十二烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-3,3-二甲基-2-(2-(2-(2-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-2-氧代乙氧基)乙氧基)乙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-3,3-二甲基-2-(3-(2-(3-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-3-氧代丙氧基)乙氧基)丙酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-3,3-二甲基-2-((3-(2-(3-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-3-氧代丙氧基)乙氧基)丙基)氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(叔丁基)-16-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-4,16-二氧代-7,10,13-三氧杂-3-氮杂十六烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(叔丁基)-19-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-4,19-二氧代-7,10,13,16-四氧杂-3-氮杂十九烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(叔丁基)-22-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-4,22-二氧代-7,10,13,16,19-五氧杂-3-氮杂二十二烷酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-3,3-二甲基-2-(4-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-4-氧代丁酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-3,3-二甲基-2-(5-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-5-氧代戊酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-3,3-二甲基-2-(6-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-6-氧代己酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-3,3-二甲基-2-(7-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-7-氧代庚酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-3,3-二甲基-2-(8-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-8-氧代辛酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-3,3-二甲基-2-(9-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-9-氧代壬酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-3,3-二甲基-2-(10-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-10-氧代癸酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-3,3-二甲基-2-(11-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-11-氧代十一烷酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-3,3-二甲基-2-(14-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-14-氧代十四烷酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-3,3-二甲基-2-(16-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-16-氧代十六烷酰氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-3,3-二甲基-2-((7-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-7-氧代庚基)氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-3,3-二甲基-2-((8-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-8-氧代辛基)氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；和
    (2S,4R)-1-((S)-3,3-二甲基-2-((9-(4-(4-((4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酰基)苄基)哌嗪-1-基)-9-氧代壬基)氨基)丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺。
  25. 一种医药组合物，其包含如权利要求1至24中任一项所述的式(I)化合物或其医药学上可接受的盐，及至少一种医药学上可接受的载体。
  26. 如权利要求25所述的医药组合物，进一步包括至少一种额外的治疗或预防癌症的药物。
  27. 如权利要求1至24中任一项所述的式(I)化合物，或其医药学上可接受的盐，其是用作药剂。
  28. 如权利要求1至24中任一项所述的式(I)化合物，或其医药学上可接受的盐，其用于预防及/或治疗癌症。
  29. 如权利要求28所述的式(I)化合物，或其医药学上可接受的盐，其中所述癌症选自：Ph +慢性粒细胞白血病；Ph +急性淋巴细胞性白血病；PDGFR基因重排相关的骨髓增生异常综合症/骨髓增殖性疾病；侵袭性***性肥大细胞增生症；高嗜酸性细胞增多综合症；慢性嗜酸性粒细胞白血病；隆突性皮肤纤维肉瘤；和Kit +胃肠道间质瘤。
  30. 如权利要求29所述的式(I)化合物，或其医药学上可接受的盐，其中所述Ph +慢性粒细胞白血病处于慢性期、加速期或急变期。
  31. 一种如权利要求1至24中任一项所述的式(I)化合物或其医药学上可接受的盐的用途，其用于制备用以预防及/或治疗癌症的药剂。
  32. 如权利要求31所述的用途，所述癌症选自由以下组成的群：Ph +慢性粒细胞白血病；Ph +急性淋巴细胞性白血病；PDGFR基因重排相关的骨髓增生异常综合症/骨髓增殖性疾病；侵袭性***性肥大细胞增生症；高嗜酸性细胞增多综合症；慢性嗜酸性粒细胞白血病；隆突性皮肤纤维肉瘤；和Kit +胃肠道间质瘤。
  33. 如权利要求32所述的用途，其中所述Ph +慢性粒细胞白血病处于慢性期、加速期或急变期。
  34. 治疗或预防癌症的方法，其包括向受试者施用治疗有效量的如权利要求2至24中任一项所述的式(I)化合物，或其医药学上可接受的盐，或如权利要求25或26所述的药物组合物。
  35. 如权利要求34所述的方法，其中所述癌症选自：Ph +慢性粒细胞白血病；Ph +急性淋巴细胞性白血病；PDGFR基因重排相关的骨髓增生异常综合症/骨髓增殖性疾病；侵袭性***性肥大细胞增生症；高嗜酸性细胞增多综合症；慢性嗜酸性粒细胞白血病；隆突性皮肤纤维肉瘤；和Kit +胃肠道间质瘤。
  36. 如权利要求35所述的方法，其中所述Ph +慢性粒细胞白血病处于慢性期、加速期或急变期。
  37. 如权利要求34-36中任一项所述的方法，其中通过至少一种选自鼻腔给药、吸入给药、局部给药、口服给药、口腔粘膜给药、直肠给药、胸膜腔给药、腹膜给药、***给药、肌内给药、皮下给药、经皮给药、硬膜外腔给药、鞘内给药和静脉给药的给药方式施用至所述受试者。
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