WO2021147889A1 - 一种异吲哚啉衍生物、其药物组合物及应用 - Google Patents
一种异吲哚啉衍生物、其药物组合物及应用 Download PDFInfo
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- WO2021147889A1 WO2021147889A1 PCT/CN2021/072840 CN2021072840W WO2021147889A1 WO 2021147889 A1 WO2021147889 A1 WO 2021147889A1 CN 2021072840 W CN2021072840 W CN 2021072840W WO 2021147889 A1 WO2021147889 A1 WO 2021147889A1
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- 0 ***(*)=*(*)*(*)=*(*)C(N1CCN(Cc2c(*)c(*)c(C*c3cccc4c3CN(C(CCC(N3)=O)C3=O)C4=O)cc2)CC1)=I Chemical compound ***(*)=*(*)*(*)=*(*)C(N1CCN(Cc2c(*)c(*)c(C*c3cccc4c3CN(C(CCC(N3)=O)C3=O)C4=O)cc2)CC1)=I 0.000 description 9
- DPBRCTOMQAMINP-UHFFFAOYSA-N COCC1CCCC1 Chemical compound COCC1CCCC1 DPBRCTOMQAMINP-UHFFFAOYSA-N 0.000 description 2
- CQJCJMZYPFBMSS-UHFFFAOYSA-N CC[BrH]CC1C(F)=CC(C(OC)=O)=CC1 Chemical compound CC[BrH]CC1C(F)=CC(C(OC)=O)=CC1 CQJCJMZYPFBMSS-UHFFFAOYSA-N 0.000 description 1
- LNNGTXUNNHMAEP-UHFFFAOYSA-N COC(C1=CCC(CN(CC2)CCN2C(C2(C3C2)F)=CC=C3C#N)C(F)=C1)O Chemical compound COC(C1=CCC(CN(CC2)CCN2C(C2(C3C2)F)=CC=C3C#N)C(F)=C1)O LNNGTXUNNHMAEP-UHFFFAOYSA-N 0.000 description 1
- QSSJZLPUHJDYKF-UHFFFAOYSA-N Cc(cc1)ccc1C(OC)=O Chemical compound Cc(cc1)ccc1C(OC)=O QSSJZLPUHJDYKF-UHFFFAOYSA-N 0.000 description 1
- SIPQJUFVJCDENO-YTTGMZPUSA-N N#Cc(cc1)c(C(F)(F)F)c(F)c1N1CCN(Cc2cc(F)c(COc3cccc4c3CN([C@](CCC(N3)=O)(C3=O)S)C4=O)cc2)CC1 Chemical compound N#Cc(cc1)c(C(F)(F)F)c(F)c1N1CCN(Cc2cc(F)c(COc3cccc4c3CN([C@](CCC(N3)=O)(C3=O)S)C4=O)cc2)CC1 SIPQJUFVJCDENO-YTTGMZPUSA-N 0.000 description 1
- LCUHGZOCWWGSLU-UHFFFAOYSA-N N#Cc(cc1)cc(F)c1N1CCN(Cc(ccc(CO)c2)c2F)CC1 Chemical compound N#Cc(cc1)cc(F)c1N1CCN(Cc(ccc(CO)c2)c2F)CC1 LCUHGZOCWWGSLU-UHFFFAOYSA-N 0.000 description 1
- YUJPDURNOYWJPN-SANMLTNESA-N N#Cc(cc1)cnc1N1CCN(Cc2cc(F)c(COc3cccc4c3CN([C@@H](CCC(N3)=O)C3=O)C4=O)cc2)CC1 Chemical compound N#Cc(cc1)cnc1N1CCN(Cc2cc(F)c(COc3cccc4c3CN([C@@H](CCC(N3)=O)C3=O)C4=O)cc2)CC1 YUJPDURNOYWJPN-SANMLTNESA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Definitions
- the invention relates to an isoindoline derivative, its intermediate, preparation method, pharmaceutical composition and application.
- Cereblon is a protein encoded by CRBN gene in humans.
- the cerebellar protein forms an E3 ubiquitin ligase complex with damage DNA binding protein 1 (DDB1), Cullin-4A (CUL4A) and the regulatory factor of cullin 1 (ROC1).
- DDB1 damage DNA binding protein 1
- CUL4A Cullin-4A
- ROC1 the regulatory factor of cullin 1
- This complex ubiquitinates many other proteins.
- DDB1 damage DNA binding protein 1
- CUL4A Cullin-4A
- ROC1 cullin 1
- lenalidomide immunomodulators can bind to cereblon protein and change the specificity of complexes that induce the ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3).
- IKZF1 and IKZF3 are key transcription factors in multiple myeloma.
- a single amino acid substitution of IKZF3 makes it resistant to degradation induced by lenalidomide immunomodulators and tolerant of cell growth inhibition induced by lenalidomide immunomodulators.
- IL2 production induced by lenalidomide immunomodulators in T cells is due to the depletion of IKZF1 and IKZF3.
- the invention provides an isoindoline derivative, a preparation method, a pharmaceutical composition and an application.
- the isoindoline derivatives of the present invention can specifically target and regulate a variety of tumor-related proteins by binding to Cereblon, thereby effectively treating cancer and other related diseases.
- the present invention provides an isoindoline derivative represented by general formula (I), and a pharmaceutically acceptable salt, solvate, crystal form, metabolite, prodrug or stereoisomer thereof:
- R 1 and R 2 are each independently selected from H, halogen, -CN, substituted or unsubstituted (C 1 -C 12 )alkyl, substituted or unsubstituted (C 1 -C 12 )alkoxy, -OH, provided that R 1 and R 2 are not H at the same time;
- X is selected from O or NH
- X 1 , X 2 , X 3 , X 4 , and X 5 are each independently selected from C or N;
- the substituents in the substituted (C 1 -C 12 )alkyl group and the substituted (C 1 -C 12 )alkoxy group are selected from one or more D, one or more halogen, or one or more ( C 3 -C 6 ) cycloalkyl;
- the carbon marked with * is the asymmetric center
- At least one of R 1 and R 2 is selected from halogen, -CN, substituted or unsubstituted (C 1 -C 12 )alkyl, substituted or unsubstituted (C 1 -C 12 )alkoxy, -OH;
- At least one of R 1 and R 2 is selected from F, Cl, Br, -CN, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 ;
- R 1 and R 2 are selected from F;
- X is selected from O
- X is selected from O, X 1 , X 2 , X 3 , X 4 , and X 5 are each independently selected from C;
- X is selected from O, and at least one of X 1 , X 2 , X 3 , X 4 , and X 5 is selected from N;
- X is selected from NH
- X is selected from NH, X 1 , X 2 , X 3 , X 4 , and X 5 are each independently selected from C;
- X is selected from NH, and at least one of X 1 , X 2 , X 3 , X 4 , and X 5 is selected from N;
- the R 4 is selected from -CN, -NO 2 , (C 1 -C 12 )alkyl substituted by one or more halogens, (C 1 -C 12 )alkoxy substituted by one or more halogens, (C 1 -C 12 ) Alkyl, or (C 1 -C 12 )alkoxy substituted with one or more D, wherein R 9 and R 10 are each independently selected from H, D, substituted or unsubstituted (C 1 -C 12 ) Alkyl; R 5 , R 6 , R 7 , and R 8 are each independently selected from H or halogen;
- R 4 is selected from -CN, (C 1 -C 12 )alkyl substituted with one or more halogens, (C 1 -C 12 )alkoxy substituted with one or more halogens, (C 1 -C 12 )alkyl substituted by one or more D, or (C 1 -C 12 )alkoxy substituted by one or more D, R 5 , R 6 , R 7 , R 8 each Independently selected from H;
- the R 5 is selected from -CN, -NO 2 , (C 1 -C 12 )alkyl substituted by one or more halogens, (C 1 -C 12 )alkoxy substituted by one or more halogens, (C 1 -C 12 ) Alkyl, or (C 1 -C 12 )alkoxy substituted with one or more D, wherein R 9 and R 10 are each independently selected from H, D, substituted or unsubstituted (C 1 -C 12 ) Alkyl; R 4 , R 6 , R 7 , and R 8 are each independently selected from H or halogen;
- R 5 is selected from -CN, (C 1 -C 12 )alkyl substituted with one or more halogens, (C 1 -C 12 )alkoxy substituted with one or more halogens, (C 1 -C 12 )alkyl substituted by one or more D, or (C 1 -C 12 )alkoxy substituted by one or more D, R 4 , R 6 , R 7 , R 8 and more Preferably, each is independently selected from H;
- the R 6 is selected from -CN, -NO 2 , (C 1 -C 12 )alkyl substituted by one or more halogens, (C 1 -C 12 )alkoxy substituted by one or more halogens, (C 1 -C 12 ) Alkyl, or (C 1 -C 12 )alkoxy substituted with one or more D, wherein R 9 and R 10 are each independently selected from H, D, substituted or unsubstituted (C 1 -C 12 ) Alkyl; R 4 , R 5 , R 7 , and R 8 are each independently selected from H or halogen;
- R 6 is selected from -CN, (C 1 -C 12 )alkyl substituted with one or more halogens, (C 1 -C 12 )alkoxy substituted with one or more halogens, (C 1 -C 12 )alkyl substituted by one or more D, or (C 1 -C 12 )alkoxy substituted by one or more D, R 4 , R 5 , R 7 , R 8 and more Preferably, each is independently selected from H;
- the R 7 is selected from -CN, -NO 2 , (C 1 -C 12 )alkyl substituted by one or more halogens, (C 1 -C 12 )alkoxy substituted by one or more halogens, (C 1 -C 12 ) Alkyl, or (C 1 -C 12 )alkoxy substituted with one or more D, wherein R 9 and R 10 are each independently selected from H, D, substituted or unsubstituted (C 1 -C 12 ) Alkyl; R 4 , R 5 , R 6 , and R 8 are each independently selected from H or halogen;
- R 7 is selected from -CN, (C 1 -C 12 )alkyl substituted with one or more halogens, (C 1 -C 12 )alkoxy substituted with one or more halogens, (C 1 -C 12 )alkyl substituted by one or more D, or (C 1 -C 12 )alkoxy substituted by one or more D, R 4 , R 5 , R 6 , R 8 and more Preferably, each is independently selected from H;
- the R 8 is selected from -CN, -NO 2 , (C 1 -C 12 )alkyl substituted by one or more halogens, (C 1 -C 12 )alkoxy substituted by one or more halogens, (C 1 -C 12 ) Alkyl, or (C 1 -C 12 )alkoxy substituted with one or more D, wherein R 9 and R 10 are each independently selected from H, D, substituted or unsubstituted (C 1 -C 12 ) Alkyl; R 4 , R 5 , R 6 and R 7 are each independently selected from H or halogen;
- R 8 is selected from -CN, (C 1 -C 12 )alkyl substituted with one or more halogens, (C 1 -C 12 )alkoxy substituted with one or more halogens, (C 1 -C 12 )alkyl substituted by one or more D, or (C 1 -C 12 )alkoxy substituted by one or more D, R 4 , R 5 , R 6 , R 7 and more Preferably, each is independently selected from H.
- the asymmetric center refers to achiral carbon, (S) configuration carbon, enriched (S) configuration carbon, (R) configuration carbon, enriched carbon The (R) configuration carbon or racemate.
- the halogen is F, Cl, Br, I.
- the substituted or unsubstituted (C 1 -C 12 )alkyl group is preferably selected from substituted or unsubstituted (C 1 -C 6 )alkyl groups, more preferably Is selected from substituted or unsubstituted (C 1 -C 4 )alkyl
- the substituted or unsubstituted (C 1 -C 4 )alkyl is best selected from substituted or unsubstituted methyl, substituted or unsubstituted Substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted tert-butyl;
- the substituent mentioned in "substituted or unsubstituted” is selected from one or more of D
- the substituted or unsubstituted (C 1 -C 12 )alkyl is preferably selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert Butyl, -CD 3 , -CD 2 H, -CDH 2 , -CF 3 , -CH 2 F, -CHF 2 , More preferably selected from methyl, ethyl, n-propyl, isopropyl, -CD 3 , -CF 3 , -CH 2 F, -CHF 2 , It is best selected from methyl, ethyl, -CD 3 , -CF 3 , -CH 2 F, -CHF 2 .
- the substitution or Unsubstituted (C 1 -C 12 )alkoxy is preferably selected from substituted or unsubstituted (C 1 -C 6 )alkoxy, more preferably selected from substituted or unsubstituted (C 1 -C 4 ) Alkoxy, the substituted or unsubstituted (C 1 -C 4 )alkoxy is best selected from substituted or unsubstituted methoxy, substituted or unsubstituted ethoxy, substituted or unsubstituted N-propoxy, substituted or unsubstituted isopropoxy, substituted or unsubstituted n-butoxy, substituted or unsubstituted isobutoxy, substituted or unsubstituted tert-butoxy; "substituted or
- the substituted or unsubstituted (C 1 -C 12 )alkoxy is preferably selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy , Isobutoxy, tert-butoxy, -OCD 3 , -OCD 2 H, -OCDH 2 , -OCF 3 , -OCH 2 F, -OCHF 2 , More preferably selected from methoxy, ethoxy, n-propoxy, isopropoxy, -OCD 3 , -OCF 3 , -OCH 2 F, -OCHF 2 , It is best selected from methoxy, ethoxy, -OCD 3 , -OCF 3 , -OCH 2 F, or -OCHF 2 .
- the substituted or unsubstituted (C 3 -C 6 )cycloalkyl group is selected from substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentan Group, or substituted or unsubstituted cyclohexyl.
- R 1 is selected from H, F, Cl, Br, -CN, methyl, methoxy, -OH; R 1 is preferably selected from F, Cl, -CH 3 , -CN,- OH, R 1 is more preferably selected from F.
- R 2 is selected from H, F, Cl, Br, -CN, methyl, methoxy, -OH; R 2 is preferably selected from F, Cl, -CH 3 , -CN , -OH, R 2 is more preferably selected from F.
- R 1 is selected from F, Cl, Br, -CN, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 ;
- R 2 is selected from H.
- R 2 is selected from F, Cl, Br, -CN, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 ;
- R 1 is selected from H.
- R 1 is selected from F; R 2 is selected from H.
- R 2 is selected from F; R 1 is selected from H.
- the isoindoline derivative represented by the general formula (I) is selected from any of the following compounds:
- Deuterium (D or 2 H) is a stable non-radioactive isotope of hydrogen with an atomic weight of 2.0144. Natural hydrogen exists in the form of a mixture of isotopes of H (hydrogen or protium), D ( 2 H or deuterium) and T ( 3 H or tritium), and the abundance of deuterium is 0.0156%. According to common technical knowledge in the art, in the structural formulas of all compounds containing natural hydrogen atoms, hydrogen atoms actually represent a mixture of H, D, and T. Therefore, when the deuterium abundance at any site in a compound is greater than 0.0156% of its natural abundance, these compounds should be considered unnatural or deuterium-enriched. Therefore, these compounds are relative to their non-enriched counterparts. Is novel.
- D deuterium or “deuterium-enriched” compound means the compound of general formula (I), its pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, metabolite or
- the abundance of deuterium at any relevant site in the compound of the prodrug is greater than its natural abundance at that site. Therefore, in a “D”, “deuterium” or “deuterium-enriched” compound, the deuterium abundance at any of its relevant sites may be in the range of greater than 0.0156% to 100%.
- Deuterium-enriched sites are represented by D
- the given percentage of deuterium in the deuterium enrichment or the percentage of deuterium in the deuterium abundance all refer to the molar percentage.
- non-deuterium enrichment refers to hydrogen in nature, that is, it exists in the form of a mixture of H (hydrogen or protium), D (2 H or deuterium) and T ( 3 H or tritium) isotopes.
- the present invention also provides a method for preparing isoindoline derivatives represented by the general formula (I), which can be synthesized using commercially available raw materials and synthesized by methods commonly used in the field of chemical synthesis, for example, refer to WO2016065980A1 , The synthesis method disclosed in WO2019014100A1, etc.
- the compound of general formula (I) can be obtained by the reaction of compound A-01,
- X, X 1 -X 5 ,*, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 8 have the same definitions as mentioned above, and Ra and Rb are defined as The other is R a'and R b'are independently H.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically and/or preventively effective amount of the isoindoline derivative represented by the general formula (I), its pharmaceutically acceptable salt, solvate, and crystal form , Metabolites, prodrugs or stereoisomers.
- the pharmaceutical composition can be formulated for administration in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or gastrointestinal External (infusion, injection, implantation, subcutaneous, intravenous, intraarterial, intramuscular) administration.
- the pharmaceutical composition of the present invention can also be a controlled release or delayed release dosage form.
- solid oral preparations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets.
- liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions.
- topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations.
- preparations for parenteral administration include, but are not limited to, solutions for injection, dry preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection.
- Examples of other suitable formulations of compounds of general formula (I), their pharmaceutically acceptable salts, solvates, crystal forms, metabolites, prodrugs or stereoisomers include, but are not limited to, eye drops and other ophthalmic preparations; Sprays: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.
- the pharmaceutical composition according to the present invention may further comprise pharmaceutically acceptable excipients, such as those widely used in the field of pharmaceutical production.
- Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to enable the subject to dissolve the active ingredient at a desired rate after administration, or to promote the activity of the subject after the administration of the composition
- the ingredients are effectively absorbed.
- the auxiliary material may be an inert filler or provide a certain function, such as stabilizing the overall pH of the composition or preventing the degradation of the active ingredients of the composition.
- pharmaceutically acceptable excipients may include one or more binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, Anti-sticking agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors or enhancers, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents and sweetening agents.
- the pharmaceutically acceptable carrier can take various forms according to the preparation form required for administration.
- suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like.
- suitable carriers and additives include starch, sugars, diluents, granulating agents, lubricants, binders, disintegrants, and the like.
- Pharmaceutically acceptable carriers or excipients should generally be non-toxic.
- the pharmaceutical composition according to the present invention may contain one or more suitable carriers/adjuvants. The amount and type of excipients will vary as needed. A person of ordinary skill in the art will be able to easily determine the appropriate carrier/adjuvant to be added to the pharmaceutical composition of the present invention based on the current disclosure.
- the pharmaceutical composition of the present invention includes a therapeutically or preventively effective amount of the compound of general formula (I) provided by the present invention, its pharmaceutically acceptable salt, solvate, crystal form, metabolite, prodrug or stereoisomer
- the pharmaceutical composition according to the present invention can be mixed with a pharmaceutically acceptable compound of formula (I), its pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, metabolite, or prodrug.
- the carrier is prepared according to conventional pharmaceutical compounding techniques, including but not limited to conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or freeze-drying processes.
- the pharmaceutical composition in addition to one or more of the compound of general formula (I), its pharmaceutically acceptable salt, solvate, crystal form, metabolite, prodrug or stereoisomer
- one or more other therapeutic agents may be further included. More details of other therapeutic agents that can be included in the pharmaceutical combination of the present invention will be disclosed below. The amount and type of other therapeutic agents will depend on the disease, disorder or condition to be treated or prevented; the severity of the disease, disorder or condition; factors of the subject receiving the composition, such as age, weight, physical condition Etc.; route of administration, etc.
- a therapeutic or prophylactic amount of the compound of general formula (I), its pharmaceutically acceptable salt, solvate, crystal form, metabolite, prodrug or stereoisomer, any Pharmaceutical compositions, preparations, etc. can be administered to a subject by the method of the present invention for a period of time (dosing period), followed by a period of not administering the compound (non-dosing period).
- the dosing cycle and non-dosing cycle can be repeated as many times as necessary.
- the required length and number of dosing cycles or non-dosing cycles will depend on the type and/or severity of the disease, disorder or condition being treated or prevented, as well as the gender, age, weight and other parameters of the individual subject ( For example, the biological, physical and physiological conditions of the individual subject, etc.). Based on the content disclosed in this document, the technical level of a person of ordinary skill in the art will be sufficient to determine the appropriate length and number of dosing cycles and/or non-dosing cycles.
- the compound represented by general formula (I), its pharmaceutically acceptable salt, solvate, crystal form, metabolite, prodrug or stereoisomer according to the present invention is combined with other therapeutic agents
- Use, according to the present disclosure can play a synergistic effect in the treatment or prevention of any disease, disorder or condition.
- other therapeutic agents may be naturally occurring, semi-synthetic or synthetic compounds.
- other therapeutic agents may be small molecules, such as synthetic organic or inorganic molecules; or larger molecules or biological molecules, such as proteins or nucleic acids with pharmacological activity.
- the other therapeutic agent may be an anti-angiogenesis, immunomodulation, immunotherapy, chemotherapy, or hormonal compound.
- a compound of general formula (I), a pharmaceutically acceptable salt, solvate, crystal form, metabolite, prodrug or stereoisomer thereof, and another treatment The composition of the agent is simultaneously administered to the subject.
- the compound of general formula (I), its pharmaceutically acceptable salt, solvate, crystal form, metabolite, prodrug or stereoisomer, and another therapeutic agent are administered sequentially .
- the compound of general formula (I), its pharmaceutically acceptable salt, solvate, crystal form, metabolite, prodrug or stereoisomer, and another therapeutic agent are administered separately.
- Another therapeutic agent can be administered before, continuously or after administration of the compound of general formula (I) according to the present invention, its pharmaceutically acceptable salt, solvate, crystal form, metabolite, prodrug or stereoisomer.
- one or more other therapeutic agents that can be administered in combination with a compound of general formula (I) or a pharmaceutically acceptable salt, solvate, crystal form, metabolite, prodrug or stereoisomer thereof will depend on Various factors, for example, diseases, disorders, or conditions that need to be prevented or treated.
- a person of ordinary skill in the art can easily determine the combination of isoindoline derivatives represented by general formula (I), pharmaceutically acceptable salts, solvates, crystal forms, and metabolites according to the disclosure of the present invention.
- Prodrugs, or other suitable therapeutic agents for the combination of stereoisomers are examples of the compounds represented by general formula (I), pharmaceutically acceptable salts, solvates, crystal forms, and metabolites.
- the compound of general formula (I) according to the present invention when the compound of general formula (I) according to the present invention, its pharmaceutically acceptable salt, solvate, crystal form, metabolite, prodrug or stereoisomer is administered in combination with other therapeutic agents
- the therapeutically effective amount is lower than that of the compound represented by general formula (I)
- its Pharmaceutically acceptable salts, solvates, crystal forms, metabolites, prodrugs, or stereoisomers will require a therapeutically effective amount when they are not administered in combination with other therapeutic agents.
- the therapeutically effective amount of another therapeutic agent is lower than if the compound of general formula (I), its pharmaceutically acceptable salt, solvate, crystal form, metabolite, prodrug or not administered according to the present invention The effective amount in the case of stereoisomers.
- a compound of general formula (I), its pharmaceutically acceptable salt, solvate, crystal form, metabolite, prodrug, or stereoisomer and other therapeutic agents when administered to a subject, the compound of general formula (I), its pharmaceutically acceptable salts, solvates, crystal forms, metabolites, prodrugs or stereoisomers and other therapeutic agents can pass through the same route Administration can also be administered by different routes.
- Other therapeutic agents can be administered by any of the routes described herein, including but not limited to oral, inhalation, injection, ocular, mucosal, rectal, emulsion, liposome, long-acting implantation, or sustained-release methods.
- the compound of general formula (I), its pharmaceutically acceptable salt, solvate, crystal form, metabolite, prodrug or stereoisomer can be used for a variety of purposes, including but not limited to being used for preparation by induction Drugs for ubiquitination and degradation of target proteins in cells to treat related diseases, disorders or conditions.
- the present invention relates to compounds of general formula (I), pharmaceutically acceptable salts, solvates, crystal forms, metabolites, prodrugs or stereoisomers used in the preparation of treatment or prevention of diseases, disorders or Application of medications for medical conditions.
- the present invention relates to a method for the treatment or prevention of related diseases, disorders or conditions by inducing the ubiquitination and degradation of target proteins in cells, said method by administering to a subject an effective amount of treatment or prevention
- the isoindoline derivative represented by the general formula (I), its pharmaceutically acceptable salt, solvate, metabolite, prodrug or stereoisomer According to the method of the present invention, examples of such diseases, disorders, and conditions to be treated or prevented include, but are not limited to, cancer.
- the disease, disorder or condition is cancer, preferably multiple myeloma.
- salts, compositions, and excipients are generally non-toxic, safe, and suitable for use by subjects, preferably Mammalian subjects are more preferably human subjects.
- pharmaceutically acceptable salt refers to a pharmaceutically acceptable organic or inorganic salt.
- the term "metabolite” refers to an active substance produced after the chemical structure of a drug molecule undergoes changes in the body.
- the active substance is generally a derivative of the aforementioned drug molecule, which can also be chemically modified.
- polymorph refers to one or more crystal structures formed by different arrangements of molecules in the lattice space during crystallization.
- solvate refers to a crystalline form of the compound of general formula (I), its pharmaceutically acceptable salt, crystal form, stereoisomer, metabolite or prodrug, which also includes a Or a variety of solvent molecules incorporated into the crystal structure.
- Solvates may include stoichiometric or non-stoichiometric amounts of solvent, and solvent molecules in the solvent may exist in an ordered or non-ordered arrangement.
- a solvate containing a non-stoichiometric amount of solvent molecules may result from the solvate losing at least one (but not all) solvent molecules.
- a solvate is a hydrate, meaning that the crystalline form of the compound further includes water molecules, with water molecules as the solvent.
- prodrug refers to a derivative of a compound containing a biologically reactive functional group such that under biological conditions (in vitro or in vivo), the biologically reactive functional group can be cleaved from the compound or otherwise occur React to provide the compound.
- the prodrug is inactive, or at least less active than the compound itself, so that the compound cannot exert its activity until the compound is cleaved from the biologically reactive functional group.
- the bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide the compound.
- prodrugs may contain biohydrolyzable groups.
- biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable Urea.
- stereoisomer refers to enantiomers, diastereomers, epimers, endo-exoisomers, atropisomers All stereoisomers including atropisomers, regioisomers, cis- and trans-isomers.
- stereoisomers herein also include “pure stereoisomers” and “enriched stereoisomers” or “racemates” of the aforementioned various stereoisomers.
- stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotation chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or salting (physical bonding, etc.).
- the "pure stereoisomer” herein means that the mass content of one stereoisomer of the compound in question relative to the other stereoisomers of the compound is not less than 95%.
- Enriched stereoisomers herein means that the mass content of one stereoisomer of the compound in question relative to the other stereoisomers of the compound is not less than 50%.
- the “racemate” herein means that the mass content of one stereoisomer of the compound in question is equal to the mass content of other stereoisomers of the compound.
- the term "subject” refers to any animal that is about to or has received administration of the compound or composition according to an embodiment of the present invention, mammals are preferred, and humans are preferred.
- the term "mammal” as used herein includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.
- treating or “under treatment” refers to the improvement, prevention or reversal of a disease or condition or at least one discernible symptom thereof, for example, by reducing or stabilizing the symptoms of the cancer or condition, treating cancer, undesired blood vessels Generate related diseases.
- “treating” or “under treatment” refers to the improvement, prevention or reversal of at least one measurable physical parameter of the disease or condition being treated, which may not have been identified in the mammal .
- “treating” or “under treatment” refers to slowing down the progression of a disease or condition, or physical, such as stabilization of discernible symptoms, or physiological, such as stabilization of physical parameters , Or both.
- “treating” or “under treatment” refers to delaying the onset of a disease or condition.
- the compound of interest is administered as a preventive measure.
- preventing or “preventing” refers to reducing the risk of acquiring a given disease or condition.
- the specified compound is administered as a preventive measure to a subject, such as a subject with a family history or tendency of cancer or autoimmune disease.
- therapeutically effective amount refers to the amount of a compound or composition capable of causing a biological or medical response in a tissue system, animal or human (which is being sought by researchers, veterinarians, doctors or other clinicians), which may include Reduce the symptoms of the disease or condition being treated.
- the therapeutically effective amount is effective to treat, ameliorate, treat, or prevent cancer, disorders, or undesirable vascular-related conditions.
- prophylactically effective amount refers to the amount of an active compound or agent capable of inhibiting the onset of a disorder in a subject (as sought by a researcher, veterinarian, doctor, or other clinician).
- the prophylactically effective amount of a compound refers to the amount of the therapeutic agent used alone or in combination with other therapeutically active compounds, which can provide therapeutic benefits in the treatment or prevention of diseases, disorders, or conditions.
- the reagents and raw materials used in the present invention are all commercially available.
- the isoindoline derivatives represented by the general formula (I) of the present invention can induce ubiquitination and degradation of target proteins in cells, thereby effectively treating cancer and other related diseases.
- Step A Under the protection of nitrogen, dissolve 3-hydroxy-2-methylbenzoic acid (CAS 603-80-5, 30.0g, 197mmol) in anhydrous methanol (400mL), add DMF (2mL) dropwise at 0°C , Thionyl chloride (70.3g, 591mmol). After the addition is complete, the reaction solution is heated to reflux and reacted overnight.
- Step B Under the protection of nitrogen, dissolve methyl 3-hydroxy-2-methylbenzoate (30.5g, 184mmol) and imidazole (31.2g, 459mmol) in anhydrous DMF (200mL), and reduce to 0°C in an ice bath .
- TBDMSCl tert-butyldimethylchlorosilane, 33.2 g, 220 mmol
- the reaction solution was concentrated under reduced pressure, ethyl acetate (250 mL) and water (250 mL) were added, and the organic phase was separated.
- Step D Combine the compound methyl 2-bromomethyl 3-((tert-butyldimethylsilyl)oxy)benzoate (5.00g, 13.9mmol) and the compound (CAS 108607-02-9, 3.65g, 15.3mmol) was dissolved in anhydrous acetonitrile (50mL), and diisopropylethylamine (5.20mL, 29.2mmol) was added dropwise at room temperature (30°C) under a nitrogen atmosphere. The temperature was raised to 40°C and stirred overnight.
- the reaction solution was concentrated under reduced pressure, diluted with dichloromethane (100 mL), washed with water (50 mL ⁇ 2), saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a pale yellow oil.
- the obtained oil was dissolved in DMF (17.2 mL), and a solution of K 2 CO 3 (884 mg, 6.40 mmol)) in water (1.89 mL) was added dropwise at 0°C. After dripping, warm to room temperature (25°C) and stir for 50 minutes.
- Step A Dissolve 2-fluoro-4-methylbenzoic acid (50g, 324.4mmol, CAS 7697-23-6) in 400mL DMF, add K 2 CO 3 (67g, 486mmol), stir at room temperature for 0.5 hours, Add methyl iodide (26.3 mL, 422 mmol) at 0°C, and react at room temperature for 16 hours.
- the reaction solution was poured into 1500mL water, extracted with EtOAc (500mL x 2), washed with saturated brine (500mL x 2), dried, and concentrated under reduced pressure to obtain the product methyl 2-fluoro-4-methylbenzoate (51g, yield: 94%) was a white solid, which was used directly in the next step without purification.
- Step B Dissolve methyl 2-fluoro-4-methylbenzoate (48g, 285mmol) in 400mL CCl 4 , add NBS (N-bromosuccinimide, 55.9g, 314mmol), BPO (13.8 g, 57.2mmol), the reaction solution was heated in an oil bath at 80°C for overnight reaction. Cooled to room temperature, filtered, concentrated under reduced pressure, the residue was dispersed in 500mL EtOAc, washed with saturated brine (500mL x 2), dried, and concentrated under reduced pressure to obtain a yellow solid product [methyl 4-(bromomethyl)-2-fluorobenzoate]( 70g).
- Step C Dissolve the compound [tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)benzyl)piperazine-1-carboxylate] (80g) in EtOAc (500mL), add HCl/EtOAc (5N, 400mL), and react The solution was stirred at room temperature for 16 hours, the precipitated solid was filtered, and the solid was concentrated and dried under reduced pressure to the hydrochloride 1-2. MS(ESI)m/z 253.2[M+H] + .
- Step A Add compound CM-1A[3,4-difluorobenzonitrile] (11.8g, 84.83mmol, CAS 64248-62-0), N-Boc-piperazine (18.96g, 101.8mmol) to DMSO (100mL) Add K 2 CO 3 (17.56g, 127.2mmol), heat in an oil bath at 100°C overnight, cool to room temperature, then pour into 600ml of water, stir for 15 minutes, then filter and wash with water, and concentrate the filter cake to dryness under reduced pressure.
- Step B Dissolve CM-1E, 2-chloro-4-methylbenzoic acid (5g, 29.3mmol, CAS 7697-25-8) in 40mL DMF, add K 2 CO 3 (6.1g, 44mmol), Stir at room temperature for 0.5 hours, add methyl iodide (5.4 g, 38.1 mmol) at 0°C, and react at room temperature for 4 hours.
- Step E Refer to the synthesis method of step BD in Example 7 compound CM-3, replace CM-3C with CM-1H, and then synthesize compound CM-1L[tert-butyl-(S)-5-amino-4-( 4-((2-chloro-4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate].
- Step F Referring to the synthesis method of step EF in Example 9 compound CM-6, replace CM-6G[tert-butyl(S)-5-amino-4-(4-((4-((4 -(4-cyano-3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-2-fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate], then compound CM-1 can be synthesized .
- Step A Compound I-2[methyl 2-fluoro-4-(piperazin-1-ylmethyl)benzoate hydrochloride] (2.70g, 9.35mmol), CM-1A[3,4-difluorobenzonitrile] (1.18g, 8.50mmol) And DIEA (3.29g, 25.5mmol) were added to DMSO (15mL), heated in an oil bath at 100°C and stirred for 3 hours.
- Step B Compound CM-3C (2.50g, 6.74mmol) was dissolved in THF/MeOH (30mL/10mL), LiBH 4 (0.51g, 23.55mmol) was added in batches at 0°C, and stirred at room temperature for 16 hours under nitrogen protection .
- the reaction solution was poured into ice water, extracted with EtOAc (50mL x 3), the organic phase was washed with saturated brine, dried and concentrated, and the product CM-3D[3-fluoro-4-(4-(3-fluoro-4) was prepared by reverse phase -(hydroxymethyl)benzyl)piperazin-1-yl)benzonitrile] (1.20g, yield: 52%), off-white solid.
- Step C SOCl 2 (1.25 g, 10.50 mmol) was slowly added to the DCM (15 mL) solution of compound CM-3D (1.20 g, 3.50 mmol) at 0° C., and stirred at room temperature for 3 hours.
- the reaction solution was concentrated to obtain the crude product CM-3E[4-(4-(4-(chloromethyl)-3-fluorobenzyl)piperazin-1-yl)-3-fluorobenzonitrile hydrochloride] (1.4g), a white solid.
- Step D Compound I-1 (611 mg, 1.83 mmol), CM-3E (800 mg, 2.01 mmol) and Cs 2 CO 3 (1.49 g, 4.57 mmol) were added to DMSO (15 mL) and stirred at room temperature for 2 hours. Filter, wash the filter cake with EtOAc, pour the filtrate into ice water, extract with EtOAc (50mL x 3), wash the organic phase with saturated brine (100mL x 3), dry and concentrate.
- the resulting crude product is prepared by reverse phase to obtain the product CM- 3G[tert-butyl(S)-5-amino-4-(4-((4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)-2-fluorobenzyl)oxy) -1-oxoisoindolin-2-yl)-5-oxopentanoate] (600mg, 0.91mmol, yield: 50%), off-white solid.
- Step E A CH 3 CN (15 mL) solution of compound CM-3G (600 mg, 0.91 mmol) and p-toluenesulfonic acid (469 mg, 2.73 mmol) was stirred at 90°C for 4 hours.
- the reaction solution was concentrated, diluted with EtOAc/THF (30mL/30mL), and NaHCO 3 aqueous solution was added at 0-5°C to pH>7.
- the organic phase was washed with saturated brine (80 mL), dried and concentrated.
- the crude product obtained was purified by Prep-HPLC to obtain the product CM-3[(S)-4-(4-(4-(((2-(2,6 -dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-3-fluorobenzyl)piperazin-1-yl)-3-fluorobenzonitrile](170mg, 0.29mmol, yield: 32%), class White solid.
- Step B Add compound CM-4D (2.23g, 9.04mmol), CM-1D (2.40g, 9.94mmol) and K 2 CO 3 (3.12g, 22.6mmol) into DMF (25mL), stir at 70°C for 16 Hour.
- the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the product CM-4E[methyl 4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)-3-fluorobenzoate was purified by preparative high performance liquid chromatography. (2.4g, yield 71%), off-white solid.
- Step C Compound CM-4E (2.40g, 6.47mmol) was dissolved in THF / MeOH (20mL / 20mL) in added portionwise at 0 °C LiBH 4 (0.35g, 16.17mmol), stirred at room temperature for 16 hours.
- the reaction solution was poured into ice water, extracted with EtOAc (50mL x 3), the organic phase was washed with saturated brine, dried and concentrated, and purified by preparative high performance liquid chromatography to obtain the product CM-4F[3-fluoro-4-(4-(2-fluoro -4-(hydroxymethyl)benzyl)piperazin-1-yl)benzonitrile] (1.3g, rate: 58%), white solid.
- Step D Slowly add SOCl 2 (1.35, 11.37 mmol) to the DCM (30 mL) solution of compound CM-4F (1.3 g, 3.79 mmol) at 0° C., and stir at room temperature for 3 hours.
- the reaction liquid was concentrated under reduced pressure to obtain the product CM-4G[4-(4-(4-(chloromethyl)-2-fluorobenzyl)piperazin-1-yl)-3-fluorobenzonitrile hydrochloride] (1.4g), which was a white solid.
- Step E Combine compound CM-4G (1.50g, 3.77mmol), compound I-1 (1.15g, 3.44mmol) and K 2 CO 3 (1.18g, 8.57mmol) in NMP (N-methylpyrrolidine, 15mL ) The mixed solution was stirred at 50°C for 16 hours. Filter, pour the filtrate into ice water, extract with EtOAc (50mL x 3), wash the organic phase with saturated brine (100mL), dry and concentrate under reduced pressure.
- NMP N-methylpyrrolidine, 15mL
- Step F A CH 3 CN (20 mL) solution of compound CM-4H (0.90 g, 1.36 mmol) and p-toluenesulfonic acid (0.705 g, 4.10 mmol) was heated in an oil bath at 90° C. and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, diluted with EtOAc/THF (30mL/30mL), and NaHCO 3 aqueous solution was added at 0-5°C until pH>7. The organic phase was washed with saturated brine (100 mL), dried and concentrated under reduced pressure.
- Step B Dissolve compound CM-6C (3.0g, 7.12mmol) in THF/MeOH (50mL, 5mL), add LiBH 4 (0.93g, 42.8mmol) into the reaction flask in batches under ice bath, and stir at room temperature 16 hours.
- Step C Dissolve compound CM-6D (2.40 g, 6.10 mmol) in CH 3 CN (15 mL), add SOCl 2 (2.18 g, 18.3 mmol) into the reaction flask under ice bath, and stir at room temperature for 2 h. Concentrate under reduced pressure to dryness, beat with EtOAc, filter and concentrate under reduced pressure to obtain the off-white solid product CM-6E[4-(4-(4-(chloromethyl)-3-fluorobenzyl)piperazin-1-yl)-2-(trifluoromethyl) benzonitrile hydrochloride] (2.4g, yield: 88%).
- Step D Dissolve compound CM-6E (1.70g, 3.79mmol) in DMSO (10mL), add Cs 2 CO 3 (3.1g, 9.5mmol), compound I-1 (1.27g, 3.80mmol) at room temperature, Stir at 25°C for 2 hours. Filter through celite, wash with EtOAc, pour the filtrate into ice water, extract with EtOAc (50mL x 3), wash the organic phase with saturated brine (100mL x 3), dry and concentrate under reduced pressure.
- Step E The compound CM-6G (1.05g, 1.48mmol) was dissolved in DMF (3mL), 4N HCl/dioxane (30mL) was added, the reaction solution was stirred at room temperature for 16 hours, and concentrated under reduced pressure to obtain a yellow oil (1.0 g)CM-6H[(S)-5-amino-4-(4-((4-((4-(4-cyano-3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-2- fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoic acid].
- Step F Dissolve compound CM-6H (1.2g, crude product) in DMF/DCM (8mL/25mL), cool to -40°C, add SOCl 2 (881mg, 7.40mmol) dropwise, and add pyridine ( 1.17g, 14.8mmol), stirred at -40°C for 1 hour, slowly added Et 3 N (747mg, 7.40mmol) dropwise and stirred for 1 hour, slowly added 10mL of water to quench the reaction.
- Step A Add iodoethane (2.56g, 16.41mmol) to compound CM-12A[2-hydroxy-4-fluorobenzonitrile] (1.50g, 10.94mmol) and K 2 CO 3 (3.02g, 21.88mmol) In DMF (20 mL) mixed solution, the reaction was carried out at room temperature for 16 hours. Water (100 mL) was added and extracted with ethyl acetate (100 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the off-white solid product CM-12B [2-ethoxy-4-fluorobenzonitrile] (1.60 g, 88% yield).
- Step B K 2 CO 3 (2.67g, 19.38mmol) was added to compound CM-12B[2-ethoxy-4-fluorobenzonitrile] (1.60g, 9.69mmol) and I-2[methyl 2-fluoro -4-(piperazin-1-ylmethyl)benzoate hydrochloride] (3.15g, 10.43mmol) in DMSO (20mL) solution, the mixture was stirred at 90°C for 16 hours. The reaction solution was poured into water (60 mL), and extracted with EtOAc (50 mL x 2). The organic phase was washed with saturated brine (60 mL x 3), dried over anhydrous Na 2 SO 4 , filtered and concentrated. The yellow solid product CM-12D[methyl 4-((4-(4-cyano-3-ethoxyphenyl)piperazin-1-yl)methyl)-2-fluorobenzoate](1.90g, yield: 49%).
- Step C Compound CM-12D (1.90 g, 4.78 mmol) was dissolved in a mixture of THF (40 mL) and MeOH (10 mL), and LiBH 4 (0.32 g, 14.36 mmol) was added in batches at 0°C. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was slowly poured into ice ammonium chloride aqueous solution, extracted with ethyl acetate (40 mL x 3), and the organic phase was washed with saturated brine (80 mL) and extracted.
- Step D SOCl 2 (1.46 g, 12.24 mmol) was slowly added to the DCM (30 mL) solution of compound CM-12E (1.20 g, 3.25 mmol) at 0° C., and stirred at room temperature for 16 hours. The reaction solution was concentrated to obtain a brown solid (1.38 g, crude).
- Step F Add a solution of HCl in dioxane (4N, 30 mL) to a solution of CM-12G (1.50 g, 2.19 mmol) in dioxane (20 mL) at room temperature. The reaction solution was stirred at 30°C for 2h. The reaction solution was concentrated to obtain an intermediate. At -45°C under nitrogen, SOCl 2 (1.30 g, 10.94 mmol) was added to the DCM/DMF (70 mL/10 mL) solution of the above intermediate. The reaction mixture was stirred at -45°C for 1 hour. Pyridine (1.73 g, 21.90 mmol) was slowly added, and the reaction was stirred at -45°C for 1 hour.
- Triethylamine (1.10g, 10.94mmol) was slowly added to the reaction solution at -45°C, and the reactants were stirred at -45°C for 1 hour.
- the reaction solution was quenched with water (10 mL), NaHCO 3 aqueous solution was added to adjust the pH>7, and the organic phase was separated.
- the organic phases were combined and washed with saturated NaCl solution, dried and concentrated to obtain a crude product, which was subjected to Prep-HPLC to obtain an off-white solid CM-12 (383 mg, yield: 29%).
- CM-10, CM-24, CM-33, CM-34, and CM-39 were synthesized using corresponding reactants.
- Step A Referring to the synthesis conditions in Example 11, from CM-1A[3,4-difluorobenzonitrile] (2.5g, 18.0mmol, CAS3939-09-1), CM-18C[methyl 4-((4-(4 -cyano-3-fluorophenyl)piperazin-1-yl)methyl)-2-fluorobenzoate] (3.0g, yield 45%) yellow solid. MS(ESI)m/z 372.2[M+H] + .
- Step B Add compound CM-18C (3.0g, 8.08mmol) into the reaction flask, dissolve it in DMSO/EtOH (60mL/160mL), then add NaOH aqueous solution (1N, 100mL, 100.0mmol), 30% H 2 O 2 (30 mL), stirring at 35°C for 16 hours.
- Step C Add compound CM-18D (3.0g crude product) into the reaction flask, dissolve it in DMF (40mL), add K 2 CO 3 (2.21g, 16.0mmol), MeI (1.13g, 8.00mmol), and stir the mixture at room temperature overnight.
- Step D Referring to the synthesis method in Example 11, compound CM-18[(S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl )-1-oxoisoindolin-4-yl)oxy)methyl)-3-fluorobenzyl)piperazin-1-yl)-2-fluorobenzamide].
- Step A Compound CM-19A [2-fluoro-4-bromobenzoic acid] (10.0g, 45.70mmol, CAS 112704-79-7) was added SOCl 2 (27.2g, 16.5mL, 0.228mol) at 0°C, 85 Reflux for 2h at °C, distill off excess SOCl 2 to obtain a brown solid compound, then dissolve in DCM (50mL), add a mixture of MeNH 2 .HCl (9.25g, 0.14mol) and Et 3 N/DCM (25mL/100mL) at 0°C React at room temperature for 2h, add water (100mL), separate the layers, extract the aqueous phase with DCM (100mL), wash with brine (200mL), dry with Na 2 SO 4 , filter, and concentrate to obtain the product CM-19B[4-bromo-2-fluoro -N-methylbenzamide](10.0g, yield: 94%).MS(ESI)m/z 233.9[M+1
- Step B Compound CM-19B (6.00g, 25.86mmol), I-2[methyl 2-fluoro-4-(piperazin-1-ylmethyl)benzoate hydrochloride] (6.51g, 25.80mmol), Pd(OAc) 2 (580mg, 2.59mmol), Xantphos (3.00g, 5.18mmol, CAS 161265-03-8) and Cs 2 CO 3 (16.8g, 51.80mmol) were added to dioxane (100mL), N 2 protected oil Heat the bath at 110°C for 16h.
- Step A The raw material CM-17A [2-fluoro-5-bromobenzonitrile] (5.00g, 25.00mmol), N-Boc piperazine (3.88g, 20.80mmol), Pd 2 (dba) 3 (0.95g, 1.04mmol), BINAP ( 1.30g, 2.08mmol) and Cs 2 CO3 (10.17g, 31.20mmol) were added to toluene (50ml) and reacted at 80°C for 16 hours under nitrogen protection.
- Step B Dissolve CM-17C (2.50g, 8.19mmol) in ethyl acetate (20mL), slowly add hydrogen chloride/ethyl acetate solution (4M, 30mL), stir at room temperature for 3 hours, concentrate to obtain intermediate (1.98 g crude).
- Step A Add sodium difluorochloroacetate (7.70g, 50.50mmol, CAS:1895-39-2) to compound CM-14A[4-bromo-2-hydroxybenzonitrile] (5.00g, 25.25mmol) and K 2 CO 3 (4.18 g, 30.30 mmol) in a DMF/H 2 O (50 mL/5 mL) mixture, and react at 100° C. for 3 hours. Water (100 mL) was added and extracted with EtOAc (80 mL x 2).
- Step B The compound CM-14B[4-bromo-2-difluoromethoxybenzonitrile] (2.00g, 8.06mmol), I-2[methyl 2-fluoro-4-(piperazin-1-ylmethyl)benzoate hydrochloride] (2.21g, 8.77mmol), xphos Pd G2 (0.32g, 0.41mmol) and Cs 2 CO 3 (3.91g, 12.00mmol) were added to dioxane (25mL) and reacted at 100°C under nitrogen protection. 16 Hour.
- Step A The raw material CM-16A[methyl 2-fluoro-4-(piperazin-1-ylmethyl)benzoate](2.20g, 8.73mmol), CM-16B[4-bromo-2-fluoro-1-(trifluoromethyl) benzene] (2.12g, 8.73mmol), Pd 2 (dba) 3 (0.80g, 0.87mmol), BINAP (1.08g, 1.74mmol) and Cs 2 CO 3 (4.27g, 13.90mmol) were added to 1,4- In dioxane (50 mL), react at 85°C for 16 hours under nitrogen protection.
- the compound CM-25 was obtained by using the corresponding reactants.
- Step A K 2 CO 3 (45.54g, 0.13mol) was added to compound CM-22A[methyl 4-(bromomethyl)-3-fluorobenzoate] (32.00g, 0.13mol) and N-Boc piperazine (24.21g, 0.13 mol) in acetonitrile (250 mL) solution, stirred at 70°C for 16 hours.
- the reaction solution was filtered, the filtrate was concentrated, and purified by column chromatography to obtain a pale yellow solid product CM-22B[tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)benzyl)piperazine-1-carboxylate] (36.00g, yield : 78%).
- Step B 4N HCl/EA (200 mL) was slowly added to the ethyl acetate (100 mL) solution of compound CM-22B (36.00 g, 0.10 mol), and reacted at room temperature for 24 hours.
- the reaction solution was concentrated to a volume of about 100 mL, filtered, and the filter cake was dried to obtain a white solid product CM-22C [methyl 3-fluoro-4-(piperazin-1-ylmethyl)benzoate dihydrochloride] (29.00 g, yield: 89%).
- Step C Referring to Example 22, the compound CM-22D[4-fluoro-2-(methoxy-d 3 )benzonitrile] was prepared by using the corresponding reactants, and K 2 CO 3 (2.22g, 16.12mmol) was added at 25°C. Add compound CM-22C[methyl 3-fluoro-4-(piperazin-1-ylmethyl)benzoate dihydrochloride] (2.62g, 8.06mmol) and CM-22D (1.25g, 8.06mmol) in DMSO (20mL) solution, The mixture was stirred at 90°C for 16 hours. The reaction solution was poured into water (60 mL), and extracted with EtOAc (50 mL x 2).
- Step A At 0-5°C, slowly add chloromethyl methyl ether (4.05g, 50.32mmol, CAS: 107-30-2) to compound CM-40A[3-hydroxy-4-fluorobenzonitrile] (4.60 g, 33.55mmol, CAS: 186590-04-5) and DIEA (8.66g, 67.10mmol) in DCM (50mL) mixed solution, react at room temperature for 16 hours. Add water (60mL) and extract with ethyl acetate (50mL x 2).
- Step B Cs 2 CO 3 (30.97g, 95.00mmol) was added to the DMSO (100mL) solution of compound CM-40B (7.00g, 38.67mmol) and piperazine (16.63g, 193.37mmol), the mixed solution was at 100 Stir at °C for 16 hours.
- the reaction solution was poured into water (200 mL), and extracted with EtOAc (150 mL x 2).
- Step C Add DIEA (6.89g, 53.44mmol) to the DMF( of compound CM-40C(6.60g, 26.69mmol) and CM-40D[methyl4-(bromomethyl)-2-fluorobenzoate](6.60g, 26.69mmol) 80mL) solution, the mixture was stirred at 100°C for 2 hours.
- Step A Add deuterated methyl iodide (2.06g, 14.23mmol) to compound CM-32A [3-hydroxy-4-fluorobenzonitrile] (1.50g, 10.95mmol) and K 2 CO 3 (3.02g, 21.88mmol) ) In DMF (20 mL) mixed solution, react at room temperature for 16 hours. Water (60 mL) was added and extracted with ethyl acetate (30 mL x 2).
- Step B Add Cs 2 CO 3 (5.50g, 16.08mmol) to compound CM-32B (1.30g, 8.44mmol) and piperazine (3.63g, 42.2mmol)) in DMSO (15mL) solution, the mixed solution is in Stir at 100°C for 16 hours. The reaction solution was poured into water (60 mL), and extracted with EtOAc (50 mL x 2).
- Step C Add DIEA (2.99g, 23.16mmol) to compound CM-32D (1.70g, 7.72mmol) and CM-40D[methyl4-(bromomethyl)-2-fluorobenzoate] (2.38g, 9.66mmol) in DMSO( 15mL) solution, the mixture was stirred at 90 °C for 8 hours. The reaction solution was concentrated and subjected to column chromatography to obtain the product CM-32F[methyl 4-((4-(4-cyano-2-(methoxy-d3)phenyl)piperazin-1-yl)methyl)-2-fluorobenzoate](1.80 g, yield 60%), yellow solid, MS(ESI) m/z 387.5[M+H] + .
- CM-41C [methyl 4-((4-(3-bromo-4-cyanophenyl)piperazin-1-yl)methyl)-2-fluorobenzoate](3.50g, 8.10mmol), ethylboronic acid (1.20g, 16.20 mmol), Pd 2 (dppf)Cl 2 (0.18g, 0.24mmol) and potassium carbonate (1.72g, 16.20mmol) were added to dioxane/water (30mL/7mL), and reacted at 90°C for 16 hours under nitrogen protection. Cool to room temperature, filter through celite, and rinse with ethyl acetate.
- CM-42F was synthesized.
- Step B Dissolve compound CM-44B (800 mg, 2.17 mmol) in THF (8 mL), cool to -15°C, add sodium hydrogen (104 mg, 4.34 mmol) in batches, and keep the temperature below -5°C. After 30 minutes, water (78 mg, 4.34 mmol) was added dropwise. After 10 minutes, CM-44C [diethyl bromofluoromethylphosphonate] (1.16 g, 4.34 mmol) was added in portions, and stirred at room temperature for 1 hour.
- reaction solution was poured into water, extracted with ethyl acetate (30mL x 3), the organic phase was washed with saturated brine (80mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated, and the product CM-44D[methyl 4 -((4-(4-cyano-2-(difluoromethoxy)phenyl)piperazin-1-yl)methyl)-2-fluorobenzoate] (0.35g, 0.83mmol, yield: 38%), white solid.
- Step B Add CuI (20.34 g, 106.49 mmol) and isoamyl nitrite (12.48 g, 106.49 mmol) to MeCN (90 mL).
- the reaction solution was heated to 65° C., CM-48B (9.00 g, 52.79 mmol) in acetonitrile (90 mL) was added dropwise, the addition was completed in 30 minutes, and the reaction was continued for 5 hours.
- compound CM-46 was synthesized by using corresponding reactants.
- CM-20, CM-21, CM-23, CM-26, and CM-45 were synthesized using corresponding reactants.
- MM.1S myeloma cells ATCC, catalog number CRL-2974.
- RPMI-640 medium Gibco, catalog number A10491-01
- Dilute the cell suspension to the required density spread 100 ⁇ l per well in a 96-well plate, with 15,000 cells, and place it in a 37°C, 5% CO2 incubator for 24 hours.
- DMSO Sigma, product catalog number D2650
- the final concentration of DMSO is 0.5%.
- the 96-well plate after adding the medicine was placed in a 37°C, 5% CO2 incubator for 72 hours. After that, add 20 ⁇ l MTS (Promega, catalog number G3581) to each well, incubate in a 37°C, 5% CO2 incubator for 2 hours, and then use an Ensight instrument to record the absorbance of each well at 490nm. The reading of Day0 cells was used as a negative control, and Day-3 cells containing 0.5% DMSO were used as a positive control. GraphPad Prism 5 software was used to draw the cell proliferation inhibition curve and calculate the IC50. The experimental results are shown in Table 1.
- CM-31 0.1657 CM-32 0.0706 CM-33 0.0781 CM-34 0.0766 CM-35 0.0962 CM-36 0.1479 CM-37 0.1193 CM-38 1.2090 CM-39 0.0631 CM-40 0.3778 CM-41 0.1158 CM-42 0.1143 CM-43 0.5762 CM-44 0.1265
- the proliferation inhibitory activity of the compound on the MM.1S myeloma cell model was determined by the CellTiter-Glo (CTG) luminescence method to measure cell viability (Promega). Resuspend the MM.1S cells (ATCC, catalog number CRL-2974) in the logarithmic growth phase in RPMI-1640 (Gibco, catalog number 11875-093) + 10% FBS + 1% penicillin/streptomycin + 2mM Glutamax medium, counted using an automatic cell counter (ViCell XR).
- CCG CellTiter-Glo
- the optimized cell plating density in the preliminary experiment spread 40 ⁇ l of cell suspension with a density of 100,000 cells/ml in the corresponding wells of the 384-well plate (4,000 cells/well) to ensure the control group during the five-day experiment period
- the cells are in a linear growth stage.
- the compound was made into a 10 mM stock solution with DMSO (Sigma, catalog number 276855-1L), and then the compound stock solution was further diluted to 20 ⁇ M and 20 nM working solution with DMSO.
- MM.1S cells The drug treatment of MM.1S cells starts from the highest concentration of 100nM, and is diluted according to 10 concentration points and a 4-fold gradient, repeated in three wells. Dosing by HPD300 micro automatic dosing device (Tecan) according to the required concentration of nano-volume compound solution is added to the corresponding wells of the 384 plate in a non-contact spray mode. The final concentration of DMSO is 0.5%. After adding the drug, the 384-well plate was placed in a 37°C, 5% CO2 incubator for 120 hours.
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Abstract
本发明公开了一种异吲哚啉衍生物、其中间体、制备方法、药物组合物及应用。本发明的异吲哚啉衍生物能够通过与Cereblon结合，特异性靶向和调节各种各样的蛋白质，从而有效地治疗癌症等相关疾病。
Description
本申请要求申请日为2020年1月20日的中国专利申请CN202010067409.0，申请日为2020年5月15日的中国专利申请CN202010413162.3的优先权。本申请引用上述中国专利申请的全文。
本发明涉及一种异吲哚啉衍生物、其中间体、制备方法、药物组合物及应用。
小脑蛋白(cereblon)是人类中由CRBN基因编码的一种蛋白质。小脑蛋白与损伤DNA结合蛋白1(DDB1)，Cullin-4A(CUL4A)和cullin 1的调节因子(ROC1)形成E3泛素连接酶复合物。此复合物泛素化多种其他蛋白质。通过未曾被完全阐明的机制，靶标蛋白质的小脑蛋白泛素化导致成纤维细胞生长因子8(FGF8)和成纤维细胞生长因子10(FGF10)的水平提高，FGF8继而调节多种发育过程。
多项研究表明，来那度胺类免疫调节剂可与cereblon蛋白结合，改变复合物诱导Ikaros(IKZF1)和Aiolos(IKZF3)的泛素化和降解的特异性。IKZF1和IKZF3是多发性骨髓瘤中的关键转录因子。IKZF3的一种单氨基酸取代物使其对来那度胺类免疫调节剂诱导的降解产生了抗性，并耐受来那度胺类免疫调节剂诱导的细胞生长抑制。同样的，我们发现在T细胞中，来那度胺类免疫调节剂诱导的IL2产生是由于IKZF1和IKZF3的耗竭导致的。这些发现揭示了一种新的治疗作用机制，改变了E3泛素连接酶活性，导致选择性降解特定目标(Jan
etc.Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells,《Science》,2014,343(6168):301-5)。
对肿瘤的有效治疗在本领域中有着持续的需求，利用小脑蛋白(cereblon)的底物特异性从而开发特异性靶向调节多种肿瘤相关的蛋白质的小分子治疗剂是本领域亟需的。
发明内容
本发明提供了一种异吲哚啉衍生物、制备方法、药物组合物及应用。本发明的异吲哚啉衍生物能够通过与Cereblon结合，特异性靶向调节多种肿瘤相关的蛋白质，从而有效地治疗癌症等相关疾病。
本发明提供一种通式(I)所示的异吲哚啉衍生物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体：
其中，R
1，R
2各自独立地选自H，卤素，-CN，取代或未取代的(C
1-C
12)烷基，取代或未取代的(C
1-C
12)烷氧基，-OH，条件是R
1，R
2不同时为H；
X选自O或NH；
X
1,X
2,X
3,X
4,X
5各自独立地选自C或N；
R
4，R
5，R
6，R
7，R
8各自独立地不存在或选自H，卤素，取代或未取代的(C
1-C
12)烷基，取代或未取代的(C
1-C
12)烷氧基，取代或未取代的(C
3-C
6)环烷基，-CH＝CH
2，-C≡CH，-OH，-CN，-NO
2，
其中R
9，R
10各自独立地选自H，D，取代或未取代的(C
1-C
12)烷基，条件是R
4，R
5，R
6，R
7，R
8中至少一个选自-CN，-NO
2，-CH＝CH
2，-C≡CH，
被一个或多个卤素取代的(C
1-C
12)烷基，被一个或多个卤素取代的(C
1-C
12)烷氧基，被一个或多个D取代的(C
1-C
12)烷基，被一个或多个D取代的(C
1-C
12)烷氧基；
所述取代的(C
1-C
12)烷基，取代的(C
1-C
12)烷氧基中的取代基选自一个或多个D,一个或多个卤素，或一个或多个(C
3-C
6)环烷基；
用*标注的碳为不对称中心；
较佳地，通式(I)中，R
1，R
2中至少有一个选自卤素,-CN,取代或未取代的(C
1-C
12)烷基,取代或未取代的(C
1-C
12)烷氧基,-OH；
较佳地，通式(I)中，R
1，R
2中至少一个选自F,Cl,Br,-CN，-CH
3,-OCH
3，-CF
3，-OCF
3；
更佳地，通式(I)中，R
1，R
2中至少一个选自F；
较佳地，通式(I)中，X选自O；
在一个实施例中，通式(I)中，X选自O，X
1,X
2,X
3,X
4,X
5各自独立地选自C；
在一个实施例中，X选自O，X
1,X
2,X
3,X
4,X
5至少有一个选自N；
较佳地，通式(I)中，X选自NH；
在一个实施例中，通式(I)中，X选自NH，X
1,X
2,X
3,X
4,X
5各自独立地选自C；
在一个实施例中，X选自NH，X
1,X
2,X
3,X
4,X
5至少有一个选自N；
在一个实施例中，通式(I)中，所述的R
4选自-CN，-NO
2，
被一个或多个卤素取代的(C
1-C
12)烷基，被一个或多个卤素取代的(C
1-C
12)烷氧基，被一个或多个D取代的(C
1-C
12)烷基，或被一个或多个D取代的(C
1-C
12)烷氧基,其中R
9，R
10各自独立地选自H，D，取代或未取代的(C
1-C
12)烷基；R
5，R
6，R
7，R
8各自独立地选自H或卤素；
在一个实施例中，R
4选自-CN，被一个或多个卤素取代的(C
1-C
12)烷基，被一个或多个卤素取代的(C
1-C
12)烷氧基，被一个或多个D取代的(C
1-C
12)烷基，或被一个或多个D取代的(C
1-C
12)烷氧基，R
5，R
6，R
7，R
8各自独立地选自H；
在一个实施例中，通式(I)中，所述的R
5选自-CN，-NO
2，
被一个或多个卤素取代的(C
1-C
12)烷基，被一个或多个卤素取代的(C
1-C
12)烷氧基，被一个或多个D取代的(C
1-C
12)烷基，或被一个或多个D取代的(C
1-C
12)烷氧基,其中R
9，R
10各自独立地选自H，D，取代或未取代的(C
1-C
12)烷基；R
4，R
6，R
7，R
8各自独立地选自H或卤素；
在一个实施例中，R
5选自-CN，被一个或多个卤素取代的(C
1-C
12)烷基，被一个或多个卤素取代的(C
1-C
12)烷氧基，被一个或多个D取代的(C
1-C
12)烷基，或被一个或多个D取代的(C
1-C
12)烷氧基，R
4，R
6，R
7，R
8更佳地各自独立地选自H；
在一个实施例中，通式(I)中，所述的R
6选自-CN，-NO
2，
被一个或多个卤素取代的(C
1-C
12)烷基，被一个或多个卤素取代的(C
1-C
12)烷氧基，被一个或多个D取代的(C
1-C
12)烷基，或被一个或多个D取代的(C
1-C
12)烷氧基,其中R
9，R
10各自独立地选自H，D，取代或未取代的(C
1-C
12)烷基；R
4，R
5，R
7，R
8各自独立地选自H或卤素；
在一个实施例中，R
6选自-CN，被一个或多个卤素取代的(C
1-C
12)烷基，被一个或多个卤素取代的(C
1-C
12)烷氧基，被一个或多个D取代的(C
1-C
12)烷基，或被一个或多个D取代的(C
1-C
12)烷氧基，R
4，R
5，R
7，R
8更佳地各自独立地选自H；
在一个实施例中，通式(I)中，所述的R
7选自-CN，-NO
2，
被一个或多个卤素取代的(C
1-C
12)烷基，被一个或多个卤素取代的(C
1-C
12)烷氧基，被一个或多个D取代的(C
1-C
12)烷基，或被一个或多个D取代的(C
1-C
12)烷氧基,其中R
9，R
10各自独立地选自H，D，取代或未取代的(C
1-C
12)烷基；R
4，R
5，R
6，R
8各自独立地选自H或卤素；
在一个实施例中，R
7选自-CN，被一个或多个卤素取代的(C
1-C
12)烷基，被一个或多个卤素取代的(C
1-C
12)烷氧基，被一个或多个D取代的(C
1-C
12)烷基，或被一个或多个D取代的(C
1-C
12)烷氧基，R
4，R
5，R
6，R
8更佳地各自独立地选自H；
在一个实施例中，通式(I)中，所述的R
8选自-CN，-NO
2，
被一个或多个卤素取代的(C
1-C
12)烷基，被一个或多个卤素取代的(C
1-C
12)烷氧基，被一个或多个D取代的(C
1-C
12)烷基，或被一个或多个D取代的(C
1-C
12)烷氧基,其中R
9，R
10各自独立地选自H，D，取代或未取代的(C
1-C
12)烷基；R
4，R
5，R
6，R
7各自独立地选自H或卤素；
在一个实施例中，R
8选自-CN，被一个或多个卤素取代的(C
1-C
12)烷基，被一个或多个卤素取代的(C
1-C
12)烷氧基，被一个或多个D取代的(C
1-C
12)烷基，或被一个或多个D取代的(C
1-C
12)烷氧基，R
4，R
5，R
6，R
7更佳地各自独立地选自H。
较佳地，通式(I)中，所述的不对称中心是指非手性碳、(S)构型碳、富集的(S)构型碳、(R)构型碳、富集的(R)构型碳或者消旋体。
较佳地，通式(I)中，所述的卤素为F，Cl，Br，I。
较佳地，通式(I)中，所述的取代或未取代的(C
1-C
12)烷基较佳地选自取代或未取代的(C
1-C
6)烷基，更佳地选自取代或未取代的(C
1-C
4)烷基，所述取代或未取代的(C
1-C
4)烷基最佳地选自取代或未取代的甲基，取代或未取代的乙基，取代或未取代的正丙基，取代或未取代的异丙基，取代或未取代的正丁基，取代或未取代的异丁基，取代或未取代的叔丁基；“取代或未取代”中所述的取代基选自D,卤素，或(C
3-C
6)环烷基中的一个或多个，较佳地选自D，F，Cl，Br，I，环丙基，环丁基，环戊基，环己基，更佳地选自D，F，Cl，环丙基，环丁基，最佳地选自F。
在一个实施例中，所述取代或未取代的(C
1-C
12)烷基较佳地选自甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，-CD
3，-CD
2H,-CDH
2,-CF
3，-CH
2F，-CHF
2，
更佳地选自甲基，乙基，正丙基，异丙基，-CD
3，-CF
3，-CH
2F，-CHF
2，
最佳地选自甲基，乙基，-CD
3，-CF
3，-CH
2F，-CHF
2。
较佳地，通式(I)所示的异吲哚啉衍生物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体中，所述的取代或未取代的(C
1-C
12)烷氧基较佳地选自取代或未取代的(C
1-C
6)烷氧基，更佳地选自取代或未取代的(C
1-C
4)烷氧基，所述取代或未取代的(C
1-C
4)烷氧基最佳地选自取代或未取代的甲氧基，取代或未取代的乙氧基，取代或未取代的正丙氧基，取代或未取代的异丙氧基，取代或未取代的正丁氧基，取代或未取代的异丁氧基，取代或未取代的叔丁氧基；“取代或未取代”中所述的取代基选自D,卤素，或(C
3-C
6)环烷基中的一个或多个，较佳地选自D，F，Cl，Br，I，环丙基，环丁基，环戊基，或环己基，更佳地选自D，F，Cl，环丙基，或环丁基，最佳地选自D，或F。
在一个实施例中，所述取代或未取代的(C
1-C
12)烷氧基较佳地选自甲氧基，乙氧基，正丙氧基，异 丙氧基，正丁氧基，异丁氧基，叔丁氧基，-OCD
3，-OCD
2H,-OCDH
2,-OCF
3，-OCH
2F，-OCHF
2，
更佳地选自甲氧基，乙氧基，正丙氧基，异丙氧基，-OCD
3，-OCF
3，-OCH
2F，-OCHF
2，
最佳地选自甲氧基，乙氧基，-OCD
3，-OCF
3，-OCH
2F，或-OCHF
2。
在一个实施例中，所述取代或未取代的(C
3-C
6)环烷基选自取代或未取代的环丙基，取代或未取代的环丁基，取代或未取代的环戊基，或取代或未取代的环己基。
在一个实施例中，R
1选自H，F，Cl，Br，-CN，甲基，甲氧基，-OH；R
1较佳地选自F，Cl，-CH
3，-CN，-OH，R
1更佳地选自F。
在一个实施例中，R
2选自H，F，Cl，Br，-CN，甲基，甲氧基，-OH；R
2选自较佳地选自F，Cl，-CH
3，-CN，-OH，R
2更佳地选自F。
在一个实施例中，R
1选自F,Cl,Br,-CN，-CH
3,-OCH
3，-CF
3，-OCF
3；R
2选自H。
在一个实施例中，R
2选自F,Cl,Br,-CN，-CH
3,-OCH
3，-CF
3，-OCF
3；R
1选自H。
在一个实施例中，R
1选自F；R
2选自H。
在一个实施例中，R
2选自F；R
1选自H。
较佳地，通式(I)中，R
4，R
5，R
6，R
7，R
8中有一个选自-CN，-NO
2，-CH＝CH
2，-C≡CH，
-OCF
3，-OCH
2F，-OCHF
2，-CD
3，-OCD
3，-CF
3。
在一个实施例中，R
4选自H，F，Cl，Br，-CH
3，-CH
2CH
3，-CF
3，-OCH
3，-OCH
2CH
3，-CH＝CH
2，-C≡CH，-OCF
3，-OCH
2F，-OCHF
2，-CD
3，-OCD
3，-CN，-NO
2，
R
4较佳地选自H，F，-CN，-OCH
3，-OCF
3，-OCD
3，-CD
3；R
4更佳地选自H，F；R
4最佳地选自H；
在一个实施例中，R
5选自H，F，Cl，Br，-CH
3，-CH
2CH
3，-CF
3，-OCH
3，-OCH
2CH
3，-CH＝CH
2，-C≡CH，-OCF
3，-OCH
2F，-OCHF
2，-CD
3，-OCD
3，-CN，-NO
2，
R
5较佳地选自H，F，-CN，-OCH
3，-OCF
3，-OCD
3，-CD
3；R
5更佳地选自H，F；R
5最佳地选自H；
在一个实施例中，R
6选自H，F，Cl，Br，-CH
3，-CH
2CH
3，-CF
3，-OCH
3，-OCH
2CH
3，-CH＝CH
2，-C≡CH，-OCF
3，-OCH
2F，-OCHF
2，-CD
3，-OCD
3，-CN，-NO
2，
R
6较佳地选自H，F，-CN，-OCH
3，-OCF
3，-OCD
3，-CD
3；R
6更佳地选自F，-CN；R
6最佳地选自-CN；
在一个实施例中，R
7选自H，F，Cl，Br，-CH
3，-CH
2CH
3，-CF
3，-OCH
3，-OCH
2CH
3，-CH＝CH
2，-C≡CH，-OCF
3，-OCH
2F，-OCHF
2，-CD
3，-OCD
3，-CN，-NO
2，
R
7较佳地选自H，F，-CN，-OCH
3，-OCF
3，-OCD
3，-CD
3；R
7更佳地选自H，F，-OCH
3；R
7最佳地选自-OCH
3；
在一个实施例中，R
8选自H，F，Cl，Br，-CH
3，-CH
2CH
3，-CF
3，-OCH
3，-OCH
2CH
3，-CH＝CH
2，-C≡CH，-OCF
3，-OCH
2F，-OCHF
2，-CD
3，-OCD
3，-CN，-NO
2，
R
8较佳地选自H，F，-CN，-OCH
3，-OCF
3，-OCD
3，-CD
3；R
8更佳地选自F，H；R
8最佳地选自F；
较佳地，通式(I)所示的异吲哚啉衍生物选自下列任一化合物：
氘(D或者
2H)是氢的一种稳定形态的非放射性同位素，其原子量为2.0144。天然中的氢是以H(氢或氕)、D(
2H或氘)和T(
3H或氚)同位素混合物的形式存在的，其中氘的丰度为0.0156％。根据本领域普通技术知识，所有含有天然氢原子的化合物结构式中，氢原子实际上表示的是H、D与T的混合物。因此，化合物中任何位点处的氘丰度大于其自然丰度0.0156％时，这些化合物都应该被认为是非天然的或氘富集的，因此，这些化合物相对于其非富集对应物来说是新颖的。
本发明中，“D”，“氘”或“氘富集”化合物意指在通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、代谢物或前药的化合物中的任何相关位点处的氘的丰度大于其在该位点处的自然丰度。因此，在“D”，“氘”或“氘富集”化合物中，其相关位点中的任一者处的氘丰度都可能在大于0.0156％到100％的范围内。氘富集的位点以D表示，非氘富集的位点用H表示。根据本领域普通技术知识，非氘富集的位点还可以省略符号H。获得氘富集化合物的方法的实例是用氘交换氢或者用氘富集起始物质合成化合物。
本发明中，所给出的氘富集中氘的百分含量或氘丰度中氘百分含量均是指摩尔百分含量。
本发明中，非氘富集是指自然中的氢，即以H(氢或氕)、D(
2H或氘)和T(
3H或氚)同位素混合物的形式存在的。
本发明还提供了一种通式(I)所示的异吲哚啉衍生物的制备方法，其可以用商业上可获得的原料，通过化学合成领域通常使用的方法合成得到，例如可参考WO2016065980A1，WO2019014100A1等中公开的合成方法。
在一个实施例中，可以由化合物A-01反应得到通式(I)化合物，
其中，X,X
1-X
5,*,R
1,R
2,R
4,R
5,R
6,R
7,R
8的定义均同前所述，Ra和Rb一个为
另一个为
R
a’，R
b’独立地为H。
本发明还提供一种药物组合物，其包括治疗和/或预防有效量的前述的通式(I)所示的异吲哚啉衍生物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体。
根据本发明的实施例，所述的药物组合物可以配制用于任何形式给药，包括注射(静脉内)、粘膜、口服(固体和液体制剂)、吸入、眼部、直肠、局部或胃肠外(输注、注射、植入、皮下、静脉内、动脉内、肌内)给药。本发明的药物组合物还可以是控释或延迟释放剂型。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干制剂、注射用悬浮液和注射用乳剂。通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、代谢物，前药或立体异构体的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂；气雾剂：如鼻腔喷雾剂或吸入剂；适于胃肠外给药的液体剂型；栓剂以及锭剂。
根据本发明的药物组合物可进一步包含药学上可接受的辅料，如药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。
根据本发明的实施例，药学上可接受的辅料可以包括一种或多种粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂或增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。药学上可接受的载体根据给药所需的制剂形式可以采取多种形式。例如，对于液体口服制剂，合适的载体和添加剂包括水、二醇类、油类、醇类、调味剂、防腐剂、着色剂等。作为另一个说明性示例，对于固体口服制剂、合适的载体和添加剂包括淀粉、糖类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。药学上可接受的载体或辅料通常应该是无毒的。根据本发明的药物组合物可以包含一种或多种合适的载体/辅料。辅料的量和类型将根据需要变化。本领域普通技术人员将能够根据当前的公开内容容易地确定要添加到本发明的药物组合物中的适当载体/辅料。
本发明的药物组合物，即包含治疗或预防有效量的本发明提供的通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体，可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如，根据本发明的药物组合物可以通过混合通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、代谢物，或前药，与药学上可接受的载体，根据常规的药物配料技术来制备，这些技术包括但不限于常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
根据本发明的实施例，药物组合物中除了通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体中的一种或多种之外，可进一步包含一种或多种其他治疗剂。可包括在本发明的药物组合中的其它治疗剂的更多内容将在下文披露。其它治疗剂的量和类型将取决于要进行治疗或预防的疾病、病症或病况；疾病、病症或病况的严重程度；接受组合物给药的受试者的因素，如年龄、体重、身体状况等；给药途径等。
在本发明中的某些实施例中，治疗或预防量的通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体、其任何药物组合物、制剂等，可以以本发明中的方法在一段时间(给药周期)内给予受试者，其后是一段不给予化合物的时期(非给药周期)。可以重复所需次数的给药周期和非给药周期。给药周期或者非给药周期的所需长度和次数将取决于正在治疗或预防的疾病、病症或病况的类型和/或严重程度，以及受试者个体的性别、年龄、体重和其他参数(例如，受试者个体的生物学、身体和生理状况等)。根据本文件公开的内容本领域普通技术人员的技术水平将足以确定给药周期和/或非给药周期的适当长度和次数。
根据本发明的实施例，根据本发明的通式(I)所示的化合物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体与其它治疗剂联合使用，根据本发明公开内容，可以在治疗或预防任何疾病、病症或病况中发挥协同作用。
根据本发明的实施例，其它治疗剂可以是天然存在的、半合成的或合成的化合物。在另一个实施例中，其它治疗剂可以是小分子，如合成的有机或无机分子；或较大的分子或生物分子，例如具有药理活性的蛋白质或核酸。在另一个实施例中，其它治疗剂可以是抗血管生成、免疫调节、免疫治疗、化学治疗或激素化合物。
在本发明的一个实施例中，将一种包含通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体，和另外一种治疗剂的组合物同时给予受试者。在另一个实施例中，通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体，和另外一种治疗剂按顺序依次给药。在另一个实施例中，通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体，和另外一种治疗剂分别单独给药。另外一种治疗剂可以在给予根据本发明的通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体之前、连续或之后给予。
根据本发明可与通式(I)化合物或其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体联合给药的一个或多个其它治疗剂将取决于多种因素，例如，需进行预防或治疗的疾病、病症或病况等。本领域普通技术人员能够根据本发明的公开内容，很容易地确定将与通式(I)所示的异吲哚啉衍生物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药，或立体异构体联合所用合适的其它治疗剂。
根据本发明的一个实施方式，当根据本发明通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体与其它治疗剂联合给药时，通式(I)所示的化合物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体的治疗有效量低于通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药，或立体异构体不与其它治疗剂联合给药时将需要的治疗有效量。在另一个实施例中，另一种治疗剂的治疗有效量低于不给予根据本发明通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体时的有效量。
根据本发明的实施例，当将通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药，或立体异构体和其它治疗剂给予受试者以治疗或预防疾病、病症或病况时，通式(I)化合物、其药 学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体和其它治疗剂可通过相同的途径给药，也可通过不同的途径给药。其它治疗剂可通过本文描述的任何途径给药，包括但不限于口服、吸入、注射、眼部、粘膜、直肠、乳剂、脂质体、长效植入或持续缓释方法。其它治疗剂的具体给药途径将依赖于其它治疗剂本身及制剂，以及需预防或治疗的疾病、病症或病况。根据本公开内容，本领域中一名普通技术人员的技能水平足以确定其它治疗剂的给药途径。
根据本发明的通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体可用于多种用途，包括但不限于用于制备通过诱导细胞中的靶标蛋白泛素化和降解从而治疗相关疾病、病症或病况的药物。
因此，在另一个总方面，本发明涉及通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构在制备治疗或预防疾病、病症或病况的药物中的应用。在另一方面，本发明涉及一种通过诱导细胞中的靶标蛋白泛素化和降解治疗或预防相关的疾病、病症或病况的方法，所述的方法通过给予受试者治疗或预防有效量的通式(I)所示的异吲哚啉衍生物、其药学上可接受的盐、溶剂化物、代谢物、前药或立体异构体。根据本发明的方法，此类待治疗或预防的疾病、病症和病况的实例包括但不限于癌症。
在一个优选实施例中，疾病、病症或病况是癌症，优选多发性骨髓瘤。
本文中引用或描述了各种出版物、文章和专利，引用或描述这些参考文献或将其整体并入本文或对之进行的讨论是为了说明本发明的背景，并非是指其中的内容构成了本发明现有技术的一部分。
除非另有定义，本文所用所有技术和科学术语与本发明所属领域的普通技术人员通常理解的含义相同。否则，此处所用的某些术语的含义具有本说明书所设定的含义。此处引用的所有专利、已经公开的专利申请和出版物均通过引用并入到本文中，如同在此处全面阐述一样。应当注意的是，除非上下文明确表示另有规定外，用于此处和所附权利要求中的单数形式均包含复数含义。
如本文中所用，当提到具体盐、组合物、辅料等“药学上可接受的”时，是指该盐、组合物、辅料等一般无毒、安全，并且适合于受试者使用，优选哺乳动物受试者，更优选为人受试者。
本文所用术语“药学上可接受的盐”指药学上可接受的有机或无机盐。
如本文所用，术语“代谢物”是指药物分子在体内所经历的化学结构的变化后产生的活性物质，该活性物质一般为前述药物分子的衍生物，其还可被化学修饰。
如本文所用并且除非另有规定，术语“晶型(polymorph)”是指在结晶时，分子在晶格空间的排列不同而形成的一种或多种晶体结构。
如本文所用，术语“溶剂化物”是指通式(I)化合物、其药学上可接受的盐、晶型、立体异构体、代谢物或前药的一种晶体形式，它还包含一种或多种融入晶体结构中的溶剂分子。溶剂化物可包括化学计量量或非化学计量量的溶剂，并且溶剂中的溶剂分子可能以有序或非有序排列的形式存在。含有非化学计量量溶剂分子的溶剂化物可能是溶剂化物至少丢失一个(但并非全部)溶剂分子得到的。在一个特定实施例中，一种溶剂化物是一种水合物，意味着化合物的结晶形式进一步包括水分子，以水分子作为溶剂。
如本文所用并且除非另有规定，术语“前药”是指包含生物反应官能团的化合物的衍生物，使得在生物条件下(体外或体内)，生物反应官能团可从化合物上裂解或以其他方式发生反应以提供所述化合物。通常，前药无活性，或者至少比化合物本身活性低，使得直到将所述化合物从生物反应官能团上裂解后才能发挥其活性。生物反应官能团可在生物条件下水解或氧化以提供所述化合物。例如，前药可包含可生物水解的基团。可生物水解的基团实例包括但不限于可生物水解的磷酸盐、可生物水解的酯、可生物水解的酰胺、可生物水解的碳酸酯、可生物水解的氨基甲酸酯和可生物水解的酰脲。
本发明的通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、代谢物或前药可以含有一个或多个不对称中心(“立体异构体”)。如本文所用，术语“立体异构体”是指对映异构体、非对映异构体、差向异构体(epimers)、内向-外向异构体(endo-exo isomers)、阻转异构体(atropisomers)、位向异构体(regioisomers)、顺式-和反式-异构体等在内的所有立体异构体。本文的“立体异构体”也包括前述各种立体异构体的“纯立体异构体”及“富集立体异构体”或“消旋体”。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集，还可以通过与其它手性化合物成键(化学结合等)或成盐(物理结合等)等方式进行手性拆分获得。本文的“纯立体异构体”是指所涉化合物的一种立体异构体相对于该化合物的其它种立体异构体的质量含量不低于95％。本文的“富集立体异构体”是指所涉化合物的一种立体异构体相对于该化合物的其它种立体异构体的质量含量不低于50％。本文的“消旋体”是指所涉化合物的一种立体异构体的质量含量与该化合物的其它种立体异构体的质量含量相等。
如本文所用，术语“受试者”是指根据本发明的实施例，即将或已经接受了该化合物或组合物给药的任何动物，哺乳动物为优，人类最优。如本文所用术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等，以人类为最优。
在一个实施例中，“治疗”或“正在治疗”是指疾病或病症或其至少一个可辨别症状的改善、预防或逆转，例如通过减少或稳定癌症或病症症状，治疗癌症、不期望的血管生成相关病症。在另一个实施例中，“治疗”或“正在治疗”是指正在治疗的疾病或病症的至少一个可测量身体参数的改善、预防或逆转，可能并未在哺乳动物中识别所述疾病或病症。然而在另一个实施例中，“治疗”或“正在治疗”是指减慢疾病或病症的进展，或者是身体上的，例如可辨别症状的稳定，或生理学上的，例如，身体参数的稳定，或两者兼而有之。在另一个实施例中，“治疗”或“正在治疗”是指延迟疾病或病症的发作。
在某些实施例中，关注化合物作为预防措施给药。如本文所用，“预防”或“正在预防”是指降低获得给定疾病或病症的风险。在实施例的优选模式中，将指定化合物作为预防措施给予受试者，例如有癌症或自身免疫性疾病家族病史或倾向的受试者。
如本文所用，“治疗有效量”是指能够引起组织系统、动物或人产生生物学或医学反应(研究员、兽医、医生或其他临床医生正在寻求的)的化合物或组合物的量，其可以包括减轻正在治疗的疾病或病症症状。在一个优选实施例中，治疗有效量是有效治疗、改善治疗或预防癌症、病症或不期望的血管相关病况。
术语“预防有效量”是指能够抑制受试者中病症发作(研究员、兽医、医生或其它临床医生所寻求的) 的活性化合物或药剂的量。化合物的预防有效量是指治疗剂单独使用或联合其它治疗活性化合物所用的量，其在治疗或预防疾病、病症或病况中能够提供治疗益处。
如无另外说明，本文所用术语的单数形式“一个”或“一种”也包括复数意义。
如无另外说明，本文使用“或”或“和”指“和/或”。
如无另外说明，本文具体基团中出现的
是指连接位置。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：
本发明通式(I)所示的异吲哚啉衍生物能够诱导细胞中的靶标蛋白泛素化和降解，从而有效的治疗癌症等相关疾病。
实验数据表明，本申请化合物针对多发性骨髓瘤有很好的抑制效果。
实施例1
化合物I-1
合成路线：
步骤A.氮气保护下，将3-羟基-2-甲基苯甲酸(CAS 603-80-5,30.0g,197mmol)溶于无水甲醇(400mL)中，0℃下滴加DMF(2mL)，氯化亚砜(70.3g,591mmol)。滴加完毕，将此反应液加热回流，反应过夜。然后冷却至室温(25℃)，将反应液减压浓缩至干，残液溶解于乙酸乙酯(250mL)，依次经饱和碳酸氢钠水溶液(250mL)，水(250mL)以及饱和食盐水(250mL)洗涤，无水硫酸钠干燥，减压浓缩可得灰色固体3-羟基-2-甲基苯甲酸甲酯(30.5g,收率:93％)。
1H NMR(CDCl
3,300MHz):δ7.41(dd,J＝8.1,1.2Hz,1H),7.10(td,J＝7.8,0.6Hz,1H),6.94(dd,J＝8.1,1.2Hz,1H),5.25(s,1H),3.89(s,3H),2.45(s,3H).
步骤B.氮气保护下，将3-羟基-2-甲基苯甲酸甲酯(30.5g,184mmol)和咪唑(31.2g,459mmol)溶解于无水DMF(200mL)中,冰浴降至0℃。向溶液中分批加入TBDMSCl(叔丁基二甲基氯硅烷，33.2g,220mmol)，升至室温搅拌过夜。反应液减压浓缩，加入乙酸乙酯(250mL)和水(250mL)，分离有机相。乙酸乙酯(250mL)反萃水相，合并有机相，依次用水(250mL)和饱和食盐水(250mL)洗涤，无水硫酸钠干燥，减压浓缩可得黄色液体3-((叔丁基二甲基硅)氧)-2-甲基苯甲酸甲酯(51.5g，收率:100％)，直接用于下一步反应。
1H NMR(CDCl
3,300MHz):δ7.42(dd,J＝7.8,1.2Hz,1H),7.05-7.11(m,1H),7.42(dd,J＝8.1,1.2Hz,1H),3.87(s,3H),2.42(s,3H),1.02(s,9H),0.21(s,6H).
步骤C.将化合物3-((叔丁基二甲基硅)氧)-2-甲基苯甲酸甲酯(51.5g,184mmol)，AIBN(1.49g,9.2mmol)和NBS(39.3g,220mmol)加入到四氯化碳(600mL)中，回流反应过夜。将反应液减压浓缩后柱层析(石油醚/乙酸乙酯＝20/1)可得浅黄色液体2-溴甲基3-((叔丁基二甲基硅)氧)苯甲酸甲酯(63.1g，收率:96％)。
1H NMR(CDCl
3,300MHz):δ7.51(dd,J＝7.5,1.2Hz,1H),7.22(t,J＝8.1Hz,1H),6.98(dd,J＝8.4,1.5Hz,1H),5.02(s,2H),3.92(s,3H),1.06(s,9H),0.30(s,6H).
步骤D.将化合物2-溴甲基3-((叔丁基二甲基硅)氧)苯甲酸甲酯(5.00g,13.9mmol)和化合物
(CAS 108607-02-9，3.65g,15.3mmol)溶于无水乙腈(50mL)中，氮气氛围下室温(30℃)滴加二异丙基乙胺(5.20mL,29.2mmol)。升温至40℃搅拌过夜。将反应液减压浓缩，用二氯甲烷(100mL)稀释，水洗(50mL×2)，饱和食盐水(30mL)洗，无水硫酸钠干燥，减压浓缩，得浅黄色油状物。所得油状物溶于DMF(17.2mL)，0℃下滴加K
2CO
3(884mg,6.40mmol))的水(1.89mL)溶液。滴毕，升至室温(25℃)，搅拌50分钟。在0℃下向反应液中滴加1N稀盐酸(11mL)至中性，减压浓缩，柱层析(二氯甲烷/甲醇＝50/1)可得白色泡状物I-1 1.40g，收率:22％。
1H NMR(CDCl
3,300MHz):δ8.81(br s,1H),7.20-7.31(m,2H),6.95-6.98(m,2H),6.09(br s,1H),4.94-4.99(m,1H),4.56(d,J＝17.7Hz,1H),4.43(d,J＝17.4Hz,1H),2.08-2.35(m,4H),1.39(s,9H).
实施例2
化合物I-2
合成路线：
步骤A.将2-氟-4-甲基苯甲酸(50g,324.4mmol,CAS 7697-23-6)溶于400mL DMF中，加入K
2CO
3(67g,486mmol)，室温搅拌0.5小时，在0℃下加入碘甲烷(26.3mL,422mmol)，室温反应16小时。反应液倒入1500mL水中，EtOAc(500mL x 2)萃取，饱和食盐水(500mL x 2)洗涤，干燥，减压浓缩得产物2-氟-4-甲基苯甲酸甲酯(51g,收率:94％)为白色固体，无需纯化直接用于下一步。
步骤B.将2-氟-4-甲基苯甲酸甲酯(48g,285mmol)溶于400mL CCl
4中，加入NBS(N-溴代丁二酰亚胺，55.9g,314mmol),BPO(13.8g,57.2mmol),反应液油浴加热80℃反应过夜。冷却至室温，过滤，减压浓缩，残余物分散于500mL EtOAc中，饱和食盐水(500mL x 2)洗涤，干燥，减压浓缩得黄色固体产品[methyl 4-(bromomethyl)-2-fluorobenzoate](70g)。将上述固体产物[methyl 4-(bromomethyl)-2-fluorobenzoate](70g)，N-Boc哌嗪(35g,0.188mol,CAS 57260-71-6),加入DMF(500mL)中，加入K
2CO
3(65g,0.47mol)，油浴加热70℃反应16h，冷却到室温，然后过滤，EtOAc(200mL)洗涤，EtOAc萃取(500mL x 3)，水洗，食盐水洗，干燥，滤液减压浓缩至干得黄色的油状 产物[tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)benzyl)piperazine-1-carboxylate](80g).MS(ESI)m/z 353.4[M+H]
+.
步骤C.将化合物[tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)benzyl)piperazine-1-carboxylate](80g)溶于EtOAc(500mL),加入HCl/EtOAc(5N，400mL),反应液室温下搅拌16小时,析出的固体过滤，固体减压浓缩干燥后到盐酸盐I-2。MS(ESI)m/z 253.2[M+H]
+.
实施例3
化合物CM-1
合成路线：
步骤A.将化合物CM-1A[3,4-difluorobenzonitrile](11.8g，84.83mmol，CAS 64248-62-0),N-Boc-哌嗪(18.96g,101.8mmol),加入到DMSO(100mL)中，加入K
2CO
3(17.56g，127.2mmol),油浴加热100℃过夜，冷却到室温，然后倒入600毫升水里，搅拌15分钟，然后过滤水洗，滤饼油泵减压浓缩至干得到白色固体CM-1C(28克)，然后加入HCl/EA(5M,300mL)，室温搅拌过夜，过滤，滤饼油泵减压浓缩至干得到白色固体CM-1D[3-fluoro-4-(piperazin-1-yl)benzonitrile hydrochloride](23.0g),MS：[M+H]
+＝206.1.
步骤B.将CM-1E，即2-氯-4-甲基苯甲酸(5g,29.3mmol,CAS 7697-25-8)溶于40mL DMF中，加入K
2CO
3(6.1g,44mmol)，室温搅拌0.5小时，在0℃下加入碘甲烷(5.4g,38.1mmol)，室温反应4小时。反应液倒入300mL水中，EtOAc(200mL x 2)萃取，饱和食盐水(200mL x 2)洗涤，干燥，减压浓缩得产物2-氯-4-甲基苯甲酸甲酯CM-1F(5.2g,收率:96％)为黄色油状物，无需纯化直接用于下一步。
步骤C.将CM-1F(5.0g,27.1mmol，CAS 195318-63-9)溶于100mL CCl4中，加入NBS(5.7g,32.5mmol),BPO(354mg,1.46mmol),反应液油浴加热80℃反应过夜。冷却至室温，过滤，饱和食盐水 (100mL x 2)洗涤，干燥，减压浓缩，硅胶柱层析纯化(PE/EtOAc＝100:1～80:1)得黄色液体CM-1G[methyl 4-(bromomethyl)-2-chlorobenzoate](4.4g,收率：61％)。
1H NMR(400MHz,CDCl
3)δ7.83-7.81(m,1H),7.69(s,1H)，7.54-7.52(m,1H),4.74(s,2H),3.86(s,3H).
步骤D.将化合物CM-1G(4.0g,15mmol)和CM-1D(3.62g,15mmol),加入到CH
3CN(80mL)，随后加入K
2CO
3(2.34g,38mmol)，油浴加热80℃ 16h，冷却到室温，然后过滤，EtOAc洗涤，EtOAc萃取(50mL x 2)，水洗，食盐水洗，干燥，滤液减压蒸发至干得黄色的固体CM-1H[methyl 2-chloro-4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)benzoate](4.5g,11.6mmol,77％).MS：[M+H]
+＝388.1.
步骤E.参照实施例7化合物CM-3中步骤B-D的合成方法，用CM-1H替换CM-3C，即可合成化合物CM-1L[tert-butyl-(S)-5-amino-4-(4-((2-chloro-4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate]。
MS:[M+H]
+＝676.2.
步骤F.参照实施例9化合物CM-6中步骤E-F的合成方法，用CM-1L替换CM-6G[tert-butyl(S)-5-amino-4-(4-((4-((4-(4-cyano-3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-2-fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate]，即可合成化合物CM-1。
1H NMR(400MHz,DMSO-d
6)δ10.96(s,1H),7.70-7.57(m,2H),7.49-7.48(m,3H),7.38-7.34(m,3H),7.14-7.09(m,1H),5.29(s,2H),5.13-5.09(m,1H),4.41(d,J＝17.6Hz,1H),4.26(d,J＝17.6Hz,1H),3.57(s,2H),3.20-3.18(m,4H),2.95-2.86(m,1H),2.59-2.39(m,6H),2.00-1.95(m,1H).
MS:[M+H]
+＝602.2.
e.e.＝99.8％
实施例4
化合物CM-2
合成路线
将1,2-二氟-4-硝基苯(1.50g,9.43mmol),I-2(2.72g,9.43mmol)和N,N,-二异丙基乙胺(4.26g,33.00mmol)加入到乙腈(30mL)中,油浴加热80℃搅拌16小时。反应液减压浓缩经制备高效液相色谱纯化得产物CM-2C[methyl 2-fluoro-4-((4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)methyl)benzoate](1.72g,收率:47％)，棕色固体。
1H NMR(400MHz,DMSO-d
6)δ8.02-7.98(m,2H),,7.89-7.85(m,1H),7.32-7.30(m,2H),7.18-7.14(m,1H),3.85(s,3H),3.62(s,2H),3.36-3.27(m,4H),2.57-2.50(m,4H).MS(ESI)m/z 392.4[M+H]
+.
参照实施例9化合物CM-6中的合成方法，用相应的底物CM-2C替换化合物CM-6C[methyl 4-((4-(4-cyano-3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-2-fluorobenzoate],即可合成化合物CM-2[(S)-3-(4-((2-fluoro-4-((4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione]。
1H NMR(400MHz,DMSO-d
6)δ10.95(s,1H),8.06-7.96(m,2H),7.61-7.48(m,2H),7.42-7.31(m,2H),7.28-7.11(m,3H),5.27(s,2H),5.13-5.08(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.58(s,2H),3.23-3.14(m,4H),2.96-2.83(m,1H),2.60-2.52(m,5H),2.48-2.37(m,1H),1.99-1.96(m,1H).
MS(ESI)m/z 606.2[M+H]
+.e.e.＝99.4％
实施例5
化合物CM-5
参照实施例4化合物CM-2的合成方法，采用化合物
(CAS 3939-09-1)代替起始化合 物CM-2A，即可合成化合物CM-5[(S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-3-fluorobenzyl)piperazin-1-yl)-2-fluorobenzonitrile]。
1H NMR(400MHz,DMSO-d
6)δ10.95(s,1H),7.61-7.49(m,3H),7.40-7.34(m,2H),7.24-7.20(m,2H),6.95-6.83(m,2H),5.27(s,2H),5.13-5.08(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.56(s,2H),3.45-3.36(m,4H),2.96-2.83(m,1H),2.61-2.53(m,1H),2.48-2.40(m,5H),1.99-1.96(m,1H).
MS(ESI)m/z 586.2[M+H]
+.
实施例6
化合物CM-7
参照实施例4化合物CM-2的合成方法，将化合物
(CAS 191014-55-8)代替起始化合物CM-2A，即可合成化合物CM-7[(S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-3-fluorobenzyl)piperazin-1-yl)-2-methoxybenzonitrile]。
1H NMR(400MHz,DMSO-d
6)δ10.95(s,1H),7.58-7.49(m,2H),7.43-7.34(m,3H),7.24-7.21(m,2H),6.60-6.52(m,2H),5.28(s,2H),5.13-5.08(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.86(s,3H),3.37(s,2H),3.40-3.34(m,4H),2.96-2.85(m,1H),2.60-2.51(m,5H),2.47-2.37(m,1H),1.99-1.96(m,1H).
MS(ESI)m/z 598.3[M+H]
+.
实施例7
化合物CM-3
合成路线：
步骤A.化合物I-2[methyl 2-fluoro-4-(piperazin-1-ylmethyl)benzoate hydrochloride](2.70g,9.35mmol),CM-1A[3,4-difluorobenzonitrile](1.18g,8.50mmol)和DIEA(3.29g,25.5mmol)加入到DMSO (15mL)中,油浴加热100℃搅拌3小时。反应液倒入冰水中，EtOAc(60mL x 3)萃取，有机相用饱和盐水洗，干燥浓缩,经反相制备得产物CM-3C[methyl 4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)-2-fluorobenzoate](2.50g,6.74mmol,yield:79％)，黄色固体。MS:[M+H]
+＝372.1.
步骤B.化合物CM-3C(2.50g,6.74mmol)溶于THF/MeOH(30mL/10mL)中，在0℃下分批加入LiBH
4(0.51g,23.55mmol)，氮气保护下室温搅拌16小时。反应液倒入冰水中，EtOAc(50mL x 3)萃取，有机相用饱和盐水洗，干燥浓缩,经反相制备得产物CM-3D[3-fluoro-4-(4-(3-fluoro-4-(hydroxymethyl)benzyl)piperazin-1-yl)benzonitrile](1.20g，收率:52％)，类白色固体。
1H NMR(400MHz,CDCl
3)δ7.39-7.34(m,2H),7.28-7.24(m,1H),7.13-7.08(m,2H),6.92-6.88(m,1H),4.75(s,2H),3.56(s,2H),3.49(s,1H),3.24-3.22(m,4H),2.63-2.60(m,4H).MS[M+H]
+＝344.4.
步骤C.在0℃下将SOCl
2(1.25g,10.50mmol)缓慢加入到化合物CM-3D(1.20g,3.50mmol)的DCM(15mL)溶液中,室温搅拌3小时。反应液浓缩得粗产物CM-3E[4-(4-(4-(chloromethyl)-3-fluorobenzyl)piperazin-1-yl)-3-fluorobenzonitrile hydrochloride](1.4g),白色固体。
MS[M+H]
+＝362.1.
步骤D.将化合物I-1(611mg,1.83mmol),CM-3E(800mg,2.01mmol)和Cs
2CO
3(1.49g,4.57mmol)加入到DMSO(15mL)中，室温下搅拌2小时。过滤，滤饼用EtOAc洗，将滤液倒入冰水中，EtOAc(50mL x 3)萃取，有机相用饱和食盐水(100mL x3)洗涤，干燥后浓缩，得到的粗品经反相制备得到产品CM-3G[tert-butyl(S)-5-amino-4-(4-((4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)-2-fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate](600mg,0.91mmol,收率:50％)，类白色固体。
1H NMR(400MHz,CDCl
3)δ7.48-7.35(m,4H),7.29-7.25(m,1H),7.18-7.12(m,3H),6.93-6.89(m,1H),6.32(m,1H),5.32(m,1H),5.19(s,2H),4.93-4.85(m,1H),4.55-4.36(m,2H),3.59(s,2H),3.28-3.22(m,4H),2.70-2.58(m,4H),2.42-2.08(m,4H),1.42(s,9H).MS[M+H]
+＝660.2.
步骤E.将化合物CM-3G(600mg,0.91mmol)和对甲苯磺酸(469mg,2.73mmol)的CH
3CN(15mL)溶液90℃下搅拌4小时。反应液浓缩，用EtOAc/THF(30mL/30mL)稀释，0-5℃下加入NaHCO
3水溶液至pH>7。有机相用饱和食盐水(80mL)洗涤，干燥后浓缩，得到的粗品经Prep-HPLC纯化得到产品CM-3[(S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-3-fluorobenzyl)piperazin-1-yl)-3-fluorobenzonitrile](170mg,0.29mmol,收率:32％)，类白色固体。
1H NMR(400MHz,DMSO-d
6)δ10.95(s,1H),7.71-7.65(m,1H),7.60-7.47(m,3H),7.42-7.31(m,2H),7.25-7.08(m,3H),5.27(s,2H),5.15-5.05(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.57(s,2H),3.23-3.14(m,4H),2.96-2.83(m,1H),2.60-2.52(m,5H),2.48-2.37(m,1H),2.02-1.92(m,1H).
MS(ESI)m/z 586.2[M+H]
+.
实施例8
化合物CM-4
步骤A.将3-氟-4-甲基苯甲酸甲酯(5g,29.8mmol,CAS：87808-48-8),NBS(5.56g,31.25mmol)和BPO(1.44g,5.95mmol)加入到CCl
4(60mL)中,油浴加热至80℃反应过夜。反应液过滤，滤液减压浓缩，硅胶柱层析纯化(PE/EtOAc＝100/1～30/1)得到化合物CM-4D[methyl 4-(bromomethyl)-3-fluorobenzoate](7g,粗品)，黄色油状。
步骤B.将化合物CM-4D(2.23g,9.04mmol),CM-1D(2.40g,9.94mmol)和K
2CO
3(3.12g,22.6mmol)加入到DMF(25mL)中,70℃搅拌16小时。反应液过滤，滤液减压浓缩，制备高效液相色谱纯化得产物CM-4E[methyl 4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)-3-fluorobenzoate](2.4g,收率71％),类白色固体。MS(ESI)m/z 372.4[M+H]
+.
步骤C.化合物CM-4E(2.40g,6.47mmol)溶于THF/MeOH(20mL/20mL)中，在0℃下分批加入LiBH
4(0.35g,16.17mmol)，室温搅拌16小时。反应液倒入冰水中，EtOAc(50mL x 3)萃取，有机相用饱和盐水洗，干燥浓缩,制备高效液相色谱纯化得产物CM-4F[3-fluoro-4-(4-(2-fluoro-4-(hydroxymethyl)benzyl)piperazin-1-yl)benzonitrile](1.3g,率:58％)，白色固体。
1H NMR(400MHz,DMSO-d
6)δ7.70-7.66(m,1H),7.57-7.54(m,1H),7.38-7.34(m,1H),7.13-7.08(m,3H),5.27(t,J＝6.4Hz,1H),4.49(d,J＝6.4Hz,2H),3.57(s,2H),3.18-3.16(m,4H),2.54-2.49(m,4H).MS(ESI)m/z 344.1[M+H]
+.
步骤D.在0℃下将SOCl
2(1.35,11.37mmol)缓慢加入到化合物CM-4F(1.3g,3.79mmol)的DCM(30mL)溶液中,室温搅拌3小时。反应液减压浓缩得产物CM-4G[4-(4-(4-(chloromethyl)-2-fluorobenzyl)piperazin-1-yl)-3-fluorobenzonitrile hydrochloride](1.4g),类白色固体。
MS(ESI)m/z 362.1,364.1[M+H]
+.
步骤E.将化合物CM-4G(1.50g,3.77mmol),化合物I-1(1.15g,3.44mmol)和K
2CO
3(1.18g,8.57mmol)的NMP(N-甲基吡咯烷，15mL)混合溶液50℃下搅拌16小时。过滤，将滤液倒入冰水中，EtOAc(50mL x 3)萃取，有机相用饱和食盐水(100mL)洗涤，干燥后减压浓缩，剩余物经制备高 效液相色谱纯化得到产品CM-4H[tert-butyl(S)-5-amino-4-(4-((4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)-3-fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate](1.80g,收率:79％)，类白色固体。
1H NMR(400MHz,DMSO-d
6)δ7.70-7.66(m,1H),7.57-7.44(m,4H),7.34-7.27(m,4H),7.17-7.08(m,2H),5.26(s,2H),4.76-4.70(m,1H),4.58-4.42(m,2H),3.60(s,2H),3.22-3.10(m,4H),2.60-2.52(m,4H),2.19-2.00(m,4H),1.32(s,9H).MS(ESI)m/z 660.2[M+H]
+.
步骤F.将化合物CM-4H(0.90g,1.36mmol)和对甲苯磺酸(0.705g,4.10mmol)的CH
3CN(20mL)溶液油浴加热90℃搅拌4小时。反应液减压浓缩，用EtOAc/THF(30mL/30mL)稀释，0-5℃下加入NaHCO
3水溶液至pH>7。有机相用饱和食盐水(100mL)洗涤，干燥后减压浓缩，剩余物经制备高效液相色谱纯化得到产品CM-4[(S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-2-fluorobenzyl)piperazin-1-yl)-3-fluorobenzonitrile](415mg,收率:52％)，白色固体。
1H NMR(400MHz,DMSO-d
6)δ10.97(s,1H),7.70-7.66(m,1H),7.7-7.44(m,3H),7.35-7.31(m,4H),7.13-7.08(m,1H),5.26(s,2H),5.14-5.09(m,1H),4.45(d,J＝17.2Hz,1H),4.29(d,J＝17.2Hz,1H),3.60(s,2H),3.24-3.11(m,4H),2.98-2.84(m,1H),2.64-2.52(m,5H),2.49-2.37(m,1H),2.05-1.93(m,1H).
MS(ESI)m/z 586.2[M+H]
+.
实施例9
化合物CM-6
步骤A.将化合物CM-6A[4-fluoro-2-(trifluoromethyl)benzonitrile](1.5g，7.93mmol，CAS 194853-86-6),I-2[methyl 2-fluoro-4-(piperazin-1-ylmethyl)benzoate hydrochloride](2.29g,7.93mmol),和K
2CO
3(2.74g,19.83mmol)，加入DMSO(20mL)中，油浴加热90℃反应7h，冷却到室温，然后过滤，EtOAc洗涤，滤液减压浓缩至干，硅胶柱层析纯化(PE:EtOAc＝5:1)得黄色固体产物CM-6C[methyl 4-((4-(4-cyano-3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-2-fluorobenzoate](3.0g，收率90％).MS(ESI)m/z 422.3[M+H]
+.
步骤B.将化合物CM-6C(3.0g,7.12mmol)溶于THF/MeOH(50mL，5mL)中，冰浴下将LiBH
4(0.93g,42.8mmol)分批加入反应瓶中，室温下搅拌16小时。冰浴下加入水淬灭反应，EtOAc(100mL x 2)萃取，食盐水洗(100mL)，干燥，减压浓缩，剩余物硅胶柱层析纯化(PE:EtOAc＝5:1,1：1,EtOAc)得白色固体产物CM-6D[4-(4-(3-fluoro-4-(hydroxymethyl)benzyl)piperazin-1-yl)-2-(trifluoromethyl)benzonitrile](2.5g,收率：90％)。
1H NMR(400MHz,DMSO-d
6)δ7.82(d,J＝8.8Hz,1H),7.42-7.30(m,1H),7.29-7.08(m,3H),5.21(t,J＝5.6Hz,1H),4.53(d,J＝5.6Hz,2H),3.53(s,2H),3.47-3.44(m,4H),2.51-2.47(m,4H).
步骤C.将化合物CM-6D(2.40g,6.10mmol)溶于CH
3CN(15mL)中，冰浴下将SOCl
2(2.18g,18.3mmol)加入反应瓶中，室温下搅拌2h。减压浓缩至干，EtOAc打浆，过滤减压浓缩得类白色固体产物CM-6E[4-(4-(4-(chloromethyl)-3-fluorobenzyl)piperazin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride](2.4g,收率：88％)。
1H NMR(400MHz,DMSO-d
6)δ11.96(s,1H),7.92(d,J＝8.8Hz,1H),7.67-7.62(m,2H),7.49-7.40(m,2H),7.31-7.28(m,1H),4.82(s,2H),4.39(s,2H),4.23-4.20(m,2H),3.55-3.49(m,2H),3.36-3.33(m,2H),3.12-3.10(m,2H).
步骤D.将化合物CM-6E(1.70g,3.79mmol)溶于DMSO(10mL)中，室温下加入Cs
2CO
3(3.1g,9.5mmol)，化合物I-1(1.27g,3.80mmol)，25℃下搅拌2小时。硅藻土过滤，EtOAc洗涤，将滤液倒入冰水中，EtOAc(50mL x 3)萃取，有机相用饱和食盐水(100mL x 3)洗涤，干燥后减压浓缩，得到的粗品经制备高效液相色谱纯化得到产品CM-6G[tert-butyl(S)-5-amino-4-(4-((4-((4-(4-cyano-3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-2-fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate](2.0g,收率:74％)，黄色固体。MS(ESI)m/z 710.3[M+H]
+.
步骤E.将化合物CM-6G(1.05g,1.48mmol)溶于DMF(3mL)中,加入4N HCl/dioxane(30mL),反应液室温下搅拌16小时,减压浓缩后得黄色油状物(1.0g)CM-6H[(S)-5-amino-4-(4-((4-((4-(4-cyano-3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-2-fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoic acid]。MS(ESI)m/z 654.6[M+H]
+.
步骤F.将化合物CM-6H(1.2g,粗品)溶于DMF/DCM(8mL/25mL)中,降温至-40℃，滴加入SOCl
2(881mg,7.40mmol)，反应1.5h后加入吡啶(1.17g,14.8mmol),-40℃搅拌1小时后缓慢滴加Et
3N(747mg,7.40mmol)搅拌1小时，缓慢加入10mL的水淬灭反应保持温度低于-40℃，-20℃下用NaHCO
3水溶液调节pH＝8,EtOAc/THF(60/30mL,x 3)萃取，Na
2SO
4干燥，减压浓缩至干得,制备HPLC纯化得白色固体产物CM-6[(S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-3-fluorobenzyl)piperazin-1-yl)-2-(trifluoromethyl)benzonitrile](202mg,两步收率：21％).
1H NMR(400MHz,DMSO-d
6)δ10.95(s,1H),7.84-7.82(m,1H),7.57-7.51(m,2H),7.40-7.20(m,6H),5.28(s,2H),5.13-5.08(m,1H),4.39(d,J＝17.6Hz,1H),4.23(d,J＝17.6Hz,1H),3.57-3.45(m,6H),2.95-2.86(m,1H),2.59-2.42(m,6H),1.99-1.95(m,1H).
MS(ESI)m/z 636.3[M+H]
+.
实施例10
参考实施例9中化合物CM-6的合成方法，采用相应的反应物制备得到化合物CM-8，CM-9，CM-11，CM-27，CM-28，CM-29，CM-30，CM-31，CM-35。
化合物CM-8
1H NMR(400MHz,DMSO-d
6)δ10.95(s,1H),8.16(d,J＝2.0Hz,1H),8.07-8.05(m,1H),7.58-7.49(m,3H),7.40-7.34(m,2H),7.24-7.20(m,2H),5.27(s,2H),5.12-5.08(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.57(s,2H),3.09-2.97(m,4H),2.96-2.83(m,1H),2.61-2.42(m,6H),2.04-1.90(m,1H).
MS(ESI)m/z 636.2[M+H]
+.
化合物CM-9
1H NMR(400MHz,DMSO-d
6)δ10.95(s,1H),7.98-7.93(m,1H),7.76-7.73(m,1H),7.58-7.49(m,2H),7.40-7.34(m,2H),7.25-7.20(m,3H),5.27(s,2H),5.13-5.08(m,1H),4.38(d,J＝17.6Hz,1H),4.23(d,J＝17.6Hz,1H),3.59(s,2H),3.12(br s,4H),2.95-2.86(m,1H),2.56-2.38(m,6H),2.00-1.95(m,1H).
MS(ESI)m/z 602.2[M+H]
+.
化合物CM-11
1H NMR(400MHz,DMSO-d
6)δ10.95(s,1H),7.58-7.48(m,3H),7.40-7.34(m,2H),7.24-7.20(m,2H),6.92(s,1H),6.84-6.82(m,1H),5.27(s,2H),5.13-5.08(m,1H),4.38(d,J＝18.0Hz,1H),4.23(d,J＝18.0Hz,1H),3.56(s,2H),3.34-3.29(m,4H),2.90-2.87(m,1H),2.59-2.54(m,1H),2.51-2.42(m,5H),2.07(s,3H),2.01-1.95(m,1H).
MS(ESI)m/z 582.3[M+H]+.
化合物CM-27
1H NMR(400MHz,DMSO-d
6)δ10.96(s,1H),7.59-7.48(m,2H),7.42-7.31(m,4H),7.24-7.19(m,2H),6.96(d,J＝8.0Hz,1H),5.27(s,2H),5.14-5.07(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.82(s,3H),3.56(s,2H),3.18-3.01(m,4H),2.96-2.82(m,1H),2.61-2.52(m,5H),2.47-2.38(m,1H),2.02-1.90(m,1H).
MS(ESI)m/z 598.2[M+H]
+.
化合物CM-28
1H NMR(400MHz,DMSO-d
6)δ10.96(s,1H),8.41(d,J＝2.4Hz,1H),7.75(d,J＝8.8Hz,1H),7.60-7.48(m,2H),7.42-7.32(m,3H),7.26-7.19(m,2H),5.27(s,2H),5.14-5.07(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.2Hz,1H),3.57(s,2H),3.46-3.37(m,4H),2.97-2.83(m,1H),2.61-2.53(m,1H),2.49-2.37(m,5H),2.02-1.91(m,1H).
MS(ESI)m/z 569.2[M+H]
+.
化合物CM-29
1H NMR(400MHz,DMSO-d
6)δ10.97(s,1H),8.47(s,1H),7.86-7.83(m,1H),7.58-7.50(m,2H),7.41-7.34(m,2H),7.24-7.20(m,2H),6.93-6.91(m,1H),5.27(s,2H),5.13-5.08(m,1H),4.41(d,J＝17.6Hz,1H),4.25(d,J＝17.6Hz,1H),3.68-3.66(m,4H),3.55(s,2H),3.12(m,4H),2.95-2.86(m,1H),2.59-2.51(m,1H),2.50-2.42(m,5H),2.00-1.95(m,1H).
MS(ESI)m/z 569.2[M+H]
+.
化合物CM-30
1H NMR(400MHz,DMSO-d
6)δ10.96(s,1H),8.25(s,1H),7.97-7.91(m,1H),7.60-7.48(m,2H),7.42-7.32(m,2H),7.26-7.20(m,3H),5.27(s,2H),5.15-5.06(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.59(s,2H),3.43-3.36(m,4H),2.96-2.83(m,1H),2.61-2.52(m,5H),2.47-2.36(m,1H),2.00-1.91(m,1H).
MS(ESI)m/z 593.2[M+H]
+.
化合物CM-31
1H NMR(400MHz,DMSO-d
6)δ10.97(s,1H),7.60-7.50(m,4H),7.41-7.34(m,2H),7.24-7.21(m,2H),7.11-7.08(m,1H),5.27(s,2H),5.13-5.09(m,1H),4.41(d,J＝17.6Hz,1H),4.25(d,J＝17.6Hz,1H),3.58(s,2H),2.95-2.86(m,5H),2.58-2.54(m,5H),2.46-2.42(m,1H),2.25(s,3H),1.99-1.95(m,1H).
MS(ESI)m/z 582.2[M+H]
+.
化合物CM-35
1H NMR(400MHz,DMSO-d
6)δ10.97(s,1H),7.64-7.50(m,4H),7.41-7.15(m,5H),5.27(s,2H),5.28(s，2H),5.13-5.09(m,1H),4.41(d,J＝17.6Hz,1H),4.20(d,J＝17.6Hz,1H),3.58(s,2H),2.92(m,5H),2.55-2.50(m,8H),1.98-1.96(m,1H),1.22(t,J＝7.2Hz,3H).
MS(ESI)m/z 596.2[M+H]
+.
实施例11
化合物CM-12
步骤A：将碘乙烷(2.56g,16.41mmol)加入到化合物CM-12A[2-羟基-4-氟苯腈](1.50g,10.94mmol)和K
2CO
3(3.02g,21.88mmol)的DMF(20mL)混合液中，室温下反应16小时。加入水(100mL)，乙酸乙酯萃取(100mL x 2)。有机相用饱和盐水洗，无水硫酸钠干燥，浓缩得到类白色固体产物CM-12B[2-乙氧基-4-氟苯腈](1.60g,88％yield)。
步骤B：将K
2CO
3(2.67g,19.38mmol)加入到化合物CM-12B[2-乙氧基-4-氟苯腈](1.60g,9.69mmol)和I-2[methyl 2-fluoro-4-(piperazin-1-ylmethyl)benzoate hydrochloride](3.15g,10.43mmol)的DMSO(20mL)溶液中,混合液在90℃搅拌16小时。将反应液倒入水(60mL)中，用EtOAc(50mL x2)萃取。有机相用饱和食盐水(60mL x 3)洗涤，无水Na
2SO
4干燥，过滤浓缩。剩余物经反相制备得黄色固体产物CM-12D[methyl 4-((4-(4-cyano-3-ethoxyphenyl)piperazin-1-yl)methyl)-2-fluorobenzoate](1.90g,收率:49％)。
步骤C：将化合物CM-12D(1.90g,4.78mmol)溶于THF(40mL)和MeOH(10mL)的混合液中，在0℃下分批加入LiBH
4(0.32g,14.36mmol)。反应液室温搅拌16小时。将反应液缓慢倒入冰氯化铵水溶液中，乙酸乙酯(40mL x 3)萃取，有机相用饱和盐水(80mL)洗涤，萃取。有机相用饱和食盐水(80mL)洗涤，无水Na
2SO
4干燥，过滤浓缩得粗产物,经反相制备得白色固体产物CM-12E[2-ethoxy-4-(4-(3-fluoro-4-(hydroxymethyl)benzyl)piperazin-1-yl)benzonitrile](1.20g,收率:68％)。
步骤D：在0℃下将SOCl
2(1.46g,12.24mmol)缓慢加入到化合物CM-12E(1.20g,3.25mmol)的DCM(30mL)溶液中,室温搅拌16小时。反应液浓缩得棕色固体(1.38g,crude)。室温下，将上述棕色固体(1.38g,3.25mmol),I-1[tert-butyl(S)-5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate](1.08g,3.25mmol)和Cs
2CO
3(3.18g,9.75mmol)加入到DMSO(20mL)中，室温下搅拌2小时。将反应液倒入冰水中，乙酸乙酯(50mL x 2)萃取，有机相用饱和食盐水(80mL x 3)洗涤，无水Na
2SO
4干燥，过滤，滤液浓缩。剩余物经反相制备得到黄色固体产品CM-12G[tert-butyl(S)-5-amino-4-(4-((4-((4-(4-cyano-3-ethoxyphenyl)piperazin-1-yl)methyl)-2-fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate](1.50g,yield:67％)。
1H NMR(400MHz,DMSO-d
6)δ7.57-7.31(m,6H),7.25-7.16(m,3H),6.57-6.54(m,2H),5.27(s,2H),4.72-4.69(m,1H),4.51(d,J＝17.6Hz,1H),4.37(d,J＝17.6Hz,1H),4.18-4.10(m,2H),3.57(s,2H),3.40-3.32(m,4H),2.49-2.43(m,4H),2.19-2.00(m,4H),1.31(s,9H).
MS(ESI)m/z 686.2[M+H]
+.
步骤F：室温下将HCl的二氧六环溶液(4N,30mL)加入到CM-12G(1.50g,2.19mmol)的二氧六环(20mL)溶液中。反应液30℃下搅拌2h。反应液浓缩得到中间体。在-45℃，氮气下，将SOCl
2(1.30g,10.94mmol)加入到上述中间体的DCM/DMF(70mL/10mL)溶液中。反应混合物在-45℃搅拌1小时。将吡啶(1.73g,21.90mmol)缓慢加入，反应物在-45℃下搅拌1小时。在-45℃下将三乙胺(1.10g,10.94mmol)缓慢加入反应液中，反应物在-45℃下搅拌1小时。反应液用水(10mL)淬灭，加入NaHCO
3水溶液调节pH>7，分离有机相。水相用EA/THF(30mL x 3,V/V＝1/1)萃取。合并有机相并用饱和NaCl溶液洗，干燥浓缩得粗品，经Prep-HPLC得到类白色固体CM-12(383mg,收率:29％)。
1H NMR(400MHz,DMSO-d
6)δ10.97(s,1H),7.59-7.50(m,2H),7.43-7.34(m,3H),7.25-7.20(m,2H),6.56-6.54(m,2H),5.27(s,2H),5.13-5.09(m,1H),4.38(d,J＝17.6Hz,1H),4.24-4.11(m,3H),3.56(s,2H),3.35-3.33(m,4H),2.90-2.87(m,1H),2.58-2.53(m,1H),2.49-2.42(m,5H),2.99-1.96(m,1H),1.34(t.J＝7.2Hz,3H).
MS(ESI)m/z 612.3[M+H]+.
实施例12
参考实施例11中化合物CM-12的合成方法，采用相应的反应物合成CM-10，CM-24，CM-33，CM-34，CM-39。
化合物CM-10
1H NMR(400MHz,DMSO-d
6)δ10.96(s,1H),7.58-7.50(m,4H),7.40-7.34(m,2H),7.24-7.20(m,2H),7.01-6.99(m,2H),5.27(s,2H),5.13-5.08(m,1H),4.41(d,J＝17.6Hz,1H),4.25(d,J＝17.6Hz,1H),3.56(s,2H),3.35-3.33(m,4H),2.95-2.86(m,1H),2.59-2.51(m,1H),2.50-2.38(m,5H),2.00-1.96(m,1H).
MS(ESI)m/z 568.3[M+H]
+.
化合物CM-24
1H NMR(400MHz,DMSO-d
6)δ10.96(s,1H),7.86(s,1H),7.65-7.41(m,4H),7.34-7.21(m,5H),7.06-7.02(m,1H),5.27(s,2H),5.13-5.08(m,1H),4.39(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.57(s,2H),3.16-3.02(m,4H),2.95-2.86(m,1H),2.64-2.52(m,5H),2.48-2.39(m,1H),1.99-1.95(m,1H).
MS(ESI)m/z 604.3[M+H]
+.
CM-33
1H NMR(400MHz,DMSO-d
6)δ10.96(s,1H),7.90(s,1H),7.78-7.70(m,2H),7.66-7.46(m,3H),7.44-7.32(m,2H),7.27-7.09(m,3H),5.26(s,2H),5.15-5.06(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.56(s,2H),3.17-3.05(m,4H),2.97-2.84(m,1H),2.62-2.54(m,1H),2.48-2.37(m,5H),2.00-1.91(m,1H).
MS(ESI)m/z 611.2[M+H]
+.
CM-34
1H NMR(400MHz,DMSO-d
6)δ10.96(s,1H),8.39-8.34(m,1H),7.78-7.66(m,2H),7.60-7.47(m,2H),7.43-7.31(m,2H),7.27-7.09(m,3H),5.27(s,2H),5.16-5.05(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.56(s,2H),3.16-3.00(m,4H),2.97-2.83(m,1H),2.80-2.70(m,3H),2.60-2.53(m,1H),2.49-2.37(m,5H),2.02-1.91(m,1H).
MS(ESI)m/z 625.2[M+H]
+.
化合物CM-39
1H NMR(400MHz,DMSO-d
6)δ10.96(s,1H),7.66-7.59(m,3H),7.58-7.50(m,2H),7.40-7.14(m,3H),6.98-6.96(m,1H),5.28(s,2H),5.13-5.08(m,1H),4.41(d,J＝17.6Hz,1H),4.25(d,J＝17.6Hz,1H),3.56(s,2H),3.39-3.32(m,4H),2.95-2.86(m,1H),2.59-2.54(m,1H),2.50-2.42(m,5H),1.99-1.96(m,1H).
MS(ESI)m/z 602.2[M+H]
+.
实施例13
化合物CM-18
步骤A：参考实施例11中的合成条件，由CM-1A[3,4-difluorobenzonitrile](2.5g，18.0mmol，CAS3939-09-1)得到CM-18C[methyl 4-((4-(4-cyano-3-fluorophenyl)piperazin-1-yl)methyl)-2-fluorobenzoate](3.0g,收率45％)黄色固体。MS(ESI)m/z 372.2[M+H]
+.
步骤B：将化合物CM-18C(3.0g,8.08mmol)加入反应瓶中,溶于DMSO/EtOH(60mL/160mL)中，然后加入NaOH水溶液(1N,100mL,100.0mmol),30％H
2O
2(30mL)，35℃下搅拌16小时。倒入水(500mL)中，浓盐酸酸化到pH＝1，静置,析出白色固体，过滤，滤饼用油泵减压浓缩至干得到白色固体产物CM-18D[4-((4-(4-carbamoyl-3-fluorophenyl)piperazin-1-yl)methyl)-2-fluorobenzoic acid](3.0g)。MS(ESI)m/z 376.2[M+H]
+.
步骤C：将化合物CM-18D(3.0g粗品)加入反应瓶中,溶于DMF(40mL)，加入K
2CO
3(2.21g,16.0mmol),MeI(1.13g,8.00mmol)，混合物室温搅拌过夜。加入水(300mL),EtOAc(150mL x 2)萃取,合并有机相,食盐水(300mL)洗涤,Na
2SO
4干燥,过滤,浓缩得到产品CM-18E[methyl 4-((4-(4-carbamoyl-3-fluorophenyl)piperazin-1-yl)methyl)-2-fluorobenzoate](1.80g,2步收率57％).MS(ESI)m/z390.2[M+H]
+.
步骤D：参考实施例11中的合成方法,由化合物CM-18E得到化合物CM-18[(S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)-3-fluorobenzyl)piperazin-1-yl)-2-fluorobenzamide]。
1H NMR(400MHz,DMSO-d
6)δ10.95(s,1H),7.63-7.50(m,3H),7.41-7.31(m,3H),7.24-7.18(m,3H),6.79-6.69(m,2H),5.27(s,2H),5.13-5.08(m,1H),4.39(d,J＝17.6Hz,1H),4.23(d,J＝17.6Hz,1H),3.56(s,2H),3.30-3.28(m,4H),2.95-2.86(m,1H),2.54-2.32(m,6H),1.99-1.95(m,1H).
MS(ESI)m/z 603.8[M+H]
+.
实施例14
化合物CM-19
步骤A：化合物CM-19A[2-氟-4-溴苯甲酸](10.0g,45.70mmol,CAS 112704-79-7)0℃下加入 SOCl
2(27.2g,16.5mL,0.228mol)，85℃回流2h,蒸掉多余SOCl
2得到棕色固体化合物，然后溶于DCM(50mL)，0℃加入MeNH
2.HCl(9.25g,0.14mol)和Et
3N/DCM(25mL/100mL)的混合物，室温反应2h,加入水(100mL)，分液，水相DCM(100mL)萃取，食盐水(200mL)洗涤，Na
2SO
4干燥,过滤,浓缩得到产品CM-19B[4-bromo-2-fluoro-N-methylbenzamide](10.0g,收率:94％).MS(ESI)m/z 233.9[M+1]
+.
步骤B：将化合物CM-19B(6.00g,25.86mmol)，I-2[methyl 2-fluoro-4-(piperazin-1-ylmethyl)benzoate hydrochloride](6.51g,25.80mmol),Pd(OAc)
2(580mg,2.59mmol),Xantphos(3.00g，5.18mmol，CAS 161265-03-8)和Cs
2CO
3(16.8g,51.80mmol)加入到二氧六环(100mL)中，N
2保护下油浴加热110℃反应16h。反应混合物倒入水中(100mL)，EtOAc萃取(100mL x 2)，有机相饱和食盐水洗涤(200mL)，Na
2SO
4干燥，过滤，减压浓缩至干，硅胶柱层析纯化(EA/PE 10-50％)得到浅黄色固体产物CM-19C[methyl 2-fluoro-4-((4-(3-fluoro-4-(methylcarbamoyl)phenyl)piperazin-1-yl)methyl)benzoate](3.70g,收率:35％).MS(ESI)m/z 404.1[M+1]
+.
其他步骤参考实施例11中的合成条件，采用相应的反应物得到化合物CM-19。
1H NMR(400MHz,DMSO-d
6)δ10.96(s,1H),7.76-7.74(m,1H),7.58-7.50(m,3H),7.41-7.34(m,2H),7.24-7.20(m,2H),6.78-6.71(m,2H),5.27(s,2H),5.13-5.09(m,1H),4.39(d,J＝17.6Hz,1H),4.23(d,J＝17.6Hz,1H),3.56(s,2H),3.32-3.28(m,4H),2.95-2.86(m,1H),2.75-2.74(m,3H),2.58-2.50(m,1H),2.50-2.42(m,5H),1.98-1.95(m,1H).
MS(ESI)m/z 618.3[M+H]
+.
实施例15
化合物CM-17
步骤A：将原料CM-17A[2-氟-5-溴苯腈](5.00g，25.00mmol),N-Boc哌嗪(3.88g,20.80mmol),Pd
2(dba)
3(0.95g,1.04mmol),BINAP(1.30g,2.08mmol)和Cs
2CO3(10.17g,31.20mmol)加入到甲苯 (50ml)中，氮气保护下80℃反应16小时。冷却到室温，经硅藻土过滤，乙酸乙酯洗涤，滤液浓缩，柱层析(PE/EA＝10/1 to 5/1)得类白色固体产物CM-17C[tert-butyl 4-(3-cyano-4-fluorophenyl)piperazine-1-carboxylate](2.50g,收率:39％).
步骤B：将CM-17C(2.50g,8.19mmol)溶于乙酸乙酯中(20mL)，缓慢加入氯化氢/乙酸乙酯溶液(4M,30mL),室温下搅拌3小时，浓缩得到中间体(1.98g crude).将中间体(1.98g,8.16mmol),化合物CM-17D[methyl 4-(bromomethyl)-2-fluorobenzoate](2.62g,10.61mmol)和K
2CO
3(3.37g,24.48mmol)加入到DMF(20mL)中,混合液在55℃搅拌5小时。将反应液乙酸乙酯洗涤，滤液浓缩，剩余物经反相制备得黄色固体产物CM-17E[methyl 4-((4-(3-cyano-4-fluorophenyl)piperazin-1-yl)methyl)-2-fluorobenzoate](1.90g,收率:62％)。MS(ESI)m/z 372.1[M+H]
+.
其余步骤参考实施例11的合成条件，采用相应的反应物得到化合物CM-17。
1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),7.58-7.49(m,2H),7.40-7.33(m,5H),7.24-7.20(m,2H),5.27(s,2H),5.13-5.08(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.56(s,2H),3.22-3.11(m,4H),2.98-2.83(m,1H),2.61-2.52(m,5H),2.48-2.37(m,1H),2.03-1.92(m,1H).
MS(ESI)m/z 586.2[M+H]
+.
实施例16
化合物CM-14
步骤A：将二氟氯乙酸钠(7.70g,50.50mmol,CAS:1895-39-2)加入到化合物CM-14A[4-溴-2-羟基苯腈](5.00g,25.25mmol)和K
2CO
3(4.18g,30.30mmol)的DMF/H
2O(50mL/5mL)混合液中，100℃下反应3小时。加入水(100mL)，EtOAc萃取(80mL x 2)。有机相用饱和盐水洗，无水硫酸钠干燥，浓缩得到粗品，经硅胶柱层析(PE/EtOAc＝100/1-20/1)得产物CM-14B[4-溴-2-二氟甲氧基苯腈](4.60g,收率：73％)，浅黄色固体。
步骤B：将化合物CM-14B[4-溴-2-二氟甲氧基苯腈](2.00g,8.06mmol),I-2[methyl 2-fluoro-4-(piperazin-1-ylmethyl)benzoate hydrochloride](2.21g,8.77mmol),xphos Pd G2(0.32g,0.41mmol)和Cs
2CO
3(3.91g,12.00mmol)加入到二氧六环(25mL)中，氮气保护下100℃反应16小时。反应液经硅藻土过滤，滤饼用EtOAc冲洗，滤液经水泵减压旋转蒸发浓缩至干，硅胶柱层析(PE/EtOAc＝10/1-4/1)纯化得产物CM-14D[methyl 4-((4-(4-cyano-3-(difluoromethoxy)phenyl)piperazin-1-yl)methyl)-2-fluorobenzoate](2.00g,4.77mmol,收率:59％)，黄色固体。MS(ESI)m/z 420.4[M+H]
+.
其余步骤参照实施例9的合成条件，得到化合物CM-14。
1H NMR(400MHz,DMSO-d
6)δ10.95(s,1H),7.61-7.34(m,6H),7.24-7.20(m,2H),6.88-6.80(m,2H),5.28(s,2H),5.13-5.08(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.57(s,2H),3.40-3.38(m,4H),2.95-2.84(m,1H),2.59-2.53(m,1H),2.50-2.40(m,5H),1.99-1.96(m,1H).
MS(ESI)m/z 634.2[M+H]
+.
实施例17
化合物CM-13
参照实施例11的步骤A的合成条件，采用碘甲基环丙烷
(CAS 33574-02-6)替换碘乙烷制备得到
其余步骤参照实施例9的方法，制备得到化合物CM-13。
1H NMR(400MHz,DMSO-d
6)δ10.98(s,1H),7.58-7.50(m,2H),7.42-7.34(m,3H),7.24-7.20(m,2H),6.56-6.52(m,2H),5.27(s,2H),5.13-5.09(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.94(d,J＝6.8Hz,2H),3.56(s,2H),3.34-3.32(m,4H),2.95-2.86(m,1H),2.61-2.53(m,1H),2.50-2.42(m,5H),1.98-1.95(m,1H),1.25-1.18(m,1H),0.60-0.56(m,2H),0.35-0.29(m,2H).
MS(ESI)m/z 638.3[M+H]
+.
实施例18
化合物CM-16
步骤A：将原料CM-16A[methyl 2-fluoro-4-(piperazin-1-ylmethyl)benzoate](2.20g,8.73mmol),CM- 16B[4-bromo-2-fluoro-1-(trifluoromethyl)benzene](2.12g,8.73mmol),Pd
2(dba)
3(0.80g,0.87mmol),BINAP(1.08g,1.74mmol)和Cs
2CO
3(4.27g,13.90mmol)加入到1,4-二氧六环(50mL)中，氮气保护下85℃反应16小时。冷却到室温，经硅藻土过滤，乙酸乙酯洗涤，滤液浓缩，柱层析(PE/EA＝10/1to 5/1)得黄色固体产物CM-16C[methyl 2-fluoro-4-((4-(3-fluoro-4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)benzoate](2.00g,收率:53.5％).MS(ESI)m/z 415.4[M+H]+.
其余步骤参考实施例11的合成，采用相应的反应物得到化合物CM-16。
1H NMR(400MHz,DMSO-d
6)δ10.97(s,1H),7.60-7.33(m,5H),7.26-7.19(m,2H),6.97-6.90(m,1H),6.86-6.81(m,1H),5.27(s,2H),5.15-5.07(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.56(s,2H),3.32-3.28(m,4H),2.96-2.84(m,1H),2.61-2.52(m,1H),2.49-2.37(m,5H),2.01-1.91(m,1H).
MS(ESI)m/z 629.2[M+H]
+.
实施例19
化合物CM-25
参考实施例11的合成方法，采用相应的反应物得到化合物CM-25。
1H NMR(400MHz,DMSO-d
6)δ10.99(s,1H),8.60(d,J＝2.4Hz,1H),7.60(d,J＝2.4Hz,1H),7.51-7.45(m,2H),7.35-7.30(m,4H),5.27(s,2H),5.15-5.10(m,1H),4.35(d,J＝17.6Hz,1H),4.28(d,J＝17.6Hz,1H),3.61-3.54(m,6H),2.99-2.85(m,1H),2.61-2.52(m,5H),2.48-2.37(m,1H),2.01-1.98(m,1H).
MS(ESI)m/z 637.3[M+H]
+.
实施例20
化合物CM-22
步骤A：将K
2CO
3(45.54g,0.13mol)加入到化合物CM-22A[methyl 4-(bromomethyl)-3-fluorobenzoate](32.00g,0.13mol)和N-Boc哌嗪(24.21g,0.13mol)的乙腈(250mL)溶液中中,70℃搅拌16小时。反应液过滤，滤液浓缩，经柱层析纯化得淡黄色固体产物CM-22B[tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)benzyl)piperazine-1-carboxylate](36.00g,收率:78％)。MS(ESI)m/z 353.4[M+H]
+.
步骤B：将4N HCl/EA(200mL)缓慢加入到化合物CM-22B(36.00g,0.10mol)的乙酸乙酯(100mL)溶液中，室温下反应24小时。反应液浓缩至体积约100mL,过滤，滤饼干燥得类白色固体产品CM-22C[methyl 3-fluoro-4-(piperazin-1-ylmethyl)benzoate dihydrochloride](29.00g,收率:89％)。MS(ESI)m/z 253.2[M+H]
+.
步骤C：参考实施例22采用相应的反应物制备得到化合物CM-22D[4-fluoro-2-(methoxy-d
3)benzonitrile]，25℃下，将K
2CO
3(2.22g,16.12mmol)加入到化合物CM-22C[methyl 3-fluoro-4-(piperazin-1-ylmethyl)benzoate dihydrochloride](2.62g,8.06mmol)和CM-22D(1.25g,8.06mmol)的DMSO(20mL)溶液中,混合液在90℃搅拌16小时。将反应液倒入水(60mL)中，用EtOAc(50mL x 2)萃取。有机相用饱和食盐水(60mL x 3)洗涤，无水Na
2SO
4干燥，过滤浓缩。剩余物经反相制备得产物CM-22E[methyl 4-((4-(4-cyano-3-(methoxy-d3)phenyl)piperazin-1-yl)methyl)-3-fluorobenzoate](1.60g,4.15mmol,yield:51％)，黄色固体。MS(ESI)m/z 387.1[M+H]
+.
其它步骤参考实施例11的合成条件，采用相应的反应物得到化合物CM-22。
1H NMR(400MHz,DMSO-d
6)δ10.98(s,1H),7.53-7.28(m,7H),6.58-6.51(m,2H),5.26(s,2H),5.16-5.08(m,1H),4.44(d,J＝17.6Hz,1H),4.29(d,J＝17.2Hz,1H),3.59(s,2H),3.40-3.32(m,4H),2.96-2.86(m,1H),2.59-2.53(m,1H),2.49-2.40(m,5H),2.01-1.97(m,1H).
MS(ESI)m/z 601.3[M+H]
+.
实施例21
化合物CM-40
步骤A：0-5℃下，将氯甲基甲醚(4.05g,50.32mmol,CAS:107-30-2)缓慢加入到化合物CM-40A[3-羟基-4-氟苯腈](4.60g,33.55mmol,CAS:186590-04-5)和DIEA(8.66g,67.10mmol)的DCM(50mL)混合液中，室温下反应16小时。加入水(60mL)，乙酸乙酯萃取(50mL x 2)。有机相用饱和盐水洗，无水硫酸钠干燥，浓缩得到产物粗品CM-40B[4-fluoro-3-(methoxymethoxy)benzonitrile](7.00g,)，淡黄色液体,直接用于下一步反应。
步骤B：将Cs
2CO
3(30.97g,95.00mmol)加入到化合物CM-40B(7.00g,38.67mmol)和哌嗪(16.63g,193.37mmol)的DMSO(100mL)溶液中,混合液在100℃搅拌16小时。将反应液倒入水(200mL)中，用EtOAc(150mL x 2)萃取。有机相用饱和食盐水(300mL x 3)洗涤，无水Na
2SO
4干燥，过滤浓缩得产物CM-40C[3-(methoxymethoxy)-4-(piperazin-1-yl)benzonitrile](6.60g,56％yield)，黄色固体，直接用于下一步反应。
步骤C：将DIEA(6.89g,53.44mmol)加入到化合物CM-40C(6.60g,26.69mmol)和CM-40D[methyl4-(bromomethyl)-2-fluorobenzoate](6.60g,26.69mmol)的DMF(80mL)溶液中,混合液在100℃搅拌2小时。将反应液浓缩经柱层析(PE/EtOAc＝4/1)得产物CM-40E[methyl 4-((4-(4-cyano-2-(methoxymethoxy)phenyl)piperazin-1-yl)methyl)-2-fluorobenzoate](8.00g,yield:72％)，黄色固体；
其余步骤参考实施例11，采用相应的反应物得到化合物CM-40。
1H NMR(400MHz,DMSO-d
6)δ10.96(s,1H),10.02(s,1H),7.60-7.47(m,2H),7.44-7.30(m,2H),7.26-7.15(m,3H),7.06-7.01(m,1H),6.94-6.87(m,1H),5.27(s,2H),5.14-5.06(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.56(s,2H),3.17-3.05(m,4H),2.94-2.85(m,1H),2.60-2.51(m,5H),2.48-2.40(m,1H),2.01-1.92(m,1H).
MS(ESI)m/z 584.3[M+H]
+.
实施例22
化合物CM-32
步骤A：将氘代碘甲烷(2.06g,14.23mmol)加入到化合物CM-32A[3-羟基-4-氟苯腈](1.50g,10.95mmol)和K
2CO
3(3.02g,21.88mmol)的DMF(20mL)混合液中，室温下反应16小时。加入水(60mL)，乙酸乙酯萃取(30mL x 2)。有机相用饱和盐水洗，无水硫酸钠干燥，浓缩得到产物CM-32B[4-fluoro-3-(methoxy-d3)benzonitrile](1.50g,收率89％)，灰色固体,直接用于下一步反应。
步骤B：将Cs
2CO
3(5.50g,16.08mmol)加入到化合物CM-32B(1.30g,8.44mmol)和哌嗪(3.63g,42.2mmol))的DMSO(15mL)溶液中,混合液在100℃搅拌16小时。将反应液倒入水(60mL)中，用EtOAc(50mL x 2)萃取。有机相用饱和食盐水(60mL x 3)洗涤，无水Na
2SO
4干燥，过滤浓缩得产物CM-32D[3-(methoxy-d
3)-4-(piperazin-1-yl)benzonitrile](1.80g,收率97％)，淡黄色固体，直接用于下一步反应。
步骤C：将DIEA(2.99g,23.16mmol)加入到化合物CM-32D(1.70g,7.72mmol)和CM-40D[methyl4-(bromomethyl)-2-fluorobenzoate](2.38g,9.66mmol)的DMSO(15mL)溶液中,混合液在90℃搅拌8小时。将反应液浓缩经柱层析得产物CM-32F[methyl 4-((4-(4-cyano-2-(methoxy-d3)phenyl)piperazin-1-yl)methyl)-2-fluorobenzoate](1.80g,收率60％)，黄色固体，MS(ESI)m/z 387.5[M+H]
+.
其余参考实施例11的合成方法，采用相应的反应物得到化合物CM-32。
1H NMR(400MHz,DMSO-d
6)δ10.96(s,1H),7.58-7.50(m,2H),7.41-7.20(m,6H),6.97-6.95(m,1H),5.27(s,2H),5.13-5.08(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.56(s,2H),3.18-3.01(m,4H),2.94-2.83(m,1H),2.58-2.51(m,1H),2.49-2.38(m,5H),1.98-1.95(m,1H).
MS(ESI)m/z 601.2[M+H]
+.
参考化合物CM-32的合成方法，采用相应的反应物得到化合物CM-15，CM-36。
化合物CM-15
1H NMR(400MHz,DMSO-d
6)δ10.95(s,1H),7.58-7.49(m,2H),7.43-7.34(m,3H),7.24-7.21(m,2H),6.57-6.54(m,2H),5.28(s,2H),5.13-5.08(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.57(s,2H),3.38-3.32(m,4H),2.93-2.85(m,1H),2.60-2.53(m,1H),2.49-2.40(m,5H),1.99-1.95(m,1H).
MS(ESI)m/z 601.3[M+H]+.
化合物CM-36
1H NMR(400MHz,DMSO-d
6)δ10.97(s,1H),7.57-7.50(m,2H),7.41-7.22(m,6H),6.96-6.94(m,1H),5.27(s,2H),5.13-5.09(m,1H),4.41(d,J＝17.6Hz,1H),4.25(d,J＝17.6Hz,1H),4.09-4.04(m,2H),3.56(s,2H),3.12(m,4H),2.95-2.86(m,1H),2.58-2.50(m,5H),2.46-2.40(m,1H),1.99-1.96(m,1H),1.34(t,J＝6.8Hz,3H).
MS(ESI)m/z 612.2[M+H]
+.
实施例23
化合物CM-41
将CM-41C[methyl 4-((4-(3-bromo-4-cyanophenyl)piperazin-1-yl)methyl)-2-fluorobenzoate](3.50g,8.10mmol),乙基硼酸(1.20g,16.20mmol),Pd
2(dppf)Cl
2(0.18g,0.24mmol)和碳酸钾(1.72g,16.20mmol)加入到dioxane/water(30mL/7mL)中，氮气保护下90℃反应16小时。冷却到室温，经硅藻土过滤，乙酸乙酯冲洗。滤液浓缩得粗品，经反向制备得白色固体产物CM-41D[methyl 4-((4-(4-cyano-3-ethylphenyl)piperazin-1-yl)methyl)-2-fluorobenzoate](1.00g,2.62mmol,yield:32％).MS(ESI)m/z 382.5[M+H]
+.
其余参考实施例11的合成方法，采用相应的反应物得到化合物CM-41。
1H NMR(400MHz,DMSO-d
6)δ10.96(s,1H),7.60-7.47(m,3H),7.42-7.32(m,2H),7.26-7.18(m,2H),6.93-6.81(m,2H),5.27(s,2H),5.15-5.06(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.56(s,2H),3.34-3.31(m,4H),2.96-2.84(m,1H),2.68(q,J＝7.2Hz,2H),2.58-2.52(m,1H),2.49-2.37(m,5H),2.01-1.93(m,1H),1.19(t,J＝7.2Hz,3H).
MS(ESI)m/z 596.2[M+H]
+.
参考化合物CM-41的合成方法，用环丙基硼酸代替乙基硼酸制备得到化合物CM-37。
化合物CM-37
1H NMR(400MHz,DMSO-d
6)δ10.96(s,1H),7.60-7.32(m,5H),7.25-7.18(m,2H),6.83-6.78(m,1H),6.42(d,J＝2.0Hz,1H),5.27(s,2H),5.15-5.06(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.55(s,2H),3.32-3.29(m,4H),2.97-2.83(m,1H),2.59-2.52(m,1H),2.49-2.37(m,5H),2.10-1.91(m,2H),1.05-0.98(m,2H),0.85-0.78(m,2H).
MS(ESI)m/z 608.2[M+H]
+.
实施例24
化合物CM-43
参考实施例11的合成方法，采用相应的反应物得到化合物CM-43G；
将化合物CM-43G(200mg,0.31mmol)，CM-43H[trimethyl((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethynyl)silane](210mg,0.93mmol,CAS 159087-46-4)溶于8mL二氧六环/水(6mL/2ml)中，加入Pd(dppf)
2Cl
2(91.5mg,0.125mmol),Et
3N(126mg,1.25mmol)，反应体系置换氮气3次，氮气保护下80℃加热2.5h，反应结束。硅藻土过滤，EtOAc(10mL)洗涤，减压浓缩，反相制备(10-80％ACN)纯化得到CM-43I[(S)-3-(4-((2-fluoro-4-((4-(2-fluoro-4-((trimethylsilyl)ethynyl)phenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6- dione](100mg,收率:42％)。
将TBAF/THF溶液(1M,1mmol,1mL)加入到CM-43I(100mg,0.15mmol)的THF(5mL)溶液中，混合液室温搅拌1小时，反应结束。EtOAc(10mL)萃取，水(10mL x 6)洗涤，浓缩，反相中压制备后，Prep-HPLC(TFA)纯化得到产物的TFA盐(15mg).盐溶于DMF，缓慢滴加到aq NaHCO
3(20mL)中析出白色固体，过滤，油泵真空干燥得到化合物CM-43(7.8mg,收率:9％)
1H NMR(400MHz,DMSO-d
6)δ10.97(s,1H),7.58-7.50(m,2H),7.41-7.21(m,6H),7.01-6.97(m,1H),5.27(s,2H),5.13-5.08(m,1H),4.41-4.13(m,3H),3.57(s,2H),3.07-2.95(m,4H),2.95-2.86(m,1H),2.58-2.51(m,4H),2.46-2.32(m,2H),1.98-1.94(m,1H).
MS(ESI)m/z[M+H]
+＝585.3.
参考化合物CM-43的合成方法，采用
(CAS 608534-34-5)替换CM-43H制备得到CM-38。
化合物CM-38
1H NMR(400MHz,DMSO-d
6)δ10.96(s,1H),7.58-7.50(m,2H),7.41-7.16(m,6H),7.00-6.95(m,1H),6.67-6.60(m,1H),5.73(d,J＝17.6Hz,1H),5.27(s,2H),5.19-5.08(m,2H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.57(s,2H),3.04-2.95(m,4H),2.95-2.86(m,1H),2.58-2.51(m,5H),2.46-2.39(m,1H),1.99-1.95(m,1H).
MS(ESI)m/z[M+H]
+＝587.2.
实施例25
化合物CM-42
参考实施例11中的方法，合成化合物CM-42F。将CM-42F[tert-butyl(S)-5-amino-4-(4-((4-((4-(3-bromo-4-cyanophenyl)piperazin-1-yl)methyl)-2-fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate](1.00g,1.46mmol),Zn(CN)
2(1.00g,256.23mmol),Pd
2(dba)
3(0.12g,0.13mmol)和dppf(0.14g,0.26mmol)加入到DMF(10mL)中，氮气保护下100℃反应5小时。冷却到室温，加入水(50mL)，乙酸乙酯(30mL x 2)萃取。合并有机相并用饱和食盐水洗(50mL x 3)，有机相用无水硫酸钠干燥，过滤浓缩得粗品，经反向制备得白色固体产物CM-42G[tert-butyl(S)-5-amino-4-(4-((4-((4-(3,4-dicyanophenyl)piperazin-1-yl)methyl)-2-fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate](700mg,收率：72％).
其余步骤参考实施例11，采用相应的反应物即可得到化合物CM-42。
1H NMR(400MHz,DMSO-d
6)δ10.95(s,1H),7.80(d,J＝9.2Hz,1H),7.60-7.48(m,3H),7.42-7.18(m,5H),5.27(s,2H),5.15-5.06(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.56(s,2H),3.48-3.42(m,4H),2.96-2.84(m,1H),2.58-2.52(m,1H),2.49-2.37(m,5H),2.01-1.93(m,1H).
MS(ESI)m/z 593.2[M+H]
+.
实施例26
化合物CM-44
步骤A：0～5℃下，将TFA(20mL)加入到化合物CM-44A[methyl 4-((4-(4-cyano-2-(methoxymethoxy)phenyl)piperazin-1-yl)methyl)-2-fluorobenzoate](3.00g,7.26mmol)的DCM(20mL)溶液中,混合液在室温搅拌1.5小时。将反应液浓缩，加EtOAc稀释，加入NaHCO
3水溶液调节pH＝8～9，EtOAc(30mL x 3)萃取。合并有机相，有机相用饱和食盐水(50mL)洗，无水Na
2SO
4干燥，过滤浓缩得黄色固体产物CM-44B[methyl 4-((4-(4-cyano-2-hydroxyphenyl)piperazin-1-yl)methyl)-2-fluorobenzoate](1.70g,yield:91％)。MS(ESI)m/z 370.1[M+H]
+
步骤B：将化合物CM-44B(800mg,2.17mmol)溶于THF(8mL)中，冷却至-15℃，分批加入钠氢(104mg，4.34mmol),保持温度低于-5℃。30分钟后，滴加水(78mg，4.34mmol)。10分钟后，分批加入CM-44C[溴氟甲基膦酸二乙酯](1.16g，4.34mmol)，并在室温下搅拌1小时。将反应液倒入水中，乙酸乙酯(30mL x 3)萃取，有机相用饱和盐水(80mL)洗涤，无水Na
2SO
4干燥，过滤浓缩,经反相制备得产物CM-44D[methyl 4-((4-(4-cyano-2-(difluoromethoxy)phenyl)piperazin-1-yl)methyl)-2-fluorobenzoate](0.35g,0.83mmol,yield:38％)，白色固体。
其他步骤参考实施例11，采用相应的反应物即可得到CM-44.
1H NMR(400MHz,DMSO-d
6)δ10.95(s,1H),7.68-7.48(m,4H),7.42-6.95(m,6H),5.27(s,2H),5.14-5.06(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.56(s,2H),3.20-3.06(m,4H),2.97-2.82(m,1H),2.62-2.52(m,5H),2.48-2.40(m,1H),2.01-1.92(m,1H).
MS(ESI)m/z 634.2[M+H]
+.
实施例27
步骤A：将化合物CM-48A(CAS 115843-99-7 15.00g,66.82mmol),1,1'-bis(diphenylphosphino)ferrocene(dppf)(3.70g,6.68mmol),Pd
2(dba)
3(3.06g,3.34mmol)and Zn(CN)
2(10.16g,86.84mmol)加入到DMF(150mL)中，氮气保护下加热至100℃反应16小时。反应液冷却过滤，滤饼用EtOAc(80mL)冲洗。滤液浓缩，经硅胶柱层析(PE/EA＝2/1)得到产物CM-48B(9.00g,52.76mmol,yield:79％),类白色固体。
步骤B：将CuI(20.34g,106.49mmol)和亚硝酸异戊酯(12.48g,106.49mmol)加入到MeCN(90mL)中。反应液加热至65℃，滴加CM-48B(9.00g,52.79mmol)的乙腈溶液(90mL)，30分钟滴加完毕，继续反应5小时。反应液浓缩，柱层析(PE/EA＝20/1)得产物CM-48C(5.00g,17.77mmol,yield:33％)，类白色固体。MS(ESI)m/z 281.9[M+H]
+.
步骤C：将化合物CM-16A(2.70g,10.71mmol),CM-48C(3.00g,10.71mmol),xphos Pd G2(0.86g,1.07mmol)and Cs
2CO
3(5.24g,16.06mmol)加入到1,4-二氧六环(30ml)中，氮气保护下110℃反应16小时。冷却到室温，经硅藻土过滤，乙酸乙酯洗涤，滤液浓缩，柱层析(PE/EA＝10/1 to 5/1)得黄色固体产物CM-48E(2.07g,5.10mmol,yield:47.6％).
其余步骤参考实施例11的合成，采用相应的反应物得到化合物CM-48。
1H NMR(400MHz,DMSO-d
6)δ10.96(s,1H),7.68(d,J＝8.8Hz,1H),7.59-7.49(m,2H),7.41-7.33(m,2H),7.24-7.19(m,2H),7.13-7.07(m,1H),5.27(s,2H),5.14-5.07(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.57(s,2H),3.30-3.27(m,4H),2.96-2.85(m,1H),2.60-2.52(m,5H),2.49-2.39(m,1H),2.00-1.94(m,1H).
MS(ESI)m/z 620.2[M+H]
+.
参考化合物CM-48的合成方法，采用相应的反应物得到化合物CM-47，CM-49。
1H NMR(400MHz,DMSO-d
6)δ10.96(s,1H),7.80(d,J＝8.8Hz,1H),7.59-7.34(m,5H),7.24-7.20(m,1H),5.27(s,2H),5.13-5.08(m,1H),4.36(d,J＝17.2Hz,1H),4.21(d,J＝17.6Hz,1H),3.57(s,2H),3.32-3.27(m,4H),2.95-2.86(m,1H),2.59-2.54(m,5H),2.50-2.38(m,1H),1.99-1.96(m,1H).
MS(ESI)m/z 654.3[M+H]
+.
1H NMR(400MHz,DMSO-d
6)δ10.97(s,1H),7.59-7.34(m,5H),7.25-7.19(m,2H),6.85-6.79(m,1H),5.27(s,2H),5.14-5.07(m,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.2Hz,1H),3.99(d,J＝1.2Hz,1H),3.57(s,2H),3.22-3.15(m,4H),2.92-2.85(m,1H),2.60-2.52(m,5H),2.49-2.39(m,1H),2.00-1.94(m,1H).
MS(ESI)m/z 616.3[M+H]
+.
实施例28
参考实施例11中化合物CM-12的合成条件，采用相应的反应物合成得到化合物CM-46。
1H NMR(400MHz,DMSO)δ10.97(s,1H),7.51-7.30(m,7H),6.55-6.53(m,2H),5.27(s,2H),5.14-5.09(m,1H),4.43(d,J＝17.2Hz,1H),4.27(d,J＝17.6Hz,1H),4.16-4.11(m,2H),3.59(s,2H),3.33(m,4H),2.96-2.87(m,1H),2.61-2.50(m,5H),2.43-2.40(m,1H),2.01-1.98(m,1H),1.33(t,J＝6.8Hz,3H).
MS(ESI)m/z 612.3[M+H]
+.
参考实施例28中化合物CM-46的合成方法，采用相应的反应物合成CM-20，CM-21，CM-23，CM-26，CM-45。
化合物CM-20
1H NMR(400MHz,DMSO-d
6)δ10.97(s,1H),7.61-7.44(m,3H),7.35-7.31(m,4H),6.95-6.91(m,1H),6.85-6.82(m,1H),5.26(s,2H),5.14-5.09(m,1H),4.45(d,J＝17.6Hz,1H),4.29(d,J＝17.6Hz,1H),3.59(s,2H),3.38-3.32(m,4H),2.91-2.87(m,1H),2.60-2.55(m,1H),2.49-2.40(m,5H),2.01-1.98(m,1H).
MS(ESI)m/z 586.2[M+H]
+.
化合物CM-21
1H NMR(400MHz,DMSO-d
6)δ10.99(s,1H),7.49-7.30(m,7H),6.56-6.54(m,2H),5.26(s,2H),5.14-5.10(m,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.86(s,2H),3.35-3.33(m,4H),2.96-2.87(m,1H),2.60-2.50(m,5H),2.50-2.40(m,1H),2.01-1.97(m,1H).
MS(ESI)m/z 598.2[M+H]
+.
化合物CM-23
1H NMR(400MHz,DMSO-d
6)δ10.98(s,1H),7.86(s,1H),7.67-7.58(m,2H),7.52-7.43(m,2H),7.36-7.27(m,5H),7.06-6.99(m,1H),5.26(s,2H),5.15-5.08(m,1H),4.45(d,J＝17.6Hz,1H),4.29(d,J＝17.6Hz,1H),3.60(s,2H),3.15-3.00(m,4H),2.98-2.83(m,1H),2.64-2.52(m,5H),2.48-2.39(m,1H),2.04-1.93(m,1H).
MS(ESI)m/z 604.2[M+H]
+.
化合物CM-26
1H NMR(400MHz,DMSO-d
6)δ10.97(s,1H),7.51-7.44(m,2H),7.35-7.31(m,4H),7.17-7.15(m,1H),6.18-6.16(m,1H),5.26(s,2H),5.14-5.09(m,1H),4.45(d,J＝17.6Hz,1H),4.31-4.22(m,3H),3.65(s,3H),3.57(s,2H),3.32-3.30(m,4H),2.96-2.87(m,1H),2.67-2.56(m,1H),2.51-2.49(m,5H),2.00-1.96(m,1H),1.28(t,.J＝6.8Hz,3H).
MS(ESI)m/z 618.2[M+H]
+.
化合物CM-45
1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),7.76-7.72(m,1H),7.59-7.43(m,3H),7.36-7.30(m,4H),6.79-6.69(m,2H),5.26(s,2H),5.15-5.07(m,1H),4.45(d,J＝17.6Hz,1H),4.29(d,J＝17.2Hz,1H),3.58(s,2H),3.30-3.24(m,4H),2.93-2.87(m,1H),2.74(d,J＝4.4Hz,3H),2.62-2.52(m,5H),2.49-2.41(m,1H),2.02-1.97(m,1H).
MS(ESI)m/z 618.2[M+H]+.
效果实施例
MTS法测试细胞增殖抑制实验方法：
将正在增殖生长的MM.1S骨髓瘤细胞(ATCC，产品目录号CRL-2974)重悬于RPMI-640培养基(Gibco，产品目录号A10491-01)，使用自动细胞计数器计数。将细胞悬浮液稀释至所需密度，在96孔平板中每孔铺100μl，15000个细胞，置于37℃,5％CO2培养箱内培养24小时。给药当天，将化合物用DMSO(Sigma，产品目录号D2650)配成20mM的储备液，用培养基稀释至所需浓度后加入相应孔中进行10个点、4倍梯度稀释的药物抑制细胞增殖实验。DMSO终浓度为0.5％。加药后的96孔板放置在37℃,5％CO2培养箱内培养72小时。之后，每孔加入20μl MTS(Promega,产品目录号G3581),在37℃,5％CO2培养箱内培养2小时，然后使用Ensight仪器记录各孔在490nm的吸光度。使用Day0细胞的读值作为阴性对照，使用含0.5％DMSO的Day-3细胞作为阳性对照。用GraphPad Prism 5软件绘制细胞增殖抑制曲线并计算IC50。实验结果见表1。
表1. MM.1S细胞增殖抑制结果
| 化合物 | MM.1S IC 50(nM) |
| 对照1 | 23.0691 |
| CM-1 | 0.1025 |
| CM-2 | 0.0139 |
| CM-3 | 0.0064 |
| CM-4 | 0.0153 |
| CM-5 | 0.0063 |
| CM-6 | 0.0409 |
| CM-7 | 0.0054 |
| CM-8 | 0.0211 |
| CM-9 | 0.0136 |
| CM-10 | 0.0105 |
| CM-11 | 0.0091 |
| CM-12 | 0.0067 |
| CM-13 | 0.0271 |
| CM-14 | 0.0148 |
| CM-15 | 0.0062 |
| CM-16 | 0.1886 |
| CM-17 | 0.0139 |
| CM-18 | 0.0188 |
| CM-19 | 0.0338 |
| CM-20 | 0.0132 |
| CM-21 | 0.0111 |
| CM-22 | 0.0136 |
| CM-23 | 0.0581 |
| CM-24 | 0.0388 |
| CM-25 | 0.0291 |
| CM-26 | 0.4648 |
| CM-27 | 0.1339 |
| CM-28 | 0.1020 |
| CM-29 | 0.2006 |
| CM-30 | 0.1092 |
| CM-31 | 0.1657 |
| CM-32 | 0.0706 |
| CM-33 | 0.0781 |
| CM-34 | 0.0766 |
| CM-35 | 0.0962 |
| CM-36 | 0.1479 |
| CM-37 | 0.1193 |
| CM-38 | 1.2090 |
| CM-39 | 0.0631 |
| CM-40 | 0.3778 |
| CM-41 | 0.1158 |
| CM-42 | 0.1143 |
| CM-43 | 0.5762 |
| CM-44 | 0.1265 |
CTG法测试细胞增殖抑制实验方法：
化合物对MM.1S骨髓瘤细胞模型的增殖抑制活性通过CellTiter-Glo(CTG)发光法测量细胞活率的方法测定(Promega)。将处于对数生长期的MM.1S细胞(ATCC，产品目录号CRL-2974)重悬于RPMI-1640(Gibco，产品目录号11875-093)+10％FBS+1％青/链霉素+2mM Glutamax培养基，使用自动细胞计数仪(ViCell XR)计数。按照在预实验中优化好的细胞铺板密度，将40μl密度为100,000细胞/ml的细胞悬液铺于384孔平板相应孔中(4,000个细胞/孔)以保证在五天的实验期内对照组细胞处于线性生长阶段。将铺好细胞的384孔板置于37℃,5％CO
2培养箱内培养24小时。给药当天，将化合物用DMSO(Sigma，产品目录号276855-1L)配成10mM的储备液，然后以DMSO将化合物储备液进一步稀释至20μM和20nM工作液。对MM.1S细胞进行的药物处理从最高100nM的浓度开始，并按照10个浓度点、4倍梯度进行稀释,三孔重复。加药通过HPD300微量自动加液器(Tecan)根据所需浓度将纳升级体积的化合物溶液以无接触喷射方式加入384板相应的孔中。DMSO终浓度为0.5％。加药后384孔板放置在37℃,5％CO2培养箱内培养120小时。五天的药物处理之后，每孔加入25μl CTG试剂(Promega,产品目录号G7573)并在振板机上振荡10分钟以保证细胞充分裂解，然后在室温静置10分钟以保证CTG与底物充分反应并产生稳定的发光信号。该信号与细胞裂解液中ATP的量，亦即代谢活跃的细胞数成正比。使用EnSpire仪器读板检测化学发光。使用Day0细胞的读值作为细胞生长起点对照，使用含0.5％DMSO的Day5细胞的读值作为细胞生长对照。用XLFit软件绘制细胞增殖抑制曲线并计算IC50。实验结果见表2。
表2. MM.1S细胞增殖抑制结果
| 化合物 | MM.1S IC 50(nM) |
| 对照1 | 119.0859 |
| CM-45 | 0.0938 |
| CM-46 | 0.0687 |
| CM-47 | 0.1351 |
| CM-48 | 0.0365 |
| CM-49 | 0.0606 |
Claims (12)
- 一种通式(I)所示的异吲哚啉衍生物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体：
其中，R 1，R 2各自独立地选自H，卤素，-CN，取代或未取代的(C 1-C 12)烷基，取代或未取代的(C 1-C 12)烷氧基，-OH，条件是R 1，R 2不同时为H；X选自O或NH；X 1,X 2,X 3,X 4,X 5各自独立地选自C或N；R 4，R 5，R 6，R 7，R 8各自独立地不存在或选自H，卤素，取代或未取代的(C 1-C 12)烷基，取代或未取代的(C 1-C 12)烷氧基，取代或未取代的(C 3-C 6)环烷基，-CH＝CH 2，-C≡CH，-CN，-OH，-NO 2，
其中R 9，R 10各自独立地选自H，D，取代或未取代的(C 1-C 12)烷基；条件是R 4，R 5，R 6，R 7，R 8中至少一个选自-CN，-NO 2，
-CH＝CH 2，-C≡CH，被一个或多个卤素取代的(C 1-C 12)烷基，被一个或多个卤素取代的(C 1-C 12)烷氧基，被一个或多个D取代的(C 1-C 12)烷基，被一个或多个D取代的(C 1-C 12)烷氧基；
所述取代的(C 1-C 12)烷基，取代的(C 1-C 12)烷氧基中的取代基选自一个或多个D,一个或多个卤素，或一个或多个(C 3-C 6)环烷基；用*标注的碳为不对称中心；所述的不对称中心是指非手性碳、(S)构型碳、富集的(S)构型碳、(R)构型碳、富集的(R)构型碳或者消旋体；较佳地，通式(I)中，R 1，R 2中至少有一个选自卤素，-CN，取代或未取代的(C 1-C 12)烷基，取代或未取代的(C 1-C 12)烷氧基，-OH；较佳地，通式(I)中，R 1，R 2中至少一个选自F,Cl,Br,-CN，-CH 3,-OCH 3，-CF 3，-OCF 3；更佳地，通式(I)中，R 1，R 2中至少一个选自F；较佳地，通式(I)中，所述的R 4选自-CN，-NO 2，被一个或多个卤素取代的(C 1-C 12)烷基，被一个或多个卤素取代的(C 1-C 12)烷氧基，被一个或多个D取代的(C 1-C 12)烷基，或被一个或多个D取代的(C 1-C 12)烷氧基；R 5，R 6，R 7，R 8各自独立地选自H、或卤素；R 5，R 6，R 7，R 8更佳地各自独立地选自H；
或，通式(I)中，所述的R 5选自-CN，-NO 2，被一个或多个卤素取代的(C 1-C 12)烷基，被一个或多个卤素取代的(C 1-C 12)烷氧基，被一个或多个D取代的(C 1-C 12)烷基，或被一个或多个D取代的(C 1-C 12)烷氧基；R 4，R 6，R 7，R 8各自独立地选自H或卤素；R 4，R 6，R 7，R 8更佳地各自独立地选自H；
或，通式(I)中，所述的R 6选自-CN，-NO 2，被一个或多个卤素取代的(C 1-C 12)烷基，被一个或多个卤素取代的(C 1-C 12)烷氧基，被一个或多个D取代的(C 1-C 12)烷基，或被一个或多个D取代的(C 1-C 12)烷氧基；R 4，R 5，R 7，R 8各自独立地选自H或卤素；R 4，R 5，R 7，R 8更佳地各自独立地选自H；
或，通式(I)中，所述的R 7选自-CN，-NO 2，被一个或多个卤素取代的(C 1-C 12)烷基，被一个或多个卤素取代的(C 1-C 12)烷氧基，被一个或多个D取代的(C 1-C 12)烷基，或被一个或多个D取代的(C 1-C 12)烷氧基；R 4，R 5，R 6，R 8各自独立地选自H或卤素；R 4，R 5，R 6，R 8更佳地各自独立地选自H；
或，通式(I)中，所述的R 8选自-CN，-NO 2，被一个或多个卤素取代的(C 1-C 12)烷基，被一个或多个卤素取代的(C 1-C 12)烷氧基，被一个或多个D取代的(C 1-C 12)烷基，或被一个或多个D取代的(C 1-C 12)烷氧基；R 4，R 5，R 6，R 7各自独立地选自H或卤素，R 4，R 5，R 6，R 7更佳地各自独立地选自H。
- 如权利要求1所述的通式(I)所示的异吲哚啉衍生物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体，其特征在于，R 1选自F,Cl,Br,-CN，-CH 3,-OCH 3，-CF 3，-OCF 3，R 2选自H；或R 2选自F,Cl,Br,-CN，-CH 3,-OCH 3，-CF 3，-OCF 3，R 1选自H；优选地，R 1选自F，R 2选自 H；或R 2选自F，R 1选自H。
- 如权利要求1所述的通式(I)所示的异吲哚啉衍生物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体，其特征在于，R 4选自H，F，Cl，Br，-CH 3，-CH 2CH 3，-CF 3，-OCH 3，-OCH 2CH 3，-CH＝CH 2，-C≡CH，-OCF 3，-OCH 2F，-OCHF 2，-CD 3，-OCD 3，-CN，-NO 2，
R 4较佳地选自H，F，-CN，-OCH 3，-OCF 3，-OCD 3，-CD 3；R 4更佳地选自H，F；R 4最佳地选自H；
R 5选自H，F，Cl，Br，-CH 3，-CH 2CH 3，-CF 3，-OCH 3，-OCH 2CH 3，-CH＝CH 2，-C≡CH，-OCF 3，-OCH 2F，-OCHF 2，-CD 3，-OCD 3，-CN，-NO 2，
R 5较佳地选自H，F，-CN，-OCH 3，-OCF 3，-OCD 3，-CD 3；R 5更佳地选自H，F；R 5最佳地选自H；
R 6选自H，F，Cl，Br，-CH 3，-CH 2CH 3，-CF 3，-OCH 3，-OCH 2CH 3，-CH＝CH 2，-C≡CH，-OCF 3，-OCH 2F，-OCHF 2，-CD 3，-OCD 3，-CN，-NO 2，
R 6较佳地选自H，F，-CN，-OCH 3，-OCF 3，-OCD 3，-CD 3；R 6更佳地选自F，-CN；R 6最佳地选自-CN；
R 7选自H，F，Cl，Br，-CH 3，-CH 2CH 3，-CF 3，-OCH 3，-OCH 2CH 3，-CH＝CH 2，-C≡CH，-OCF 3，-OCH 2F，-OCHF 2，-CD 3，-OCD 3，-CN，-NO 2，
R 7较佳地选自H，F，-CN，-OCH 3，-OCF 3，-OCD 3，-CD 3；R 7更佳地选自H，F，-OCH 3；R 7最佳地选自-OCH 3；
R 8选自H，F，Cl，Br，-CH 3，-CH 2CH 3，-CF 3，-OCH 3，-OCH 2CH 3，-CH＝CH 2，-C≡CH，-OCF 3，-OCH 2F，-OCHF 2，-CD 3，-OCD 3，-CN，-NO 2，
R 8较佳地选自H，F，-CN，-OCH 3，-OCF 3，-OCD 3，-CD 3；R 8更佳地选自F，H；R 8最佳地选自F。
- 如权利要求1所述的通式(I)所示的异吲哚啉衍生物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体，其特征在于，X为O。
- 如权利要求1所述的通式(I)所示的异吲哚啉衍生物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体，其特征在于，X 1,X 2,X 3,X 4,X 5各自独立地为C。
- 如权利要求1-5任一项所述的通式(I)所示的异吲哚啉衍生物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体，其特征在于，所述卤素为F，Cl，Br，I。
- 如权利要求1-5任一项所述的通式(I)所示的异吲哚啉衍生物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体，其特征在于，所述通式(I)化合物为下列任一化合物：
- 一种如权利要求1-7任一项所述的通式(I)所示的异吲哚啉衍生物的制备方法，其特征在于包括以下步骤：由化合物A-01反应得到通式(I)化合物，
其中，X,X 1-X 5,*,R 1,R 2,R 4,R 5,R 6,R 7,R 8的定义均如权利要求1-7任一项所述，Ra和Rb一个为另一个为
R a’，R b’独立地为H。
- 一种药物组合物，特征在于，其包括治疗和/或预防有效量的如权利要求1-7任一项所述的通式(I)所示的异吲哚啉衍生物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体中。
- 如权利要求9所述的药物组合物，其特征在于，所述的药物组合物还进一步包含其他治疗剂。
- 一种如权利要求1-7任一项所述的通式(I)所示的异吲哚啉衍生物、其药学上可接受的盐、溶剂化物、晶型、代谢物、前药或立体异构体，在制备通过诱导细胞中的靶标蛋白泛素化和降解从而治疗相关疾病、病症或病况的药物中的应用。
- 如权利要求11所述的应用，其特征在于，所述的疾病、病症或病况是癌症，优选多发性骨髓瘤。
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| WO2023122615A1 (en) * | 2021-12-22 | 2023-06-29 | Gilead Sciences, Inc. | Ikaros zinc finger family degraders and uses thereof |
| US11897862B2 (en) | 2022-03-17 | 2024-02-13 | Gilead Sciences, Inc. | IKAROS zinc finger family degraders and uses thereof |
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| CN115038694A (zh) | 2022-09-09 |
| US20230114674A1 (en) | 2023-04-13 |
| AU2021209727A1 (en) | 2022-09-15 |
| KR20220124228A (ko) | 2022-09-13 |
| ZA202209293B (en) | 2023-05-31 |
| CA3168456A1 (en) | 2021-07-29 |
| AU2021209727B2 (en) | 2024-01-11 |
| EP4095132A1 (en) | 2022-11-30 |
| BR112022014020A2 (pt) | 2022-10-11 |
| JP2023511146A (ja) | 2023-03-16 |
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