WO2016065980A1 - 异吲哚啉衍生物、其中间体、制备方法、药物组合物及应用 - Google Patents

异吲哚啉衍生物、其中间体、制备方法、药物组合物及应用 Download PDF

Info

Publication number
WO2016065980A1
WO2016065980A1 PCT/CN2015/088312 CN2015088312W WO2016065980A1 WO 2016065980 A1 WO2016065980 A1 WO 2016065980A1 CN 2015088312 W CN2015088312 W CN 2015088312W WO 2016065980 A1 WO2016065980 A1 WO 2016065980A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
substituted
formula
group
alkyl
Prior art date
Application number
PCT/CN2015/088312
Other languages
English (en)
French (fr)
Inventor
戈传生
李文成
廖柏松
张雷
Original Assignee
康朴生物医药技术（上海）有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CA2966038A priority Critical patent/CA2966038C/en
Priority to DK15855986.4T priority patent/DK3214081T3/da
Priority to PL15855986T priority patent/PL3214081T3/pl
Priority to JP2017542243A priority patent/JP6546997B2/ja
Application filed by 康朴生物医药技术（上海）有限公司 filed Critical 康朴生物医药技术（上海）有限公司
Priority to ES15855986T priority patent/ES2812877T3/es
Priority to RU2017118453A priority patent/RU2695521C9/ru
Priority to US15/523,651 priority patent/US10017492B2/en
Priority to KR1020177014411A priority patent/KR102191256B1/ko
Priority to NZ731789A priority patent/NZ731789A/en
Priority to AU2015341301A priority patent/AU2015341301B2/en
Priority to EP19214472.3A priority patent/EP3643709B1/en
Priority to PL19214472T priority patent/PL3643709T3/pl
Priority to EP15855986.4A priority patent/EP3214081B1/en
Publication of WO2016065980A1 publication Critical patent/WO2016065980A1/zh
Priority to CY20201100896T priority patent/CY1123361T1/el

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to an isoindoline derivative, an intermediate thereof, a process for the preparation, a pharmaceutical composition and use thereof.
  • Tumor necrosis factor-alpha is a pro-inflammatory cytokine that plays an important role in immune homeostasis, inflammation and host defense.
  • TNF- ⁇ has been shown to be one of the major mediators of inflammation.
  • TNF- ⁇ can also be produced by tumors and can act to promote tumor formation and also cause programmed cell death of tumor cells.
  • TNF- ⁇ also affects processes such as apoptosis, necrosis, angiogenesis, immune cell activation, differentiation, and cell migration, all of which play an important role in tumorigenesis and tumor progression.
  • Uncontrolled TNF- ⁇ activity or overproduction of TNF- ⁇ is associated with pathology of a variety of diseases including, but not limited to, cancer, eg, colon, rectum, prostate, breast, brain, and intestinal cancer; and inflammatory diseases, particularly Inflammation associated with cancer.
  • Abnormal TNF- ⁇ regulation can also cause autoimmune diseases, toxic shock syndrome, cachexia, arthritis, psoriasis, HIV infection and AIDS, nervous system diseases and central nervous system diseases, sepsis, congestive heart Failure, transplant rejection, and viral infection.
  • TNF-[alpha] levels, or modulating TNF-[alpha] activity is a promising strategy for the treatment of many immunological, inflammatory and malignant diseases such as cancer and inflammation.
  • Lenalidomide (3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinone) is a small molecule immunization Modulators have been shown to inhibit the secretion of TNF-[alpha] and other pro-inflammatory cytokines and increase the secretion of anti-inflammatory cytokines. Lenalidomide is approved for the treatment of multiple myeloma (2006), myelodysplastic syndrome (2005) and mantle cell lymphoma (2013).
  • lenalidomide can be administered alone or in combination with other therapeutic agents for the treatment of non-Hodgkin's lymphoma, papillary and follicular thyroid cancer, prostate cancer, chronic lymphocytic leukemia, amyloidosis, Type I complex local pain syndrome, malignant melanoma, radiculopathy, myelofibrosis, glioblastoma, gliosarcoma, malignant glioma, myeloid leukemia, refractory plasmacytoma, chronic granule Nuclear cell leukemia, follicular lymphoma, ciliary body and chronic melanoma, iris melanoma, recurrent interocular melanoma, melanoma extraocular spread, solid tumor, T cell lymphoma, erythroid lymphoma, Monocyte and monocyte white Blood disease; myeloid leukemia, brain tumor, meningioma, spinal cord tumor, thyroid cancer, mant
  • lenalidomide has many side effects.
  • the prescription information for lenalidomide clearly indicates that the drug has bone marrow suppression, deep vein thrombosis, pulmonary embolism and teratogenic risk.
  • most patients taking lenalidomide need to reduce their dose due to hematological toxicity.
  • lenalidomide has beneficial activity, its effectiveness is limited by the significant side effects. Therefore, there is a need in the art for an improved structure of lenalidomide derivatives to optimize their performance.
  • the present invention provides an isoindoline derivative, an intermediate thereof, a preparation method, a pharmaceutical composition, and use.
  • the isoindoline derivatives of the present invention are capable of modulating the production or activity of cytokines such as TNF- ⁇ , thereby effectively treating cancer and inflammatory diseases.
  • the present invention provides an isoindoline derivative of the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite or prodrug thereof:
  • n1 is selected from 0 or 1;
  • Z is Wherein the carbon marked with * is an asymmetric center
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from H or D;
  • R 2 is selected from H, D or halogen
  • L 1 and L 2 are independently selected from CD 2 , CHD or CH 2 ;
  • X is selected from NH, ND or O;
  • R 10 is H, D or Wherein R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from the group consisting of H, D, halogen, cyano, hydroxy, Substituted or unsubstituted (C 1 -C 12 )alkyl, substituted or unsubstituted (C 1 -C 12 )alkoxy, (C 2 -C 20 )heterocycloalkyl or deuterated (C 2 -C 20 ) a heterocycloalkyl group; wherein R a and R b are independently H, (C 1 -C 12 )alkyl or (C 1 -C 12 )alkyl acyl; R c and R d are independently H or (C 1 -C 12 )alkyl; R e is Or (C 2 -C 20 )heterocycloalkyl; R e1 and R e2 are independently H or (C 1 -C 12
  • the substituent in the substituted (C 1 -C 12 ) alkoxy group is selected from one or more of the following groups: D, halogen, hydroxy, (C 1 -C 12 ) alkoxy, (C 2 -C 20 )heterocycloalkyl, (C 1 -C 12 )alkyl-substituted (C 2 -C 20 )heterocycloalkyl, or Wherein R f and R g are independently H or (C 1 -C 12 )alkyl; R h is (C 2 -C 20 ) heterocycloalkyl;
  • the substituent in the substituted (C 1 -C 12 )alkyl group is selected from one or more of the following groups: D, (C 2 -C 20 )heterocycloalkyl, deuterated (C 2 - C 20 )heterocycloalkyl, (C 1 -C 12 )alkyl substituted (C 2 -C 20 )heterocycloalkyl or deuterated (C 1 -C 12 )alkyl substituted (C 2 -C 20 a heterocycloalkyl group;
  • condition is: in the general formula (I), when n1 is 0, R 1 , R 3 and R 10 are H or D, X is NH or ND, and R 2 is halogen;
  • the asymmetric center refers to achiral carbon, (S) configuration carbon, enriched (S) configuration carbon, (R) configuration carbon, and enrichment. (R) configuration carbon or racemate.
  • the Z is preferably any of the following structures:
  • the (C 2 -C 20 ) heterocycloalkyl group the deuterated (C 2 -C 20 ) heterocycloalkyl group, the (C 1 -C 12 ) alkane (C 2 -C 20 )heterocycloalkyl or the substituted (C 2 -C 12 )alkyl substituted (C 2 -C 20 )heterocycloalkyl group (C 2 -
  • the C 20 )heterocycloalkyl group preferably means a (C 2 -C 6 )heterocycloalkyl group in which the hetero atom is N or O and the number of hetero atoms is 1-2.
  • the (C 2 -C 6 )heterocycloalkyl group is preferably a tetrahydropyrrole (for example ), morpholinyl (eg Or piperazinyl (for example) ).
  • the (C 1 -C 12 )alkyl group described in the cycloalkyl group is preferably a (C 1 -C 4 )alkyl group.
  • the (C 1 -C 4 )alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group or a t-butyl group.
  • Said deuterated (C 2 -C 20 )heterocycloalkyl group is preferably The (C 1 -C 12 )alkyl-substituted (C 2 -C 20 )heterocycloalkyl group is preferably The deuterated (C 1 -C 12 )alkyl-substituted (C 2 -C 20 )heterocycloalkyl group is preferably
  • R 10 is R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from Or substituted (C 1 -C 12 ) alkoxy
  • R a and R b are independently (C 1 -C 12 )alkyl or (C 1 -C 12 )alkyl acyl
  • R c and R d independently Is a (C 1 -C 12 ) alkyl group
  • R e is R e1 and R e2 are independently (C 1 -C 12 )alkyl
  • the substituent in the substituted (C 1 -C 12 ) alkoxy group is
  • R f and R g are independently (C 1 -C 12 )alkyl
  • the structure of the (C 1 -C 12 )alkyl acyl group is R a1 is (C 1 -C 12 )alkyl; R a , R b , R a1 , R c , R
  • the (C 1 -C 4 )alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group or a t-butyl group.
  • R 10 is R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from substituted (C 1 -C 12 ) alkoxy, said substituted (C 1 -C 12 ) alkane
  • the substituent in the oxy group is selected from a (C 1 -C 12 ) alkoxy group
  • the (C 1 -C 12 ) alkoxy group is preferably a (C 1 -C 4 ) alkoxy group.
  • the (C 1 -C 4 ) alkoxy group is preferably a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group or a t-butoxy group.
  • R 10 is R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from substituted (C 1 -C 12 ) alkoxy, said substituted (C 1 -C 12 ) alkane
  • the substituent in the oxy group is selected from When said Preferably
  • R 10 is R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from substituted (C 1 -C 12 ) alkoxy, said substituted (C 1 -C 12 ) alkane
  • the substituent in the oxy group is selected from When said Preferably
  • R 10 when R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from a halogen, the halogen is preferably F, Cl, Br or I.
  • R 10 when R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from substituted or unsubstituted (C 1 -C 12 )alkyl, the substituted or unsubstituted (C)
  • the 1- C 12 )alkyl group is preferably a substituted or unsubstituted (C 1 -C 4 )alkyl group.
  • the substituted or unsubstituted (C 1 -C 4 )alkyl group is preferably a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted n-propyl group, a substituted or unsubstituted group. Isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted t-butyl.
  • the substituted (C 1 -C 12 ) alkyl group is preferably
  • R 10 when R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from a substituted or unsubstituted (C 1 -C 12 ) alkoxy group, the substituted or unsubstituted ( The C 1 -C 12 ) alkoxy group is preferably a substituted or unsubstituted (C 1 -C 4 ) alkoxy group.
  • the substituted or unsubstituted (C 1 -C 4 ) alkoxy group is preferably a substituted or unsubstituted methoxy group, a substituted or unsubstituted ethoxy group, a substituted or unsubstituted n-propoxy group, Substituted or unsubstituted n-butoxy, substituted or unsubstituted isobutoxy or substituted or unsubstituted tert-butoxy.
  • Said substituted (C 1 -C 12 ) alkoxy group is preferably
  • R 10 is R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from When said Preferably
  • R 10 is R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from When said Preferably
  • R 10 is R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from When said Preferably
  • R 2 is H or D.
  • R 10 is Preferably, in R 10 , R 5 ' is selected from H or D, and one of R 2 ', R 3 ' and R 4 ' is selected from the group consisting of halogen, cyano, hydroxyl, Substituted or unsubstituted (C 1 -C 12 )alkyl, substituted or unsubstituted (C 1 -C 12 )alkoxy, (C 2 -C 20 )heterocycloalkyl or deuterated (C 2 -C 20 ) heterocycloalkyl; the remainder is selected from H or D; in the above case, when R 2 ', R 4 ' and R 5 ' are selected from H or D, R 3 ' is selected from halogen, cyano, Substituted or unsubstituted (C 1 -C 12 )alkyl, substituted or unsubstituted (C 1 -C 12 )alkyl, substituted or unsubstituted (C 1
  • R 1 ', R 4 ' and R 5 ' are H
  • R 2 ' is selected from halogen or substituted or unsubstituted (C 1 -C 12 )alkyl
  • R 3 ' is selected from halogen, substituted Or unsubstituted (C 1 -C 12 )alkyl or substituted or unsubstituted (C 1 -C 12 )alkoxy.
  • the compound of formula (I) is any of the following compounds:
  • Niobium (D or 2 H) is a non-radioactive isotope of a stable form of hydrogen with an atomic weight of 2.0144. Hydrogen in nature is in the form of a mixture of H (hydrogen or hydrazine), D ( 2 H or hydrazine) and T ( 3 H or hydrazine) isotopes, wherein the abundance of hydrazine is 0.0156%. According to the ordinary skill in the art, in all structural formulas containing a natural hydrogen atom, the hydrogen atom actually represents a mixture of H, D and T. Thus, when the abundance of ruthenium at any site in the compound is greater than its natural abundance of 0.0156%, these compounds should be considered unnatural or ruthenium-enriched, so that these compounds are relative to their non-enriched counterparts. It is novel.
  • a “deuterium-enriched” compound means a compound of the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite or prodrug thereof.
  • the abundance of ⁇ at any relevant site is greater than its natural abundance at that site.
  • the abundance of enthalpy at any of its associated sites may be in the range of greater than 0.0156% to 100%.
  • the ⁇ enriched site is represented by D
  • the non- ⁇ enriched site is represented by H.
  • the non- ⁇ enriched sites may also omit the symbol H, as is known in the art.
  • An example of a method for obtaining a ruthenium-enriched compound is to synthesize a compound by exchanging hydrogen with hydrazine or enriching the starting material with hydrazine.
  • the percentage of cerium rich in cerium or the percentage of cerium in abundance is referred to as a molar percentage.
  • the non-natural deuterium enrichment means hydrogen, i.e. H (hydrogen or protium), D (2 H, or deuterium) and T (3 H or tritium) in the form of a mixture of isotopes present.
  • the present invention also provides a process for producing an isoindoline derivative represented by the above formula (I) which can be synthesized by a known method using a commercially available raw material, preferably.
  • the method A comprises the following steps: the compound A-06 (1) is subjected to a deprotection reaction as shown below to obtain a compound A (06a1); and the compound A (06a1) is further subjected to the following Said amidation reaction to obtain a compound of the formula (I);
  • the compound of the formula (I) when n1 is 0, can be further prepared by the method B, and the method B preferably comprises the following steps: the compound I-RS is carried out as follows a reduction reaction shown to produce a compound of the formula (I);
  • R 2 is halogen, n1 is 0, X is NH or ND, R 10 is H or D; definitions of L 1 , Z, R 1 and R 3 All are as described above.
  • the compound of the formula (I) may be further prepared by the method C, which preferably comprises the steps of: P-01 and Performing a reductive amination reaction as shown below to obtain a compound of the formula (I);
  • X is NH or ND
  • n1 is 1
  • R p1 , R p2 and R p3 are independently H or D
  • R 10 is The definitions of R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are as described above.
  • the deprotection reaction, the amidation reaction, the reduction reaction or the method and conditions of the reductive amination reaction may be conventional for such reactions in the art.
  • compound A-06 (1) or compound A-06 (a1), and in compound I-RS, compound P-01 or Z in formula (I) when * When the labeled carbon is an asymmetric center, the compound A-06 (1), the compound A-06 (a1), the compound I-RS, the compound P-01 or the general formula (I) can be subjected to chiral separation conventional in the art.
  • the method of fractionation is carried out to obtain (R) configuration compound, enriched (R) configuration compound, (S) configuration compound or enriched (S) configuration compound, and then react accordingly.
  • a compound of the formula (I) is obtained.
  • the method for producing the compound of the formula (I), which may further comprise the step of: the compound A-05(1) is as follows The reduction reaction, the compound A-06 (1);
  • L 1 , L 2 , R 1 to R 8 , R a and R b are as defined above; compound A-06(1) Where X is NH or ND, n1 is 0; and R 10 is H or D.
  • the methods and conditions for the reduction reaction can be conventional methods and conditions for such reactions in the art.
  • the preparation method of the compound of the formula (I) may further comprise the following steps: the compound A-05 ( 2) and The reductive amination reaction shown below is carried out to obtain the compound A-06 (1);
  • L 1 , L 2 , R 1 to R 8 , R a and R b are as defined above; compound A-06(1) Where X is NH or ND and n1 is 1; Where R p3 is H or D; R 10 is The definitions of R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are as described above.
  • the methods and conditions for the reductive amination reaction can be conventional methods and conditions for such reactions in the art.
  • the method for producing the compound of the formula (I) may further comprise the following steps: the compound A-05 (3) versus The nucleophilic substitution reaction shown below is carried out to obtain the compound A-06(1);
  • L 1 , L 2 , R 1 to R 8 , R a and R b are as defined above; compound A-06(1) Where X is O and n1 is 1; Where Hal is halogen (eg F, Cl, Br or I); R 10 is In R 10 , R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are as defined above.
  • the methods and conditions for the nucleophilic substitution reaction can be conventional methods and conditions for such reactions in the art.
  • the preparation method of the compound A-06 (1) which may further comprise the following steps: preparing the compound Q-03 and the compound A-04 (1) by a coupling reaction as shown below and then deprotecting the group. Said compound A-05 (3);
  • L 1 , *, R 1 to R 8 are as defined above; Hal is halogen (for example, Cl, Br or I); R a and R b one for The other is Where R a "and R b " are independently H or D.
  • the preparation method of the compound A-05(3) which may further comprise the following steps: the commercially available raw material phenol Q-01 is protected by TBDMS to obtain Q-02, and then reacted with a halogenated reagent (for example, NBS). A benzyl halide Q-03 is obtained.
  • a halogenated reagent for example, NBS
  • the compound I-RS is prepared according to a conventional method for preparing the compound in the art, preferably by using the method D or the method E;
  • the method D preferably comprises the following steps: the compound A-03, and the compound A-04 (2) or a salt thereof are subjected to a coupling reaction as shown below to obtain the compound I-RS;
  • the salt of the compound A-04(2) generally means a salt of the compound A-04(2) with an acid, preferably the hydrochloride of the compound A-04(2).
  • the method E preferably comprises the steps of: deprotecting the compound A-05(1) as shown below to obtain the compound A-06(a2), and then the compound A-06(a2) is as follows The amidation reaction shown to produce the compound I-RS;
  • the method for preparing the compound of the formula (I), which may further comprise the steps of: I-RS The reduction reaction shown below is carried out to obtain the compound P-01;
  • R 2 is H, D or halogen; R p1 and R p2 are independently H or D; L 1 , L 2 , Z, R 1 and R 3 are as defined above. Said.
  • the methods and conditions for the reduction reaction can be conventional methods and conditions for such reactions in the art.
  • the preparation method of the compound A-06(1) preferably further comprises the following steps: preparing the compound A-03 and the compound A-04(1) by the coupling reaction as shown below. Said compound A-05 (1);
  • L 1 , *, R 1 to R 8 , R a and R b are as defined above, and Hal is a halogen (for example, Cl). , Br or I).
  • the methods and conditions for the coupling reaction can be conventional methods and conditions for such reactions in the art.
  • the preparation method of the isoindoline derivative represented by the formula (I) comprises the following steps, specifically, the reaction scheme A and the reaction scheme P:
  • Reaction Scheme A product A-05(1) formed by coupling of benzyl halide starting material A-03 with amino acid derivative A-04(1), deprotected to give compound A-05(2), with aldehyde The reductive amination reaction is converted to the amine A-06 (1). Finally, the target product (I) is obtained by deprotection and shutting down, as follows:
  • Starting material A-03 is commercially available or in accordance with known methods (see Synthesis by et al. Org. Syn. (2003) 80, 75; US 4, 678, 500; US 2012/0053159 and US 2007/0255076).
  • the amino acid derivative A-04 is commercially available or according to known methods (see Chen et al. Biotechnol. Lett. (1992) 14, 269; WO 2012/015986; WO 2012/068512; US 2012/0053159; Manesis et al. J. Org. Chem. (1987) 52, 5342; Stogniew et al. J. Labelled Compd. RAD. (1981) 18, 897; Blomquist et al. J. Org. Chem. (1966) 31, 4121) Synthesis, see reaction scheme Formulas F1, F2, and G.
  • Heating F1-06 in D 2 O-DCl forms a hydrazine-rich amino acid F1-07, and the amino group (for example, Boc, Cbz) is protected by an amino protecting group, and the acetic anhydride is dehydrated and converted into an acid anhydride F1-08.
  • the target compound F1-11 can be obtained by deprotection.
  • F1-08, F1-09 and F1-10 W1 is a conventional amino protecting group in the art.
  • F2-04 (commercially available) was treated with reagent F2-05 (Blomquist et al. J. Org. Chem. (1966) 31, 4121) to give triethyl F2-06.
  • Heating F2-06 in D 2 O-DCl forms a hydrazine-rich amino acid F1-07, and the amino group (for example, Boc, Cbz) is protected by an amino protecting group, and the acetic anhydride is dehydrated and converted into an acid anhydride F2-08.
  • F2-08 with benzyl alcohol, it is reacted with ethyl chloroformate and ammonia water respectively, and finally the target compound F2-11 can be obtained by deprotection.
  • W1 is a conventional amino protecting group in the art.
  • W is W1 is a conventional amino protecting group in the art, such as Boc, Cbz, and the like.
  • Ester G-01 was treated with benzaldehyde in deuterated acetic acid to form hydrazine-rich compound G-02. After protecting the amino group in G-02 with an amino protecting group, it is further reacted with ethyl chloroformate and aqueous ammonia to obtain amide G-04.
  • the amino protecting group in G-04 can be removed (e.g., acidolyzed or reduced) by conventional deprotection methods in the art to be converted to the target compound G-05.
  • the present invention also provides an intermediate compound A-06(1), A-06(a1), I-RS or P-01 for preparing an isoindoline derivative of the formula (I):
  • R 1 to R 10 , R a , R b , R a1 , R b1 , R p1 and R p2 are as defined above; in compound A-06(1), one of R a and R b is The other is In compound A-06(a1), one of R a1 and R b1 is The other is Wherein R a "and R b " are independently H or D; in compound P-01, R p1 and R p2 are independently H or D.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of an isoindoline derivative of the formula (I) of the present invention, a pharmaceutically acceptable salt thereof, One or more of a solvate, a crystalline form, a stereoisomer, an isotope compound, a metabolite, and a prodrug.
  • the pharmaceutical composition may be formulated for administration in any form, including injection (intravenous), mucosa, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or gastrointestinal. Administration (infusion, injection, implantation, subcutaneous, intravenous, intraarterial, intramuscular).
  • the pharmaceutical compositions of the invention may also be in a controlled release or delayed release dosage form.
  • solid oral formulations 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 formulations 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 which can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection.
  • Examples of other suitable formulations of a compound of formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite, or prodrug thereof include, but are not limited to, eye drops and others Ophthalmic preparations; aerosols: 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 a pharmaceutically acceptable excipient such as those widely used in the field of pharmaceutical production.
  • the excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition, and may also provide means for the subject to be dissolved at the desired rate after administration, or to promote the subject's activity after administration of the composition.
  • the ingredients are effectively absorbed.
  • the excipients can be inert fillers or provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition.
  • the pharmaceutically acceptable excipient may include one or more binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, Anti-adhesives, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors or enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.
  • the pharmaceutically acceptable carrier can take a wide variety of forms depending on the form of preparation desired for administration.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like.
  • suitable carriers and additives include starches, saccharides, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like.
  • Pharmaceutically acceptable carriers or excipients should generally be non-toxic.
  • the pharmaceutical compositions according to the invention may comprise one or more suitable carriers/auxiliaries. The amount and type of excipients will vary as needed. One of ordinary skill in the art will be able to readily determine appropriate carriers/auxiliaries to be added to the pharmaceutical compositions of the present invention in light of the present disclosure.
  • the pharmaceutical composition of the present invention comprises a therapeutically or prophylactically effective amount of a compound of the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite thereof provided by the present invention.
  • a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite thereof provided by the present invention.
  • One or more of the prodrugs and prodrugs can be prepared according to the disclosure using any method known to those skilled in the art.
  • the pharmaceutical composition according to the present invention may be prepared by mixing a compound of the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite, or prodrug thereof, and pharmaceutically acceptable Acceptable carriers are prepared according to conventional pharmaceutical compounding techniques including, but not limited to, conventional mixing, dissolving, granulating, emulsifying, pulverizing, encapsulating, embedding or lyophilizing processes.
  • pharmaceutically acceptable salts, solvates, crystal forms, stereoisomers, isotopic compounds, metabolites and prodrugs thereof in the pharmaceutical composition
  • one or more additional therapeutic agents may be further included. Further content of other therapeutic agents that may be included in the pharmaceutical combinations of the invention will be disclosed below. The amount and type of other therapeutic agent will depend on the disease, condition or condition to be treated or prevented; the severity of the disease, condition or condition; factors of the subject to whom the composition is administered, such as age, weight, physical condition Etc.; route of administration, etc.
  • controlled release dosage form refers to a dosage form wherein the rate of release of the therapeutically active ingredient of the composition is controllable or has a specific delay to control the therapeutic activity in a subject receiving the administration of the composition.
  • a controlled release dosage form can contain a controlled release agent such as a sustained release agent (sustained release or delayed release) and a delayed release agent (delayed release).
  • sustained release and “delayed release” refer to the prolonged release of a therapeutically active ingredient from a pharmaceutical composition.
  • the term “delayed release” refers to a therapeutically active component from a pharmaceutical combination after the subject has received the composition to reach the desired environment within the subject, or after a particular period of time after the subject has received the administration. The release is such that the release occurs at a particular location or desired environment.
  • sustained release agent and “delayed release agent” refer to a compound or additive that provides controlled release of a therapeutically active ingredient from a composition such that release occurs gradually and the release time is prolonged.
  • the sustained or delayed release agent allows the subject to release the therapeutically active ingredient for a specified period of time after administration of the composition.
  • a compound of formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite, or prodrug thereof is from the composition of the invention
  • Controlled release can be achieved by a variety of conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • the pharmaceutical compound according to the present invention may further comprise an enteric coating, wherein the enteric coating controls a compound of the formula (I) or a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotopic compound thereof, Release of the metabolite, or prodrug, such that it is gradually and continuously released from the composition over a desired period of time, allowing the compound to be extended Play a therapeutic or preventive role for a long period of time.
  • the enteric coating controls a compound of the formula (I) or a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotopic compound thereof, Release of the metabolite, or prodrug, such that it is gradually and continuously released from the composition over a desired period of time, allowing the compound to be extended Play a therapeutic or preventive role for a long period of time.
  • the controlled release pharmaceutical composition may further comprise one or more additional therapeutic agents or agents as disclosed below.
  • controlled release agents that can be incorporated into the pharmaceutical compositions of the present invention to provide controlled release compositions include polymers such as hydroxypropyl methylcellulose; gels; permeable membranes; microparticles; liposomes; Ball and its combination. Any of the compositions described herein can be applied to controlled release formulations such as tablets, capsules, soft capsules and caplets.
  • the drug, any of its pharmaceutical compositions, preparations and the like can be administered to the subject for a period of time (dosing period) by the method of the present invention, followed by a period of time during which no compound is administered (non-administration period).
  • the desired number of dosing cycles and non-dosing cycles can be repeated.
  • the desired length and number of administration cycles or non-dosing cycles will depend on the type and/or severity of the disease, condition 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.). The level of skill of one of ordinary skill in the art in light of the disclosure herein will be sufficient to determine the appropriate length and number of dosing cycles and/or non-dosing cycles.
  • the compounds of formula (I), pharmaceutically acceptable salts, solvates, crystal forms, stereoisomers, isotopic compounds, metabolites or prodrugs thereof according to the invention may be used in a variety of applications including, but not limited to, A medicament for treating or preventing a disease, disorder or condition caused by TNF- ⁇ or dysregulated by TNF- ⁇ activity is prepared.
  • the invention relates to a therapeutically or prophylactically effective amount of a compound of formula (I), a pharmaceutically acceptable salt, solvate, stereoisomer, isotope compound, metabolite or prodrug thereof, Use in the preparation of a medicament for treating or preventing a disease, disorder or condition.
  • the present invention relates to a method of treating or preventing a disease, disorder or condition caused by TNF- ⁇ , or dysregulated by TNF- ⁇ activity, by administering to a subject for treatment or prevention An effective amount of one or more of an isoindoline derivative represented by the formula (I), a pharmaceutically acceptable salt, a solvate, a stereoisomer, an isotope compound, a metabolite, and a prodrug.
  • an isoindoline derivative represented by the formula (I) a pharmaceutically acceptable salt, a solvate, a stereoisomer, an isotope compound, a metabolite, and a prodrug.
  • diseases, disorders and conditions to be treated or prevented according to the methods of the invention include, but are not limited to, cancer: including solid tumors, TNF- ⁇ related disorders, undesired angiogenesis-related diseases and conditions, pain, macular degeneration (MD) related syndrome, skin disease, keratosis, respiratory diseases (such as lung disease), immunodeficiency disease, central nervous system (CNS) disease, autoimmune disease, atherosclerosis, heredity, allergy, Virus, sleep disorder and related syndrome, inflammatory disease, PDE-4 related disease or IL-2 related disease.
  • diseases, disorders, or conditions that are well known in the art include, but are not limited to, those described in PCT Patent Publications WO2012015986 and WO2006018182, and U.S. Patent Publication No. US20100204227, each of which is incorporated herein in its entirety by reference.
  • the disease, disorder or condition is selected from the group consisting of: a neoplastic or cancerous disease; an autoimmune disease such as Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, atopic dermatitis, Autoimmune alopecia areata, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome (alps), Behcet's disease, bullous pemphigoid, cardiomyopathy, Celiac disease, chronic fatigue syndrome immunodeficiency syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, scar pemphigoid, cold agglutinin disease, CREST syndrome, Crohn's disease, Dego Disease, dermatomyositis, juvenile dermatomyositis, discoid lupus erythematosus, eczema, primary mixed cryoglobulinemia, fibromyal
  • cancerous or neoplastic conditions include, but are not limited to, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloid leukemia, karyotype acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic granules Cellular leukemia, hairy cell leukemia, myeloid leukemia, adrenocortical carcinoma, Burkitt's lymphoma, AIDS Related lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, low-grade follicular lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma , smoldering myeloma, myelodysplastic syndrome, mantle cell lymphoma, inert myeloma, chronic myeloproliferative
  • the disease, condition or condition is selected from the group consisting of myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, central nervous system lymphoma, non-Hodgkin's lymphoma Papillary and follicular thyroid cancer; breast cancer, prostate cancer, chronic lymphocytic leukemia, amyloidosis, type I complex local pain syndrome, malignant melanoma, radiculopathy, myelofibrosis, glioblasts Tumor, gliosarcoma, malignant glioma, refractory plasmacytoma, chronic myelomonocytic leukemia, follicular lymphoma, ciliary body and chronic melanoma, iris melanoma, recurrent interocular melanoma , extraocular extension of melanoma, solid tumor, T cell lymphoma, erythroid lymphoma
  • the methods of treatment described herein can be administered to a subject using any suitable method, including injection, transmucosal, oral, inhalation, ocular, rectal, long-term implantation, liposomes, emulsions or sustained release methods. .
  • the therapeutically or prophylactically effective amount of the compound to be used in the present invention may vary from subject to subject, for a particular subject, such as age, diet, health, etc., seeking treatment or prophylaxis or The severity of the disease, condition or condition as well as the complications and type, the formulation used, and the like.
  • a therapeutically or prophylactically effective amount of a compound to be administered to a subject to elicit a desired biological or medical response in the subject.
  • a compound represented by the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite, or prodrug thereof can be used to modulate TNF - Activity or production of - ⁇ or IL-2.
  • modulation when “modulation” is used to describe the activity or production of a particular molecule, it is meant to inhibit the activity or production of that molecule.
  • modulation when “modulation” is used to describe the activity or production of a particular molecule, it is meant to increase or promote the activity or production of the molecule.
  • when “modulation” is used to describe the activity or production of a particular molecule it is meant to reduce or increase the activity or production of the molecule.
  • the present invention also provides methods of modulating TNF-[alpha] or IL-2 production or activity.
  • a compound of the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite, or prodrug thereof, or a combination thereof according to an embodiment of the present invention
  • the subject can be administered to modulate the production or activity of TNF-[alpha] or IL-2 for the treatment or prevention of diseases characterized by TNF-[alpha] or IL-2 dysregulation or characterized by TNF-[alpha] or IL-2 dysregulation. , illness or condition.
  • a compound of the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite or prodrug thereof, according to the present invention, Or a composition thereof is administered to a subject to modulate the production or activity of TNF-[alpha] or IL-2 for the treatment or prevention of cancer or inflammation.
  • a compound of the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite, or former thereof according to the present invention
  • the drug may be used alone or in combination with radiation therapy or radioimmunotherapy, or may be used in combination with one or more other pharmacologically active therapeutic agents (hereinafter referred to as "other therapeutic agents").
  • a compound of the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite, or prodrug thereof according to the present invention
  • Other therapeutic agents are used in combination to provide a synergistic effect in the treatment or prevention of any disease, condition or condition in accordance with the present disclosure.
  • the additional therapeutic agent may be a naturally occurring, semi-synthetic or synthetic compound.
  • the other therapeutic agent can be a small molecule, such as a synthetic organic or inorganic molecule; or a larger fraction A sub or biomolecule, such as a protein or nucleic acid having pharmacological activity.
  • the additional therapeutic agent can be an anti-angiogenic, immunomodulatory, immunotherapeutic, chemotherapeutic or hormonal compound.
  • Examples of other therapeutic agents suitable for use in the present invention include, but are not limited to, monoclonal and polyclonal antibodies such as obinutuzumab ( ), nivolumab ( ), pembrolizumab ( ), elotuzumab, anti-Her2/neu antibody (eg, trastuzumab (trastuzumab, trade name: ) and pertuzumab (trade name: Omnitarg TM ); abciximab (abciximab, trade name: ), rituximab (rituximab, trade name: ), basiliximab (basiliximab, trade name: ), palivizumab (trade name: ), Infliximab (infliximab, trade name: ), trastuzumab (Trastuzumab, trade name: ), alemtuzumab (alemtuzumab, trade name: ), temimumab t
  • acivicin aclarubicin; acadazole hydrochloride; acronine; Acylfulvene (acyl fulvene); adenocyclopentanol; adozelesin; aldesleukin; altretamine; ambastamustine; amphomycin ); ametantrone acetate; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide Anastrozole; anthramycin; anti-dorsalizing morphogenetic protein-1; antineoplaston; aphidicolin glycinate; Apuric acid; ara-CDP-DL-PTBA; asparaginase; asperlin; asaculine; atamestane; Attin (inrimustine); Axinsi Axin 1; axinstatin 2; axinstatin 3;
  • the additional therapeutic agent is selected from the group consisting of elotuzumab, palbociclib, panobinostat, nivolumab, pembrolizumab, pemetrexed, topotecan (topotecan), doxorubicin, Bortezomib, gemcitabine, dacarbazine, Dexamethasone, biaxin, vincristine, azacitidine, CAR-T, rituximab, trastuzumab , PD-1 inhibitor, PDL-1 inhibitor, HDAC inhibitor, androgen receptor inhibitor, androgen biosynthesis inhibitor, prednisone, docetaxel, clofarabine injection One or more of liquid, Ublituximab, romidepsin, BTK inhibitor, red blood cell growth hormone, eltrombopag, minocycline and melphalan.
  • a compound of formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite, or prodrug thereof, and Another composition of the therapeutic agent is administered to the subject simultaneously.
  • the compound of formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite, or prodrug thereof, and another therapeutic agent are The order is administered sequentially.
  • the compound of formula (I), a pharmaceutically acceptable salt, solvate, stereoisomer, isotope compound, metabolite, or prodrug thereof, and another therapeutic agent are administered separately .
  • the additional therapeutic agent may be administered continuously prior to administration of a compound of formula (I) according to the invention, a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite, or prodrug thereof. Or after giving.
  • One or more other therapies according to the invention which may be administered in combination with a compound of formula (I) or a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite, or prodrug thereof
  • the agent will depend on a variety of factors, such as the disease, condition or condition in which prevention or treatment is desired.
  • an isoindoline derivative represented by the formula (I) a pharmaceutically acceptable salt thereof, a solvate, a crystal form, a stereoscopic Suitable other therapeutic agents for use in combination with a conformation, an isotope compound, a metabolite, or a prodrug.
  • Therapeutically effective amounts of other therapeutic agents used in the methods of the invention are well known to those skilled in the art, and administration guidelines can be found in the patents and published patent applications cited herein and in Wells et al, eds., Pharmacotherapy Handbook, 2nd. Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000) and other medical literature. However, one of ordinary skill in the art is well able to determine the optimal effective dosage range for other therapeutic agents.
  • a compound of the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite, or prodrug thereof and other treatments according to the invention
  • the agent When the agent is administered in combination, the therapeutically effective amount of the compound represented by the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite or prodrug thereof is lower than that of the agent.
  • a therapeutically effective amount would be required if a compound of formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite, or prodrug thereof, is administered in combination with other therapeutic agents.
  • the therapeutically effective amount of the other therapeutic agent is lower than the non-administration of the general formula according to the present invention.
  • a compound of formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite, or prodrug thereof, and other therapeutic agents are administered to A compound of formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite, or prodrug thereof, and the like, in the treatment or prevention of a disease, disorder or condition.
  • the therapeutic agent can be administered by the same route or 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, liposomal, long-acting, or sustained release methods.
  • the particular route of administration of other therapeutic agents will depend on the other therapeutic agent itself and the formulation, as well as the disease, condition or condition to be prevented or treated. In accordance with the present disclosure, the skill level of one of ordinary skill in the art is sufficient to determine the route of administration of other therapeutic agents.
  • salt, composition, excipient, etc. it is meant that the salt, composition, excipient, and the like are generally non-toxic, safe, and suitable for use by a subject, preferably A mammalian subject, more preferably a human subject.
  • salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, hydrogen sulfates, phosphates, acid phosphates, isonicotinic acid Salt, lactate, salicylate, acid citrate, tartrate, oleate, tannic acid, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, gentisinate , fumarate, gluconate, glucuronate, sugar, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, besylate , p-toluenesulfonate and pamoate (ie, 1-1-methylene-bis(2-hydroxy-3-naphthoate)
  • the compounds used in the present invention can form pharmaceutically acceptable salts with various amino acids.
  • Suitable base salts include, but are not limited to, aluminum salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, zinc salts, barium salts, and diethanolamine salts.
  • Pharmaceutically acceptable salt For a review, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).
  • the term "metabolite” refers to an active substance produced by a change in the chemical structure experienced by a drug molecule in vivo, which is typically a derivative of the aforementioned drug molecule, which may also be chemically modified.
  • polymorph refers to one or more crystal structures formed by the different arrangement of molecules in the lattice space upon crystallization.
  • solvate refers to a crystalline form of a compound of formula (I), a pharmaceutically acceptable salt, crystal form, stereoisomer, isotope compound, metabolite or prodrug thereof. Contains one or more solvent molecules that are incorporated into the crystal structure.
  • the solvate may include a stoichiometric or non-stoichiometric amount of solvent, and the solvent molecules in the solvent may be present in an ordered or non-ordered arrangement. Solvates containing non-stoichiometric amounts of solvent molecules may be obtained by solvating at least one, but not all, solvent molecules.
  • a solvate is a hydrate, meaning that the crystalline form of the compound further comprises water molecules with water molecules as a solvent.
  • prodrug refers to a derivative of a compound comprising 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.
  • the reaction is provided to provide the compound.
  • the prodrug is inactive, or at least less active than the compound itself, such that the compound does not exert its activity until it is cleaved from the biologically reactive functional group.
  • the bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide the compound.
  • a prodrug can comprise a biohydrolyzable group.
  • biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable Acyl urea.
  • biohydrolyzable phosphates include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable Acyl urea.
  • the compound of the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite or prodrug thereof of the present invention may contain one or more asymmetric centers ("Stereo Structure”).
  • stereoisomer refers to enantiomers, diastereomers, epimers, endo-exo isomers, steric hindrance All stereoisomers of atropisomers, regioisomers, cis- and trans-isomers, and the like.
  • “Stereoisomers” herein also include “pure stereoisomers” and “enriched stereoisomers” or “racemates” of the various stereoisomers described above.
  • stereoisomers can be isolated, purified and enriched by asymmetric synthesis or chiral separation methods including, but not limited to, thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc. It is obtained by chiral separation by bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds.
  • pure stereoisomer herein is meant the compound in question One stereoisomer has a mass content of not less than 95% relative to other stereoisomers of the compound.
  • enriched stereoisomer herein is meant that the stereoisomer of the compound in question has a mass content of not less than 50% relative to the other stereoisomers of the compound.
  • racemate herein is meant that the mass of one stereoisomer of the compound in question is equal to the mass content of the other stereoisomers of the compound.
  • isotopic compound means that the compound of the formula (I) of the present invention, a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, metabolite, or prodrug thereof contains one or more Atomic isotope of natural or non-natural abundance.
  • Non-natural abundance of atomic isotopes including, but not limited to, hydrazine ( 2 H or D), hydrazine ( 3 H or T), iodine-125 ( 125 I), phosphorus-32 ( 32 P), carbon-13 ( 13 C) Or carbon-14 ( 14 C).
  • the aforementioned isotopic compounds can also be used as therapeutic or diagnostic agents (i.e., in vivo developers), or as research tools. All isotopic variations of the compounds of the invention, whether or not they are radioactive, are included within the scope of the invention.
  • isotopic enrichment refers to one or more of a compound of formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite or prodrug thereof.
  • “Isotopic enrichment” also refers to a compound of formula (I), a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound, metabolite, or prodrug compound thereof containing at least one non-naturally abundant Degree isotope atom.
  • the term "subject” refers to any animal that is or has been administered a compound or composition according to an embodiment of the invention, which is superior to mammals and optimal for humans.
  • 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., which are optimal for humans.
  • treating refers to amelioration, prevention, or reversal of a disease or condition, or at least one discernible symptom thereof, for example, by reducing or stabilizing the symptoms of a cancer or condition, treating cancer, undesired blood vessels A related disorder or a TNF- ⁇ related disorder is generated.
  • “treating” or “treating” refers to an improvement, prevention or reversal of at least one measurable physical parameter of a disease or condition being treated, which may not be recognized in a mammal.
  • cancer, undesired angiogenesis-related disorders, or TNF- ⁇ related disorders are treated by inhibiting TNF-[alpha] production or modulating TNF-[alpha] activity.
  • treating refers to slowing the progression of a disease or condition, or physical, such as the identification of stable symptoms, or physiological, for example, stabilization of body parameters. , or both.
  • treating or “treating” refers to delaying the onset of a disease or condition.
  • the compound of interest is administered as a preventative measure.
  • preventing or “preventing” refers to reducing the risk of obtaining a given disease or condition.
  • the indicated compound is administered to the subject as a preventive measure, such as a subject having a family history or predisposition to cancer or an autoimmune disease.
  • therapeutically effective amount refers to an amount of a compound or composition that is capable of causing a tissue system, animal or human to produce a biological or medical response (a researcher, veterinarian, doctor or other clinician is seeking), which may include Reduce the symptoms of the disease or condition being treated.
  • the therapeutically effective amount is an amount effective to treat, ameliorate, or prevent a cancer, disorder, or undesirable vascular-related condition or TNF-[alpha]-related disorder.
  • prophylactically effective amount refers to an amount of an active compound or agent that is capable of inhibiting the onset of a condition in a subject (as sought by a researcher, veterinarian, medical practitioner, or other clinician).
  • a prophylactically effective amount of a compound refers to an amount of the therapeutic agent used alone or in combination with other therapeutically active compounds that provides a therapeutic benefit in the treatment or prevention of a disease, disorder or condition.
  • the reagents and starting materials used in the present invention are commercially available.
  • the isoindoline derivative of the formula (I) of the present invention is capable of regulating the production and/or activity of a cytokine such as TNF- ⁇ , thereby effectively treating cancer and inflammatory diseases.
  • Step A 5-Fluoro-2-methylbenzoic acid (6.0 g, 38.9 mmol) was dissolved in 98% sulfuric acid (60 mL). The temperature was lowered to -5 to 0 ° C, and 65% nitric acid (3.3 g, 50.7 mmol) was slowly added dropwise, and the mixture was stirred at this temperature for 1 hour.
  • Step B The crude 5-fluoro-2-methyl-3-nitrobenzoic acid (7.0 g) obtained in Step A was dissolved in methanol (70 mL), and 98% sulfuric acid (2 mL) was added. The mixture was stirred at 70 ° C overnight. After the reaction mixture was concentrated, water (50 mL) and ethyl acetate (150 mL) The organic phase was combined and washed with brine (30 mL) EtOAc. Methyl methyl-3-nitrobenzoate (3.5 g, 42% yield in two steps).
  • Step C Methyl 5-fluoro-2-methyl-3-nitrobenzoate (3.5 g, 16.4 mmol), BPO (388 mg, 1.6 mmol) and NBS (3.2 g, 18.1 mmol) were dissolved in CCl 4 ( In 40 mL), the reaction was carried out at a bath temperature of 95 ° C overnight. The mixture was cooled to room temperature and then filtered. EtOAcjjjjjjjjjjjjjjjjjjjj Methyl 2-bromomethyl-5-fluoro-3-nitrobenzoate (3.7 g, yield: 77%).
  • Step D 3-Aminopiperidine-2,6-dione hydrochloride (2.5 g, 15.1 mmol) and methyl 2-bromomethyl-5-fluoro-3-nitrobenzoate (4.0 g, 13.7 in mmol) and KHCO 3 (3.5g, 34.2mmol) was added CH 3 CN (80mL), 95 °C bath temperature overnight. The reaction solution was concentrated, and then ice water (100 g) was added and stirred for 0.5 h.
  • Step E Compound I-28A (2.8 g, 9.1 mmol) and Pd/C (10%, 280 mg, 50% water) was taken in DMF (30 mL) The reaction mixture was filtered, and the ⁇ jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Step A To a solution of the deuterated acetic acid AcOD (150 mL) containing L-glutamic acid-5-benzyl ester (50.0 g, 211 mmol) was added benzaldehyde (1.34 g, 12.6 mmol), heated to 65 ° C, and stirred for 18 hours. The solvent was removed by concentration under reduced pressure. Methanol (25 mL), acetonitrile (50 mL) and methyl tert-butyl ether (200 mL) were added to the residue and the mixture was stirred for half an hour and then filtered, and the filter cake was rinsed with methyl t-butyl ether (200 mL).
  • Step B a mixed solvent of Compound I-31A (32.5g, 137mmol) was dissolved in THF (600ml) and water (600ml), the ice bath was added NaHCO 3 (12.6g, 150mmol), after 10 minutes (Boc) 2 O (32.7 g, 150 mmol) was slowly added to the reaction system. After the temperature was naturally raised to room temperature, stirring was continued for 4 hours, and the mixture was concentrated under reduced pressure, and the residue was dissolved in a saturated aqueous NaHCO 3 solution. It was extracted with methyl tert-butyl ether (200 ml ⁇ 2), and the aqueous phase was cooled with ice and then acidified to pH-1 with 3N HCl.
  • Step C Compound I-31B (46.5 g, 137 mmol) was dissolved in THF (300 mL). After the reaction mixture was cooled to 5 ° C, methyl morpholine (NMM, 16.5 g, 164 mmol) and ethyl chloroformate (17.8). After stirring at 0 to 5 ° C for one hour, saturated aqueous ammonia (150 ml) was added to the reaction mixture, and stirred vigorously at room temperature for 2 hours.
  • NMM methyl morpholine
  • ethyl chloroformate 17.8
  • saturated aqueous ammonia 150 ml
  • Step D Compound I-31C (41.0 g, 121 mmol) was dissolved in 1,4-dioxane (200 mL), and 6N HCl/dioxane solution (300 mL) was added and stirred at room temperature for 2 hr. The reaction mixture was concentrated to dryness and then evaporated to ethyl ether (ethyldiethyl ether) and filtered to afford white solid I-31D (31.3 g, yield: 95%).
  • Step E Methyl 2-bromomethyl-5-fluoro-3-nitrobenzoate (31.8 g, 109 mmol) and compound I-31D (29.7 g, 109 mmol) were dissolved in acetonitrile (550 mL). TEA (22.1 g, 218 mmol). The temperature was raised to 75 ° C and allowed to react overnight. And concentrated to dryness under reduced pressure, the residue was added CH 3 CN (100mL) to give a pale yellow solid slurried Compound I-31E (34.5g, yield: 76.2%).
  • Compound I-32 Compound I-31F2 (2.2 g, 5.3 mmol) and Pd/C (10%, 200 mg, 50% water) were taken in anhydrous methanol (30 mL). The reaction mixture was filtered with suction ⁇ Obtained crude white (1.4 g). Take 1.1g (3.7mmol) in a mixed solvent of dry THF (10mL) and DCE (40mL), slowly add SOCl 2 (0.74g, 9.3mmol) at -30 °C, add the stirring reaction for 2h, drop Pyridine (1.1 g, 9.3 mmol) was added to this temperature and stirred for 40 minutes. TEA (1.3 g, 13 mmol) was added and the reaction was continued for 2 h.
  • the compound I-01 of Example 4 can be synthesized by referring to the synthesis method of the compound of Example 3 using the corresponding racemic mixture I-31E as a substrate.
  • the synthesis method of the compound I-33 to the compound I-56 can be referred to the embodiment 2 or 3.
  • Step B To a solution of the compound I-28 and 2-fluoro-3-methoxybenzaldehyde (85 mg, 0.551 mmol) in EtOAc (3 mL). After adding NaBH(OAc) 3 (235 mg, 1.09 mmol) for 18 hours, the reaction was complete, and NaBH(OAc) 3 (50 mg, 0.236 mmol) was added for 30 hours at 30 ° C. Additional 2-fluoro-3-methoxy The benzaldehyde (30 mg, 0.195 mmol) was reacted for 16 hours at 40 ° C. The solvent was evaporated to dryness and purified to purified crystals eluted eluted eluted eluted elute
  • Step A Dissolve 4-(morpholinemethyl)benzyl alcohol 1.5 g, 7.2 mmol) in dichloromethane (20 mL), warm to 0 ° C, and slowly add thionyl chloride (2.6 g, 21.8 mmol). After the completion of the dropwise addition, the reaction was allowed to proceed overnight at 25 °C. The reaction was completed by LCMS. The reaction mixture was concentrated to give white crystals (yel.
  • Step B 5-Fluoro-2-methyl-3-nitro-benzoic acid methyl ester (2.0 g, 9.4 mmol) and Pd/C (10%, 200 mg, 50% water) dissolved in MeOH (20 mL) 50 Psi of hydrogen was stirred in the greenhouse overnight. The reaction was completed by TLC and LCMS. The reaction mixture was suction filtered, and then evaporated, mjjjjjjj
  • Step D 5-Fluoro-3-hydroxy-2-methyl-benzoic acid methyl ester (1.2 g, 6.5 mmol) and imidazole (1.33 g, 19.5 mmol) were dissolved in DCM (20 mL) TBDMSCl (1.96 g, 13 mmol) was added portionwise at ° C. After the addition was completed, the mixture was stirred for 10 minutes and then stirred at 25 ° C for 2 hours. The reaction was completed by TLC. The reaction mixture was washed with water (50 mL), EtOAc (EtOAc)EtOAc. The pale yellow oil was obtained as methyl 3-(tert-butyl-dimethyl-silyloxy)-5-fluoro-2-methyl-benzoate (1.4 g, yield: 72%).
  • Step E Dissolving methyl 3-(tert-butyl-dimethyl-silanoxy)-5-fluoro-2-methyl-benzoate (1.4 g, 4.7 mmol) and NBS (1.0 g, 5.6 mmol) In CCl 4 (20 mL), benzoyl peroxide (0.12 g, 0.5 mmol) was then added and allowed to react overnight at 80 ° C under nitrogen. The reaction was completed by TLC. The reaction mixture was filtered with suction ⁇ 100:1), 2-bromomethyl-3-(tert-butyl-dimethyl-silyloxy)-5-fluoro-benzoic acid methyl ester (1.4 g, purity: 90%).
  • Step F 2-Bromomethyl-3-(tert-butyl-dimethyl-silyloxy)-5-fluoro-benzoic acid methyl ester (500 mg, 1.33 mmol) and iso-n- succinate tert-butyl ester hydrochloride ( 349mg, 1.46mmol) and triethylamine (405mg, 4.0mmol) was dissolved in CH 3 CN (10mL), under nitrogen protection reaction overnight at 80 deg.] C. The reaction was completed by TLC. After concentrating the reaction mixture, THF (10 mL), THF (4 mL, 1M in THF), and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was concentrated and purified mjjjjlilililililililililili
  • Step G A327A (200mg, 0.57mmol) and 4- (4- (chloromethyl) benzyl) morpholine hydrochloride (445mg, crude) in dry DMF (10mL), the room temperature under nitrogen was added K 2 CO 3 (393mg, 2.90 mmol). After the addition was completed, the mixture was stirred at room temperature and allowed to react overnight. The reaction was not completed by LCMS, and then 4-(4-Chloromethyl-benzyl)-morpholine (445 mg, crude) was added, and the reaction was continued for 6 hours. After the reaction mixture was concentrated, EtOAc ⁇ : 1 to 1:1 to EtOAc) gave white solid A327B (250 mg, yield: 81%).
  • Step H A327B (250 mg, 0.46 mmol) was dissolved in dry DCM (10 mL). The reaction was completed by TLC. After concentrating the reaction mixture, EtOAc m.
  • Step I The A327C (230mg crude) was dissolved in CH 3 CN (15mL), at room temperature under nitrogen was added CDI (115mg, 0.71mmol), after completion of the addition, the reaction mixture was 95 deg.] C overnight. The reaction was completed by LCMS. After the reaction mixture was concentrated, purified by Prep-HPLC to afford A327 (yield:
  • Step A 2-fluoro-4-methoxybenzaldehyde (1.0g, 6.49mmol) was dissolved in MeOH (10mL) was added NaBH 4 (370mg, 9.74mmol), the reaction was stirred at room temperature 1h, TLC showed complete reaction. The reaction was quenched with 1N EtOAc (EtOAc (EtOAc) (EtOAc) (EtOAc) The aqueous solution was dried (MgSO4), filtered, evaporated, evaporated.
  • Step B A mixture of 2-fluoro-4-methoxybenzyl alcohol (400mg, 2.56mmol) dissolved in dry DCM (10mL) was added SOCl 2 (458mg, 3.85mmol), the reaction was stirred at room temperature 3h. LCMS showed the reaction was completed. The reaction mixture was concentrated to dryness crystals crystals crystals crystals crystals
  • Step C Compound A329B (200mg, 0.68mmol) was dissolved in DMF (15mL) was added K 2 CO 3 (283mg, 2.05mmol ) and 2-fluoro-4-methoxy-benzyl chloride (239mg, 1.37mmol), The reaction was stirred at room temperature overnight. LCMS showed the residue in the reaction mixture. 2-fluoro-4-methoxybenzyl chloride (100 mg, 0.57 mmol) was added and stirring was continued for 3 hours. LCMS showed the reaction was complete. The solvent was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAcjjjjjjjjjjjjjjj The mother liquor was concentrated under reduced pressure to dryness crystals crystals crystals crystals crystals crystals crystals crystals crystals
  • Step D A329A (190mg, 0.44mmol) was dissolved in DMF (10mL), K 2 CO 3 was added after the reaction flask (183mg, 1.33mmol), the reaction was stirred and heated to a nitrogen blanket overnight at 80 °C. LCMS showed the reaction was completed. The reaction mixture was filtered under reduced pressure.
  • Step A (S)-Isoglutamine tert-butyl ester hydrochloride (1.91 g, 8.00 mmol) was added to methyl 2-bromomethyl-3-nitrobenzoate (2.00 g, 7.30 mmol). In a CH 3 CN solution (40 mL), then Et 3 N (1.63 g, 16.1 mmol) was added and the reaction mixture was heated to 75 ° C and stirred overnight. TLC showed the reaction was complete.
  • reaction mixture was concentrated with EtOAc EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Step B A340A (1.20 g, 3.30 mmol) was dissolved in methanol, then Pd/C (10%, 200 mg, 50% water) was added, hydrogen was ventilated three times, and hydrogenated at 25 ° C under hydrogen pressure of 50 psi overnight. LCMS showed the reaction was completed. The reaction solution was filtered under reduced pressure of Pd/C, and the filtrate was concentrated to dryness. The pale yellow solid product A340B (1.19 g, crude) was taken directly to next.
  • Step D A340C (1.15 g, 2.44 mmol) was dissolved in DCM (20 mL), cooled to 0 ° C, then TFA (4 mL) was added dropwise to the reaction flask, and the mixture was slowly warmed to 25 ° C and stirred overnight. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj
  • Step E A340D (700 mg, 1.69 mmol) was dissolved in dry DCM (70 mL), cooled to -40 ° C under nitrogen atmosphere, and SOCl 2 (1.00 g, 8.40 mmol) was slowly added dropwise. After the addition was completed, DMF was added. (10 mg) in DCM (1mL) was added the reaction to complete mixing 2h, added dropwise pyridine (666mg, 8.42mmol) maintained at that temperature for 40 minutes, was added Et 3 N (852mg, 8.42mmol) , the addition, the reaction was continued for 2h. LCMS showed the reaction was completed.
  • Step A 2-bromomethyl-3-nitrobenzoate (1.00g, 3.65mmol) was dissolved in CH 3 CN (50mL), was added the (R) added to the reaction flask - t-isoglutamine ester hydrochloride (955mg, 4.00mmol) and Et 3 N (815mg, 8.05mmol) , nitrogen, and heated to 75 deg.] C and stirred overnight. TLC showed the reaction was complete. The reaction mixture was concentrated with EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The mixture was dried, filtered, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated
  • Step B A341A (800 mg, 2.20 mmol) was dissolved in methanol, then Pd/C (10%, 80 mg, 50% water) was added and hydrogenated at 25 ° C under hydrogen pressure of 50 psi overnight. LCMS showed the reaction was completed. The reaction mixture was filtered under reduced pressure of EtOAc (EtOAc).
  • Step C A341C (680 mg, 2.04 mmol) and 2-fluoro-5-methoxybenzaldehyde (472 mg, 3.06 mmol) were dissolved in MeOH, then HOAc (0.5 mL) was added to the reaction flask and stirred at 25 °C hour. Pd/C (10%, 50 mg, 50% water) was added, hydrogen was exchanged three times, and hydrogenation was carried out overnight at 25 ° C (balloon). LCMS showed the reaction was complete, The Pd/C was filtered off under reduced pressure, and the filtrate was evaporated. mjjjjjjjjjj
  • Step D A341E (650 mg, 1.38 mmol) was dissolved in DCM (20 mL), cooled to 0 ° C, then TFA (4 mL) was added dropwise to the reaction flask, and the mixture was slowly warmed to 25 ° C and stirred overnight. The reaction mixture was concentrated under reduced pressure. EtOAc m.
  • Step E A341G (450 mg, 1.08 mmol) was dissolved in dry DCM (50 mL), cooled to -40 ° C under nitrogen atmosphere, slowly added SOCl 2 (644 mg, 5.41 mmol), and added DMF (10 mg) The reaction mixture was stirred for 2 h. pyridine (428 mg, 5.41 mmol) was added dropwise, and the mixture was stirred at the same temperature for 40 minutes. Et 3 N (547 mg, 5.41 mmol) was added, and the reaction was continued for 2 h. LCMS showed the reaction was completed.
  • Step A The A343F (31.7g, 115.5mmol) was suspended in CH 3 CN (560mL), was added after A343G (31.5g, 115.5mmol) and Et 3 N (23.3g, 231.0mmol) added to the reaction flask, a nitrogen Protect, heat to 75 ° C and stir the reaction overnight. The reaction mixture was concentrated with EtOAc EtOAc EtOAc.
  • Step B A342E (R) (2.5 g, 6.3 mmol) was dissolved in MeOH (150 mL) / THF (150 mL), then Pd/C (10%, 500 mg, 50% water), hydrogen gas three times, 50 Psi Hydrogenation at 25 ° C under hydrogen pressure overnight. LCMS showed the reaction was completed. The reaction solution was filtered under reduced pressure of Pd/C, and the filtrate was concentrated to dryness. After adding CH 3 CN/DCE (50 mL / 150 mL), EtOAc (EtOAc m. In the next step.
  • Step C A342C and 2-fluoro-5-methoxybenzaldehyde (831 mg, 5.39 mmol) were dissolved in MeOH, then EtOAc (0.5 mL). Pd/C (10%, 100 mg, 50% water) was added, hydrogen was exchanged three times, and hydrogenation was carried out overnight at 25 ° C (hydrogen balloon). LCMS showed the reaction was complete. The Pd/C was filtered off under reduced pressure, and the filtrate was concentrated under reduced pressure.
  • Step D A342A (450 mg, 1.10 mmol) was dissolved in dry DCM (50 mL), cooled to -40 ° C under nitrogen atmosphere, slowly added SOCl 2 (572 mg, 4.81 mmol), and added DMF (10 mg) After the DCM (1 mL) solution was added, the reaction was stirred for 2 hr, pyridine (380 mg, 4.80 mmol) was added dropwise, and the mixture was stirred at this temperature for 40 minutes. Et 3 N (486 mg, 4.80 mmol) was added, and the reaction was continued for 2 h. LCMS showed the reaction was completed. .
  • Example 19 Referring to the synthesis method in the foregoing Example 18, A342E(R) in the step B was replaced with the corresponding substrate. The compound of the following Example 19 can be synthesized.
  • A346A (119 mg, 0.58 mmol) and A308A (100 mg, 0.39 mmol) were dissolved in a mixed solution of acetic acid (2.5 mL) and dichloromethane (2.5 mL) at 30 ° C for 1 hour, and NaBH(OAc) 3 (246 mg) was added. , 1.16 mmol), stirred under nitrogen for 18 hours. TLC showed the reaction was complete.
  • Step A Following the synthesis method in the above Example 20, the following compound A391G was synthesized by substituting the corresponding substrate for A346A in Example 20.
  • Step B To a solution of A391G (400 mg, 0.83 mmol) in EtOAc. Preparative HPLC dry reaction mixture was concentrated and treated with CH 3 CN (4mL), Et 3 N (100mg) was dissolved to give a white solid product A391 (130mg, yield: 41% ).
  • Step A Following the synthesis in the above Example 20, the following compound A397A was synthesized by substituting the corresponding substrate for A346A in Example 20.
  • Step A To a solution of A373C 4-(morpholinomethyl)benzaldehyde (0.8 g, 3.9 mmol) and A356C (0.7 g, 2.5 mmol) in methanol (100 mL) The reaction was carried out overnight at 40 ° C under N 2 protection. Then Pd/C (50% wet, 10%, 150 mg) was added, and the reaction was carried out for 5 h under a pressure of 1 atm after hydrogen substitution. About 90% of the raw materials are reacted. Filtration and concentration of the filtrate were purified by dry phase reversed phase HPLC to afford product A373A (1.0 g, yield: 86%).
  • Step B -40 °C to A373A (200mg, 0.428mmol) in DCM (12mL) / THF (12mL ) was added SOCl 2 (204mg, 1.71mmol) in DCM (1.7 mL) solution. The reaction was carried out at -40 ° C for 2 hours under N 2 protection. Then pyridine (135 mg, 1.71 mmol) was added and stirred for 30 minutes, then triethylamine (173 mg, 1.71 mmol) was added and the mixture was stirred at room temperature. The reaction was quenched by the addition of 0.5 mL of water. The solvent was evaporated to dryness (mjjqqqqqqqqqqqq
  • Step A The under nitrogen pyrrolidine (3.77g, 53mmol), 2- bromoethanol (6.25g, 50mmol), K acetonitrile 2 CO 3 (6.9g, 50mmol) in (70 mL) was heated to reflux overnight. Filtration, evaporation of the solvent, EtOAc (EtOAc:EtOAc:EtOAc
  • Step B A SOCl 2 (3.6g, 30.0mmol) was added to a A374A (2.3g, 14.4mmol) in chloroform (50mL), the addition was complete the reaction was refluxed for 1.5h. The white solid A374C (2.0 g, yield: 78%) was obtained.
  • Step C under a nitrogen blanket to A374C (802mg, 4.52mmol), 2- fluoro-5-hydroxybenzaldehyde (280mg, 2.0mmol), K 2 CO 3 (828mg, 6.0mmol) in DMF (10mL) was heated to 90 The reaction was carried out overnight at °C. The reaction mixture was poured with EtOAc EtOAc EtOAc. Used directly in the next step.
  • Step D A374E (206 mg, 0.732 mmol) and A308A (150 mg, 0.578 mmol) were dissolved in a mixed solution of acetic acid (6 mL) and dichloromethane (6 mL), and stirred for 4 hr, then NaBHCN (109 mg, 1.74 mmol) The reaction was carried out overnight under nitrogen. The reaction mixture was concentrated under reduced pressure and purified with EtOAc (EtOAc).
  • Examples 51-55 can be synthesized by referring to the synthesis method in the above Example 50, substituting the corresponding substrate for A350A in Example 50.
  • Step A A356C (300 mg, 1.08 mmol) and 2-fluoro-4-methoxybenzaldehyde (249 mg, 1.62 mmol) were dissolved in methanol (30 mL). The mixture was stirred at 30 ° C (external temperature) for 5 hours. Pd/C (10%, 100 mg, 50% water) was added and hydrogenated at 30 ° C (external temperature) overnight (hydrogen balloon). The Pd/C was filtered off under reduced pressure, and the filtrate was concentrated under reduced pressure.
  • Step B A356A (160 mg, 0.39 mmol) was dissolved in dry DCM (20 mL), cooled to -40 ° C under nitrogen atmosphere, and SOCI 2 (229 mg, 1.92 mmol) was slowly added dropwise, and DMF (5 mg) was added. After the addition of the DCM (1 mL) solution, the reaction was stirred for 2 h, pyridine (152 mg, 1.92 mmol) was added dropwise, and the mixture was stirred at the same temperature for 40 minutes. Et 3 N (195 mg, 1.92 mmol) was added, and the reaction was continued for 2 h. LCMS showed the reaction was completed. .
  • Example 57 The compound of the following Example 57 can be synthesized by referring to the synthesis method in the above Example 56, substituting the corresponding substrate for 2-fluoro-4-methoxybenzaldehyde in the step A.
  • Step A A379A1 (10.0g, 27.8mmol) and A379A2 (8.01g, 33.4mmol) was suspended in CH 3 CN (250mL), was added to the reaction flask after DIPEA (7.92g, 61.3mmol), nitrogen, heated The reaction was stirred at 45 ° C overnight. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Step B A379A (12.3 g, crude) was dissolved in THF (100 mL), 1N TBAF in THF (100 mL), and hydrogenated at 25 ° C overnight. LCMS showed the reaction was completed. To the reaction mixture was added EtOAc (200mL) and H 2 O (200mL), separated and the aqueous phase was extracted with EtOAc (200mL ⁇ 2), the combined organic phases were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and the mother liquor The residue was taken with EtOAc EtOAc (EtOAc)EtOAc. Or the mother liquid was purified by silica gel column chromatography (EtOAc/EtOAc:EtOAc)
  • Step C A379B (1.18 g, 3.52 mmol) and 2-fluoro-5-methoxybenzyl chloride (1.23 g, 7.04 mmol) were dissolved in DMF (20 mL) and then K 2 CO 3 ( 972 mg, 7.03 mmol), and the reaction was stirred at room temperature overnight. LCMS showed the reaction was complete. Of DMF was concentrated off under reduced pressure, the residue was added EtOAc (50mL) and H 2 O (30mL) was dissolved, the aqueous phase was extracted with EtOAc (50mL), the combined organic phases were washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered The mother liquid was concentrated under reduced pressure. EtOAc m. m. A white solid product was resolved by hand column A379C (650 mg) and A379D (650 mg).
  • Sample concentration 100 mg/ml (in mobile phase).
  • Chiral column IC; column model: 20 mm (ID) ⁇ 250 mm (L); Diameter: 5 um; column temperature: 35 ° C; injection amount: 250 ⁇ L; flow rate: 10 ml/min; detection wavelength: 205 nm.
  • Step D A379C (650 mg, 1.37 mmol) was dissolved in dichloromethane (20 mL), and then cooled to 0 ° C, then trifluoroacetic acid (10 mL) was added dropwise to the reaction flask, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in (40% aqueous solution of acetonitrile) 4mL CH 3 CN column purified using C18 reverse lyophilized to give a light yellow solid A379E (566mg, yield: 99%).
  • Step E A379E (366 mg, 0.88 mmol) was dissolved in dry DCM (35 mL) and THF (5 mL), cooled to -40 ° C under nitrogen atmosphere, and slowly added SOCl 2 (522 mg, 4.39 mmol). DMF (5mg) in DCM (1mL) was added the reaction was stirred IH completed, dropwise addition of pyridine (347mg, 4.39mmol) maintained at that temperature for 40 minutes, was added Et 3 N (444mg, 4.39mmol) , the addition, the reaction was continued for 1h. LCMS showed the reaction was completed.
  • Example 59 The compound of the following Example 59 can be synthesized by referring to the synthesis method in the above Example 58 by substituting the corresponding substrate for 2-fluoro-5-methoxybenzyl chloride in Step C.
  • Step A To a solution of Compound A379 (EtOAc, EtOAc. 2-Trimethylsilylethanol (3.55 g, 30 mmol), EDCI (2.3 g, 12.0 mmol) and DMAP (733 mg, 6.0 mmol) were added to the above crude product (1.7 g) in DMF (5 mL), 35 After stirring at ° C overnight, the reaction mixture was evaporated. m.jjjjjjjjjjjj
  • Example 60 Referring to the synthesis method of the foregoing Example 60, A393E was replaced with the corresponding substrate.
  • the compound of the following Example 61 can be synthesized.
  • Step A The compound 2-fluoro-3-methylaminobenzyl alcohol was dissolved in DCM (10 mL), SOCI 2 (0.5 mL) was added, and the reaction was stirred for 4 hours. The reaction mixture was concentrated to give a crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal
  • Step B A329B (300 mg, 1.03 mmol) was dissolved in DMF (10 mL), 3-chloromethyl 2-fluoro-N-methylaniline hydrochloride (259 mg) and K 2 CO 3 (355 mg, 2.57 mmol) After stirring overnight, LCMS showed a large amount of material remaining, and then added 3-chloromethyl 2-fluoro-N-methylaniline hydrochloride (150 mg) and K 2 CO 3 (100 mg, 0.72 mmol). The raw materials are basically completely reacted.
  • Step C A385A (242 mg, 0.56 mmol) was dissolved in DMF (10 mL), K 2 CO 3 (234 mg, 1.69 mmol), and the mixture was stirred at 80 ° C overnight. The reaction was concentrated and the residue was purified EtOAcjjjjj
  • Examples 63-66 can be synthesized by referring to the synthesis method in the above Example 62, replacing the 3-chloromethyl 2-fluoro-N-methylaniline hydrochloride in Step B with the corresponding substrate. .
  • Step A A327A (300 mg, 0.85 mmol) and 4-(4-chloromethyl)-3-fluorophenylmorpholine hydrochloride (359 mg, 1.28 mmol) were dissolved in DMF (15 mL) K 2 CO 3 (352 mg, 2.55 mmol) was added and stirred at 40 ° C overnight. Filtration, concentrating of DMF, EtOAc (EtOAc: EtOAc)
  • Step B A407B (430 mg, 0.77 mmol) was dissolved in DCM (20 mL). TFA (5 mL) was added dropwise to the reaction flask at room temperature, and the reaction was stirred at 25 ° C for 3 h. LCMS showed the disappearance of the starting material. The reaction mixture was evaporated to dryness crystals crystals crystals
  • Step A A379B (1.0 g, 3.59 mmol) and 4-(3-(chloromethyl)-4-fluorophenyl)morpholine hydrochloride (1.23 g, 7.05 mmol). K 2 CO 3 (972 mg, 7.04 mmol) was added to a reaction mixture and stirred at 25 ° C overnight. Filtration, concentrating of DMF, EtOAc (EtOAc)
  • Step B Chiral separation.
  • A403A was resolved by chiral silica gel column to give A403C (500 mg) and A403E (500 mg).
  • Step C A403C (500 mg, 1.0 mmol) was dissolved in dichloromethane (12 mL) and cooled to 0 ° C, then trifluoroacetic acid (3 mL) was added dropwise to the reaction flask, and the mixture was slowly stirred to 25 ° C and stirred overnight.
  • Step D A403D (400 mg, 0.82 mmol) was dissolved in dry DMF (1 mL), DCM (40mL) and THF (20mL), cooled to -40 ° C under nitrogen atmosphere, slowly adding SOCl 2 (488 mg, 4.1 mmol) After completion, the reaction was stirred for 1 h, pyridine (324 mg, 4.1 mmol) was added dropwise, and the mixture was stirred at the same temperature for 40 minutes, and Et 3 N (415 mg, 4.1 mmol) was added, and the reaction was continued for 1 h. LCMS showed the reaction was completed.
  • Example 68 Compound A404(S)-3-deuterium-3-(4-((2-fluoro-3-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, A404.
  • Step A To a solution of the compound A356C (400 mg, 1.44 mmol) in MeOH (30 mL), EtOAc (EtOAc (EtOAc) After stirring overnight, Pd/C (150 mg, 10%, 50% water) was added to the reaction mixture, and the mixture was vigorously stirred under a hydrogen atmosphere for 3 hours, and the solid was filtered, and the filtrate was concentrated under reduced pressure to give product A400A (580 mg).
  • Step B A solution of A400A (480 mg, 0.99 mmol) in DCM (20 mL) was cooled to -40 ° C, then DMF (1 mL) and SOCI 2 (589 mg, 4.95 mmol) was added dropwise. After stirring for 2 hours, pyridine (383 mg, 4.95 mmol) was added. After stirring for another 30 minutes, Et 3 N (501 mg, 4.95 mmol) was added to the reaction mixture, and the mixture was further stirred at -40 ° C for 1 hour. The reaction mixture was poured into water (80 mL) and then quenched with DCM (80 mL) 3) After extracting, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated.
  • the 2-fluoro-3-(morpholinemethyl)benzaldehyde in the step A was replaced with the corresponding substrate by referring to the synthesis method in the above Example 70.
  • the compounds of the following Examples 71-72 were synthesized.
  • Step A (COCl) 2 (152 mg, 1.2 mmol) was added to a solution of DMSO (156 mg, 2.0 mmol) in DCM (10 mL), and the mixture was stirred at a temperature of -70 ° C for 30 minutes, then added 4 -(morpholinemethyl)-benzyl alcohol (207 mg, 1.0 mmol) in 3 mL DCM was then stirred for 1 hour.
  • Et 3 N (405 mg, 4.0 mmol) was added dropwise, stirring was continued at -70 ° C for 1 hour, then the mixture was warmed to 25 ° C, and water (10 mL) was added dropwise to quench the reaction, and NaHCO 3 solution (5 mL) was added. The mixture was separated and dried with EtOAc EtOAc EtOAc.
  • Step B A405A (111 mg, 0.54 mmol) and I-28 (100 mg, 0.36 mmol) were dissolved in a mixed solution of HOAc (6 mL) and DCM (6 mL) at 25 ° C for 3 hours, then NaBH 3 CN (45 mg, 0.72 mmol), reacted at room temperature overnight. A405A (40 mg, 0.14 mmol) was added and the mixture was reacted at 40 ° C for 6 hours. The solvent was removed and concentrated under reduced pressure, added NaHCO 3 (10mL) and DCM (25 mL), separated, the aqueous phase was extracted with DCM (20mL ⁇ 2), the combined organic phases. The solvent was concentrated under reduced pressure to remove the solvent.
  • Step A To 2-fluoro-4-morpholin-methylbenzyl alcohol (1.0g, 4.4mmol) in chloroform (25mL) was added SOCl 2 (1.1g, 9.2mmol). After heating under reflux for 2 hours, the solvent was evaporated to dryness.
  • Step B A386A, A386B (0.8 g, 2.4 mmol), K 2 CO 3 (1.3 g, 9.6 mmol) in DMF (20 mL). The reaction mixture was poured into EtOAc (2 mL, EtOAc) (EtOAc) :1) A white solid product A386C (1.2 g, yield: 92%).
  • Step D A386E (421mg, 0.867mmol) was dissolved in DCM / THF post (50mL / 5mL) cooled to -40 °C was added SOCl 2 (516mg, 4.33mmol) in DCM (10mL) was added. After reacting at -40 to -20 ° C for 2 hours, pyridine (339 mg, 4.33 mmol) was added, and stirred at -40 ° C for half an hour, then Et 3 N (438 mg, 4.33 mmol) was added. The temperature was slowly raised to 25 ° C and quenched by the addition of 0.5 mL of water.
  • the compound A425 of Example 75 can be synthesized by referring to the synthesis method in the above Example 67 using the corresponding racemic mixture A403A as a substrate.
  • the compound A426 of Example 77 can be synthesized by referring to the synthesis method in the above Example 70 using the corresponding racemic mixture A400A as a substrate.
  • Example 78, A428, can be synthesized by referring to the synthesis method in the above Example 70, substituting the corresponding substrate for 2-fluoro-3-(morpholinyl)benzaldehyde in Step A.
  • Peripheral blood from healthy volunteers was collected and collected using an EDTA anticoagulation tube.
  • the blood was diluted 5-fold with 1640 medium (Gibco, Cat. No. 11875-093, USA) and added to a 96-well cell culture plate (Costar, Cat. No. 3599, USA), followed by 10 ⁇ L of the formula (I) of the present invention.
  • the compound was treated with a solution of DMSO (Sigma, Cat. No. D2650, USA) with a final concentration of 100 nM and a final concentration of DMSO of 0.2%.
  • MM.1S cells (myeloma cells) (ATCC, catalog number CRL-2974) were inoculated at 1.8 ⁇ 10 3 per well into 96-well containing RPMI-1964 medium (Gibco, Cat. No. A10491-01) The plate was placed in a 37 ° C, 5% CO 2 incubator for 24 hours. The compound was formulated into a 20 mM stock solution with DMSO (Sigma, Cat. No. D2650), diluted with the medium to the desired concentration (0.5% final concentration of DMSO), and added to each well at 37 ° C in a 5% CO 2 incubator. Incubate for 72 hours.
  • DMSO Sigma, Cat. No. D2650
  • Rec-1 cells (sleeve cell lymphoma cells) (ATCC, catalog number CRL-3004), Namalwa.CSN/70 cells (Burkitt lymphoma cells) (DSMZ, catalog number ACC-70), WSU- DLCL-2 cells (diffuse large B-cell lymphoma cells) (DSMZ, Cat. No. ACC-575), inoculated to each well (5-15) ⁇ 10 3 to the bottom of the white containing 96 - Well culture plates (Corning, Cat. No. CLS3903) were placed in a 37 ° C, 5% CO 2 incubator for 24 hours. The compound was formulated into a 150 mM stock solution with DMSO (Sigma, Cat. No.
  • A ⁇ 100nM
  • B 100-400nM
  • C 401nM-300 ⁇ M
  • D >300 ⁇ M.

Abstract

提供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。该异吲哚啉衍生物及其药物组合物能够调节免疫细胞因子的产生或活性，从而有效的治疗癌症和炎症性疾病。

Description

异吲哚啉衍生物、其中间体、制备方法、药物组合物及应用
本申请要求申请日为2014年10月30日的中国专利申请CN201410605148.8的优先权和申请日为2014年11月11日的中国专利申请CN201410632870.0的优先权。本申请引用上述中国专利申请的全文。
技术领域
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。
背景技术
肿瘤坏死因子-α(TNF-α)是一种促炎性细胞因子，在免疫稳态、炎症和宿主防御中起着重要作用。TNF-α已被证明是炎症的主要介质之一。TNF-α也可以由肿瘤产生，并且可以起到促肿瘤形成的作用，也可引起肿瘤细胞的程序性死亡。此外，TNF-α也影响诸如细胞凋亡、坏死、血管生成、免疫细胞活化、分化和细胞迁移过程，所有这些过程在肿瘤发生和肿瘤进展中发挥着重要作用。
无节制TNF-α活性或TNF-α的过度产生与多种疾病的病理学有关，包括但不限于癌症，例如，结肠、直肠、前列腺、乳腺、脑和肠癌；以及炎性疾病，特别是与癌症有关的炎症。TNF-α调节异常也可引起自身免疫性疾病、中毒性休克综合征、恶病质、关节炎、银屑病癣、HIV感染和AIDS、神经系统疾病和中枢神经系统疾病、脓毒症、充血性心力衰竭、移植排斥反应以及病毒感染。因此降低TNF-α水平，或调节TNF-α活性是许多免疫学、炎症性和恶性疾病(如癌症和炎症)治疗的很有前途的策略。例如，Sethi et al.Front.Biosci.(2008)13,5094-5107和Results Prob.Cell Differ.(2009)49,1-15。
来那度胺(3-(4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮)是一种小分子免疫调节剂，已证明其能够抑制TNF-α和其他促炎性细胞因子分泌，并增加抗炎性细胞因子分泌。来那度胺获得批准用于治疗多发性骨髓瘤(2006年)、骨髓增生异常综合征(2005年)和套细胞淋巴瘤(2013年)。此外，在临床试验中，来那度胺可单独或与其它治疗剂联合用药，治疗非霍奇金淋巴瘤、乳头状和滤泡状甲状腺癌、前列腺癌、慢性淋巴细胞白血病、淀粉样变性、I型复杂性局部疼痛综合征、恶性黑色素瘤、神经根病、骨髓纤维化、成胶质细胞瘤、胶质肉瘤、恶性胶质瘤、髓性白血病、难治性浆细胞瘤、慢性粒单核细胞性白血病、滤泡性淋巴瘤、睫状体和慢性黑色素瘤、虹膜黑色素瘤、复发性两眼间黑色素瘤、黑色素瘤眼外蔓延、实体瘤、T细胞淋巴瘤、红系淋巴瘤、成单核细胞和单核细胞白 血病；髓性白血病、脑肿瘤、脑膜瘤、脊髓肿瘤、甲状腺癌、套细胞淋巴瘤、非小细胞肺癌、卵巢癌、肾细胞癌、骨髓纤维化、伯基特淋巴瘤、霍奇金淋巴瘤、大细胞淋巴瘤和巨球蛋白血症(参见WO 2012/015986)。
然而，来那度胺有许多副作用。事实上，来那度胺的处方信息中明确表明：该药物具有骨髓抑制、深静脉血栓形成、肺栓塞和致畸风险。在临床试验期间，大多数服用来那度胺的患者因血液学毒性而需要减少剂量。因此，尽管来那度胺具有有益的活性，但是其有效性受到显著发生的副作用的限制。因此，本领域亟需一种改良结构的来那度胺衍生物，以优化其性能。
发明内容
本发明提供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调节细胞因子(如TNF-α)的产生或活性，从而有效的治疗癌症和炎症性疾病。
本发明提供了一种通式(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、立体异构体、同位素化合物、代谢物或前药：
Figure PCTCN2015088312-appb-000001
通式(I)中，n1选自0或1；
Z为
Figure PCTCN2015088312-appb-000002
其中，用*标注的碳为不对称中心；
R1、R3、R4、R5、R6、R7、R8和R9独立地选自H或D；
R2选自H、D或卤素；
L1和L2独立地选自CD2、CHD或CH2；
X选自NH、ND或O；
R10为H、D或
Figure PCTCN2015088312-appb-000003
其中R1’、R2’、R3’、R4’和R5’分别独立地选自H、D、卤素、氰基、羟基、
Figure PCTCN2015088312-appb-000004
取代或未取代的(C1-C12)烷基、取代或未取代的(C1-C12)烷氧基、(C2～C20)杂环烷基或氘代(C2～C20)杂环烷基；其中，Ra和Rb独立地为H、(C1-C12)烷基或(C1-C12)烷基酰基；Rc和Rd独立地为H或(C1～C12)烷基；Re为
Figure PCTCN2015088312-appb-000005
或(C2-C20)杂环烷基；Re1和Re2独立地为H或(C1-C12)烷基；
所述的取代的(C1-C12)烷氧基中的取代基选自下列基团中的一个或多个：D、卤素、羟基、(C1-C12)烷氧基、(C2-C20)杂环烷基、(C1-C12)烷基取代的(C2-C20)杂环烷基、
Figure PCTCN2015088312-appb-000006
或
Figure PCTCN2015088312-appb-000007
其中Rf和Rg独立地为H或(C1-C12)烷基；Rh为(C2-C20)的杂环烷基；
所述的取代的(C1-C12)烷基中的取代基选自下列基团中的一个或多个：D、(C2-C20)杂环烷基、氘代(C2-C20)杂环烷基、(C1-C12)烷基取代的(C2-C20)杂环烷基或氘代(C1-C12)烷基取代的(C2-C20)杂环烷基；
当所述的取代的(C1-C12)烷氧基或所述的取代的(C1-C12)烷氧基中的取代基为多个时，所述的取代基相同或不同；
上述各基团中，所述的(C2-C20)的杂环烷基、所述的氘代(C2-C20)杂环烷基、所述的(C1-C12)烷基取代的(C2-C20)杂环烷基或所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基中所述的(C2-C20)杂环烷基中的杂原子选自O、N和S中的一个或多个；
条件是：通式(I)中，当n1为0时，R1、R3和R10为H或D，X为NH或ND，R2为卤素；
条件是：通式(I)中，当n1为1，X为O，R2为H或D时，R10为
Figure PCTCN2015088312-appb-000008
Figure PCTCN2015088312-appb-000009
当R10为
Figure PCTCN2015088312-appb-000010
时，Re为(C2-C20)杂环烷基；
条件是：通式(I)中，当n1为1，X为NH时，R10为
Figure PCTCN2015088312-appb-000011
条件是：通式(I)和Z中，当n1为1，X为NH，R1～R9均为H，L1和L2均为CH2时，R10不为
Figure PCTCN2015088312-appb-000012
或者
Figure PCTCN2015088312-appb-000013
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。
通式(I)中，所述的Z较佳地为下列任一结构：
Figure PCTCN2015088312-appb-000014
Figure PCTCN2015088312-appb-000015
其中，*的定义如前所述。
上述各基团中，所述的(C2-C20)的杂环烷基、所述的氘代(C2-C20)杂环烷基、所述的(C1-C12)烷基取代的(C2-C20)杂环烷基或所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基中所 述的(C2-C20)杂环烷基较佳地是指杂原子为N或O，杂原子数为1-2个的(C2-C6)杂环烷基。所述的(C2-C6)杂环烷基较佳地为四氢吡咯(例如
Figure PCTCN2015088312-appb-000016
)、吗啉基(例如
Figure PCTCN2015088312-appb-000017
)或哌嗪基(例如
Figure PCTCN2015088312-appb-000018
)。所述的(C1-C12)烷基取代的(C2-C20)杂环烷基或所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基中所述的(C1-C12)烷基较佳地为(C1-C4)烷基。所述的(C1-C4)烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。所述的氘代(C2-C20)杂环烷基较佳地为
Figure PCTCN2015088312-appb-000019
所述的(C1-C12)烷基取代的(C2-C20)杂环烷基较佳地为
Figure PCTCN2015088312-appb-000020
Figure PCTCN2015088312-appb-000021
所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基较佳地为
Figure PCTCN2015088312-appb-000022
通式(I)中，当R10为
Figure PCTCN2015088312-appb-000023
R1’、R2’、R3’、R4’和R5’分别独立地选自
Figure PCTCN2015088312-appb-000024
Figure PCTCN2015088312-appb-000025
或取代的(C1-C12)烷氧基，Ra和Rb独立地为(C1-C12)烷基或(C1-C12)烷基酰基，Rc和Rd独立地为(C1～C12)烷基，Re为
Figure PCTCN2015088312-appb-000026
Re1和Re2独立地为(C1-C12)烷基，所述的取代的(C1-C12)烷氧基中的取代基为
Figure PCTCN2015088312-appb-000027
Rf和Rg独立地(C1-C12)烷基时，所述的(C1-C12)烷基酰基的结构为
Figure PCTCN2015088312-appb-000028
Ra1为(C1-C12)烷基；Ra、Rb、Ra1、Rc、Rd、Re1、Re2、 Rf和Rg中，所述的(C1-C12)烷基较佳地为(C1-C4)烷基。所述的(C1-C4)烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
通式(I)中，当R10为
Figure PCTCN2015088312-appb-000029
R1’、R2’、R3’、R4’和R5’分别独立地选自取代的(C1-C12)烷氧基，所述的取代的(C1-C12)烷氧基中的取代基选自(C1-C12)烷氧基时，所述的(C1-C12)烷氧基较佳地为(C1-C4)烷氧基。所述的(C1-C4)烷氧基较佳地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基。
通式(I)中，当R10为
Figure PCTCN2015088312-appb-000030
R1’、R2’、R3’、R4’和R5’分别独立地选自取代的(C1-C12)烷氧基，所述的取代的(C1-C12)烷氧基中的取代基选自
Figure PCTCN2015088312-appb-000031
时，所述的
Figure PCTCN2015088312-appb-000032
较佳地为
Figure PCTCN2015088312-appb-000033
通式(I)中，当R10为
Figure PCTCN2015088312-appb-000034
R1’、R2’、R3’、R4’和R5’分别独立地选自取代的(C1-C12)烷氧基，所述的取代的(C1-C12)烷氧基中的取代基选自
Figure PCTCN2015088312-appb-000035
时，所述的
Figure PCTCN2015088312-appb-000036
较佳地为
Figure PCTCN2015088312-appb-000037
通式(I)中，当R10为
Figure PCTCN2015088312-appb-000038
R1’、R2’、R3’、R4’和R5’分别独立地选自卤素时，所述的卤素较佳地为F、Cl、Br或I。
通式(I)中，当R10为
Figure PCTCN2015088312-appb-000039
R1’、R2’、R3’、R4’和R5’分别独立地选自取代 或未取代的(C1-C12)烷基时，所述的取代或未取代的(C1-C12)烷基较佳地为取代或未取代的(C1-C4)烷基。所述的取代或未取代的(C1-C4)烷基较佳地为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或者取代或未取代的叔丁基。所述的取代的(C1-C12)烷基较佳地为
Figure PCTCN2015088312-appb-000040
Figure PCTCN2015088312-appb-000041
通式(I)中，当R10为
Figure PCTCN2015088312-appb-000042
R1’、R2’、R3’、R4’和R5’分别独立地选自取代或未取代的(C1-C12)烷氧基时，所述的取代或未取代的(C1-C12)烷氧基较佳地为取代或未取代的(C1-C4)烷氧基。所述的取代或未取代的(C1-C4)烷氧基较佳地为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、取代或未取代的正丁氧基、取代或未取代的异丁氧基或者取代或未取代的叔丁氧基。所述的取代的(C1-C12)烷氧基较佳地为
Figure PCTCN2015088312-appb-000043
Figure PCTCN2015088312-appb-000044
通式(I)中，当R10为
Figure PCTCN2015088312-appb-000045
R1’、R2’、R3’、R4’和R5’分别独立地选自
Figure PCTCN2015088312-appb-000046
时，所述的
Figure PCTCN2015088312-appb-000047
较佳地为
Figure PCTCN2015088312-appb-000048
通式(I)中，当R10为
Figure PCTCN2015088312-appb-000049
R1’、R2’、R3’、R4’和R5’分别独立地选自
Figure PCTCN2015088312-appb-000050
时，所述的
Figure PCTCN2015088312-appb-000051
较佳地为
Figure PCTCN2015088312-appb-000052
通式(I)中，当R10为
Figure PCTCN2015088312-appb-000053
R1’、R2’、R3’、R4’和R5’分别独立地选自
Figure PCTCN2015088312-appb-000054
时，所述的
Figure PCTCN2015088312-appb-000055
较佳地为
Figure PCTCN2015088312-appb-000056
通式(I)中，所述的
Figure PCTCN2015088312-appb-000057
较佳地为
Figure PCTCN2015088312-appb-000058
Figure PCTCN2015088312-appb-000059
Figure PCTCN2015088312-appb-000060
Figure PCTCN2015088312-appb-000061
通式(I)中，较佳地，当n1为1时，R2为H或D。
通式(I)中，较佳地，当n1为1，R2为H或D时，R10为
Figure PCTCN2015088312-appb-000062
较佳地，R10中，R5’选自H或D，R2’、R3’和R4’其中一个选自卤素、氰基、羟基、
Figure PCTCN2015088312-appb-000063
Figure PCTCN2015088312-appb-000064
取代或未取代的(C1-C12)烷基、取代或未取代的(C1-C12)烷氧基、(C2～C20)杂环烷基或氘代(C2～C20)杂环烷基；其余选自H或D；上述情况下，当R2’、R4’和R5’选自H或D时，R3’选自卤素、氰基、
Figure PCTCN2015088312-appb-000065
取代或未取代的(C1-C12)烷基、取代或未取代的(C1-C12)烷氧基、(C2～C20)杂环烷基或氘代(C2～C20)杂环烷基。
通式(I)中，当n1为1，R2为H或D，X为NH或ND，R10为
Figure PCTCN2015088312-appb-000066
时，较佳地，R1’、R4’和R5’为H，R2’选自卤素或取代或未取代的(C1-C12)烷基；R3’选自卤素、取代或未取代的(C1-C12)烷基或取代或未取代的(C1-C12)烷氧基。
通式(I)中，较佳地，当n1为1，R2为卤素，R10为
Figure PCTCN2015088312-appb-000067
时，R1’或R5’不为卤素。较佳地，通式(I)化合物为下列任一化合物：
Figure PCTCN2015088312-appb-000068
Figure PCTCN2015088312-appb-000069
Figure PCTCN2015088312-appb-000070
Figure PCTCN2015088312-appb-000071
Figure PCTCN2015088312-appb-000072
Figure PCTCN2015088312-appb-000073
Figure PCTCN2015088312-appb-000074
Figure PCTCN2015088312-appb-000075
Figure PCTCN2015088312-appb-000076
Figure PCTCN2015088312-appb-000077
Figure PCTCN2015088312-appb-000078
Figure PCTCN2015088312-appb-000079
Figure PCTCN2015088312-appb-000080
Figure PCTCN2015088312-appb-000081
Figure PCTCN2015088312-appb-000082
Figure PCTCN2015088312-appb-000083
Figure PCTCN2015088312-appb-000084
Figure PCTCN2015088312-appb-000085
Figure PCTCN2015088312-appb-000086
Figure PCTCN2015088312-appb-000087
Figure PCTCN2015088312-appb-000088
Figure PCTCN2015088312-appb-000089
Figure PCTCN2015088312-appb-000090
Figure PCTCN2015088312-appb-000091
Figure PCTCN2015088312-appb-000092
Figure PCTCN2015088312-appb-000093
Figure PCTCN2015088312-appb-000094
Figure PCTCN2015088312-appb-000095
Figure PCTCN2015088312-appb-000096
Figure PCTCN2015088312-appb-000097
Figure PCTCN2015088312-appb-000098
Figure PCTCN2015088312-appb-000099
Figure PCTCN2015088312-appb-000100
Figure PCTCN2015088312-appb-000101
Figure PCTCN2015088312-appb-000102
Figure PCTCN2015088312-appb-000103
氘(D或者2H)是氢的一中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，“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、同位素化合物、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“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如前所述的通式(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，通过已知的方法合成得到，较佳地采用方法A制备，所述的方法A包括下列步骤：将化合物A-06(1)进行如下所示的脱保护反应，制得化合物A(06a1)；再将化合物A(06a1)进行如下所示的酰胺化反应，制得通式(I)化合物；
Figure PCTCN2015088312-appb-000104
方法A中，化合物A-06(1)、A-06(a1)或通式(I)中，L1、L2、X、Z、*、R1～R10、n1的定义均同前所述；Ra和Rb一个为
Figure PCTCN2015088312-appb-000105
另一个为
Figure PCTCN2015088312-appb-000106
Ra1和 Rb1其中一个为
Figure PCTCN2015088312-appb-000107
另一个为
Figure PCTCN2015088312-appb-000108
中，Ra”和Rb”独立地为H或D。
通式(I)中，当n1为0时，所述的通式(I)化合物还可进一步采用方法B制备，所述的方法B较佳地包括下列步骤：将化合物I-RS进行如下所示的还原反应，制得通式(I)化合物；
Figure PCTCN2015088312-appb-000109
方法B中，化合物I-RS或通式(I)中，R2为卤素，n1为0，X为NH或ND，R10为H或D；L1、Z、R1和R3的定义均同前所述。
当通式(I)中，n1为1，X为NH或ND时，所述的通式(I)化合物还可进一步采用方法C制备，所述的方法C较佳地包括下列步骤：将化合物P-01与
Figure PCTCN2015088312-appb-000110
进行如下所示的还原胺化反应，制得通式(I)化合物；
Figure PCTCN2015088312-appb-000111
方法C中，
Figure PCTCN2015088312-appb-000112
化合物P-01或通式(I)中，X为NH或ND，n1为1，Rp1、Rp2和Rp3独立地为H或D；L1、L2、Z、R1、R2和R3的定义均同前所述；
Figure PCTCN2015088312-appb-000113
中，R10为
Figure PCTCN2015088312-appb-000114
R1’、R2’、R3’、R4’和R5’的定义均同前所述。
方法A、方法B或方法C中，所述的脱保护反应、所述的酰胺化反应、所述的还原反应或所述的还原胺化反应的方法和条件可为本领域此类反应常规的方法和条件。化合物A-06(1)或化合物A-06(a1)中，以及化合物I-RS、化合物P-01或通式(I)的Z中，当用* 标注的碳为不对称中心时，可将化合物A-06(1)、化合物A-06(a1)、化合物I-RS、化合物P-01或通式(I)采用本领域常规的手性拆分的方法进行拆分，分别得到(R)构型化合物、富集的(R)构型化合物、(S)构型化合物或者富集的(S)构型化合物，再进行相应地反应，制得通式(I)化合物。
方法A中，当通式(I)中，n1为0时，所述的通式(I)化合物的制备方法，其还可进一步包含下列步骤：将化合物A-05(1)进行如下所示的还原反应，制得所述的化合物A-06(1)；即可；
Figure PCTCN2015088312-appb-000115
其中，化合物A-05(1)和A-06(1)中，L1、L2、R1～R8、Ra和Rb的定义均同前所述；化合物A-06(1)中，X为NH或ND，n1为0；R10为H或D。所述的还原反应的方法和条件可为本领域此类反应常规的方法和条件。
方法A中，当通式(I)中，X为NH或ND，n1为1时，所述的通式(I)化合物的制备方法，其还可进一步包含下列步骤：将化合物A-05(2)与
Figure PCTCN2015088312-appb-000116
进行如下所示的还原胺化反应，制得所述的化合物A-06(1)；即可；
Figure PCTCN2015088312-appb-000117
其中，化合物A-05(2)和A-06(1)中，L1、L2、R1～R8、Ra和Rb的定义均同前所述；化合物A-06(1)中，X为NH或ND，n1为1；
Figure PCTCN2015088312-appb-000118
中，Rp3为H或D；R10为
Figure PCTCN2015088312-appb-000119
R1’、R2’、R3’、R4’和R5’的定义同前所述。所述的还原胺化反应的方法和条件可为本领域此类反应常规的方法和条件。
方法A中，当通式(I)化合物中X为O，n1为1时，所述的通式(I)化合物的制备方法，其还可进一步包含下列步骤：将化合物A-05(3)与
Figure PCTCN2015088312-appb-000120
进行如下所示的亲核取代反应，制得所述的化合物A-06(1)；即可；
Figure PCTCN2015088312-appb-000121
其中，化合物A-05(3)和A-06(1)中，L1、L2、R1～R8、Ra和Rb的定义均同前所述；化合物A-06(1)中，X为O，n1为1；
Figure PCTCN2015088312-appb-000122
中，Hal为卤素(例如F、Cl、Br或I)；R10为
Figure PCTCN2015088312-appb-000123
R10中，R1’、R2’、R3’、R4’和R5’的定义同前所述。所述的亲核取代反应的方法和条件可为本领域此类反应常规的方法和条件。
所述的化合物A-06(1)的制备方法，其还可进一步包含下列步骤：将化合物Q-03与化合物A-04(1)进行如下所示的偶合反应再脱保护基后，制得所述的化合物A-05(3)；
Figure PCTCN2015088312-appb-000124
其中，化合物Q-03或化合物A-04(1)中，L1、*、R1～R8的定义均同前所述；Hal为卤素(例如Cl、Br或I)；Ra和Rb一个为
Figure PCTCN2015088312-appb-000125
另一个为
Figure PCTCN2015088312-appb-000126
Figure PCTCN2015088312-appb-000127
中，Ra”和Rb”独立地为H或D。
所述的化合物A-05(3)的制备方法，其还可进一步包含下列步骤：市售所得原料酚Q-01经TBDMS保护后制得Q-02，再与卤代试剂(例如NBS)反应得到苄卤Q-03。
Figure PCTCN2015088312-appb-000128
其中，化合物Q-01中，R1～R3和L1的定义均同前所述。
方法B中，所述的通式(I)化合物的制备方法中，化合物I-RS按照本领域制备该类化合物的常规方法制备得到，较佳地为采用方法D或方法E制备得到；所述的方法D较佳地包含下列步骤：将化合物A-03，与化合物A-04(2)或其盐进行如下所示的偶合反应，制得所述的化合物I-RS；
Figure PCTCN2015088312-appb-000129
其中，化合物A-03、A-04(2)或I-RS中，L1、Z、*、R1～R8的定义均同前所述；化合物A-03中，Hal为卤素(例如Cl、Br或I)。所述的偶合反应的方法和条件可为本领域此类反应常规的方法和条件。化合物A-04(2)的盐一般是指化合物A-04(2)与酸形成的盐，较佳地为化合物A-04(2)的盐酸盐。
所述的方法E较佳地包含下列步骤：将化合物A-05(1)先后进行如下所示的脱保护，制得化合物A-06(a2)，再将化合物A-06(a2)进行如下所示的酰胺化反应，制得所述的化合物I-RS；
Figure PCTCN2015088312-appb-000130
其中，A-05(1)、A-06(a2)或I-RS中，L1、Z、*、R1～R8、Ra和Rb的定义均同前所述；Ra2和Rb2其中一个为
Figure PCTCN2015088312-appb-000131
另一个为
Figure PCTCN2015088312-appb-000132
中，Ra”和Rb”独立地为H或D。所述的脱保护及酰胺化反应可为本领域此类反应常规的方法和条件。
方法C中，所述的通式(I)化合物的制备方法，其还可进一步包括下列步骤：将I-RS 进行如下所示的还原反应，制得化合物P-01；
Figure PCTCN2015088312-appb-000133
化合物I-RS或化合物P-01中，R2为H、D或卤素；Rp1和Rp2独立地为H或D；L1、L2、Z、R1和R3的定义均同前所述。所述的还原反应的方法和条件可为本领域此类反应常规的方法和条件。
方法A中，所述的化合物A-06(1)制备方法，较佳地还可进一步包含下列步骤：将化合物A-03与化合物A-04(1)进行如下所示的偶合反应，制得所述的化合物A-05(1)；
Figure PCTCN2015088312-appb-000134
其中，化合物A03、A-04(1)或A-05(1)中，L1、*、R1～R8、Ra和Rb的定义均同前所述，Hal为卤素(例如Cl、Br或I)。所述的偶合反应的方法和条件可为本领域此类反应常规的方法和条件。
所述的通式(I)所示的异吲哚啉衍生物的制备方法，其包含下列步骤，具体见反应流程式A和反应流程式P：
反应流程式A：苄卤原料A-03与氨基酸衍生物A-04(1)偶合生成的产物A-05(1)，经去保护得到化合物A-05(2)，通过与醛
Figure PCTCN2015088312-appb-000135
的还原胺化反应转化为胺A-06(1)。最后进行脱保护关环制得目标产物(I)，具体如下：
Figure PCTCN2015088312-appb-000136
反应流程式A中：各字母和基团的定义均同前所述。
原料A-03市售可得或按照公知方法(参见
Figure PCTCN2015088312-appb-000137
et al.Org.Syn.(2003)80,75；US4,678,500；US 2012/0053159以及US 2007/0255076)合成。
氨基酸衍生物A-04市售可得或按照公知方法(参见Chen et al.Biotechnol.Lett.(1992)14,269；WO 2012/015986；WO 2012/068512；US 2012/0053159；Manesis et al.J.Org.Chem.(1987)52,5342；Stogniew et al.J.Labelled Compd.RAD.(1981)18,897；Blomquist et al.J.Org.Chem.(1966)31,4121)合成，具体见反应流程式F1、F2和G。
反应流程式F1：
Figure PCTCN2015088312-appb-000138
在重水中用Na-Hg还原F1-01得到氘富集物F1-02。二酸F1-02用乙酰氯脱水转化为酸酐F1-03，再分别与无水乙醇、氧化银和溴反应则形成溴代物F1-04。用试剂F1-05(Blomquist et al.J.Org.Chem.(1966)31,4121)处理F1-04得三乙酯F1-06。在D2O-DCl中加热F1-06就形成了氘富集氨基酸F1-07，并通过氨基保护基保护氨基(例如Boc、Cbz)、醋酐脱水转化为酸酐F1-08。以苄醇处理F1-08后再分别与氯甲酸乙酯及氨水反应，最后经脱保护就可以取得目标化合物F1-11。F1-08、F1-09和F1-10中，W1为本领域常规的氨基保护基。
反应流程式F2：
Figure PCTCN2015088312-appb-000139
用试剂F2-05(Blomquist et al.J.Org.Chem.(1966)31,4121)处理F2-04(市售可得)得三乙酯F2-06。在D2O-DCl中加热F2-06就形成了氘富集氨基酸F1-07，并通过氨基保护基保护氨基(例如Boc、Cbz)、醋酐脱水转化为酸酐F2-08。以苄醇处理F2-08后再分别与氯甲酸乙酯及氨水反应，最后经脱保护就可以取得目标化合物F2-11。F2-08、F2-09和F2-10中，W1为本领域常规的氨基保护基。
反应流程式G：
Figure PCTCN2015088312-appb-000140
反应流程式G中W为
Figure PCTCN2015088312-appb-000141
W1为本领域常规的氨基保护基，例如Boc、Cbz等。
酯G-01在氘代乙酸中用苯甲醛处理生成氘富集化合物G-02。用氨基保护基保护G-02中的氨基后，再分别与氯甲酸乙酯和氨水反应得到酰胺G-04。G-04中的氨基保护基可以用本领域常规的去保护方法脱去(例如酸解或还原)，从而转化为目标化合物G-05。
原料A-03与氨基化合物P-03反应后得到化合物P-02。再通过还原、与醛
Figure PCTCN2015088312-appb-000142
的还原胺化反应制得通式(I)化合物。氨基化合物P-03市售可得或可按公知文献方法合成(参见WO 2012/015986；WO 2012/068512；Muller et al.Bioorganic&Medicinal Chemistry Letters(1999)9,1625)。
反应流程式P：
Figure PCTCN2015088312-appb-000143
反应流程式P中：各字母和基团的定义同前所述。
上述反应路线中涉及的化学反应所采用的条件和步骤均可参照本领域此类反应常规的条件和步骤进行，并且上述方法所得的化合物还可以进一步通过对外周位置进行修饰而获得本发明的其它目标化合物。
本发明还提供了一种制备通式(I)所示的异吲哚啉衍生物的中间体化合物A-06(1)、A-06(a1)、I-RS或P-01：
Figure PCTCN2015088312-appb-000144
化合物A-06(1)、A-06(a1)、I-RS或P-01中，L1、L2、n1、Z、*、R1～R10、Ra、Rb、Ra1、Rb1、Rp1和Rp2的定义均同前所述；化合物A-06(1)中，Ra和Rb一个为
Figure PCTCN2015088312-appb-000145
另一个为
Figure PCTCN2015088312-appb-000146
化合物A-06(a1)中，Ra1和Rb1其中一个为
Figure PCTCN2015088312-appb-000147
另一个为
Figure PCTCN2015088312-appb-000148
中，Ra”和Rb”独立地为H或D；化合物P-01中，Rp1和Rp2独立地为H或D。
本发明还提供了一种药物组合物，该药物组合物中包括治疗和/或预防有效量的本发明通式(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、立体异构体、同位素化合物、代谢物和前药中的一种或多种。
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、立体异构体、同位素化合物、代谢物，或前药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、立体异构体、同位素化合物、代谢物和前药中的一种或多种，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、同位素化合物、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、立体异构体、同位素化合物、代谢物和前药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。
在某些实施例中，本发明涉及通式(I)所示的化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物，或前药的控释剂型。如本文所用，“控释剂型”指的是一种剂型，其中组合物的治疗活性成分的释放速率可控，或者是具有特定的延迟，以控制接受组合物给药的受试者中治疗活性成分的释放部位。一种控释剂型可以包含一种控释剂，如持续释放剂(持续释放或延迟释放)和延迟释放剂(延迟释放)。
如本文所用，术语“持续释放”和“延迟释放”是指治疗活性成分从药物组合物中释放的时间延长。如本文所用，术语“延迟释放”是指受试者接受给药后组合物到达受试者内所需环境后，或受试者接受给药后经过特定时间后，治疗活性组分从药物组合物中释放，使得释放发生在特定部位或所需的环境。
如本文所用，术语“持续释放剂”和“延迟释放剂”是指提供使治疗活性成分从组合物中控制释放的化合物或添加剂，以便释放逐渐发生，并且释放的时间延长。持续或延迟释放剂可使受试者接受组合物给药后治疗活性成分在特定长时间内释放。
根据本发明的实施例，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、同位素化合物、代谢物，或前药从本发明的组合物中的控制释放可以通过各种条件来实现，这些条件包括但不限于pH值、温度、酶、水或其它生理条件或化合物。例如，根据本发明的药物化合物可以进一步包含肠溶衣，其中肠溶包衣控制通式(I)化合物或其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物，或前药的释放，使其在所需的一段时间内从组合物中逐渐和连续地释放，使得该化合物能在延 长的时间期内发挥治疗或预防作用。
根据本发明的实施例，控释药物组合物可进一步包含一种或多种如下所公开的其它治疗剂或药剂。
本领域技术人员根据公开的内容可以熟知那些合适的控释制剂、持续和延迟释放剂。可以并入本发明的药物组合物以提供控释组合物的控制释放剂的非限制性实例包括聚合物，如羟丙基甲基纤维素；凝胶；渗透膜；微粒；脂质体；微球以及其组合。本文所述的任何组合物可适用于控释制剂，如片剂、胶囊、软胶囊和囊片。
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、立体异构体、同位素化合物、代谢物，或前药、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、同位素化合物、代谢物或前药可用于多种用途，包括但不限于用于制备治疗或预防由TNF-α产生的、或由TNF-α活性调节异常相关的疾病、病症或病况的药物。
因此，在另一个总方面，本发明涉及包含治疗或预防有效量的通式(I)化合物、其药学上可接受的盐、溶剂化物、立体异构体、同位素化合物、代谢物或前药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，本发明涉及一种治疗或预防由TNF-α产生的、或由TNF-α活性调节异常相关的疾病、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、立体异构体、同位素化合物、代谢物和前药中的一种或多种。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：包括实体瘤、TNF-α相关病症、不期望的血管生成相关疾病和病症、疼痛、黄斑变性(MD)相关综合征、皮肤病、角化病、呼吸系统疾病(例如肺部疾病)、免疫缺陷病、中枢神经系统(CNS)疾病、自身免疫性疾病、动脉粥样硬化、遗传、过敏、病毒、睡眠病症及相关综合征、炎性疾病、PDE-4相关疾病或IL-2相关疾病。本领域中众所周知的此类疾病、病症或病况的实例包括但不限于在PCT专利出版物WO2012015986和WO2006018182以及美国专利出版物US20100204227中描述的那些，其中一些在此通过引用将其整体并入本文。
在一个实施例中，疾病、病症或病况选自：瘤原性或癌性疾病；自身免疫性疾病，如阿狄森氏病、强直性脊柱炎、抗磷脂抗体综合征、特应性皮炎、自身免疫性斑秃、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性内耳病、自身免疫性淋巴增生综合征(alps)、白塞氏病、大疱性类天疱疮、心肌病、乳糜泻、慢性疲劳综合征性免疫缺陷综合征(CFIDS)、慢性炎症性脱髓鞘性多发性神经病、瘢痕性类天疱疮、冷凝集素病、CREST综合征、克罗恩病、德戈氏病、皮肌炎、幼年型皮肌炎、盘状红斑狼疮、湿疹、原发性混合型冷球蛋白血症、纤维肌痛-纤维肌炎、Grave’s病、吉兰-巴雷综合征、桥本氏甲状腺炎、化脓性汗腺炎、特发性肺纤维化、特发性血小板减少性紫癜(ITP)、特发性血小板减少性紫癜、IgA肾病、胰岛素依赖型糖尿病(I型)、幼年型关节炎、红斑狼疮、美尼尔氏病、混合性结缔组织病、多发性硬化、重症肌无力、寻常性天疱疮、恶性贫血、结节性多动脉炎、多软骨炎、polyglancular综合征、风湿性多肌痛、多肌炎和皮肌炎、原发性丙种球蛋白血症、原发性胆汁性肝硬化、银屑病、雷诺氏现象、莱特尔氏综合征、风湿热、类风湿性关节炎、结节病、硬皮病、干燥综合征、系统性红斑狼疮、僵人综合征、多发性大动脉炎、颞动脉炎/巨细胞动脉炎、溃疡性结肠炎、葡萄膜炎、血管炎、白癜风、韦格纳氏肉芽肿病以及自身免疫性威尔逊氏病；肺部疾病，如哮喘、慢性阻塞性肺疾病；神经系统疾病，如阿尔茨海默氏病、帕金森氏症、抑郁症、癫痫症和双相型障碍；心血管疾病，如动脉粥样硬化、心肌梗死、骨质疏松症；代谢性疾病，如肥胖、2-型糖尿病；成人呼吸窘迫综合征；骨吸收疾病，如关节炎；高钙血症；移植物抗宿主反应；脑型疟疾；炎性疾病，如寻常痤疮、关节炎、哮喘、动脉粥样硬化、乳糜泻、慢性前列腺炎、结肠炎、克罗恩氏病、皮炎、憩室炎、肾小球肾炎、肝炎、超敏反应、炎性肠病、间质性膀胱炎、肠易激综合征(IBS)、红斑狼疮、肾炎、盆腔炎、再灌注损伤、类风湿性关节炎、结节病、移植排斥、溃疡性结肠炎、脉管炎、慢性肺部炎性疾病、中风、循环性休克；HIV感染、AIDS以及AIDS机会性感染；其他病症，例如，类风湿性脊椎炎、骨关节炎和其他关节炎病症、脓毒性休克、脓毒症、内毒素性休克、移植物抗宿主病、消瘦、克罗恩氏病、溃疡性结肠炎、麻风结节性红斑、cAMP相关病症，如脓毒性休克、脓毒症、内毒素性休克、血液动力学休克和脓毒症综合征、缺血后再灌注损伤、疟疾、分枝杆菌感染、脑膜炎、充血性心力衰竭、纤维化疾病、恶病质、移植排斥、辐射损伤、高氧肺泡损伤；病毒感染，如由疱疹病毒引起的那些感染；病毒性结膜炎；或特应性皮炎。
癌性或瘤原性病症的实例包括但不限于：急性成淋巴细胞白血病、急性髓性白血病、急性骨髓性白血病、核型急性成髓性白血病、慢性淋巴细胞白血病、慢性髓性白血病、慢性粒细胞性白血病、毛细胞白血病、髓性白血病、肾上腺皮质癌、伯基特淋巴瘤、AIDS 相关淋巴瘤、皮肤T-细胞淋巴瘤、皮肤B细胞淋巴瘤、弥漫性大B细胞淋巴瘤、低级别滤泡性淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、多发性骨髓瘤、冒烟型骨髓瘤、骨髓增生异常综合征、套细胞淋巴瘤、惰性骨髓瘤、慢性骨髓增生性疾病、中枢神经系统(CNS)淋巴瘤、肛门癌、星形细胞瘤、非典型畸胎样/横纹肌样瘤、基底细胞癌、胆管癌、膀胱癌、骨瘤、骨样骨瘤、骨软骨瘤、骨母细胞瘤、骨肉瘤、内生软骨瘤、动脉瘤样骨囊肿、骨纤维异常增殖症、软骨肉瘤、尤因氏肉瘤、纤维肉瘤、多形性未分化肉瘤、脑肿瘤、脑干神经胶质瘤、髓母细胞瘤、髓上皮瘤、成松果体细胞瘤、乳腺癌、支气管肿瘤、类癌瘤、宫颈癌、脊索瘤、结肠癌、结肠直肠癌、颅咽管瘤、胚胎瘤、室管膜母细胞瘤、室管膜瘤、食道癌、嗅神经母细胞瘤、颅外生殖细胞瘤、性腺外生殖细胞瘤、肝外胆管癌、眼内黑色素瘤眼癌、视网膜母细胞瘤眼癌、胆囊癌、胃癌、胃肠道间质瘤、妊娠滋养细胞肿瘤、神经胶质瘤、头颈癌、肝癌、下咽癌、眼内黑色素瘤、胰岛细胞瘤、卡波西肉瘤、肾癌、朗格汉斯细胞组织细胞增生症、喉癌、唇和口腔癌、肺癌、Merkel细胞癌、间皮瘤、多发性内分泌腺瘤综合征、蕈样肉芽肿、鼻腔和鼻窦癌、鼻咽癌、神经母细胞瘤、口腔癌、口咽癌、卵巢癌、卵巢上皮癌、卵巢生殖细胞肿瘤、卵巢低度恶性潜能瘤、胰腺癌、胰岛细胞瘤胰腺癌、乳头状瘤病、副神经节瘤、甲状旁腺癌、阴茎癌、咽癌、嗜铬细胞瘤、浆细胞瘤、胸膜肺母细胞瘤、激素难治性前列腺癌、雄激素非依赖性前列腺癌、雄激素依赖性IV期非转移性前列腺癌、激素不敏感性前列腺癌、化疗不敏感前列腺癌、直肠癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、软组织肉瘤、子宫肉瘤、皮肤癌(黑色素瘤)、鳞状细胞癌、Merkel细胞皮肤癌、小肠癌、鳞状颈癌、睾丸癌、咽喉癌、胸腺瘤和胸腺癌、甲状腺癌、尿道癌、子宫内膜癌、子宫肉瘤、阴道癌、外阴癌、星状细胞瘤、肝细胞癌、Waldenstrom巨球蛋白血症、肾母细胞瘤。
在一个优选实施例中，疾病、病症或病况选自骨髓增生异常综合征、多发性骨髓瘤、套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、中枢神经系统淋巴瘤、非霍奇金淋巴瘤；乳头状和滤泡状甲状腺癌；乳腺癌、前列腺癌、慢性淋巴细胞白血病、淀粉样变性、I型复杂性局部疼痛综合征、恶性黑色素瘤、神经根病、骨髓纤维化、成胶质细胞瘤、胶质肉瘤、恶性胶质瘤、难治性浆细胞瘤、慢性粒单核细胞白血病、滤泡性淋巴瘤、睫状体和慢性黑色素瘤、虹膜黑色素瘤、复发性两眼间黑色素瘤、眼外延伸黑色素瘤、实体瘤、T细胞淋巴瘤、红系淋巴瘤、成单核细胞和单核细胞白血病；髓性白血病、脑肿瘤、脑膜瘤、脊髓肿瘤、甲状腺癌、非小细胞肺癌、卵巢癌、肾细胞癌、骨髓纤维化、伯基特淋巴瘤、霍奇金淋巴瘤、大细胞淋巴瘤、星状细胞瘤、肝细胞癌或原发性巨球蛋白血症(Waldenstrom巨球蛋白血症)。在一个具体实施例中，所述癌症是转移性的。在另一个实施例中，所述癌 症是化疗或放疗难治或无效的。
本文所述的治疗方法可使用任何合适的方法将药物组合物给予受试者，包括注射、经粘膜、口服、吸入、眼部、直肠、长效植入、脂质体、乳剂或持续释放方法。
本领域技术人员会认识到，本发明中要所用化合物的治疗或预防有效量可以随着因素的不同而不同，对于特定受试者，如年龄、饮食、健康等，寻求治疗或预防的症状或疾病、病症或病况的严重程度以及并发症和类型，所用制剂等。根据本发明公开内容，本领域普通技术人员将能够很容易地确定需给予受试者的化合物的治疗或预防有效量，以便在受试者中引起期望的生物学或医学响应。
根据本发明的实施例，通式(I)所示的化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物，或前药可以用来调节TNF-α或IL-2的活性或产生。在一个实施例中，当使用“调节”来描述特定分子的活性或产生时，是指抑制该分子的活性或产生。在另一个实施例中，当使用“调节”来描述特定分子的活性或产生时，是指增加或促进该分子的活性或产生。然而在另一个实施例中，当使用“调节”来描述特定分子的活性或产生时，是指减少或增加该分子的活性或产生。
因此，本发明还提供了调节TNF-α或IL-2产生或活性的方法。根据本发明的实施例，通式(I)所示的化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物，或前药，或其组合物可以给予受试者以调节TNF-α或IL-2的产生或活性，用于治疗或预防由TNF-α或IL-2调节异常相关或以TNF-α或IL-2调节异常为特征的疾病、病症或病况。
在一个优选实施例中，将根据本发明的通式(I)所示的化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物或前药，或其组合物给予给受试者，以调节TNF-α或IL-2的产生或活性，用于治疗或预防癌症或炎症。
在本文所述的任何方法中，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、立体异构体、同位素化合物、代谢物，或前药，可单独使用或与放射疗法或放射免疫疗法等配合使用，还可与一种或多种其它具有药理学活性的治疗剂(以下简称“其它治疗剂”)联合使用。
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、立体异构体、同位素化合物、代谢物，或前药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。
适合于本发明所用其它治疗剂的实例包括但不限于单克隆和多克隆抗体如obinutuzumab(
Figure PCTCN2015088312-appb-000149
)、nivolumab(
Figure PCTCN2015088312-appb-000150
)、pembrolizumab(
Figure PCTCN2015088312-appb-000151
)、elotuzumab、抗Her2/neu抗体(例如，曲妥珠单抗(trastuzumab，商品名：
Figure PCTCN2015088312-appb-000152
)和帕妥珠单抗(pertuzumab，商品名：OmnitargTM)；阿昔单抗(abciximab，商品名：
Figure PCTCN2015088312-appb-000153
)、利妥昔单抗(rituximab，商品名：
Figure PCTCN2015088312-appb-000154
)、巴利昔单抗(basiliximab，商品名：
Figure PCTCN2015088312-appb-000155
)、帕利珠单抗(palivizumab，商品名：
Figure PCTCN2015088312-appb-000156
)、英夫利西单抗(infliximab，商品名：
Figure PCTCN2015088312-appb-000157
)、曲妥珠单抗(Trastuzumab，商品名：
Figure PCTCN2015088312-appb-000158
)、阿仑单抗(alemtuzumab，商品名：
Figure PCTCN2015088312-appb-000159
)、替伊莫单抗(ibritumomab tiuxetan，商品名：
Figure PCTCN2015088312-appb-000160
)、阿达木单抗(adalimumab，商品名：
Figure PCTCN2015088312-appb-000161
)、奥马珠单抗(omalizumab，商品名：
Figure PCTCN2015088312-appb-000162
)、托西莫单抗-I-131(tositumomab-I-131，商品名：
Figure PCTCN2015088312-appb-000163
)、西妥昔单抗(cetuximab，商品名：
Figure PCTCN2015088312-appb-000164
)、那他珠单抗(natalizumab，商品名：
Figure PCTCN2015088312-appb-000165
)、托珠单抗(tocilizumab，商品名：
Figure PCTCN2015088312-appb-000166
)、帕尼单抗(panitumumab，商品名：
Figure PCTCN2015088312-appb-000167
)、雷珠单抗(ranibizumab，商品名：
Figure PCTCN2015088312-appb-000168
)、依库珠单抗(eculizumab，商品名：
Figure PCTCN2015088312-appb-000169
)、赛妥珠单抗(certolizumab pegol，商品名：
Figure PCTCN2015088312-appb-000170
)、戈利木单抗(golimumab，商品名：
Figure PCTCN2015088312-appb-000171
)、康纳单抗(canakinumab，商品名：
Figure PCTCN2015088312-appb-000172
)、优特克单抗(ustekinumab，商品名：
Figure PCTCN2015088312-appb-000173
)、奥法木单抗(ofatumumab，商品名：
Figure PCTCN2015088312-appb-000174
Figure PCTCN2015088312-appb-000175
)、德尼单抗(denosumab，商品名：
Figure PCTCN2015088312-appb-000176
)、莫维珠单抗(motavizumab，商品名：
Figure PCTCN2015088312-appb-000177
)、依决洛单抗(edrecolomab，商品名：
Figure PCTCN2015088312-appb-000178
)、瑞西巴库(raxibacumab，商品名：
Figure PCTCN2015088312-appb-000179
Figure PCTCN2015088312-appb-000180
)、贝利单抗(belimumab，商品名：
Figure PCTCN2015088312-appb-000181
)、伊匹单抗(ipilimumab，商品名：
Figure PCTCN2015088312-appb-000182
Figure PCTCN2015088312-appb-000183
)、贝伦妥单抗-维多汀(brentuximab vedotin，商品名：
Figure PCTCN2015088312-appb-000184
)、帕妥珠单抗(pertuzumab，商品名：
Figure PCTCN2015088312-appb-000185
或OmnitarTM)、阿恩曲珠单抗(ado-Trastuzumab emtansine，商品名：
Figure PCTCN2015088312-appb-000186
)、抗-CD40单克隆抗体、抗TNF-α抗体和VEGFR抗体(例如，贝伐单抗(bevacizumab，商品名：安维汀TM)；Akt抑制剂；ALK抑制剂；AMPK抑制剂；反义寡核苷酸；烷化化学治疗剂，如氮芥类(例如，环磷酰胺(Cyclophosphamide)、二氯甲基二乙胺(Mechlorethamine)、氮芥气(HN2)(商品名：Mustardgen)、乌拉莫司汀(Uramustine)、尿嘧啶氮芥(uracil mustard)、美法仑(Melphalan)、苯丁酸氮芥(Chlorambucil)、异环磷酰胺(Ifosfamide)和苯达莫司汀(Bendamustine)；亚硝基脲类(例如卡莫司汀(Carmustine)、洛莫司汀(Lomustine)和链佐星(Streptozocin)；烷基磺酸盐(例如白消安(Busulfan))；以及乙撑亚胺类如塞替派(Thiotepa)；基于铂的化疗剂(例如顺铂(Cisplatin)、卡铂(Carboplatin)、奈达铂(Nedaplatin)、奥沙利铂(Oxaliplatin)、沙铂(Satraplatin)和四硝酸三钼(Triplatin tetranitrate)、 丙卡巴肼(Procarbazine)、六甲蜜胺(Altretamine)、达卡巴嗪(Dacarbazine)米托唑胺(Mitozolomide)和替莫唑胺(Temozolomide)；APC抑制剂；细胞凋亡基因调节剂；细胞凋亡调节剂；ATM/ATR抑制剂；极光激酶抑制剂；Axl抑制剂；Bcl-2抑制剂；BCR/ABL拮抗剂；bFGF抑制剂；BTK抑制剂；酪蛋白激酶抑制剂(ICOS)；半胱胺酸蛋白酶抑制剂；CAR-T；CDK抑制剂如palbociclib；ChK抑制剂；c-Kit抑制剂；c-Met抑制剂；EGFR抑制剂；c-Myc抑制剂；C-RET抑制剂；CSF-1R抑制剂；细胞因子；DNA-PK抑制剂；动力蛋白抑制剂；EGF受体抑制剂；EGFR抑制剂；EGFR/ERBB抑制剂；肝配蛋白受体抑制剂；ERK抑制剂；雌激素激动剂；雌激素拮抗剂；FAK抑制剂；FGFR抑制剂；FLT3抑制剂；GF受体拮抗剂；谷胱甘肽抑制剂；GSK-3抑制剂；热休克蛋白-90抑制剂(例如17-AAG)；造血生长因子；HDAC抑制剂；雄激素受体抑制剂、雄激素生物合成抑制剂、HER2抑制剂；HIF抑制剂；组蛋白去乙酰化酶抑制剂(例如SAHA和LAQ 824)；HSP抑制剂；IAP抑制剂；IGF-1R抑制剂；IkB激酶抑制剂；胰岛素样生长因子-1受体抑制剂；整合素抑制剂；干扰素激动剂；干扰素；白介素；JAK抑制剂；JNK抑制剂；白血病抑制因子；白细胞α干扰素；溶血磷脂酸酰基转移酶抑制剂；基质溶解素抑制剂；基质金属蛋白酶抑制剂；Mdm2抑制剂；MEK抑制剂；MIF抑制剂；mTOR抑制剂；寡核苷酸；P13K抑制剂(例如，渥曼青霉素)；p38MAPK抑制剂；p53抑制剂；PAK抑制剂；PARP抑制剂；PDGFR抑制剂；PDK-1抑制剂；PD-1抑制剂；PDL-1抑制剂；磷酸酶抑制剂；Pim抑制剂；PKC抑制剂；PLK抑制剂；基于蛋白A的免疫调节剂；蛋白激酶C抑制剂；蛋白质酪氨酸磷酸酶抑制剂；嘌呤核苷磷酸化酶抑制剂；RacGTPase抑制剂；Raf抑制剂；Ras法尼基蛋白转移酶抑制剂；Ras抑制剂；Ras-GAP抑制剂；ROCK抑制剂；S6激酶抑制剂；信号转导抑制剂；去乙酰化酶抑制剂；Src抑制剂；STAT抑制剂；生存素抑制剂；Syk抑制剂；端粒酶抑制剂；TNF-α抑制剂；拓扑异构酶抑制剂；Trk受体抑制剂；酪氨酸激酶抑制剂；尿激酶受体拮抗剂；血管内皮生长因子受体激酶抑制剂(例如，PTK787)；VDA抑制剂；VEGFR抑制剂(例如，flk-1特异性激酶抑制剂、SU5416和ptk787/zk222584)；Wee1抑制剂；和Wnt信号通路抑制剂。
适合用于本发明的其他具体治疗剂包括，但不限于，阿西维辛(acivicin)；阿柔比星(aclarubicin)；盐酸阿考达唑(acodazole hydrochloride)；阿克罗宁(acronine)；acylfulvene(酰基富烯)；腺环戊醇(adecypenol)；阿多来新(adozelesin)；阿地白介素(aldesleukin)；六甲蜜胺(altretamine)；氨莫司汀(ambamustine)；安波霉素(ambomycin)；醋酸阿美蒽醌(ametantrone acetate)；amidox；阿米福汀(amifostine)；氨基乙酰丙酸(aminolevulinic acid)；氨柔比星(amrubicin)；安吖啶(amsacrine)；阿那格雷(anagrelide)；阿那曲唑；穿心莲内酯； antarelix；anthramycin；抗背部化形态发生蛋白-1(anti-dorsalizing morphogenetic protein-1)；抗瘤酮(antineoplaston)；甘氨酸阿非迪霉素(aphidicolin glycinate)；无嘌呤酸(apurinic acid)；ara-CDP-DL-PTBA；天门冬酰胺酶(asparaginase)；曲林菌素(asperlin)；奥沙那宁(asulacrine)；阿他美坦(atamestane)；阿莫司汀(atrimustine)；阿新司坦汀1；阿新司坦汀2；阿新司坦汀3；阿糖胞苷(azacitidine)；阿扎司琼(azasetron)；阿扎托新(azatoxin)；重氮酪氨酸(azatyrosine)；阿扎替派(azetepa)；阿佐霉素(azotomycin)；班兰诺(balanol)；巴马司他(batimastat)；苯并二氢卟酚(benzochlorins)；苯佐替派(benzodepa)；苯甲酰基星形抱菌素(benzoylstaurosPorine)；β-内酰胺衍生物(beta lactam derivatives)；β-阿立辛(β-alethine)；betaclamycin B；白桦脂酸(betulinic acid)；比卡鲁胺(bicalutamide)；盐酸比生群(bisantrene hydrochloride)；二吖丙啶精胺(bisaziridinylspermine)；双奈法德二甲磺酸酯(bisnafide dimesylate)；双崔特A(bistratene A)；bizelesin(比折来新)；硫酸博莱霉素(bleomycin sulfate)；硼替佐米(吉西他滨(gemcitabine)；布喹那钠(brequinar sodium)；bretlate；溴匹立明(bropirimine)；布度钛(budotitane)；布度钛(busulfan)；丁硫堇(buthionine sulfoximine)；放线菌素(cactinomycin)；卡泊三醇(calcipotriol)；钙磷酸蛋白C(calphostin C)；卡普睾酮(calusterone)；喜树碱衍生物(camptothecin derivatives)；卡培他滨(capecitabine)；卡醋胺(caracemide)；卡贝替姆(carbetimer)；卡铂(carboplatin)；甲酰胺-氨基-三唑(carboxamide-amino-triazole)；羧基酰氨基三唑(carboxyamidotriazole)；羧胺三唑(carboxyamidotriazole)；卡莫司汀(carmustine)；carubicin hydrochloride(盐酸卡米诺霉素)；卡折来新(carzelesin)；澳粟精胺(castanospermine)；抗菌肽B(cecropin B)；西地芬戈(cedefingol)；塞来昔布(celecoxib)；西曲瑞克(cetrorelix)；苯丁酸氮芥(chlorambucil)；二氢卟酚(chlorins)；氯代喹喔啉磺胺(chloroquinoxaline sulfonamide)；西卡前列素(cicaprost)；cirolemycin(西罗霉素)；顺铂(cisplatin)；顺式卟啉(cis-porphyrin)；克拉屈滨(cladribine)；氯米芬类似物(clomifene analogues)；克霉唑(clotrimazole)；克立霉素A(collismycin A)；克立霉素B(collismycin B)；考布他汀A4(combretastatin A4)；考布他汀衍生物(combretastatin derivatives)；康纳京尼(conagenin)；卡那贝西汀816(crambescidin 816)；克立那托甲磺酸(crisnatol mesylate)；克立那托(crisnatol)；念珠藻环肽8(cryptophycin 8)；念珠藻环肽A类似物(cryptophycin A analogues)；卡拉新A(curacin A)；环戊蒽醌(cyclopentanthraquinones)；环磷酰胺(cyclophosphamide)；环普兰姆(cycloplatam)；环孢菌素(cyclosporin)；西匹霉素(cypemycin)；阿糖胞苷十八烷基磷酸钠(cytarabine ocfosfate)；阿糖胞苷(cytarabine)；磷酸己烧雌酹(cytostatin)；达卡巴嗪(dacarbazine)；达昔单抗(dacliximab)；更生霉素(dactinomycin)；盐酸柔红霉素(daunorubicin hydrochloride)；地西他滨(decitabine)；去氢膜海鞘素 B(dehydrodidemnin B)；地洛瑞林(deslorelin)；地塞米松(dexamethasone)；右异环磷酰胺(dexifosfamide)；奥马铂(ormaplatin)；右奥马铂(dex奥马铂(ormaplatin)；右雷佐生(Dextrazoxane)；右旋维拉帕米(dexverapamil)；甲磺酸地扎胍宁(dezaguanine mesylate)；地扎胍宁(dezaguanine)；地吖醌(diaziquone)；膜海鞘素B(didemnin B)；地多西(didox)；二乙基去甲精胺(diethylnorspermine)；二氢-5-氮胞苷(dihydro-5-azacytidine)；9-二氢紫杉醇(dihydrotaxol,9-)-；二恶霉素(dioxamycin)二苯基螺莫司汀(diphenyl spiromustine)；多西他赛(docetaxel)；二十二烷醇(docosanol)；多拉司琼(dolasetron)；去氧氟尿苷(doxifluridine)；盐酸表柔比星(doxorubicin hydrochloride)；阿霉素(doxorubicin)；多西环素(doxycycline)；枸橼酸屈洛昔芬(droloxifene citrate)；屈洛昔芬(droloxifene)；屈他雄酮丙酸酯(dromostanolone propionate)；屈大麻酚(dronabinol)；达佐霉素(duazomycin)；卡霉素SA(duocarmycin SA)；依布硒(ebselen)；依考莫司汀(ecomustine)；依达曲沙(edatrexate)；依地福新(edelfosine)；依决洛单抗(edrecolomab)；盐酸依氟鸟氨酸(eflornithine hydrochloride)；依氟鸟氨酸(eflornithine)；榄香烯(elemene)；elotuzumab；依沙芦星(elsamitrucin)；乙嘧替氟(emitefur)；恩洛铂(enloplatin)；恩普氨酯(enpromate)；依匹哌啶(epipropidine)；盐酸表柔比星(epirubicin hydrochloride)；表柔比星(epirubicin)；爱普列特(epristeride)；爱必妥(erbitux)；厄布洛唑(erbulozole)；盐酸依索比星(esorubicin hydrochloride)；雌莫司汀衍生物(estramustine derivatives)；雌莫司汀磷酸钠(estramustine phosphate sodium)；雌莫司汀(estramustine)；依那西普(etanercept)；依他硝唑(etanidazole)；磷酸依托泊苷(etoposide phosphate)；依托泊苷(etoposide)；艾托卜宁(etoprine)；依西美坦(exemestane)；盐酸法倔唑(fadrozole hydrochloride)；法倔唑(fadrozole)；法扎拉滨(fazarabine)；芬维A胺(fenretinide)；非格司亭(filgrastim)；非那雄胺(finasteride)；夫拉平度(flavopiridol)；氟卓斯汀(flezelastine)；氟脲苷(floxuridine)；夫斯特隆(fluasterone)；磷酸氟达拉滨(fludarabine phosphate)；氟达拉滨(fludarabine)；fluorocitabine；盐酸氟柔红霉素(fluorodaunorunicin hydrochloride)；氟尿嘧啶(fluorouracil)；福酚美克(forfenimex)；福美司坦(formestane)；磷喹酮(fosquidone)；福司曲星钠(fostriecin sodium)；福司曲星(fostriecin)；福莫司汀(fotemustine)；钆特沙弗林(gadolinium texaphyrin)；硝酸镓(gallium nitrate)；加洛他滨(galocitabine)；加尼瑞克(ganirelix)；盐酸吉西他滨(gemcitabine hydrochloride)；吉西他滨(gemcitabine)；和普苏姆(hepsulfam)；调蛋白(heregulin)；六亚甲基二乙酰胺(hexamethylene bisacetamide)；羟基脲(hydroxyurea)；金丝桃素(hypericin)；伊班膦酸(ibandronic acid)；依鲁替尼(ibrutinib)；盐酸伊达比星(idarubicin hydrochloride)；伊达比星(idarubicin)；艾多昔芬(idoxifene)；伊决孟酮(idramantone)；异环磷酰胺(ifosfamide)；伊莫 福新(ilmofosine)；伊洛马司他(ilomastat)；伊马替尼(imatinib，商品名：
Figure PCTCN2015088312-appb-000187
)；咪喹莫特(imiquimod)；免疫刺激肽(immunostimulant peptides)；碘苄胍(iobenguane)；碘阿霉素(iododoxorubicin)；4-甘薯苦醇(ipomeanol,4-)-；异丙铂(iproplatin)；盐酸伊立替康(irinotecan hydrochloride)；伊立替康(irinotecan)；伊罗普拉(iroplact)；伊索拉定(irsogladine)；异苯胍唑(isobengazole)；异高软海绵素B(isohomohalicondrin B)；伊他司琼(itasetron)；jasplakinolide；kahalalide F；片螺素-N三醋酸酯(lamellarin-N triacetate)；醋酸兰瑞肽(lanreotide acetate)；兰瑞肽(lanreotide)；拉帕替尼(lapatinib，商品名：
Figure PCTCN2015088312-appb-000188
)；leinamycin；来格司亭(lenograstim)；香菇多糖硫酸酯(lentinan sulfate)；leptolstatin；来曲唑(letrozole)；醋酸亮丙瑞林(leuprolide acetate)；醋酸亮丙瑞林+雌激素+孕激素(leuprolide+estrogen+progesterone)；亮丙瑞林(leuprorelin)；左旋咪唑(levamisole)；盐酸利阿唑(liarozole hydrochloride)；利阿唑(liarozole)；亲脂性双糖肽(lipophilic disaccharide peptide)；脂溶性铂类似物(lipophilic platinum analogues)；立索克林酰胺7(lissoclinamide 7)；洛铂(lobaplatin)；蚯吲磷脂(lombricine)；洛美曲索钠(lometrexol sodium)；洛美曲索(lometrexol)；洛莫司汀(lomustine)；氯尼达明(lonidamine)；盐酸洛索蒽醌(losoxantrone hydrochloride)；洛索蒽醌(losoxantrone)；洛索立宾(loxoribine)；勒托替康(lurtotecan)；镥特沙弗林(lutetium texaphyrin)；lysofylline；裂解肽(lytic peptides)；美坦新(maitansine)；麦洛坦汀A(Amannostatin A)；马马司他(marimastat)；马索罗酚(masoprocol)；乳腺丝抑蛋白(maspin)；美登素(maytansine)；盐酸氮芥(mechlorethamine hydrochloride)；醋酸甲地孕酮(megestrol acetate)；醋酸美伦孕酮(melengestrol acetate)；美法仑(melphalan)；美诺立尔(menogaril)；麦尔巴隆(merbarone)；巯嘌呤(mercaptopurine)；美替瑞林(meterelin)；蛋氨酸(methioninase)；甲氨蝶呤钠(methotrexate sodium)；甲氨蝶呤(methotrexate)；甲氧氯普胺(metoclopramide)；氯苯氨啶(metoprine)；美妥替哌(meturedepa)；米非司酮(mifepristone)；米替福新(miltefosine)；米立司亭(mirimostim)；米丁度胺(mitindomide)；米托卡星(mitocarcin)；丝裂红素(mitocromin)；米托洁林(mitogillin)；米托胍腙(mitoguazone)；二溴卫矛醇(mitolactol)；米托马星(mitomalcin)；丝裂霉素衍生物(mitomycin derivatives)；丝裂霉素(mitomycin)；米托萘胺(mitonafide)；米托司培(mitosper)；米托坦(mitotane)；有丝分裂毒素成纤维细胞生长因子-月巴皂草毒蛋白(mitotoxin fibroblast growth factor-saporinmitotoxin)；盐酸米托蒽醌(mitoxantrone hydrochloride)；米托蒽醌(mitoxantrone)；莫法罗汀(mofarotene)；莫拉司亭(molgramostim)；莫哌达醇(mopidamol)；mycaperoxide B；霉酚酸(mycophenolic acid)；myriaporone；N-乙酰基地那林(N-acetyldinaline)；那法瑞林(nafarelin)；nagrestip；纳洛酮+喷他佐辛(naloxone+pentazocine)；napavin；naphterpin；那 托司亭(nartograstim)；奈达铂(nedaplatin)；奈莫柔比星(nemorubicin)；奈立膦酸(neridronic acid)；尼鲁米特(nilutamide)；nisamycin；nitrullyn；nivolumab(
Figure PCTCN2015088312-appb-000189
)；诺考达唑(nocodazole)；诺加霉素(nogalamycin)；O6-苄基鸟嘌呤(O6-benzylguanine)；oblimersen(奥利默森，商品名：
Figure PCTCN2015088312-appb-000190
)；奥曲肽(octreotide)；奥克恩(okicenone)；奥那司酮(onapristone)；昂丹司琼(ondansetron)；奥拉新(oracin)；奥马铂(ormaplatin)；奥沙特隆(osaterone)奥沙利铂(oxaliplatin)；厄诺霉素(oxaunomycin)；奥昔舒仑(oxisuran)；紫杉醇(paclitaxel)；紫杉醇衍生物(paclitaxel derivatives)；帕诺明(palauamine)；palbociclib；棕榈酰根霉素(palmitoylrhizoxin)；帕米膦酸(pamidronic acid)；人参炔三醇(panaxytriol)；帕诺米芬(panomifene)；panobinostat；帕拉贝新(parabactin)；帕折普汀(pazelliptine)；培门冬酶(pegaspargase)；皮地新(peldesine)；培利霉素(peliomycin)；pembrolizumab(
Figure PCTCN2015088312-appb-000191
)；戊氮芥(pentamustine)；多硫酸戊聚糖钠(pentosan polysulfate sodium)；喷司他丁(pentostatin)；喷唑(pentrozole)；硫酸培洛霉素(peplomycin sulfate)；全氟溴烷(perflubron)；培磷酰胺(perfosfamide)；紫苏子醇(perillyl alcohol)；苯连氮霉素(phenazinomycin)；乙酸苯酯(phenylacetate)；溶链菌(picibanil)；盐酸毛果芸香碱(pilocarpine hydrochloride)；哌泊溴烷(pipobroman)；哌泊舒凡(piposulfan)；吡柔比星(pirarubicin)；吡曲克辛(piritrexim)；盐酸吡罗蒽醌(piroxantrone hydrochloride)；普来司汀A(placetin A)；普来司汀B(placetin B)；铂络合物(platinum complex)；普卡霉素(plicamycin)；普洛美坦(plomestane)；卟吩姆钠(porfimer sodium)；泊非霉素(porfiromycin)；泼尼氮芥(prednimustine)；强的松；盐酸丙卡巴肼(procarbazine hydrochloride)；丙基双吖啶酮(propyl bis-acridone)；前列腺素J2(prostaglandin J2)；盐酸嘌呤霉素(puromycin hydrochloride)；嘌呤霉素(puromycin)；羟基茜草素(purpurins)；吡唑呋喃菌素(pyrazofurin)；甲氧基吡唑啉吖啶(pyrazoloacridine)；雷替曲塞(raltitrexed)；雷莫司琼(ramosetron)；雷帕霉素(rapamycin)；雷帕霉素衍生物(rapamycin derivatives)(例如，依维莫司(everolimus)；merilimus；olcorolimus；ridaforolimus；西罗莫司(sirolimus)；temsirolimus西罗莫司脂化物(sirolimus，商品名：Torisel)；umirolimus和佐他莫司(zotarolimus)；去甲基瑞替利汀(retelliptine demethylated)；铼186依替膦酸钠(rhenium Re 186etidronate)；根霉素(rhizoxin)；利波腺苷(riboprine)；核酶(ribozymes)；RII维甲酸(RII retinamide)；罗希吐碱(rohitukine)；罗莫肽(romurtide)；罗喹美克(roquinimex)；鲁滨吉隆B1(rubiginone B1)；鲁泊塞(ruboxyl)；盐酸沙芬戈(safingol hydrochloride)；沙芬戈(safingol)；saintopin；SarCNU；肌肉叶绿醇A(sarcophytol A)；沙格司亭(sargramostim)；Sdi1类似物(Sdi 1mimetics)；马沙尼(semaxanib)；司莫司汀(semustine)；辛曲秦(simtrazene)；sizofuran；索布佐生(sobuzoxane)；硼卡钠(sodium borocaptate)；苯乙酸钠(sodium  phenylacetate)；索佛罗(solverol)；生长调节素结合蛋白(somatomedin binding protein)；索纳明(sonermin)；斯帕磷酸钠(sparfosate sodium)；斯帕磷酸(sparfosate)；稀疏霉素(sparsomycin)；穗霉素D(spicamycin D)；盐酸锗螺胺(spirogermanium hydrochloride)；螺莫司汀(spiromustine)；螺铂(spiroplatin)；斯兰罗皮汀(splenopentin)；海绵素1(spongistatin 1)；角鲨胺(squalamine)；斯替皮米德(stipiamide)；链黑菌素(streptonigrin)；链佐星(streptozocin)；sulfinosine；磺氯苯脲(sulofenur)；suradista；苏拉明(suramin)；苦马豆素(swainsonine)；他利霉素(talisomycin)；他莫司汀(tallimustine)；他莫昔芬甲碘化物(tamoxifen methiodide)；牛磺莫司汀(tauromustine)；泰索帝(taxotere)；他扎罗汀(taxotere)；替可加兰钠(tecogalan sodium)；替加氟(tegafur)；tellurapyrylium；盐酸替洛蒽醌(teloxantrone hydrochloride)；替莫泊芬(temoporfin)；替尼泊苷(teniposide)；替罗昔隆(teroxirone)；睾内酯(teroxirone)；四氯十氧化物(tetrachlorodecaoxide)；替唑明(tetrazomine)；噻立拉斯汀(thaliblastine)；硫咪嘌呤(thiamiprine)；噻可拉林(thiocoraline)；硫鸟嘌呤(thioguanine)；噻替哌(thiotepa)；血小板生成素模拟物(thrombopoietin mimetics)；血小板生成素(thrombopoietin)；胸腺法新(thymalfasin)；胸腺曲南(thymotrinan)；噻唑呋林(tiazofurin)；乙基锡初紫红素(tin ethyl etiopurpurin)；替拉扎明(tirapazamine)；二茂钛二氯化物(titanocene bichloride)；托普升替(topsentin)；枸橼酸托瑞米芬(toremifene citrate)；托瑞米芬(toremifene)；醋酸曲托龙(trestolone acetate)；维甲酸(tretinoin)；三乙酰尿苷(triacetyluridine)；磷酸曲西立滨(triciribine phosphate)；曲西立滨(triciribine)；三甲曲沙葡糖醛酸脂(trimetrexate glucuronate)；三甲曲沙(trimetrexate)；曲普瑞林(triptorelin)；托烷司琼(tropisetron)；盐酸妥布氯(tubulozole hydrochloride)；妥罗雄脲(turosteride)；tyrphostins；乌苯美司(ubenimex)；尿嘧啶氮芥(uracil mustard)；乌瑞替派(uredepa)；伐普肽(vapreotide)；凡瑞林B(variolin B)；维拉雷琐(velaresol)；藜芦胺(veramine)；verdins；维替泊芬(verteporfin)；硫酸长春碱(vinblastine sulfate)；硫酸长春新碱(vincristine sulfate)；硫酸长春新碱(vindesine sulfate)；长春地辛(vindesine)；硫酸长春匹定(vinepidine sulfate)；硫酸长春甘酯(vinglycinate sulfate)；硫酸长春罗新(vinleurosine sulfate)；酒石酸长春瑞滨(vinorelbine tartrate)；长春瑞滨(vinorelbine)；硫酸长春罗定(vinrosidine sulfate)；维萨汀(vinxaltine)；硫酸长春利定(vinzolidine sulfate)；vitaxin；伏氯唑(vorozole)；扎诺特隆(zanoterone)；折尼铂(zeniplatin)；净司他丁(zinostatin)；5-乙炔基尿嘧啶(5-ethynyluracil)和盐酸佐柔比星(zorubicin hydrochloride)。
在一个优选实施方案中，其它治疗剂选自elotuzumab、palbociclib、panobinostat、nivolumab、pembrolizumab、培美曲塞(pemetrexed)、托泊替康(拓扑替康)(topotecan)、阿霉素(doxorubicin)、硼替佐米(bortezomib)、吉西他滨(gemcitabine)、达卡巴嗪(dacarbazine)、 地塞米松(dexamethasone)、克拉霉素(biaxin)、长春新碱(vincristine)、阿糖胞苷(azacitidine)、CAR-T、利妥昔单抗(rituximab)、曲妥珠单抗(trastuzumab)、PD-1抑制剂、PDL-1抑制剂、HDAC抑制剂、雄激素受体抑制剂、雄激素生物合成抑制剂、泼尼松(prednisone)、多西他赛(docetaxel)、氯法拉滨注射液、Ublituximab、romidepsin、BTK抑制剂、红血球生长激素、eltrombopag、米诺四环素和美法仑(melphalan)中的一种或多种。
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、立体异构体、同位素化合物、代谢物，或前药，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、立体异构体、同位素化合物、代谢物，或前药，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、立体异构体、同位素化合物、代谢物，或前药，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、立体异构体、同位素化合物、代谢物，或前药之前、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、立体异构体、同位素化合物、代谢物，或前药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、立体异构体、同位素化合物、代谢物，或前药联合所用合适的其它治疗剂。
本发明中方法中将所用其它治疗剂的治疗有效量是本领域熟练技术人员所熟知的，并且给药指导可见本文引用的专利和公布的专利申请以及Wells et al,eds.,Pharmacotherapy Handbook,2nd Edition,Appleton and Lange,Stamford,Conn.(2000)；PDR Pharmacopoeia,Tarascon Pocket Pharmacopoeia 2000,Deluxe Edition,Tarascon Publishing,Loma Linda,Calif.(2000)和其它医学文献。但是，普通技术人员的技术水平完全能够确定其它治疗剂的最佳有效剂量范围。
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、立体异构体、同位素化合物、代谢物，或前药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、立体异构体、同位素化合物、代谢物或前药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、立体异构体、同位素化合物、代谢物，或前药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、立体异构体、同位素化合物、代谢物，或前药时的有效量。以这种方式，与任何一种药物的高剂量相关的副作用可以降至最低。其他潜在的优势，例如，改善给药方案和/或降低药物成本，对于本领域技术人员将是显而易见的。
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、立体异构体、同位素化合物、代谢物，或前药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、立体异构体、同位素化合物、代谢物，或前药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。
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。示例性盐包括但不限于：硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、单宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、gentisinate、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲烷磺酸盐、乙烷磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1-1-亚甲基-双(2-羟基-3-萘甲酸盐))。本发明中所用化合物可与各种氨基酸形成药学上可接受的盐。合适的碱盐包括但不限于铝盐、钙盐、锂盐、镁盐、钾盐、钠盐、锌盐、铋和二乙醇胺盐。药学上可接受的盐 的综述见Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
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、同位素化合物、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。有关前药的综述参见，例如，J.Rautio et al.,Nature Reviews Drug Discovery(2008)7,255-270and Prodrugs:Challenges和Rewards(V.Stella et al.ed.,Springer,2007)。
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、同位素化合物、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。
本文所用术语“同位素化合物”是指本发明的通式(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，或前药中含有一个或多个天然或非天然丰度的原子同位素。非天然丰度的原子同位素包括但不限于氘(2H或D)、氚(3H或T)、碘-125(125I)、磷-32(32P)、碳-13(13C)或碳-14(14C)。前述同位素化合物还可用作治疗或诊断剂(即，体内显影剂)，或研究工具。本发明的化合物的所有同位素变体，无论是否具有放射性，都包括在本发明的范围内。
本文所用术语“同位素富集”是指通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物或前药中含有一个或多个非天然丰度的原子同位素。“同位素富集”也指通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物，或前药化合物中至少含有一个非天然丰度同位素原子。
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或TNF-α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，例如，通过抑制TNF-α产生或调节TNF-α活性治疗癌症、不期望的血管生成相关病症或TNF-α相关病症。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或TNF-α相关病症的量。
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
Figure PCTCN2015088312-appb-000192
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调节细胞因子(如TNF-α)的产生和/或活性，从而有效的治疗癌症和炎症性疾病。
具体实施方式
实施例1化合物I-28
Figure PCTCN2015088312-appb-000193
步骤A：将5-氟-2-甲基苯甲酸(6.0g，38.9mmol)溶解于98％硫酸(60mL)。降温至-5-0℃，缓慢滴加65％硝酸(3.3g,50.7mmol)，加毕维持此温度下搅拌1小时。反应液加入冰水(200g)中，水相用甲基叔丁基醚萃取(150mL×3)，有机相用饱和食盐水洗一次(20mL)，无水硫酸钠干燥，过滤，旋干溶剂，得到7.0克粗品黄色固体5-氟-2-甲基-3-硝基苯甲酸粗品。粗品未经纯化，直接用于下一步。1H NMR(DMSO-d6，300M Hz)，δ8.05(dd,J＝8.1Hz,3.0Hz,1H),7.85(dd,J＝8.7,3.0Hz,1H),2.44(s,3H).
步骤B：将步骤A所得5-氟-2-甲基-3-硝基苯甲酸粗品(7.0g)溶解在甲醇里(70mL)，加入98％硫酸(2mL)。混合物于70℃搅拌过夜。反应液浓缩后，加入水(50mL)和乙酸 乙酯(150mL)分层，水相乙酸乙酯萃取(100mL×2)。合并有机相并用饱和食盐水洗一次(30mL)，无水硫酸钠干燥，过滤，旋干溶剂，柱层析(PE:EtOAc＝10:1～3:1)得到淡黄色固体5-氟-2-甲基-3-硝基苯甲酸甲酯(3.5g，两步收率为42％)。1H NMR(DMSO-d6，300M Hz)，δ8.10(dd,J＝8.1,3.0Hz,1H),7.88(dd,J＝8.7,3.0Hz,1H),3.86(s,3H),2.41(s,3H).
步骤C：将5-氟-2-甲基-3-硝基苯甲酸甲酯(3.5g,16.4mmol)、BPO(388mg,1.6mmol)和NBS(3.2g,18.1mmol)溶于CCl4(40mL)中，95℃浴温下反应过夜。混合物冷却至室温后过滤，滤液以饱和食盐水(20mL)洗一次，无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化(PE:EtOAc＝10:1～5:1)得到淡黄色油状物2-溴甲基-5-氟-3-硝基苯甲酸甲酯(3.7g，收率：77％)。1H NMR(DMSO-d6,300MHz):δ8.21-8.25(dd,J＝8.1,3.0Hz,1H),7.99-8.03(dd,J＝8.7,2.7Hz,1H),4.97(s,2H),3.93(s,3H).
步骤D：将3-氨基哌啶-2,6-二酮盐酸盐(2.5g,15.1mmol)和2-溴甲基-5-氟-3-硝基苯甲酸甲酯(4.0g,13.7mmol)和KHCO3(3.5g,34.2mmol)加入CH3CN(80mL)中，95℃浴温反应过夜。反应液浓缩后加入冰水(100g)搅拌0.5h。过滤，固体用水洗(50mL×3)，干燥后得到黄色固体I-28A[3-(6-fluoro-4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione](3.8g，收率：90％)。1H NMR(DMSO-d6，400MHz)，δ11.04(s,1H),8.38(dd,J＝8.8,2.4Hz,1H),8.11(dd,J＝6.8,2.4Hz,1H),5.18(dd,J＝13.2,5.2Hz,1H),4.88(d,J＝19.2Hz,1H),4.78(d,J＝19.2Hz,1H),2.87-2.96(m,1H),2.54-2.63(m,2H),2.01-2.05(m,1H)。
步骤E：将化合物I-28A(2.8g，9.1mmol)和Pd/C(10％,280mg,50％水)加于DMF(30mL)中，50Psi氢气下室温反应6h。反应液过滤，固体用DMF(50mL×1洗涤，滤液浓缩，浓缩物加水(100ml)搅拌0.5h，抽滤，固体用水洗涤(50mL×3)后浓缩并干燥，得到类白色粗品(2.1g，收率:84％)。取其中200mg，用制备HPLC纯化得到148.8mg类白色固体I-28[3-(4-amino-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione]。1H NMR(DMSO-d6，400MHz)，11.01(s,1H),6.55-6.63(m,2H),5.79(s,2H),5.10(dd,J＝13.2,4.8Hz,1H),4.18(d,J＝17.2Hz,1H),4.08(d,J＝17.2Hz,1H),2.87-2.95(m,1H),2.59-2.63(m,1H),2.27-2.31(m,1H),2.02-2.06(m,1H)。LCMS:278.1([M+1]+)。
化合物I-01～化合物I-27的合成方法参照实施例1。
实施例2化合物I-29和I-30的合成
Figure PCTCN2015088312-appb-000194
800mg化合物I-28溶于28mL DMF中，通过HPLC手性拆分(色谱柱：CHIRALPAK  IA,5μm,30×250mm；流动相CH3CN；流速21mL/min；温度26-28℃；检测波段230nM；单次进样体积350μL)得到300mg I-29[Rt＝4.81min；>99％ee；1H NMR(DMSO-d6，400MHz)，δ11.01(s,1H),6.55-6.63(m,2H),5.80(s,2H),5.07-5.12(m,1H),4.18(d,J＝16.8Hz,1H),4.08(d,J＝16.8Hz,1H),2.87-2.93(m,1H),2.59-2.63(m,1H),2.27-2.31(m,1H),2.02-2.07(m,1H)。LCMS:278.1([M+1]+)]和260mg I-30[Rt＝7.08min；>97.5％ee；1H NMR(DMSO-d6，400MHz)，δ11.01(s,1H),6.55-6.63(m,2H),5.79(s,2H),5.08-5.12(m,1H),4.19(d,J＝17.2Hz,1H),4.08(d,J＝17.2Hz,1H),2.87-2.95(m,1H),2.59-2.64(m,1H),2.27-2.31(m,1H),2.04-2.07(m,1H)。LCMS:278.1([M+1]+)]。
实施例3化合物I-31和I-32
Figure PCTCN2015088312-appb-000195
步骤A：向含有L-谷氨酸-5-苄酯(50.0g,211mmol)的氘代醋酸AcOD(150mL)中加入苯甲醛(1.34g,12.6mmol)，加热至65℃，搅拌18小时。减压浓缩去除溶剂。向剩余 固体中加入甲醇(25mL)、乙腈(50mL)和甲基叔丁基醚(200mL)，打浆搅拌半小时后过滤，滤饼用甲基叔丁基醚(200mL)淋洗。固体经减压干燥后用同样方法重新反应一次后得I-31A(32.5g，收率65％)。1H NMR[(CD3OD+D2O)，300MHz]：δ7.33-7.42(m,5H)，5.14(s,2H)，3.70(t,<0.05H)，2.58-2.63(m,2H)，2.13-2.17(m,2H)。
步骤B：将化合物I-31A(32.5g,137mmol)溶于THF(600ml)和水(600ml)的混合溶剂中，冰浴下加入NaHCO3(12.6g,150mmol)，10分钟后将(Boc)2O(32.7g,150mmol)缓慢加入反应体系中。自然升温至室温后继续搅拌4小时，减压浓缩，剩余物加入适量饱和NaHCO3溶液使之溶清。用甲基叔丁基醚萃取(200ml×2)，水相冰浴冷却后用3N的HCl溶液酸化至pH～1。EtOAc萃取(300ml×2)，无水Na2SO4干燥，过滤，浓缩得白色固体中间体I-31B(46.5g,收率：100％)。产品无需进一步纯化直接用于下一步。1H NMR(CD3OD,300MHz):δ7.29-7.35(m,5H),5.12(s,2H),4.13(br s,0.05H)，2.45-2.50(m,2H),2.12-2.21(m,1H),1.85-1.94(m,1H),1.42(s,9H)。
步骤C：将化合物I-31B(46.5g,137mmol)溶于THF(300mL)中，反应液冷却至5℃后，加入甲基吗啉(NMM,16.5g,164mmol)和氯甲酸乙酯(17.8g，164mmol)，0-5℃搅拌一小时后，将饱和的氨水(150ml)加入反应液中，室温下剧烈搅拌2小时。加入乙酸乙酯(200mL)萃取分液，水相再次用乙酸乙酯(200mL)萃取一次。合并有机相，分别用饱和碳酸氢钠溶液(200mL×2)和饱和食盐水洗涤(200ml)，无水硫酸钠干燥，过滤浓缩后得白色固体产品I-31C(41g，收率：90％)。1H NMR(DMSO-d6,300MHz):δ7.30-7.41(m,5H),7.24(s,1H),6.99(s,1H),6.79(s,1H),5.06(s,2H),3.90(m,<0.05H)，2.33-2.38(m,2H),1.70-1.94(m,2H),1.35(s,9H)。
步骤D：将化合物I-31C(41.0g,121mmol)溶于1,4-二氧六环(200mL)中,加入6N的HCl/二氧六环溶液(300mL)，室温搅拌2小时。反应液浓缩蒸干后加入200mL甲基叔丁基醚打浆，过滤后干燥得白色固体I-31D(31.3g,收率：95％)。1H NMR(DMSO-d6,400MHz):δ8.37(br s,3H),8.04(s,1H),7.56(m,1H),7.33-7.38(m,5H),5.10(s,2H),3.77(t,<0.05H),2.48-2.52(m,2H),2.01-2.05(m,2H)。
步骤E：将2-溴甲基-5-氟-3-硝基苯甲酸甲酯(31.8g，109mmol)和化合物I-31D(29.7g，109mmol)溶于乙腈中(550mL)，搅拌下加入TEA(22.1g，218mmol)。升温至75℃反应过夜。减压浓缩至干，剩余物加入CH3CN(100mL)打浆得浅黄色固体化合物I-31E(34.5g，收率：76.2％)。1H NMR(DMSO-d6，300MHz):δ8.33(dd,J＝8.7,2.4Hz,1H),8.04(dd,J＝6.9,2.4Hz,1H),7.66(s,1H),7.26-7.36(m,6H),4.82-5.05(m,4H),2.20-2.39(m,3H),2.06-2.15(m,1H)。
步骤F：化合物I-31E通过HPLC手性拆分(色谱柱：DAICEL CHIRALPAK IA,10μm,25×250mm；流动相MeOH/DCM 80/20(v/v)；流速30mL/min；温度35℃；检测波段254nM)得到I-31F1[1H NMR(DMSO-d6，300MHz):δ8.31-8.35(m,1H),8.03(dd,J＝7.2,2.1Hz,1H),7.66(s,1H),7.29-7.35(m,6H),4.83-5.04(m,4H),2.22-2.40(m,3H),2.06-2.16(m,1H)]和I-31F2[1H NMR(DMSO-d6，300MHz):δ8.33(dd,J＝9.3,2.4Hz,1H),8.03(dd,J＝7.2,2.4Hz,1H),7.67(s,1H),7.29-7.36(m,6H),4.83-5.05(m,4H),2.20-2.42(m,3H),2.09-2.16(m,1H)]。
化合物I-32：化合物I-31F2(2.2g,5.3mmol)和Pd/C(10％,200mg,50％水)加入无水甲醇(30mL)中，50Psi氢气压力下室温反应4h。反应液抽滤，滤液浓缩至干，剩余固体加入DCE(15mL)搅拌5分钟，减压浓缩至干。得到类白色粗品(1.4g)。取1.1g(3.7mmol)溶于干燥的THF(10mL)和DCE(40mL)的混合溶剂中，于-30℃下缓慢滴加SOCl2(0.74g,9.3mmol)，加毕搅拌反应2h，滴加吡啶(1.1g,9.3mmol)维持此温度搅拌40分钟，加入TEA(1.3g,13mmol)，继续反应2h。加水(0.1mL)，反应混合物减压浓缩至干后再加水(5mL)，EtOAc萃取(70mL×5)，无水硫酸钠干燥，过滤，减压浓缩至干，剩余物经Pre-HPLC得到浅绿色固体I-32(340mg，收率：33％；99％ee)。1H NMR(DMSO-d6，400MHz)，11.00(s,1H),6.56-6.61(m,2H),5.78(s,2H),5.05-5.11(m,0.05H),4.17(d,J＝17.1Hz,1H),4.05(d,J＝17.1Hz,1H),2.84-2.96(m,1H),2.56-2.62(m,1H),2.20-2.32(m,1H),1.98-2.05(m,1H)。LCMS:279.1([M+1]+)。
化合物I-31：用化合物I-32的同样合成方法，以I-31F1替换I-31F2可以得到化合物I-31(99％ee)。1H NMR(DMSO-d6，400MHz)，10.99(s,1H),6.52-6.61(m,2H),5.71(br s,2H),5.08(dd,J＝18.0,7.2Hz,0.04H),4.17(d,J＝17.4Hz,1H),4.06(d,J＝17.4Hz,1H),2.83-2.96(m,1H),2.56-2.62(m,1H),2.21-2.32(m,1H),1.98-2.05(m,1H)。LCMS:279.1([M+1]+)。
实施例4化合物I-01
Figure PCTCN2015088312-appb-000196
参照实施例3中化合物的合成方法，用相应的外消旋混合物I-31E为底物，就可以合成实施例4中的化合物I-01。
1H NMR(DMSO-d6，300MHz):δ10.94(br s,1H),6.52-6.61(m,2H),5.78(s,2H),5.05-5.11(m,0.05H),4.16(d,J＝16.8Hz,1H),4.05(d,J＝16.8Hz,1H),2.84-2.96(m,1H),2.54- 2.62(m,1H),2.21-2.31(m,1H),1.98-2.04(m,1H).LCMS:279.1([M+1]+)。
化合物I-33～化合物I-56的合成方法可参照实施例2或3。
实施例5化合物A195
3-(4-((2-fluoro-5-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A195.
合成路线
Figure PCTCN2015088312-appb-000197
实验部分
A340D(40mg,0.096mmol)溶于CH3CN(3mL)，加入CDI(20mg,0.13mmol)，90℃氮气氛围下搅拌反应过夜。减压浓缩。残液溶于DCM(30mL)，依次经0.1N HCl(10mL)，饱和NaHCO3水溶液(10mL)，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残液经制备薄层色谱纯化(DCM/MeOH＝25/1)2次，可得白色固体A195(46mg,收率：81％)。
1H NMR(DMSO-d6,300MHz):δ10.98(s,1H),7.23(t,J＝7.8Hz,1H),7.11(t,J＝9.6Hz,1H),6.90-6.95(m,2H),6.78-6.84(m,1H),6.66(d,J＝7.8Hz,1H),6.24(t,J＝5.7Hz,1H),5.10(dd,J＝13.2,5.4Hz,1H),4.36(d,J＝5.4Hz,2H),4.30(d,J＝17.7Hz,1H),4.17(d,J＝17.7Hz,1H),3.65(s,3H),2.85-2.97(m,1H),2.57-2.64(m,1H),2.24-2.36(m,1H),2.00-2.07(m,1H).LCMS:398.1([M+1]+).
参照实施例5中化合物的合成方法，用相应的底物替换A340D，就可以合成下列实施例6-7中的化合物。
实施例6化合物A196
3-(4-((2-fluoro-3-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneA196.
Figure PCTCN2015088312-appb-000198
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.21(t,J＝7.8Hz,1H),7.00-7.04(m,2H),6.90-6.95(m,2H),6.62(d,J＝7.8Hz,1H),6.30(t,J＝6.0Hz,1H),5.10(dd,J＝13.2,5.7Hz,1H),4.40(d,J＝6.0Hz,2H),4.28(d,J＝17.4Hz,1H),4.16(d,J＝17.4Hz,1H),3.81(s, 3H),2.85-2.97(m,1H),2.56-2.63(m,1H),2.26-2.32(m,1H),1.99-2.07(m,1H).LCMS:398.1([M+1]+).
实施例7化合物A197
3-(4-((2-fluoro-3-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneA197.
Figure PCTCN2015088312-appb-000199
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.19-7.31(m,2H),6.92(d,J＝7.2Hz,1H),6.80(dd,J＝12.0,2.4Hz,1H),6.71(dd,J＝8.4,2.4Hz,1H),6.65(d,J＝7.8Hz,1H),6.20(t,J＝5.7Hz,1H),5.10(dd,J＝13.2,5.1Hz,1H),4.24-4.33(m,3H),4.14(d,J＝17.1Hz,1H),3.72(s,3H),2.85-2.97(m,1H),2.57-2.62(m,1H),2.21-2.36(m,1H),1.98-2.05(m,1H).LCMS:398.1([M+1]+).
实施例8化合物A318
3-(6-fluoro-4-((2-fluoro-3-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione A318.
合成路线
Figure PCTCN2015088312-appb-000200
实验部分
步骤A：将Pd/C(0.18g,10％,50％wet)加入到I-28A(1.0g,3.3mmol)的DMF溶液(10mL)中，氢气置换三次后于50psi，25℃下反应5小时。过滤,滤液减压浓缩至干，剩余物用PE/EtOAc(5:1,10mL)打浆三次，得绿色固体产品I-28(粗品0.9g)。
1H NMR(DMSO-d6,300MHz):δ10.98(s,1H),6.52-6.61(m,2H),5.77(s,2H),5.07(dd,J＝5.4,13.2Hz,1H),4.17(d,J＝17.1Hz,1H),4.06(d,J＝17.1Hz,1H),2.83-2.95(m,1H), 2.55-2.62(m,1H),2.20-2.34(m,1H),1.97-2.07(m,1H).
步骤B：向化合物I-28和2-氟-3-甲氧基苯甲醛(85mg,0.551mmol)的HOAc(3mL)溶液中加入DCE(15mL)，搅拌1小时。加入NaBH(OAc)3(235mg,1.09mmol)反应18小时后未反应完全，补加NaBH(OAc)3(50mg,0.236mmol后30℃反应8小时。再补加2-氟-3-甲氧基苯甲醛(30mg,0.195mmol)后于40℃反应16小时。蒸干溶剂，Prep-TLC纯化到粗品后用1mL MeOH打浆得类白色固体产品(A318,30mg，收率:20％)。
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.05-7.07(m,2H),6.91-6.94(m,1H),6.61-6.65(m,2H),6.44(dd,J＝1.8,12.9Hz,1H),5.06-5.12(m,1H),4.39(d,J＝5.7Hz,2H),4.26(d,J＝17.1Hz,1H),4.13(d,J＝17.1Hz,1H),3.81(s,3H),2.86-2.90(m,1H),2.57-2.63(m,1H),2.24-2.30(m,1H),2.02-2.06(m,1H).LCMS:416.1([M+1]+).
参照前述实施例8中的合成方法，用相应的底物替换步骤B中的2-氟-3-甲氧基苯甲醛。就可以合成下列实施例9-10中的化合物。
实施例9化合物A319
3-(6-fluoro-4-((2-fluoro-4-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione,A319.
Figure PCTCN2015088312-appb-000201
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.30(t,J＝9.0Hz,1H),6.71-6.84(m,2H),6.55-6.64(m,2H),6.47(dd,J＝2.1,12.6Hz,1H),5.05-5.11(m,1H),4.31(d,J＝5.1Hz,2H),4.24(d,J＝17.4Hz,1H),4.11(d,J＝17.4Hz,1H),3.73(s,3H),2.84-2.96(m,1H),2.57-2.62(m,1H),2.19-2.34(m,1H),2.03-2.06(m,1H).LCMS:416.1([M+1]+).
实施例10化合物A320
3-(6-fluoro-4-((2-fluoro-5-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)-piperidine-2,6-dioneA320.
Figure PCTCN2015088312-appb-000202
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.12(t,J＝9.3Hz,1H),6.81-6.94(m, 2H),6.60-6.66(m,2H),6.48(dd,J＝2.4,12.6Hz,1H),5.06-5.12(m,1H),4.36(d,J＝5.4Hz,2H),4.27(d,J＝17.7Hz,1H),4.14(d,J＝17.7Hz,1H),3.67(s,3H),2.83-2.97(m,1H),2.57-2.62(m,1H),2.20-2.35(m,1H),2.00-2.08(m,1H).LCMS:416.1([M+1]+).
实施例11化合物A327
3-(6-fluoro-4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione,A327.
合成路线
Figure PCTCN2015088312-appb-000203
实验部分
步骤A：将4-(吗啉甲基)苯甲醇1.5g,7.2mmol)溶解于二氯甲烷(20mL)中，降温至0℃，缓慢滴加氯化亚砜(2.6g,21.8mmol)，滴加完毕后，25℃下反应过夜。LCMS检测反应完成。反应液浓缩后，得到类白色固体4-(4-氯甲基)苯基吗啉盐酸盐1.9g粗品)。
1H NMR(DMSO-d6，400M Hz):δ11.70(br s,1H),7.65-7.67(m,2H),7.50-7.52(m,2H),4.79(s,2H),4.32-4.33(m,2H),3.81-3.93(m,4H),3.16-3.19(m,2H),3.02-3.11(m,2H).
步骤B：5-氟-2-甲基-3-硝基-苯甲酸甲酯(2.0g,9.4mmol)和Pd/C(10％，200mg，50％water)溶于MeOH(20mL)中，50Psi氢气下温室搅拌过夜。TLC和LCMS检测反应完成。反应液抽滤，固体用甲醇洗涤(50mL×1),滤液浓缩，得到无色液体3-氨基-5-氟-2-甲基-苯甲酸甲酯(1.3g粗品)。
1H NMR(DMSO-d6，300M Hz):δ6.57-6.60(m,1H),5.44(s,2H),3.77(s,3H),2.11(s,3H).
步骤C：3-氨基-5-氟-2-甲基-苯甲酸甲酯(1.3g crude)和10％H2SO4(43g,42.6mmol)溶解在MeOH(20mL)中，0℃氮气下反应下滴加亚硝酸钠(750mg,10.87mmol)溶液，滴 加完毕后，在此温度下反应1小时。加入50％H2SO4(42.6g,213mmol)溶液，100℃下反应1小时。TLC检测反应完成。反应液浓缩，浓缩液用水(20mL)和EtOAc(100mL)摇匀分液，水相用EtOAc萃取(100mL×3)，合并有机相，无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化(PE:EtOAc＝5:1)得到淡黄色固体5-氟-3-羟基-2-甲基-苯甲酸甲酯(660mg,两步收率：38％)。
1H NMR(DMSO-d6,400MHz):δ10.25(s,1H),6.93-6.96(m,1H),6.78-6.82(m,1H),3.81(s,3H),2.23(s,3H).
步骤D：5-氟-3-羟基-2-甲基-苯甲酸甲酯(1.2g,6.5mmol)和咪唑(1.33g,19.5mmol)溶解在DCM(20mL)中，然后在氮气保护下0℃分批加入TBDMSCl(1.96g,13mmol)，加入完毕后搅拌10分钟，升至25℃搅拌2小时。TLC检测反应完成。反应液加入水(50mL)洗一次，水相用DCM萃取(150mL×3)，合并有机相，无水硫酸钠干燥浓缩，硅胶柱层析纯化(PE:EtOAc＝20:1～10:1)，得到淡黄色油状物3-(叔丁基-二甲基-硅氧基)-5-氟-2-甲基-苯甲酸甲酯(1.4g,收率：72％)。
1H NMR(DMSO-d6,400MHz):δ7.12-7.15(m,1H),6.84-6.87(m,1H),3.82(s,3H),2.26(s,3H),0.98(s,9H),0.23(s,6H).
步骤E：将3-(叔丁基-二甲基-硅氧基)-5-氟-2-甲基-苯甲酸甲酯(1.4g,4.7mmol)和NBS(1.0g,5.6mmol)溶解在CCl4(20mL)中，然后加入过氧化苯甲酰(0.12g,0.5mmol)，氮气下80℃反应过夜。TLC检测反应完成。反应液抽滤，固体用DCM(50mL)洗涤后，滤液水(50mL)洗涤，水相用DCM萃取(100mL×3)，合并有机相，干燥、浓缩，硅胶柱层析纯化(PE:EtOAc＝100:1)，得到白色固体2-溴甲基-3-(叔丁基-二甲基-硅氧基)-5-氟-苯甲酸甲酯(1.4g，纯度：90％)。
1H NMR(DMSO-d6,400MHz):δ7.28-7.31(m,1H),7.00-7.03(m,1H),4.93(s,2H),3.91(s,3H),1.07(s,9H),0.36(s,6H).
步骤F：2-溴甲基-3-(叔丁基-二甲基-硅氧基)-5-氟-苯甲酸甲酯(500mg,1.33mmol)和异谷酰胺叔丁酯盐酸盐(349mg,1.46mmol)和三乙胺(405mg,4.0mmol)溶解在CH3CN(10mL)中，氮气保护下80℃下反应过夜。TLC检测反应完成。反应液浓缩后，溶于THF(10mL)中，然后滴加TBAF(4mL,1M in THF)，混合物室温搅拌0.5小时，TLC检测反应完成。反应液浓缩，硅胶柱层析纯化(PE:EtOAc＝5:1～1:1～EA)，得到淡黄色固体A327A(200mg,3步收率：34％)。
1H NMR(MeOD,400MHz):δ6.95-6.98(m,1H),6.72-6.76(m,1H),4.90-4.94(m,1H),4.54(d,J＝17.6Hz,1H),4.42(d,J＝17.6Hz,1H),2.25-2.30(m,3H),2.16-2.21(m,1H),1.39 (s,9H).
步骤G：将A327A(200mg,0.57mmol)和4-(4-(chloromethyl)benzyl)morpholine hydrochloride(445mg,粗品)溶于干燥的DMF(10mL)中，室温氮气下加入K2CO3(393mg,2.90mmol)。加入完毕后，室温搅拌，反应过夜。LCMS检测反应未完，补加4-(4-Chloromethyl-benzyl)-morpholine(445mg,粗品)，继续反应6小时。反应液浓缩后，加入水(10mL)和EtOAc(30mL)摇匀分液，水相用EtOAc萃取(10mL×3)，合并有机相，干燥、浓缩，硅胶柱层析纯化(PE:EtOAc＝5:1～1:1～EtOAc)，得到白色固体A327B(250mg,收率:81％)。
1H NMR(DMSO-d6,400MHz):δ7.57(s,1H),7.44-7.46(m,2H),7.34-7.36(m,2H),7.19-7.27(m,2H),7.06-7.08(m,1H),5.23(s,2H),4.68-4.72(m,1H),4.50(d,J＝17.6Hz,1H),4.39(d,J＝17.6Hz,1H),3.56-3.58(m,4H),3.47(s,2H),2.30-2.38(m,4H),2.13-2.17(m,3H),2.00-2.05(m,1H),1.32(s,9H).
步骤H：将A327B(250mg,0.46mmol)溶解在干燥的DCM(10mL)中，0℃氮气下加入TFA(4mL)，加入完毕后，混合物搅拌4小时。TLC检测反应完成。反应液浓缩后，得到淡黄色固体A327C(230mg粗品)。
步骤I：将A327C(230mg crude)溶解在CH3CN(15mL)中，室温氮气下加入CDI(115mg,0.71mmol),加入完毕后，混合物95℃下反应过夜。LCMS检测反应完成。反应液浓缩后,Prep-HPLC纯化得到黄色固体A327(24mg,两步收率:11％)。
1H NMR(DMSO-d6,400MHz):δ10.98(s,1H),7.43-7.45(m,2H),7.28-7.35(m,3H),7.11-7.13(m,1H),5.23(s,2H),5.08-5.13(m,1H),4.39(d,J＝17.2Hz,1H),4.23(d,J＝17.2Hz,1H),3.55-3.58(m,4H),3.47(s,2H),2.87-2.91(m,1H),2.54-2.59(m,1H),2.42-2.45(m,1H),2.35-2.41(m,4H),1.97-1.99(m,1H).LCMS:468.2([M+1]+).
实施例12化合物A329
3-(4-((2-fluoro-4-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A329.
合成路线
Figure PCTCN2015088312-appb-000204
步骤A：将2-氟-4-甲氧基苯甲醛(1.0g,6.49mmol)溶于MeOH(10mL)中，加入NaBH4 (370mg,9.74mmol)，室温搅拌反应1h，TLC显示反应完成。加入1N HCl淬灭反应和调pH(4-5)，加入DCM(50mL)和水(40mL)，水相用DCM萃取(50mL×2)，合并的有机相用食盐水洗一次(50mL)，无水硫酸钠干燥，过滤，母液减压浓缩，得淡黄色油状产品2-氟-4-甲氧基苯甲醇(910mg,收率：90％)，无需纯化直接用于下一步。
1H NMR(DMSO-d6,300MHz):δ7.31(t,J＝8.4Hz,1H),6.72-6.76(m,2H),5.08(t,J＝5.7Hz,1H),4.43(d,J＝5.7Hz,2H),3.73(m,3H).
步骤B：将2-氟-4-甲氧基苯甲醇(400mg,2.56mmol)溶于干燥的DCM(10mL)中，加入SOCl2(458mg,3.85mmol)，室温搅拌反应3h。LCMS显示反应完成。反应液直接减压浓缩，得淡黄色油状物2-氟-4-甲氧基苄氯(450mg)，无需纯化直接用于下一步。
1H NMR(DMSO-d6,300MHz):δ7.42(t,J＝8.7Hz,1H),6.85(dd,J＝12.0,2.7Hz,1H),6.77(dd,J＝11.4,2.7Hz,1H),4.72(s,2H),3.76(s,3H).
步骤C：将化合物A329B(200mg,0.68mmol)溶于DMF(15mL)中，加入K2CO3(283mg,2.05mmol)和2-氟-4-甲氧基苄氯(239mg,1.37mmol),室温搅拌反应过夜。LCMS显示反应有原料剩余，加入2-氟-4-甲氧基苄氯(100mg,0.57mmol)，继续搅拌反应3小时。LCMS显示反应完全。减压浓缩掉溶剂，加入EtOAc(50mL)和水(30mL)溶解分层，水相用EtOAc萃取(50mL×2)，合并的有机相用食盐水洗一次(50mL),无水硫酸钠干燥，过滤，母液减压浓缩得剩余物，剩余物用制备TLC纯化(MeOH/DCM＝1/20)得白色固体产物A329A(190mg,收率：65％)。
1H NMR(DMSO-d6,300MHz):δ7.57(br s,1H),7.45-7.54(m,2H),7.36(d,J＝8.1Hz,1H),7.30(d,J＝7.5Hz,1H),7.17(br s,1H),6.87-6.92(m,1H),6.81-6.85(m,1H),5.19(s,2H),4.69-4.74(m,1H).4.47(d,J＝17.7Hz,1H),4.33(d,J＝17.7Hz,1H),3.79(s,3H),3.50(s,3H),2.13-2.27(m,3H),2.00-2.10(m,1H),
步骤D：将A329A(190mg,0.44mmol)溶解于DMF(10mL)中,后向反应瓶中加入K2CO3(183mg,1.33mmol)，氮气保护加热至80℃搅拌反应过夜。LCMS显示反应完成。反应液减压抽滤，母液减压浓缩，剩余物制备HPLC纯化冻干得白色固体产物A329(120mg,收率：68％)。
1H NMR(DMSO-d6,300MHz):δ10.79(br s,1H),7.48-7.54(m,2H),7.33-7.41(m,2H),6.89(dd,J＝12.3,2.4Hz,1H),6.81(dd,J＝8.4,2.4Hz,1H),5.19(s,2H),5.08-5.13(m,1H),4.35(d,J＝17.7Hz,1H),4.18(d,J＝17.7Hz,1H),3.78(s,3H),2.84-2.94(m,1H),2.57-2.61(m,1H),2.38-2.46(m,1H),1.92-2.00(m,1H).
LCMS:399.1([M+1]+).
参照前述实施例12中的合成方法，用相应的底物替换步骤A中的2-氟-4-甲氧基苯甲醛。就可以合成下列实施例13-14中的化合物。
实施例13化合物A331
3-(4-((2-fluoro-5-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A331.
Figure PCTCN2015088312-appb-000205
1H NMR(DMSO-d6,300MHz):δ10.65(br s,1H),7.51(t,J＝7.8Hz,1H),7.34-7.40(m,2H),7.13-7.23(m,2H),6.93-6.99(m,1H),5.25(s,2H),5.10(dd,J＝10.2,5.1Hz,1H),4.39(d,J＝17.7Hz,1H),4.23(d,J＝17.7Hz,1H),3.74(s,3H),2.84-2.96(m,1H),2.54-2.60(m,1H),2.39-2.47(m,1H),1.93-2.00(m,1H).LCMS:399.1([M+1]+).
实施例14化合物A334
3-(4-((2-fluoro-3-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A334.
Figure PCTCN2015088312-appb-000206
1H NMR(DMSO-d6，400MHz):10.96(s,1H),7.50(t,J＝7.6Hz,1H),7.34-7.38(m,2H),7.13-7.20(m,3H),5.28(s,2H),5.10(dd,J＝12.8,4.4Hz,1H),4.38(d,J＝17.6Hz,1H),4.22(d,J＝17.6Hz,1H),3.85(s,3H),2.87-2.90(m,1H),2.50-2.58(m,1H),2.40-2.43(m,1H),1.95-1.98(m,1H).LCMS:399.1([M+1]+).
实施例15化合物A336
3-[4-(2-Fluoro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione,A336.
Figure PCTCN2015088312-appb-000207
1H NMR(DMSO-d6，400MHz):10.92(s,1H),6.53-6.63(m,1H),7.50(t,J＝8.0Hz,1H),7.40-7.47(m,2H),7.36(t,J＝8.0Hz,1H),7.23-7.29(m,2H),5.30(s,2H),5.11(dd,J＝12.8, 5.2Hz,1H),4.38(d,J＝17.6Hz,1H),4.23(d,J＝17.6Hz,1H),2.86-2.95(m,1H),2.54-2.59(m,1H),2.38-2.47(m,1H),1.97-2.00(m,1H).LCMS:369.1([M+1]+).
实施例16化合物A340
(S)-3-(4-((2-fluoro-5-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A340.
合成路线
Figure PCTCN2015088312-appb-000208
实验部分
步骤A：氮气保护下将(S)-异谷酰胺叔丁酯盐酸盐(1.91g,8.00mmol)加入到2-溴甲基-3-硝基苯甲酸甲酯(2.00g,7.30mmol)的CH3CN溶液中(40mL)，然后加入Et3N(1.63g,16.1mmol)，反应混合物加热至75℃搅拌反应过夜。TLC显示反应完成。反应液减压浓缩，剩余物溶解在EtOAc(50mL)和水(50mL)中，分层，水相用EtOAc萃取(50mLx2)，合并有机相，食盐水洗一次(50mL)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物用石油醚和EtOAc的混合溶液(4/1，v/v)打浆，过滤得白色固体产物A340A(2.2g,收率：83％)。
1H NMR(DMSO-d6,300MHz):δ8.45(dd,J＝0.9,8.1Hz,1H),8.16(dd,J＝0.9,8.1Hz,1H),7.82(t,J＝8.1Hz,1H),7.65(br s,1H),7.27(br s,1H),5.05(d,J＝19.5Hz,1H),4.90(d,J＝19.5Hz,1H),4.75-4.80(m,1H),2.14-2.27(m,3H),2.00-2.10(m,1H),1.33(s,9H).
步骤B：将A340A(1.20g,3.30mmol)溶解在甲醇中，后加入Pd/C(10％，200mg，50％water)，氢气换气三次，50Psi氢气压力下25℃氢化反应过夜。LCMS显示反应完成。反应液减压抽滤掉Pd/C，滤液减压浓缩至干。得淡黄色固体产物A340B(1.19g,粗品)直接用于下一步。
1H NMR(DMSO-d6,300MHz):δ7.50(br s,1H),7.11-7.16(m,2H),6.85(d,J＝7.2Hz,1H),6.74(d,J＝7.2Hz,1H),5.41(br s,2H),4.68-4.73(m,1H),4.38(d,J＝17.7Hz,1H),4.16 (d,J＝17.7Hz,1H),2.09-2.19(m,3H),1.92-2.01(m,1H),1.32(s,9H).
步骤C：将A340B(1.00g,粗品)和2-氟-5-甲氧基苯甲醛(601mg,3.90mmol)溶解于甲醇中,后向反应瓶中加入HOAc(0.5mL)，25℃搅拌3小时。加入Pd/C(10％，100mg，50％water)，氢气换气三次，25℃氢化(氢气球)反应过夜。LCMS显示反应完全。减压抽滤除掉Pd/C，滤液减压浓缩，剩余物用硅胶柱纯化(石油醚/EtOAc＝1/4)得淡黄色固体A340C(1.15g，两步收率：88％)。
1H NMR(DMSO-d6,300MHz):δ7.56(br s,1H),7.09-7.24(m,3H),6.91-6.96(m,2H),6.80-6.85(m,1H),6.63(d,J＝8.4Hz,1H),6.34-6.38(m,1H),4.74(dd,J＝10.2,4.5Hz,1H),4.50(d,J＝18.0Hz,1H),4.37(d,J＝6.0Hz,2H),4.28(d,J＝18.0Hz,1H),3.67(s,3H),2.12-2.21(m,3H),1.91-2.02(m,1H),1.33(s,9H).
步骤D：将A340C(1.15g,2.44mmol)溶解于DCM(20mL)中，冷却至0℃，后向反应瓶中滴加TFA(4mL)，慢慢升至25℃搅拌反应过夜。反应液减压浓缩，剩余物用C18柱层析纯化(40％乙腈的水溶液)，冷冻干燥得淡黄色固体A340D(800mg,收率:79％)。
1H NMR(DMSO-d6,400MHz):δ12.14(br s,1H),7.57(br s,1H),7.10-7.23(m,3H),6.91-6.96(m,2H),6.81-6.85(m,1H),6.63(d,J＝8.0Hz,1H),6.35(t,J＝6.0Hz,1H),4.72-4.76(m,1H),4.51(d,J＝17.6Hz,1H),4.37(d,J＝5.6Hz,2H),4.31(d,J＝17.6Hz,1H),3.67(s,3H),2.18-2.23(m,3H),1.96-2.02(m,1H).
步骤E：将A340D(700mg,1.69mmol)溶于干燥的DCM(70mL)中，氮气保护下冷至-40℃，缓慢滴加SOCl2(1.00g,8.40mmol)，滴加完毕后，加入DMF(10mg)的DCM(1mL)溶液加毕搅拌反应2h，滴加吡啶(666mg,8.42mmol)维持此温度搅拌40分钟，加入Et3N(852mg,8.42mmol)，加毕，继续反应2h。LCMS显示反应完成。加入H2O(10mL)淬灭反应，水相用DCM萃取(20mL×2)，食盐水洗(50mL×1)，无水硫酸钠干燥，过滤，减压浓缩至干，剩余物经Prep-HPLC得到浅绿色固体A340(460mg,收率:68％,ee:98％)。
1H NMR(DMSO-d6,300MHz):δ11.00(br s,1H),7.23(t,J＝7.8Hz,1H),7.11(t,J＝9.6Hz,1H),6.90-6.95(m,2H),6.78-6.84(m,1H),6.65(d,J＝8.1Hz,1H),6.26(t,J＝6.0Hz,1H),5.10(dd,J＝13.2,5.1Hz,1H),4.37(d,J＝6.0Hz,2H),4.30(d,J＝17.1Hz,1H),4.17(d,J＝17.1Hz,1H),3.65(s,3H),2.85-2.96(m,1H),2.56-2.63(m,1H),2.24-2.37(m,1H),2.00-2.07(m,1H).LCMS:398.1([M+1]+).
实施例17化合物A341
(R)-3-(4-((2-fluoro-5-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A341.
合成路线
Figure PCTCN2015088312-appb-000209
实验部分
步骤A：将2-溴甲基-3-硝基苯甲酸甲酯(1.00g,3.65mmol)溶解于CH3CN(50mL)中，后向反应瓶中加入(R)-异谷酰胺叔丁酯盐酸盐(955mg,4.00mmol)和Et3N(815mg,8.05mmol)，氮气保护，加热至75℃搅拌反应过夜。TLC显示反应完成。反应液减压浓缩，剩余物溶解在EtOAc(50mL)和水(50mL)中，分层，水相用EtOAc萃取(50mL×2)，合并有机相，食盐水洗一次(50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物用硅胶柱纯化(石油醚/EtOAc＝1/4)得白色固体A341A(800mg,收率：60％)。
1H NMR(DMSO-d6,300MHz):δ8.45(d,J＝6.0Hz,1H),8.16(d,J＝5.4Hz,1H),7.82(t,J＝6.0Hz,1H),7.64(br s,1H),7.27(br s,1H),5.05(d,J＝14.4Hz,1H),4.91(d,J＝14.4Hz,1H),4.76-4.80(m,1H),2.15-2.25(m,3H),2.02-2.11(m,1H),1.33(s,9H).
步骤B：将A341A(800mg,2.20mmol)溶解在甲醇中，后加入Pd/C(10％，80mg，50％water)，50Psi氢气压力下25℃氢化反应过夜。LCMS显示反应完成。反应液减压抽滤掉Pd/C，滤液减压浓缩至干，得淡黄色固体A341C(680mg,收率：93％)，直接用于下一步。
1H NMR(DMSO-d6,300MHz):δ7.54(br s,1H),7.13-7.18(m,2H),6.88(d,J＝7.2Hz,1H),6.76(d,J＝7.8Hz,1H),5.44(br s,2H),4.70-4.75(m,1H),4.41(d,J＝17.7Hz,1H),4.18(d,J＝17.7Hz,1H),2.09-2.21(m,3H),1.92-2.06(m,1H),1.34(s,9H).
步骤C：将A341C(680mg,2.04mmol)和2-氟-5-甲氧基苯甲醛(472mg,3.06mmol)溶解于MeOH中，后向反应瓶中加入HOAc(0.5mL)，25℃搅拌3小时。加入Pd/C(10％，50mg，50％water)，氢气换气三次，25℃氢化反应过夜(气球)。LCMS显示反应完全， 减压抽滤掉Pd/C，滤液减压浓缩，剩余物用硅胶柱纯化(石油醚/EtOAc＝1/4)，得淡黄色固体A341E(650mg,收率：68％)。
1H NMR(DMSO-d6,400MHz):δ7.56(br s,1H),7.18-7.23(m,2H),7.12(t,J＝9.2Hz,1H),6.91-6.95(m,2H),6.81-6.85(m,1H),6.63(d,J＝8.0Hz,1H),6.36(t,J＝5.6Hz,1H),4.72-4.76(m,1H),4.50(d,J＝17.6Hz,1H),4.37(d,J＝6.0Hz,2H),4.29(d,J＝17.6Hz,1H),3.67(s,3H),2.14-2.22(m,3H),1.94-2.04(m,1H),1.33(s,9H).
步骤D：将A341E(650mg,1.38mmol)溶解于DCM(20mL)中，冷却至0℃，后向反应瓶中滴加TFA(4mL)，慢慢升至25℃搅拌反应过夜。反应液减压浓缩，剩余物用C18柱层析纯化(40％乙腈的水溶液)冷冻干燥得淡黄色固体A341G(450mg,收率：79％)。
1H NMR(DMSO-d6,300MHz):δ7.56(br s,1H),7.07-7.22(m,3H),6.89-6.94(m,2H),6.78-6.83(m,1H),6.61(d,J＝7.8Hz,1H),6.34(t,J＝6.3Hz,1H),4.69-4.73(m,1H),4.50(d,J＝17.7Hz,1H),4.35(d,J＝5.7Hz,2H),4.29(d,J＝17.7Hz,1H),3.65(s,3H),2.12-2.19(m,3H),1.93-1.98(m,1H).
步骤E：将A341G(450mg,1.08mmol)溶于干燥的DCM(50mL)中，氮气保护下冷至-40℃，缓慢滴加SOCl2(644mg,5.41mmol)，毕，加入DMF(10mg)的DCM(1mL)溶液加毕搅拌反应2h，滴加吡啶(428mg,5.41mmol)维持此温度搅拌40分钟，加入Et3N(547mg,5.41mmol)，加毕，继续反应2h，LCMS显示反应完成。加入H2O(10mL)淬灭反应，水相用DCM萃取(30mL×2)，食盐水洗(50mL×1)，无水硫酸钠干燥，过滤，减压浓缩至干，剩余物经Prep-HPLC得到浅绿色固体A341(260mg,收率:61％,ee:96％)。
1H NMR(DMSO-d6,300MHz):δ10.98(br s,1H),7.23(t,J＝7.8Hz,1H),7.11(t,J＝9.3Hz,1H),6.90-6.95(m,2H),6.78-6.84(m,1H),6.65(d,J＝8.1Hz,1H),6.26(t,J＝6.0Hz,1H),5.10(dd,J＝13.2,5.1Hz,1H),4.36(d,J＝5.7Hz,2H),4.30(d,J＝17.1Hz,1H),4.17(d,J＝17.1Hz,1H),3.65(s,3H),2.85-2.97(m,1H),2.56-2.63(m,1H),2.22-2.35(m,1H),2.00-2.07(m,1H).LCMS:398.1([M+1]+).
实施例18化合物A342
(R)-3-deuterium-3-(4-((2-fluoro-5-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A342.
合成路线
Figure PCTCN2015088312-appb-000210
实验部分：
步骤A.将A343F(31.7g,115.5mmol)悬浊于CH3CN(560mL)中，后向反应瓶中加入A343G(31.5g,115.5mmol)和Et3N(23.3g,231.0mmol)，氮气保护，加热至75℃搅拌反应过夜。反应液减压浓缩，剩余物溶解在EtOAc(50mL)和4M HCl水溶液(150mL)中搅拌，过滤，滤饼水洗(30mL)。滤液用EtOAc萃取(250mL×2)，合并有机相，食盐水洗(30mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，合并所得两批固体用CH3CN(40mL×2)打浆，过滤得白色固体A343E(37g,收率：81％)。通过手性拆分得到类白色固体Peak 1A343E(S)(14.4g,yield(收率):77.8％,Rt＝7.30min,100％ee)and Peak 2A342E(R)(14.8g,yield:80％,Rt＝11.87min,100％ee)
手性拆分制备条件：手性柱：CHIRALPAK IE，柱子粒径：10μm,柱子型号：50×250mm；检测波长：254nm；流动相：MeOH/DCM＝80/20(V/V)；进样量：48mL；流速：60mL/min；柱温：35℃；溶剂：流动相17.1mg/mL。
A343E(S):1H NMR(DMSO-d6,300MHz):δ8.43(d,J＝8.1Hz,1H),8.13(d,J＝7.5Hz,1H),7.79(t,J＝8.1Hz,1H),7.66(br s,1H),7.26-7.35(m,6H),4.86-5.07(m,4H),2.42-2.21-2.43(m,3H),2.06-2.16(m,1H).
A342E(R):1H NMR(DMSO-d6,300MHz):δ8.43(d,J＝8.4Hz,1H),8.13(d,J＝7.2Hz,1H),7.77-7.82(m,1H),7.65(br s,1H),7.35-7.23-7.35(m,6H),4.86-5.07(m,4H),2.20-2.42(m,3H),2.06-2.15(m,1H).
步骤B.将A342E(R)(2.5g,6.3mmol)溶解在MeOH(150mL)/THF(150mL)中，后加入Pd/C(10％，500mg，50％water)，氢气换气三次，50Psi氢气压力下25℃氢化反应过 夜。LCMS显示反应完成。反应液减压抽滤掉Pd/C，滤液减压浓缩至干。加入CH3CN/DCE(50mL/150mL)减压浓缩至干，再用THF(300mL)溶解减压浓缩至干，除去残余的甲醇得白色固体A342C(1.68g,收率：97％)直接用于下一步。
1H NMR(DMSO-d6,300MHz):δ12.11(br s,1H),7.54(s,1H),7.11-7.16(m,2H),6.85(d,J＝7.8Hz,1H),6.74(d,J＝7.8Hz,1H),5.43(br s,2H),4.68-4.73(m,0.02H),4.41(d,J＝17.4Hz,1H),4.17(d,J＝17.4Hz,1H),2.10-2.18(m,3H),1.94-1.97(m,1H).
步骤C：将A342C和2-氟-5-甲氧基苯甲醛(831mg,5.39mmol)溶解于MeOH中，后向反应瓶中加入HOAc(0.5mL)，25℃搅拌20小时。加入Pd/C(10％，100mg，50％water)，氢气换气三次，25℃氢化反应过夜(氢气球)。LCMS显示反应完全。减压抽滤掉Pd/C，滤液减压浓缩，剩余物用C18柱层析纯化(CH3CN:H2O＝5％-35％,30min；35％-45％,30min；45％-55％20min)冷冻干燥得淡黄色固体A342A(800mg,收率：53％)。
1H NMR(DMSO-d6,300MHz):δ12.10(br s,1H),7.56(br s,1H),7.07-7.22(m,3H),6.89-6.94(m,2H),6.78-6.83(m,1H),6.61(d,J＝8.1Hz,1H),6.34(t,J＝6.0Hz,1H),4.70-4.74(m,0.03H),4.50(d,J＝17.7Hz,1H),4.35(d,J＝5.7Hz,2H),4.28(d,J＝17.7Hz,1H),3.65(s,3H),2.10-2.21(m,3H),1.92-2.02(m,1H).
步骤D.将A342A(450mg,1.10mmol)溶于干燥的DCM(50mL)中，氮气保护下冷至-40℃，缓慢滴加SOCl2(572mg,4.81mmol)，毕，加入DMF(10mg)的DCM(1mL)溶液加毕，搅拌反应2hr，滴加吡啶(380mg,4.80mmol)维持此温度搅拌40分钟，加入Et3N(486mg,4.80mmol)，加毕，继续反应2h，LCMS显示反应完成。加入H2O(10mL)淬灭反应，水相用DCM萃取(30mL×2)，食盐水洗(50mL×1)，无水硫酸钠干燥，过滤，减压浓缩至干，剩余物经C18柱(CH3CN:H2O＝5％-35％,30min；35％-45％,30min；45％-55％20min)纯化得到淡黄色固体A342(220mg,收率:58％,ee:99％)。
1H NMR(DMSO-d6,300MHz):δ11.00(br s,1H),7.23(t,J＝7.8Hz,,1H),7.11(t,J＝9.6Hz,,1H),6.90-6.95(m,2H),6.79-6.84(m,1H),6.65(d,J＝7.8Hz,1H),6.26(t,J＝5.4Hz,1H),5.07-5.14(m,0.01H),4.36(d,J＝5.7Hz,2H),4.30(d,J＝17.1Hz,1H),4.17(d,J＝17.1Hz,1H),3.65(s,3H),2.85-2.97(m,1H),2.57-2.63(m,1H),2.24-2.34(m,1H),2.00-2.06(m,1H).LCMS:399.1([M+1]+).
参照前述实施例18中的合成方法，用相应的底物替换步骤B中的A342E(R)。就可以合成下列实施例19中的化合物。
实施例19化合物A343
(S)-3-deuterium-3-(4-((2-fluoro-5-methoxybenzyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione,A343.
Figure PCTCN2015088312-appb-000211
1H NMR(DMSO-d6,300MHz):δ11.00(br s,1H),7.23(t,J＝8.1Hz,,1H),7.11(t,J＝9.6Hz,1H),6.90-6.95(m,2H),6.78-6.84(m,1H),6.65(d,J＝8.1Hz,1H),6.26(t,J＝6.3Hz,1H),5.07-5.13(m,0.02H),4.36(d,J＝5.7Hz,2H),4.29(d,J＝17.1Hz,1H),4.17(d,J＝17.1Hz,1H),3.65(s,3H),2.85-2.97(m,1H),2.56-2.64(m,1H),2.24-2.34(m,1H),2.00-2.05(m,1H).LCMS:399.1([M+1]+).
实施例20化合物A346
(S)-3-(4-((4-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A346.
合成路线
Figure PCTCN2015088312-appb-000212
实验部分
30℃下将A346A(119mg,0.58mmol)和A308A(100mg,0.39mmol)溶解于醋酸(2.5mL)和二氯甲烷(2.5mL)的混合溶液中搅拌1小时，加入NaBH(OAc)3(246mg,1.16mmol)，氮气保护下搅拌18小时。TLC显示反应完成。反应液减压浓缩至干加入饱和碳酸氢钠水溶液(5mL)调pH至8，加入DCM萃取(25mL×5)，有机相无水Na2SO4干燥，过滤，滤液减压浓缩，剩余物用石油醚和乙酸乙酯的混合溶液(1/1)(25mL×2)打浆得250mg粗品，用Prep-HPLC制备得白色固体产物A346(140mg,收率：80％)。
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),.7.16-7.33(m,5H),6.90(d,J＝7.2Hz,1H),6.62(d,J＝7.8Hz,1H),6.33(t,J＝5.7Hz,1H),5.07-5.13(m,1H),4.35(d,J＝5.4Hz,2H),4.29(d,J＝17.1Hz,1H),4.16(d,J＝17.1Hz,1H),3.53(t,J＝4.5Hz,4H),3.39(s,2H),2.85-2.93(m,1H),2.58-2.63(m,1H),2.28-2.31(m,5H),2.01-2.06(m,1H).LCMS:449.2([M+1]+).
参照前述实施例20中的合成方法，用相应的底物替换实施例20中的A346A。就可 以合成下列实施例21-45中的化合物
实施例21化合物A359
3-(4-((2-fluoro-3-hydroxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A359.
Figure PCTCN2015088312-appb-000213
1H NMR(DMSO-d6,300MHz):δ10.96(br,1H),9.79(br,1H),7.21(t,J＝7.8Hz,1H),6.73-6.93(m,4H),6.63(d,J＝7.8Hz,1H),6.25(t,J＝6.0Hz,1H),5.10(dd,J＝13.2,5.1Hz,1H),4.37(d,J＝5.7Hz,2H),4.28(d,J＝17.4Hz,1H),4.15(d,J＝17.4Hz,1H),2.85-2.97(m,1H),2.57-2.63(m,1H),2.22-2.36(m,1H),2.01-2.05(m,1H).LCMS:384.1([M+1]+).
实施例22化合物A360
3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-2-fluorobenzonitrile,A360.
Figure PCTCN2015088312-appb-000214
1H NMR(300MHz,DMSO-d6):δ11.03(s,1H),7.81-7.86(m,1H),7.71-7.76(m,1H),7.36(t,J＝7.8Hz,1H),7.25(t,J＝7.8Hz,1H),6.97(d,J＝7.5Hz,1H),6.66(d,J＝7.8Hz,1H),6.41(t,J＝5.7Hz,1H),5.13,(dd,J＝12.9,5.1Hz,1H),4.50(d,J＝5.7Hz,1H),4.32(d,J＝17.1Hz,1H),4.19(d,J＝17.1Hz,1H),2.87-2.95(m 1H),2.50-2.65(m 1H),2.29-2.34(m1H),2.02-2.07(m 1H).
实施例23化合物A361
3-(((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-2-fluorobenzamide,A361.
Figure PCTCN2015088312-appb-000215
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.75(s,1H),7.63(s,1H),7.45-7.53(m,2H),7.16-7.27(m,2H),6.96(d,J＝7.2Hz,1H),6.64(d,J＝8.1Hz,1H),6.35-6.38(m,1H),5.13(dd,J＝13.2,4.8Hz,1H),4.46(d,J＝5.4Hz,2H),4.33(d,J＝17.4Hz,1H),4.20(d,J＝ 17.4Hz,1H),2.87-2.98(m,1H),2.60-2.65(m,1H),2.25-2.39(m,1H),2.03-2.07(m,1H).LCMS:411.1([M+1]+).
实施例24化合物A362
3-(((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-2-fluoro-N-methylbenzamide,A362.
Figure PCTCN2015088312-appb-000216
1H NMR(DMSO-d6,300MHz):δ11.01(s,1H),8.28(d,J＝3.3Hz,1H),7.46(t,J＝7.2Hz,2H),7.15-7.26(m,2H),6.95(d,J＝7.5Hz,1H),6.63(d,J＝8.4Hz,1H),6.37(t,J＝5.7Hz,1H),5.12(dd,J＝13.5,4.8Hz,1H),4.45(d,J＝5.1Hz,2H),4.32(d,J＝17.4Hz,1H),4.20(d,J＝17.4Hz,1H),2.87-2.99(m,1H),2.78(d,J＝4.8Hz,3H),2.60-2.65(m,1H),2.25-2.39(m,1H),1.99-2.11(m,1H).LCMS:425.1([M+1]+)
实施例25化合物A363
3-(4-((5-(2-(Dimethylamino)ethoxy)-2-fluorobenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A363.
Figure PCTCN2015088312-appb-000217
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.24(t,J＝8.1Hz,1H),7.11(t,J＝9.3Hz,1H),6.90-6.96(m,2H),6.80-6.86(m,1H),6.65(d,J＝8.4Hz,1H),6.29(t,J＝6.0Hz,1H),5.12(dd,J＝13.2,4.8Hz,1H),4.29-4.39(m,3H),4.19(d,J＝17.1Hz,1H),3.94(t,J＝5.7Hz,2H),2.87-2.99(m,1H),2.51-2.65(m,3H),2.24-2.38(m,1H),2.15(s,6H),2.00-2.10(m,1H).LCMS:455.2([M+1]+).
实施例26化合物A364
3-(4-((2-fluoro-5-hydroxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A364.
Figure PCTCN2015088312-appb-000218
1H NMR(300MHz,DMSO-d6):δ11.01(s,1H),9.24(s,1H),7.22(t,J＝7.8Hz,1H),6.92- 6.99(m,2H),6.70-6.73(m,1H),6.55-6.60(m,2H),6.31(t,J＝5.7Hz,1H),5.11,(dd,J＝13.2,5.1Hz,1H),4.27-4.34(m,3H),4.17(d,J＝17.1Hz,1H),2.86-2.96(m 1H),2.57-2.64(m 1H),2.24-2.33(m 1H),2.02-2.06(m 1H).
实施例27化合物A367
3-(4-((2-fluoro-3-methylbenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A367.
Figure PCTCN2015088312-appb-000219
1H NMR(DMSO-d6,300MHz):δ11.03(s,1H),7.14-7.26(m,3H),6.93-7.04(m,2H),6.64(d,J＝7.5Hz,1H),6.30(br s,1H),5.09-5.16(m,1H),4.42(s,2H),4.31(d,J＝17.4Hz,1H),4.18(d,J＝17.4Hz,1H),2.89-2.98(m,1H),2.59-2.65(m,1H),2.25-2.46(m,4H),2.02-2.07(m,1H).LCMS:382.2([M+1]+).
实施例28化合物A368
3-(4-((2-fluoro-5-(2-morpholinoethoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A368.
Figure PCTCN2015088312-appb-000220
1H NMR(DMSO-d6,300MHz):δ10.98(s,1H),7.23(t,J＝7.5Hz,1H),7.09(t,J＝9.6Hz,1H),6.79-6.95(m,3H),6.64(d,J＝7.5Hz,1H),6.24(br,1H),5.10(dd,J＝13.2,5.1Hz,1H),4.36(d,J＝5.7Hz,2H),4.30(d,J＝17.1Hz,1H),4.18(d,J＝17.1Hz,1H),3.97(t,J＝5.7Hz,2H),3.51(t,J＝4.5Hz,4H),2.85-2.97(m,1H),2.56-2.63(m,3H),2.27-2.39(m,5H),2.00-2.05(m,1H).LCMS:497.2([M+1]+).
实施例29化合物A369
3-(4-((2-fluoro-5-(3-morpholinopropoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A369.
Figure PCTCN2015088312-appb-000221
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.22(t,J＝7.8Hz,1H),7.09(t,J＝9.3Hz,1H),6.88-6.95(m,2H),6.77-6.83(m,1H),6.63(d,J＝8.1Hz,1H),6.27(t,J＝5.7Hz,1H),5.11(dd,J＝13.2,5.4Hz,1H),4.36(d,J＝5.7Hz,2H),4.30(d,J＝17.4Hz,1H),4.17(d,J＝17.4Hz,1H),3.88(t,J＝6.3Hz,2H),3.52(t,J＝3.9Hz,4H),2.85-2.96(m,1H),2.57-2.63(m,1H),2.22-2.41(m,7H),1.99-2.05(m,1H),1.73-1.84(m,2H).LCMS:511.2([M+1]+).
实施例30化合物A370
3-(4-((2-fluoro-5-(2-methoxyethoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A370.
Figure PCTCN2015088312-appb-000222
1H NMR(300MHz,DMSO-d6):δ10.98(s,1H),7.23(t,J＝7.8Hz,1H),7.06-7.12(m,1H),6.90-6.95(m,2H),6.79-6.84(m,1H),6.64(d,J＝8.1Hz,1H),6.24(t,J＝5.4Hz,1H),5.10(dd,J＝13.2,5.1Hz,1H),4.28-4.38(m,3H),4.19(d,J＝17.1Hz,1H),3.96-3.99(m,2H),3.55-3.58(m,2H),3.23(s,3H),2.85-2.95(m 1H),2.57-2.64(m 1H),2.24-2.36(m 1H),1.98-2.09(m 1H).
实施例31化合物A371
3-(((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-4-fluorophenyl methylcarbamate,A371.
Figure PCTCN2015088312-appb-000223
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.52-7.56(m,1H),7.15-7.25(m,2H),6.93-7.06(m,3H),6.63(d,J＝7.8Hz,1H),6.28-6.32(m,1H),5.10(dd,J＝13.5,4.5Hz,1H),4.40(d,J＝4.8Hz,2H),4.30(d,J＝17.4Hz,1H),4.18(d,J＝17.4Hz,1H),2.84-2.97(m,1H),2.59-2.69(m,4H),2.23-2.37(m,1H),1.99-2.08(m,1H).LCMS:441.1([M+1]+).
实施例32化合物A372
3-(4-((2-fluoro-3-(methylamino)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A372.
Figure PCTCN2015088312-appb-000224
1H NMR(DMSO-d6,300MHz):δ10.99(s,1H),7.21(t,J＝7.8Hz,1H),6.85-6.92(m,2H),6.63(d,J＝8.1Hz,1H),6.48-6.55(m,2H),6.21(t,J＝5.4Hz,1H),5.48-6.49(m,1H),5.09(dd,J＝13.2,5.1Hz,1H),4.35(d,J＝5.4Hz,2H),4.27(d,J＝17.4Hz,1H),4.15(d,J＝17.4Hz,1H),2.85-2.97(m,1H),2.69(d,J＝4.5Hz,3H),2.49-2.63(m,1H),2.21-2.35(m,1H),1.98-2.05(m,1H).LCMS＝397.1([M+1]+)
实施例33化合物A375
3-(4-((2-fluoro-5-(2-hydroxyethoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A375.
Figure PCTCN2015088312-appb-000225
1H NMR(DMSO-d6,300MHz):δ9.35(br s,1H),7.22(t,J＝8.1Hz,1H),7.10(t,J＝9.3Hz,1H),6.88-6.95(m,2H),6.78-6.83(m,1H),6.63(d,J＝8.4Hz,1H),6.31(t,J＝6.0Hz,1H),5.11(dd,J＝13.5,5.1Hz,1H),4.82(br s,1H),4.37(d,J＝5.7Hz,2H),4.30(d,J＝17.1Hz,1H),4.17(t,J＝17.1Hz,1H),3.85(t,J＝4.8Hz,2H),3.62(t,J＝4.8Hz,2H),2.85-2.97(m,1H),2.55-2.65(m,1H),2.24-2.36(m,1H),2.01-2.05(m,1H).LCMS:428.1[(M+1)+].
实施例34化合物A376
3-(4-((2-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A376.
Figure PCTCN2015088312-appb-000226
1H NMR(300MHz,DMSO-d6):δ11.02(s,1H),7.22(t,J＝8.1Hz,1H),7.06-7.13(m,1H),6.89-6.95(m,2H),6.78-6.84(m,1H),6.63(d,J＝7.8Hz,1H),6.29(t,J＝5.7Hz,1H),5.11,(dd,J＝13.2,5.1Hz,1H),4.27-4.37(m,3H),4.17(d,J＝17.1Hz,1H),3.94(t,J＝6.0Hz,1H),2.85-2.97(m 1H),2.57-2.69(m 3H),2.22-2.42(m 5H),1.98-2.06(m 1H),1.56-1.66(m4H).
实施例35化合物A377
3-(4-((2-fluoro-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A377.
Figure PCTCN2015088312-appb-000227
1H NMR(DMSO-d6,300MHz):δ11.03(s,1H),7.22(t,J＝7.8Hz,1H),7.09(t,J＝9.6Hz,1H),6.91-6.95(m,2H),6.79-6.89(m,1H),6.63(d,J＝8.1Hz,1H),6.29(t,J＝6.0Hz,1H),5.11(dd,J＝13.5,4.8Hz,1H),4.27-4.37(m,3H),4.17(d,J＝17.4Hz,1H),3.94(t,J＝5.7Hz,2H),2.85-2.98(m,1H),2.55-2.62(m,4H),2.20-2.42(m,8H),2.12(s,3H),1.98-2.07(m,1H).LCMS:510.2([M+1]+).
实施例36化合物A378
3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-4-fluorophenyl dimethylcarbamate,A378.
Figure PCTCN2015088312-appb-000228
1H NMR(300MHz,DMSO-d6):δ11.00(s,1H),7.17-7.26(m,2H),7.08-7.11(m,1H),6.94-7.04(m,2H),6.78-6.84(m,1H),6.62(d,J＝8.1Hz,1H),6.30(t,J＝5.9Hz,1H),5.11,(dd,J＝13.2,5.4Hz,1H),4.40(d,J＝5.7Hz,1H),4.31(d,J＝17.4Hz,1H),4.18(d,J＝17.4Hz,1H),2.84-2.96(m 7H),2.57-2.63(m 1H),2.23-2.37(m 1H),2.00-2.05(m 1H).
实施例37化合物A382
3-(4-((2-fluoro-5-(3-morpholinopropoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione,A382.
Figure PCTCN2015088312-appb-000229
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.32(t,J＝7.8Hz,1H),7.22(t,J＝7.8Hz,1H),7.05-7.13(m,2H),6.93(d,J＝7.5Hz,1H),6.64(d,J＝7.8Hz,1H),6.28(t,J＝6.3Hz,1H),5.07-5.13(m,1H),4.38(d,J＝5.7Hz,2H),4.28(d,J＝17.4Hz,1H),4.16(d,J＝17.4Hz,1H),3.54(t,J＝4.5Hz,4H),3.42(s,2H),2.85-2.97(m,1H),2.57-2.63(m,1H),2.26-2.38(m,5H),2.00-2.09(m,1H).LCMS:467.2([M+1]+).
实施例38化合物A383
3-(4-((2-fluoro-5-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A383.
Figure PCTCN2015088312-appb-000230
1H NMR(DMSO-d6,300MHz):δ10.98(br s,1H),7.34(d,J＝0.9Hz,1H),7.10-7.32(m,3H),6.95(d,J＝7.5Hz,1H),6.64(d,J＝7.8Hz,1H),6.27(br s,1H),5.12(dd,J＝13.5,5.1Hz,1H),4.43(d,J＝5.7Hz,2H),4.32(d,J＝17.1Hz,1H),4.21(d,J＝17.1Hz,1H),3.45-3.48(m,4H),3.38(s,2H),2.87-2.99(m,1H),2.30-2.36(m,1H),2.23-2.25(m,4H),2.22-2.36(m,1H),2.01-2.09(m,1H).LCMS＝467.2[(M+1)+].
实施例39化合物A381
3-(4-((2-fluoro-3-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A381.
Figure PCTCN2015088312-appb-000231
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.20-7.31(m,3H),7.10(t,J＝7.8Hz,1H),6.95(d,J＝7.5Hz,1H),6.65(d,J＝8.1Hz,1H),6.31(t,J＝5.7Hz,1H),5.12(dd,J1＝ 13.8Hz,J2＝5.4Hz,1H),4.43(d,J＝5.4Hz,2H),4.31(d,J＝17.4Hz,1H),4.19(d,J＝17.4Hz,1H),3.53-3.58(m,6H),2.87-2.99(m,1H),2.57-2.66(m,1H),2.24-2.39(m,5H),2.00-2.10(m,1H).LCMS＝467.2[(M+1)+].
实施例40化合物A384
3-(4-((3-amino-2-fluorobenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A384.
Figure PCTCN2015088312-appb-000232
1H NMR(DMSO-d6,300MHz):δ9.76(br s,1H),7.23(t,J＝8.1Hz,1H),6.93(d,J＝7.5Hz,1H),6.77(t,J＝7.8Hz,1H),6.61-6.67(m,2H),6.49-6.54(m 1H),6.22(t,J＝5.7Hz,1H),5.09-5.15(m,3H),4.35(d,J＝5.4Hz,2H),4.29(d,J＝17.4Hz,1H),4.17(d,J＝17.4Hz,1H),2.87-2.99(m,1H),2.58-2.67(m,1H),2.23-2.36(m,1H),2.00-2.10(m,1H).LCMS＝383.1([M+1]+).
实施例41化合物A388
N-(3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-2-fluorophenyl)acetamide,A388.
Figure PCTCN2015088312-appb-000233
1H NMR(DMSO-d6,300MHz):δ10.96(br s,1H),9.71(s,1H),7.74(t,J＝6.9Hz,1H),7.22(t,J＝7.8Hz,1H),7.02-7.13(m,2H),6.93(d,J＝7.5Hz,1H),6.64(d,J＝7.8Hz,1H),6.31(t,J＝6.0Hz,1H),5.10(dd,J＝12.9,5.1Hz,1H),4.42(d,J＝5.4Hz,2H),4.29(d,J＝17.1Hz,1H),4.16(d,J＝17.1Hz,1H),2.85-2.95(m,1H),2.55-2.64(m,1H),2.22-2.36(m,1H),1.99-2.07(m,4H).LCMS＝425.1[(M+1)+].
实施例42化合物A389
3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-2-fluorobenzenesulfonamide,A389.
Figure PCTCN2015088312-appb-000234
1H NMR(300MHz,DMSO-d6):δ11.02(s,1H),7.85-7.88(m,1H),7.73-7.78(m,1H),7.39-7.45(m,3H),7.24(t,J＝7.8Hz,1H),6.96(d,J＝7.5Hz,1H),6.63(d,J＝8.1Hz,1H),6.43(t,J＝6.0Hz,1H),5.11,(dd,J＝13.2,5.1Hz,1H),4.46(d,J＝5.4Hz,2H),4.29(d,J＝17.4Hz,1H),4.18(d,J＝17.4Hz,1H),2.85-2.97(m 1H),2.58-2.63(m 1H),2.24-2.36(m 5H),2.02-2.07(m 1H).
实施例43化合物A387
3-(4-((2-fluoro-5-(methylamino)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A387.
Figure PCTCN2015088312-appb-000235
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.22(t,J＝7.5Hz,1H),6.87-6.93(m,2H),6.62(d,J＝8.1Hz,1H),6.50-6.53(m,1H),6.31-6.36(m,1H),6.25(t,J＝5.7Hz,1H),5.47-5.52(m,1H),5.11(dd,J＝4.8,13.2Hz,1H),4.25-4.30(m,3H),4.15(d,J＝17.4Hz,1H),2.85-2.97(m,1H),2.54-2.63(m,4H),2.22-2.37(m,1H),1.99-2.06(m,1H).LCMS:397.21([M+1]+).
实施例44化合物A396
3-(4-((2-fluoro-4-hydroxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A396.
Figure PCTCN2015088312-appb-000236
1H NMR(DMSO-d6,300MHz):δ11.00(br s,1H),9.74(br s,1H),7.14-7.25(m,2H),6.92(d,J＝7.2Hz,1H),6.66(d,J＝8.1Hz,1H),6.52-6.55(m,2H),6.13(t,J＝6.0Hz,1H),5.07-5.13(m,1H),4.24-4.29(m,3H),4.14(d,J＝17.1Hz,1H),2.87-2.97(m,1H),2.56-2.65(m,1H),2.21-2.36(m,1H),1.98-2.06(m,1H).LCMS:384.1[(M+1)+]
实施例45化合物A391
[3-(4-((5-amino-2-fluorobenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione],A391.
步骤A：参照前述实施例20中的合成方法，用相应的底物替换实施例20中的A346A，就可以合成下列化合物A391G。
1H NMR(DMSO-d6,400MHz):δ11.03(s,1H),9.31(s,1H),7.37-7.44(m,2H),7.24(t,J＝7.6Hz,1H),7.09(t,J＝9.2Hz,1H),6.95(d,J＝7.2Hz,1H),6.62(d,J＝8.0Hz,1H),6.33(t,J＝5.6Hz,1H),5.11-5.16(m,1H),4.36(t,J＝5.2Hz,2H),4.29(d,J＝16.8Hz,1H),4.19(d,J＝17.2Hz,1H),2.89-2.98(m,1H),2.60-2.64(m,1H),2.26-2.37(m,1H),2.03-2.06(m,1H),1.42(s,9H).
Figure PCTCN2015088312-appb-000237
步骤B：向A391G(400mg,0.83mmol)的DCM(12mL)溶液中滴加TFA(4m L)后35℃搅拌0.5小时。反应液浓缩干并用CH3CN(4mL)、Et3N(100mg)溶解后HPLC制备得白色固体产物A391(130mg,yield:41％)。
1H NMR(DMSO-d6,400MHz):δ10.83(s,1H),9.37(t,J＝5.6Hz,1H),8.03(d,J＝8.8Hz,2H),7.78-7.86(m,3H),7.58(s,1H),7.50(d,J＝8.0Hz,2H),7.17(s,1H),4.64(d,J＝5.6Hz,2H),4.50-4.54(m,1H),2.37-2.41(m,1H),2.21-2.26(m,1H),1.89-1.93(m,2H).LCMS:523.1([M+1]+).
实施例46化合物A397
3-(4-((5-amino-2-fluorobenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A397.
步骤A：参照前述实施例20中的合成方法，用相应的底物替换实施例20中的A346A，就可以合成下列化合物A397A。
1H NMR(DMSO-d6,400MHz):δ11.04(br s,1H),9.54(br s,1H),7.38(d,J＝12.8Hz,1H),7.22-7.28(m,2H),7.13(d,J＝8.4Hz,1H),6.94(d,J＝7.6Hz,1H),6.65(d,J＝8.0Hz,1H),6.24(t,J＝5.6Hz,1H),5.10-5.14(m,1H),4.27-4.34(m,3H),4.17(d,J＝17.2Hz,1H),2.89-2.97(m,1H),2.64-2.67(m,1H),2.25-2.36(m,1H),2.03-2.06(m,1H),1.46(s,9H).
Figure PCTCN2015088312-appb-000238
步骤B：将A397A(100mg,0.21mmol)溶解在二氧六环(20mL)中，向反应瓶中滴加6N HCl二氧六环溶液，搅拌反应2.5小时，反应液浓缩，溶解在DMF(10mL)中， 饱和NaHCO3调节pH＝7-8，过滤，母液浓缩，剩余物Prep-HPLC纯化得淡黄色固体产物A397(35mg，收率：44％)。
1H NMR(DMSO-d6,400MHz):δ11.02(br s,1H),7.24(t,J＝8.4Hz,1H),7.02(t,J＝8.4Hz,1H),6.93(d,J＝7.6Hz,1H),6.69(d,J＝8.0Hz,1H),6.04(t,J＝5.6Hz,1H),5.30(br s,2H),5.09-5.14(m,1H),4.25(d,J＝17.2Hz,1H),4.20(d,J＝5.6Hz,1H),4.14(d,J＝17.2Hz,1H),2.88-2.97(m,1H),2.59-2.64(m,1H),2.24-2.35(m,1H),2.02-2.08(m,4H).LCMS:383.2[(M+1)+].
实施例47化合物A373
(S)-3-deuterium-3-(4-((4-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A373.
Figure PCTCN2015088312-appb-000239
步骤A：向A373C 4-(morpholinomethyl)benzaldehyde(0.8g,3.9mmol)和A356C(0.7g,2.5mmol)的甲醇(100mL)溶液中加入1mL HOAc。N2保护下40℃反应过夜。然后加入Pd/C(50％wet,10％,150mg)，氢气置换后1atm压力下反应5h。约90％原料反应完。过滤，滤液浓缩干反相HPLC制备得浅黄色固体产品A373A(1.0g，收率：86％)。
1H NMR(DMSO-d6,300MHz):δ9.96(br,1H),7.59(s,1H),7.41-7.49(m,4H),7.11-7.18(m,2H),6.87(d,J＝7.2Hz,1H),6.54(d,J＝8.1Hz,1H),4.25-4.55(m,7H),3.93(d,J＝12.0Hz,2H),3.58(t,J＝12.3Hz,2H),3.01-3.24(m,4H),2.13-2.21(m,3H),1.93-2.00(m,1H).
步骤B：-40℃向A373A(200mg,0.428mmol)的DCM(12mL)/THF(12mL)溶液中加入SOCl2(204mg,1.71mmol)的DCM溶液(1.7mL)。N2保护下-40℃反应2小时。然后加入吡啶(135mg,1.71mmol)搅拌30分钟，再加入三乙胺(173mg,1.71mmol)升至室温搅拌。加0.5mL水淬灭反应。蒸干溶剂后用反相Prep-HPLC制备两次(流动相为纯水/乙腈)得白色固体产品A373(20mg，收率：10％)。
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.15-7.34(m,5H),6.89(d,J＝7.2Hz,1H),6.61(d,J＝7.8Hz,1H),6.38(t,J＝4.8Hz,1H),5.08-5.14(m,0.04H),4.35(d,J＝5.1Hz,2H),4.29(d,J＝17.4Hz,1H),4.16(d,J＝17.4Hz,1H),3.55(br s,4H),3.42(br.s,2H),2.85-2.98(m,1H),2.57-2.63(m,1H),2.24-2.34(m,5H),1.99-2.05(m,1H).
LCMS:450.2([M+1]+).
实施例48化合物A374
2-(3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-4-fluorophenoxy)ethyl pyrrolidine-1-carboxylate,A374.
合成路线
Figure PCTCN2015088312-appb-000240
实验部分
步骤A.氮气保护下将四氢吡咯(3.77g,53mmol)，2-溴乙醇(6.25g,50mmol)，K2CO3(6.9g,50mmol)的乙腈溶液(70mL)加热至回流反应过夜。过滤，蒸干溶剂，柱层析(DCM:MeOH＝100:1to 10:1)得浅黄油状产品A374A(4g,收率:50％)。
1H NMR(CDCl3,300MHz):δ4.25-4.28(m,2H),3.80-3.85(m,2H),3.36-3.43(m,4H),2.92(t,J＝5.7,1H),1.88-1.92(m,4H).
步骤B.将SOCl2(3.6g,30.0mmol)加入到A374A(2.3g,14.4mmol)的氯仿溶液(50mL)中，加完回流反应1.5h。浓缩得白色固体A374C(2.0g，收率：78％)。
1H NMR(CDCl3,300MHz):δ4.21(t,J＝5.7,2H),3.77(t,J＝5.7,2H),3.21-3.32(m,4H),1.75-1.83(m,4H).
步骤C.氮气保护下将A374C(802mg,4.52mmol)，2-氟-5-羟基苯甲醛(280mg,2.0mmol)，K2CO3(828mg,6.0mmol)的DMF(10mL)溶液加热至90℃反应过夜。反应液倒入冰水(100mL)中搅拌，过滤，滤饼经水(20mL)洗后溶解于EtOAc(50mL)，干燥，蒸干后得白色固体产品A374E(560mg)。直接用于下一步。
1H NMR(CDCl3,300MHz):δ10.32(s,1H),7.31-7.34(m,1H),7.09-7.17(m,2H),4.42(t,J＝5.1Hz,2H),4.20(t,J＝5.1Hz,2H)3.30-3.41(m,4H),1.85(br s,4H).
步骤D.室温下将A374E(206mg,0.732mmol)和A308A(150mg,0.578mmol)溶解于醋酸(6mL)和二氯甲烷(6mL)的混合溶液中搅拌4小时后加入NaBHCN(109mg,1.74mmol)，氮气保护下反应过夜。反应液减压浓缩用乙腈溶解后HPLC制备得白色固体产物A374(105mg，收率35％)。
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.20-7.25(m,1H),7.11(t,J＝9.3Hz,1H),6.93-6.95(m,2H),6.82-6.87(m,1H),6.64(d,J＝8.1Hz,1H),6.24-6.29(m,1H),5.11(dd, J＝13.5,5.1Hz,1H),4.33-4.37(m,2H),4.20-4.27(m,4H),4.08-4.14(m,2H),3.12-3.22(m,4H),2.86-2.97(m,1H),2.62-2.71(m,1H),2.24-2.33(m,1H),2.01-2.06(m,1H),1.69-1.77(m,4H).LCMS:525.2([M+1]+).
实施例49化合物A349
[3-(4-((3,4-dimethoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione],A349.
Figure PCTCN2015088312-appb-000241
N2保护下，向A349A(100mg,0.23mmol)的DMF(5mL)溶液中加入K2CO3(47.0mg,0.34mmol)，于80℃(油浴)搅拌过夜。TCL显示反应完成。过滤，滤液减压浓缩，剩余物用反相HPLC纯化得白色固体A349(40mg,收率43％)。
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.20(t,J＝7.5Hz,1H),7.01(s,1H),6.85-6.92(m,3H),6.68(d,J＝7.8Hz,1H),6.24-6.28(m,1H),5.08-5.14(m,1H),4.25-4.33(m,3H),4.18(d,J＝17.1Hz,1H),3.72(s,3H),3.70(s,3H),2.87-2.99(m,1H),2.59-2.65(m,1H),2.24-2.37(m,1H),2.00-2.08(m,1H).LCMS:410.2([M+1]+).
实施例50化合物A350
3-(4-((3,4-dimethylbenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A350.
Figure PCTCN2015088312-appb-000242
N2保护下，向A350A(100mg,0.25mmol)的CH3CN(5mL)溶液中加入CDI(62.0mg,0.38mmol)，于95℃(油浴)搅拌过夜。TCL显示反应完成。过滤，滤液减压浓缩，剩余物用反相HPLC纯化得白色固体A350(61mg,收率65％)。
1H NMR(DMSO-d6,300MHz):δ11.01(s,1H),7.15-7.21(m,2H),7.04-7.10(m,2H),6.91(d,J＝7.2Hz,1H),6.62(d,J＝8.1Hz,1H),6.27-6.31(m,1H),5.11(dd,J＝13.2,5.1Hz,1H),4.28-4.33(m,3H),4.18(d,J＝17.7Hz,1H),2.87-2.99(m,1H),2.60-2.65(m,1H),2.24-2.37(m,1H),2.19(s,3H),2.17(s,3H),2.02-2.07(m,1H).LCMS:378.2([M+1]+).
参照前述实施例50中的合成方法，用相应的底物替换实施例50中的A350A，就可以合成下列实施例51-55中的化合物。
实施例51化合物A351
3-(4-((4-fluoro-3-methylbenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A351.
Figure PCTCN2015088312-appb-000243
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.29(d,J＝6.0Hz,1H),7.18-7.23(m,2H),7.06(t,J＝9.6Hz,1H),6.92(d,J＝7.2Hz,1H),6.63(d,J＝7.8Hz,1H),6.34(t,J＝6.0Hz,1H),5.12(dd,J＝13.2,5.1Hz,1H),4.28-4.33(m,3H),4.18(d,J＝17.4Hz,1H),2.87-2.99(m,1H),2.59-2.65(m,1H),2.26-2.37(m,1H),2.21(s,3H),2.01-2.08(m,1H).LCMS:382.1([M+1]+).
实施例52化合物A352
3-(4-((3-chloro-4-methylbenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A352.
Figure PCTCN2015088312-appb-000244
1H NMR(DMSO-d6,300MHz):δ11.01(s,1H),7.41(s,1H),7.17-7.30(m,3H),6.92(d,J＝7.5Hz,1H),6.61(d,J＝8.1Hz,1H),6.39(t,J＝6.0Hz,1H),5.12(dd,J＝13.2,5.4Hz,1H),4.29-4.37(m,3H),4.18(d,J＝17.1Hz,1H),2.87-2.99(m,1H),2.59-2.65(m,1H),2.25-2.39(m,4H),2.02-2.07(m,1H).LCMS:398.1([M+1]+).
实施例53化合物A353
3-(4-((3-fluoro-4-methylbenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A353.
Figure PCTCN2015088312-appb-000245
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.11-7.24(m,4H),6.92(d,J＝7.2Hz,1H),6.61(d,J＝7.5Hz,1H),6.36-6.40(m,1H),5.12(dd,J＝13.5,5.1Hz,1H),4.29-4.37(m,3H),4.19(d,J＝17.4Hz,1H),2.86-2.99(m,1H),2.59-2.65(m,1H),2.24-2.39(m,1H),2.18(s,3H),2.01-2.07(m,1H).LCMS:382.1([M+1]+).
实施例54化合物A354
3-(4-((3-chloro-4-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A354.
Figure PCTCN2015088312-appb-000246
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.44(d,J＝1.8Hz,1H),7.32(dd,J＝8.4,1.8Hz,1H),7.21(t,J＝7.8Hz,1H),7.09(d,J＝8.7Hz,1H),6.93(d,J＝7.2Hz,1H),6.65(d,J＝8.1Hz,1H),6.35(t,J＝5.9Hz,1H),5.09-5.15(m,1H),4.28-4.33(m,3H),4.18(d,J＝16.8Hz,1H),3.81(s,3H),2.87-2.99(m,1H),2.58-2.67(m,1H),2.24-2.37(m,1H),2.01-2.09(m,1H).LCMS:414.1([M+1]+).
实施例55化合物A355
3-(4-((3,5-dimethoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A355.
Figure PCTCN2015088312-appb-000247
1H NMR(DMSO-d6,300MHz):δ11.03(s,1H),7.18-7.24(m,1H),6.92(d,J＝7.5Hz,1H),6.64(d,J＝8.4Hz,1H),6.55(d,J＝2.1Hz,2H),6.31-6.35(m,2H),5.12(dd,J＝13.2,4.8Hz,1H),4.28-4.34(m,3H),4.19(d,J＝16.8Hz,1H),3.33(s,6H),2.87-2.99(m,1H),2.58-2.67(m,1H),2.26-2.37(m,1H),2.02-2.08(m,1H).LCMS:410.2([M+1]+).
实施例56化合物A356
(S)-3-deuterium-3-(4-((2-fluoro-4-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A356.
合成路线:
Figure PCTCN2015088312-appb-000248
实验部分
步骤A：将A356C(300mg,1.08mmol)和2-氟-4-甲氧基苯甲醛(249mg,1.62mmol)溶解于甲醇(30mL)中，后向反应瓶中加入冰醋酸(0.5mL)，加热30℃(外温)搅拌5小 时。加入Pd/C(10％，100mg，50％water)，30℃(外温)氢化反应过夜(氢气球)。减压抽滤掉Pd/C，滤液减压浓缩，剩余物用反向C18(CH3CN:H2O＝5％-35％,30min；35％-45％,30min；45％-55％20min)冻干得淡黄色固体A356A(160mg,yield:35％)。
1H NMR(DMSO-d6,300MHz):δ12.06(br s,1H),7.55(br s,1H),7.29(t,J＝9.0Hz,1H),7.16-7.22(m,2H),6.88(d,J＝7.5Hz,1H),6.80(dd,J＝12.6,2.4Hz,1H),6.71(dd,J＝8.7,2.7Hz,1H),6.61(d,J＝8.1Hz,1H),6.28(t,J＝6.0Hz,1H),4.68-4.74(m,0.01H),4.48(d,J＝17.7Hz,1H),4.23-4.31(m,3H),3.72(s,3H),2.10-2.19(m,3H),1.93-2.01(m,1H).
步骤B：将A356A(160mg,0.39mmol)溶于干燥的DCM(20mL)中，氮气保护下冷至-40℃，缓慢滴加SOCl2(229mg,1.92mmol)，毕，加入DMF(5mg)的DCM(1mL)溶液加毕，搅拌反应2h，滴加吡啶(152mg,1.92mmol)维持此温度搅拌40分钟，加入Et3N(195mg,1.92mmol)，加毕，继续反应2h，LCMS显示反应完成。加入H2O(10mL)淬灭反应，水相用DCM萃取(30mL×2)，合并有机相，食盐水洗(50mL×1)，无水硫酸钠干燥，过滤，减压浓缩至干，剩余物经反向C18制备柱纯化(CH3CN:H2O＝5％-35％,30min；35％-45％,30min；45％-55％20min)纯化得到白色固体A356(70mg,收率:46％,ee:97％)。
1H NMR(DMSO-d6,300MHz):δ10.99(br s,1H),7.31(t,J＝9.0Hz,,1H),7.24(t,J＝7.8Hz,1H),6.94(d,J＝7.2Hz,1H),6.82(dd,J＝12.3,2.7Hz,1H),6.71-6.75(m,1H),6.68(d,J＝7.8Hz,1H),6.20(t,J＝6.0Hz,1H),5.08-5.14(m,0.04H),4.26-4.35(m,3H),4.17(d,J＝16.8Hz,1H),3.74(s,3H),2.87-2.97(m,1H),2.57-2.66(m,1H),2.25-2.34(m,1H),2.00-2.09(m,1H).LCMS:399.1([M+1]+).
参照前述实施例56中的合成方法，用相应的底物替换步骤A中的2-氟-4-甲氧基苯甲醛，就可以合成下列实施例57中的化合物。
实施例57化合物A357
(S)-3-deuterium-3-(4-((2-fluoro-3-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A357.
Figure PCTCN2015088312-appb-000249
1H NMR(DMSO-d6,300MHz):δ11.00(br s,1H),7.21(t,J＝7.8Hz,,1H),7.00-7.07(m,2H),6.89-6.93(m,2H),6.78-6.84(m,1H),6.61(d,J＝8.4Hz,1H),6.30(t,J＝5.4Hz,1H),5.07-5.13(m,0.03H),4.40(d,J＝5.7Hz,2H),4.28(d,J＝17.1Hz,1H),4.16(d,J＝17.1Hz, 1H),3.81(s,3H),2.85-2.97(m,1H),2.57-2.63(m,1H),2.24-2.34(m,1H),2.00-2.06(m,1H).LCMS:399.1([M+1]+).
实施例58化合物A379
(S)-3-deuterium-3-(4-((2-fluoro-5-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A379.
合成路线
Figure PCTCN2015088312-appb-000250
实验部分
Figure PCTCN2015088312-appb-000251
步骤A：将A379A1(10.0g,27.8mmol)和A379A2(8.01g,33.4mmol)悬浮于CH3CN(250mL)中，后向反应瓶中加入DIPEA(7.92g,61.3mmol)，氮气保护，加热至45℃搅拌反应过夜。反应液减压浓缩，剩余物溶解在DCM(300mL)和水(100mL)中搅拌，水层用DCM萃取(200mL×1)，合并有机相，食盐水(200mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色固体粗产物A379A(12.3g)。
Figure PCTCN2015088312-appb-000252
步骤B.将A379A(12.3g,粗品)溶解在THF(100mL)中，加入1N TBAF的THF溶液(100mL)，25℃氢化反应过夜。LCMS显示反应完成。向反应液中加入EtOAc(200mL)和H2O(200mL)，分层，水相用EtOAc(200mL×2)萃取，合并有机相，用食盐水洗(300mL)，无水硫酸钠干燥，过滤母液减压浓缩至干，剩余物用EtOAc(20mL)打浆，EtOAc(10mL)洗滤饼，固体干燥得白色固体产物A379B(5.7g)。或者母液硅胶柱层析纯化(PE/EtOAc＝1:4)得白色固体产物A379B(1.5g，两步收率：77％)。
1H NMR(DMSO-d6,300MHz):δ10.01(s,1H),7.54(br s,1H),7.29(t,J＝7.8Hz,1H),7.12-7.16(m,2H),6.96(dd,J＝8.1,0.6Hz,1H),4.66-4.71(m,0.01H),4.47(d,J＝17.7Hz,1H),4.29(d,J＝17.7Hz,1H),2.08-2.17(m,3H),1.95-2.02(m,1H),1.31(s,9H).
Figure PCTCN2015088312-appb-000253
步骤C：将A379B(1.18g,3.52mmol)和2-氟-5-甲氧基苄氯(1.23g,7.04mmol)溶解于DMF(20mL)中，后向反应瓶中加入K2CO3(972mg,7.03mmol)，室温搅拌反应过夜。LCMS显示反应完全。减压浓缩掉DMF，剩余物加入EtOAc(50mL)和H2O(30mL)溶解，水相用EtOAc(50mL)萃取，合并有机相，食盐水洗(50mL)，无水Na2SO4干燥，过滤，母液减压浓缩，剩余物用硅胶柱纯化(MeOH/DCM＝1/30)，得白色固体产物(1.46g,收率：87％)。白色固体产物用手性柱拆分A379C(650mg)和A379D(650mg)。
手性拆分制备条件：
流动相：Hexane/EtOH＝40/60(V/V).样品浓度：100mg/ml(在流动相中).手性柱：IC；柱子型号：20mm(I.D)×250mm(L)；柱子粒径：5um；柱温：35℃；进样量：250μL；流速：10ml/min；检测波长：205nm。
A379C:1H NMR(DMSO-d6,300MHz):δ7.55(br s,1H),7.46(t,J＝8.1Hz,1H),7.28-7.34(m,2H),7.11-7.21(m,3H),6.92-6.97(m,1H),5.22(s,2H),4.49(d,J＝18.0Hz,1H),4.36(d,J＝18.0Hz,1H),3.73(s,3H),2.05-2.13(m,3H),1.96-2.02(m,1H),1.30(s,9H).
Figure PCTCN2015088312-appb-000254
步骤D：将A379C(650mg,1.37mmol)溶解于二氯甲烷(20mL)中,冷却至0℃，后向反应瓶中滴加三氟乙酸(10mL)，慢慢升至室温搅拌反应过夜。反应液减压浓缩，剩余物溶解在4mL CH3CN中用反向C18柱纯化(40％乙腈的水溶液)冻干得淡黄色固体A379E(566mg,收率:99％)。
1H NMR(DMSO-d6,300MHz):δ12.08(br s,1H),7.58(br s,1H),7.46(t,J＝8.1Hz,1H),7.28-7.35(m,2H),7.11-7.21(m,3H),6.92-6.97(m,1H),5.22(s,2H),4.51(d,J＝17.7Hz,1H),4.37(d,J＝17.7Hz,1H),3.73(s,3H),2.08-2.20(m,3H),1.96-2.05(m,1H).
Figure PCTCN2015088312-appb-000255
步骤E：将A379E(366mg,0.88mmol)溶于干燥的DCM(35mL)和THF(5mL)中，氮气保护下冷至-40℃，缓慢滴加SOCl2(522mg,4.39mmol)，毕，加入DMF(5mg)的DCM(1mL)溶液加毕搅拌反应1h，滴加吡啶(347mg,4.39mmol)维持此温度搅拌40分钟，加入Et3N(444mg,4.39mmol)，加毕，继续反应1h。LCMS显示反应完成。加入H2O(10mL)淬灭反应，水相用DCM萃取(50mL)，食盐水洗(50mL×1)，无水硫酸钠干燥，过滤，减压浓缩至干，剩余物经C18柱纯化得到白色固体A379(270mg,yield:77％,ee:100％)。
1H NMR(DMSO-d6,300MHz):δ10.96(br s,1H),7.49(t,J＝8.1Hz,1H),7.32-7.38(m,2H),7.11-7.21(m,2H),6.91-6.97(m,1H),5.23(s,2H),5.06-5.12(m,0.01H),4.37(d,J＝17.4Hz,1H),4.21(d,J＝17.4Hz,1H),3.72(s,3H),2.82-2.94(m,1H),2.57-2.60(m,1H),2.38-2.48(m,1H),1.92-1.97(m,1H).LCMS＝400.1([M+1]+).
参照前述实施例58中的合成方法，用相应的底物替换步骤C中的2-氟-5-甲氧基苄氯，就可以合成下列实施例59中的化合物。
实施例59化合物A380
(S)-3-deuterium-3-(4-((2-fluoro-3-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A380.
Figure PCTCN2015088312-appb-000256
1H NMR(DMSO-d6,300MHz):δ10.95(br s,1H),7.49(t,J＝7.8Hz,1H),7.31-7.37(m,2H),7.07-7.19(m,3H),5.26(s,2H),5.05-5.11(m,0.01H),4.36(d,J＝17.4Hz,1H),4.20(d,J＝17.4Hz,1H),3.83(s,3H),2.82-2.94(m,1H),2.51-2.60(m,1H),2.37-2.46(m,1H),1.92-1.99(m,1H).LCMS＝400.1([M+1]+).
实施例60化合物A393
(S)-3-deuterium-3-(4-((2-fluoro-4-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A393.
Figure PCTCN2015088312-appb-000257
步骤A：向化合物A379B(2.0g,6.0mmol)的DCM(30mL)溶液中加入TFA(5mL)25℃下搅拌3小时,减压浓缩后得粗产品(1.7g)。将2-三甲基硅基乙醇(3.55g,30mmol)，EDCI(2.3g,12.0mmol)和DMAP(733mg,6.0mmol)加入到上述粗产品(1.7g)的DMF(5mL)溶液中，35℃下搅拌过夜，反应液减压浓缩后经硅胶柱层析纯化(DCM/MeOH＝40/1)得到产品A393A(1.6g,两步收率70％).
1H NMR(DMSO-d6,300MHz):δ9.99(s,1H),7.54(s,1H),7.28(t,J＝7.8Hz,1H),7.11-7.14(m,2H),6.96(d,J＝7.8Hz,1H),4.47(d,J＝18.0Hz,1H),4.28(d,J＝18.0Hz,1H),3.92-3.99(m,2H),2.00-2.25(m,4H),0.80-0.85(m,2H),0.04(s,9H).
Figure PCTCN2015088312-appb-000258
步骤B：将K2CO3(750mg,5.40mmol)和2-氟-4-甲氧基苄氯(720mg,4.10mmol)加 入到A393A(1.02g,2.70mmol)的DMF(20mL)溶液中,反应液加热到30℃,搅拌17小时后过滤去除固体,滤液浓缩后得到粗品，硅胶柱层析纯化(DCM/MeOH＝60/1)得到产品A393C(1.0g,72％).
1H NMR(DMSO-d6,300MHz):δ7.43-7.54(m,3H),7.26-7.35(m,2H),7.14(s,1H),6.80-6.90(m,2H),5.16(s,2H),4.45(d,J＝17.4Hz,1H),4.30(d,J＝17.4Hz,1H),3.92-3.98(m,2H),3.77(s,3H),2.01-2.22(m,4H),0.79-0.84(m,2H).
步骤C:手性拆分
Figure PCTCN2015088312-appb-000259
手性拆分制备条件：
流动相：MeOH/EtOH＝50/50(V/V).样品浓度：120mg/mL.手性柱：IF；柱子型号：20mm(I.D)×250mm(L)；柱子粒径：5um；柱温：35℃；进样量：300μL；流速：9mL/min；检测波长：205nm。
A393E
1H NMR(DMSO-d6,300MHz):δ7.59(s,1H),7.45-7.54(m,2H),7.36(d,J＝7.8Hz,1H),7.29(d,J＝7.2Hz,1H),7.20(s,1H),6.80-6.92(m,2H),5.18(s,2H),4.47(d,J＝17.4Hz,1H),4.32(d,J＝17.4Hz,1H),3.92-4.01(m,2H),3.78(s,3H),2.01-2.20(m,4H),0.80-0.85(m,2H),0.04(s,9H).
Figure PCTCN2015088312-appb-000260
步骤D：
将TBAF(1N/THF,5mL)加入到A393E(500mg,0.97mmol)的THF(5mL)溶液中,加热50℃搅拌过夜,冷却后过滤,浓缩母液后经C18制备柱纯化得到粗品(420mg)，将300mg粗品的DCM(15mL)溶液冷却到-40℃后滴加DMF(1mL)和SOCl2(428mg, 3.60mmol)，搅拌2小时后加入吡啶(281mg,3.60mmol)，继续搅拌30分钟后，将Et3N(363mg,3.60mmol)加入反应液，-40℃下继续搅拌1小时后,将反应液倒入水(80mL)中淬灭反应，用DCM(80mL×3)萃取，合并有机相后，无水硫酸钠干燥，过滤浓缩后经Prep-HPLC制备分离得到产品A393(200mg,两步收率72％).
1H NMR(DMSO-d6,300MHz):δ10.95(s,1H),7.48-7.53(m,2H),7.32-7.40(m,2H),6.80-6.91(m,2H),5.19(s,2H),4.35(d,J＝17.4Hz,1H),4.19(d,J＝17.4Hz,1H),3.78(s,3H),2.84-2.96(m,1H),2.37-2.59(m,2H),1.93-1.99(m,1H).LCMS:400.1([M+1]+).
参照前述实施例60中的合成方法，用相应的底物替换A393E。就可以合成下列实施例61中的化合物。
实施例61化合物A392
(R)-3-deuterium-3-(4-((2-fluoro-4-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A392.
Figure PCTCN2015088312-appb-000261
1H NMR(DMSO-d6,300MHz):δ10.95(s,1H),7.48-7.53(m,2H),7.32-7.40(m,2H),6.80-6.91(m,2H),5.19(s,2H),5.07-5.13(m,0.05H),4.35(d,J＝17.7Hz,1H),4.19(d,J＝17.7Hz,1H),3.78(s,3H),2.84-2.96(s,1H),2.36-2.59(m,2H),1.93-1.98(m,1H).LCMS:400.1([M+1]+).
实施例62化合物A385
3-(4-((2-fluoro-3-(methylamino)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A385.
合成路线
实验部分
步骤A：将化合物2-氟-3-甲氨基苯甲醇溶解在DCM(10mL)中，加入SOCl2(0.5mL)，搅拌反应4小时。反应液浓缩得黄色固体3-氯甲基2-氟-N-甲基苯胺盐酸盐(430 mg)，不纯化直接用于下一步。
1H NMR(DMSO-d6,300MHz):δ9.97(br s,2H),7.05(t,J＝8.1Hz,1H),6.84-6.92(m,2H),4.72(s,2H),2.74(s,3H).
步骤B：将A329B(300mg,1.03mmol)溶解在DMF(10mL)中，加入3-氯甲基2-氟-N-甲基苯胺盐酸盐(259mg)和K2CO3(355mg,2.57mmol)，搅拌反应过夜，LCMS显示大量原料剩余，补加3-氯甲基2-氟-N-甲基苯胺盐酸盐(150mg)和K2CO3(100mg,0.72mmol)，搅拌反应过夜，原料基本反应完全。减压浓缩掉DMF，剩余物中加入EtOAc(20mL)和水(10mL)，分层，水相用EtOAc(20mL×2)萃取，合并的有机相用食盐水(20mL)洗，无水Na2SO4干燥，过滤，滤液减压浓缩，剩余物Prep-TLC(乙酸乙酯/石油醚＝4/1)纯化得白色固体A385A(242mg，收率：55％)。
1H NMR(DMSO-d6,300MHz):δ7.55(br s,1H),7.45(t,J＝7.8Hz,1H),7.27-7.33(m,2H),7.15(br s,1H),6.99(t,J＝8.1Hz,1H),6.61-6.71(m,2H),5.59(br s,1H),5.20(s,2H),4.70(dd,J＝10.5,4.5Hz,1H),4.47(d,J＝17.7Hz,1H),4.33(d,J＝17.7Hz,1H),3.48(s,3H),2.71(d,J＝4.2Hz,3H),2.12-2.25(m,3H),1.99-2.09(m,1H).
步骤C：将A385A(242mg,0.56mmol)溶解在DMF(10mL)中，加入K2CO3(234mg,1.69mmol)，80℃搅拌反应过夜。反应物浓缩，剩余物制备HPLC纯化，冻干得白色固体产物A385(100mg，收率：45％)。
1H NMR(DMSO-d6,300MHz):δ10.71(br s,1H),7.50(t,J＝8.1Hz,1H),7.32-7.38(m,2H),7.00(t,J＝7.8Hz,1H),6.63-6.72(m,2H),5.61-5.62(m,1H),5.23(s,2H),5.10(dd,J＝13.2,5.1Hz,1H),4.37(d,J＝17.7Hz,1H),4.21(d,J＝17.7Hz,1H),2.84-2.96(m,1H),2.72(d,J＝4.8Hz,3H),2.51-2.60(m,1H),2.37-2.47(m,1H),1.93-2.00(m,1H).LCMS＝398.1([M+1]+).
参照前述实施例62中的合成方法，用相应的底物替换步骤B中的3-氯甲基2-氟-N-甲基苯胺盐酸盐，就可以合成下列实施例63-66中的化合物。
实施例63化合物A390
3-(4-((2-fluoro-5-(methylamino)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A390.
Figure PCTCN2015088312-appb-000263
1H NMR(DMSO-d6,300MHz):δ10.97(s,1H),7.48(t,J＝7.8Hz,1H),7.33(t,J＝7.2 Hz,2H),6.96(t,J＝9.3Hz,1H),6.63-6.66(m,1H),6.46-6.51(m,1H),5.58-5.63(m,1H),5.16(s,2H),5.06-5.12(m,1H),4.35(d,J＝17.4Hz,1H),4.19(d,J＝17.4Hz,1H),2.83-2.95(m,1H),2.54-2.62(m,4H),2.34-2.45(m,1H),1.91-1.99(m,1H).LCMS:398.1([M+1]+).
实施64化合物A398
3-(4-((2-fluoro-5-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione,A398.
Figure PCTCN2015088312-appb-000264
1H NMR(DMSO-d6,300MHz):δ10.92(br s,1H),7.46-7.51(m,2H),7.31-7.37(m,3H),7.16-7.22(m,1H),5.27(s,2H),5.05-5.11(m,1H),4.35(d,J＝17.4Hz,1H),4.20(d,J＝17.4Hz,1H),3.50-3.53(m,4H),3.43(s,2H),2.82-2.92(m,1H),2.53-2.60(m,1H),2.34-2.44(m,1H),2.23-2.29(m,4H),1.90-2.00(m,1H).LCMS＝468.2[(M+1)+].
实施例65化合物A399
3-(4-((2-fluoro-3-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A399.
Figure PCTCN2015088312-appb-000265
1H NMR(DMSO-d6,300MHz):δ10.98(s,1H),7.49-7.54(m,2H),7.34-7.45(m,3H),7.19-7.24(m,1H),5.29(s,2H),5.08-5.14(m,1H),4.39(d,J＝17.7Hz,1H),4.22(d,J＝17.7Hz,1H),3.50-3.57(m,6H),2.84-2.98(m,1H),2.54-2.60(m,1H),2.34-2.47(m,5H),1.92-2.01(m,1H).LCMS:468.2([M+1]+).
实施例66化合物A407
3-(4-((2-fluoro-4-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A407.
合成路线：
Figure PCTCN2015088312-appb-000266
实验部分
步骤A：将A327A(300mg,0.85mmol)和4-(4-氯甲基)-3-氟苯基吗啉盐酸盐(359mg,1.28mmol)溶解于DMF(15mL)中，后向反应瓶中加入K2CO3(352mg,2.55mmol)，40℃搅拌过夜。过滤，浓缩掉DMF，剩余物用Prep-TLC(MeOH/DCM＝1/15)纯化，得白色固体产物A407B(430mg,收率：90％)。
1H NMR(DMSO-d6,300MHz):δ7.51-7.56(m,2H),7.33(dd,J＝11.4,1.5Hz,1H),7.17-7.21(m,3H),7.07(dd,J＝7.5,1.5Hz,1H),5.24(s,2H),4.66-4.69(m,1H),4.44(d,J＝17.7Hz,1H),4.32(d,J＝17.7Hz,1H),3.55-3.58(m,4H),3.48(s,2H),2.29-2.39(m,4H),2.05-2.18(m,3H),1.95-2.01(m,1H),1.29(s,9H).
步骤B：将A407B(430mg,0.77mmol)溶解于DCM(20mL)中，室温向反应瓶中滴加TFA(5mL)，25℃搅拌反应3h。LCMS显示原料消失。反应液减压浓缩得黄色固体A407C(387mg,收率:100％)。
1H NMR(DMSO-d6,300MHz):δ10.33(br s,1H),7.71(t,J＝7.8Hz,1H),7.61(s,1H),7.33-7.47(m,3H),7.19(s,1H),7.09-7.11(m,1H),5.31(s,2H),4.69-4.72(m,1H),4.48(d,J＝17.7Hz,1H),4.38(s,2H),4.35(d,J＝17.7Hz,1H),3.89-3.99(m,2H),3.57-3.67(m,2H),3.14-3.34(m,4H),3.10-2.17(m,3H),1.95-2.01(m,1H).
步骤C:将A407C(215mg,0.39mmol)溶于CH3CN(15mL)中，加入CDI(190mg,1.17mmol),氮气保护下加热回流过夜。LCMS显示原料消失。减压浓缩至干，剩余物经Prep-HPLC纯化得到白色固体A407(80mg,yield:43％)。
1H NMR(DMSO-d6,300MHz):δ10.96(br s,1H),7.51-7.56(m,1H),7.34-7.39(m,1H),7.11-7.21(m,3H),5.25(s,2H),5.05-5.11(m,1H),4.33(d,J＝18.0Hz,1H),4.16(d,J＝18.0Hz,1H),3.54-3.57(m,4H),3.48(s,2H),2.82-2.94(m,1H),2.49-2.56(m,1H),2.30-2.44(m,5H),1.91-1.99(m,1H).LCMS:486.2([M+1]+).
实施例67化合物A403
(S)-3-deuterium-3-(4-((2-fluoro-5-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A403.
Figure PCTCN2015088312-appb-000267
步骤A:将A379B(1.0g,3.59mmol)和4-(3-(氯甲基)-4-氟苯基)吗啉盐酸盐(1.23g,7.05mmol)溶解于DMF(20mL)中，向反应瓶中加入K2CO3(972mg,7.04mmol)，25℃搅拌过夜。过滤，浓缩掉DMF，剩余物用硅胶柱纯化，得白色固体产物A403A(1.3g,收率：80％)。
[A403A]1H NMR(DMSO-d6,300MHz):δ7.54(br s,1H),7.43-7.49(m,2H),7.28-7.34(m,3H),7.14-7.22(m,2H),5.26(s,2H),4.67-4.72(m,0.05H),4.50(d,J＝17.4Hz,1H),4.33(d,J＝17.4Hz,1H),3.49-3.56(m,4H),3.44(s,2H),2.25-2.34(m,4H),2.09-2.15(m,3H),1.94-2.03(m,1H),1.29(s,9H).
步骤B:手性拆分.
A403A用手性硅胶柱拆分得到A403C(500mg)和A403E(500mg)。
手性拆分制备条件：流动相：Hexane/IPA＝70/30(V/V)。样品浓度：100mg/mL；手性柱：IA；柱子型号：30mm(I.D)×250mm(L)；柱子粒径：5um；柱温：35℃；进样量：250μL；检测波长：205nm；流速：50mL/min。
A403C:
(S)-tert-butyl 5-amino-4-(4-((2-fluoro-5-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate
Figure PCTCN2015088312-appb-000268
1H NMR(DMSO-d6,300MHz):δ7.55(br s,1H),7.43-7.49(m,2H),7.28-7.34(m,3H),7.16-7.22(m,2H),5.26(s,2H),4.66-4.71(m,1H),4.49(d,J＝17.4Hz,1H),4.33(d,J＝17.4Hz,1H),3.51-3.53(m,4H),3.43(s,23H),2.26-2.33(m,4H),2.02-2.16(m,3H),1.94-1.99(m,1H),1.29(s,9H).
Figure PCTCN2015088312-appb-000269
步骤C：将A403C(500mg,1.0mmol)溶解于二氯甲烷(12mL)中，冷却至0℃，后向反应瓶中滴加三氟乙酸(3mL)，慢慢升至25℃搅拌反应过夜。反应液减压浓缩，剩余物溶解在CH2Cl2(20mL)中，加入饱和NaHCO3调节pH＝8-9，浓缩，剩余物用反向C18柱纯化(CH3CN:H2O＝5-40％,40min)冻干得淡黄色固体A403D(400mg,收率:82％)。
1H NMR(DMSO-d6,300MHz):δ7.93(br s,1H),7.41-7.49(m,2H),7.26-7.32(m,3H),7.16-7.22(m,1H),7.06(br s,1H),5.25(s,2H),5.05-5.13(m,0.00H),4.60(d,J＝17.7Hz,1H),4.30(d,J＝17.7Hz,1H),3.50-3.52(m,4H),3.42(s,2H),2.22-2.32(m,4H),2.03-2.10(m,1H),1.81-1.94(m,3H).
步骤D：将A403D(400mg,0.82mmol)溶于干燥的DMF(1mL)、DCM(40mL)和THF(20mL)中，氮气保护下冷至-40℃，缓慢滴加SOCl2(488mg,4.1mmol)，毕，搅拌反应1h，滴加吡啶(324mg,4.1mmol)维持此温度搅拌40分钟，加入Et3N(415mg,4.1mmol)，加毕，继续反应1h。LCMS显示反应完成。DCM(50mL)和加入H2O(2mL)淬灭反应，水相用DCM萃取(50mL×2)，食盐水洗(50mL×1)，无水硫酸钠干燥，过滤，减压浓缩至干，剩余物经C18柱纯化(CH3CN:H2O＝5％-45％,40min)得到白色固体A403(300mg,yield:78％,ee:99％)。
1H NMR(DMSO-d6,300MHz):δ10.96(br s,1H),7.46-7.51(m,2H),7.31-7.37(m,3H),7.16-7.22(m,1H),5.27(s,2H),5.05-5.13(m,0.04H),4.35(d,J＝17.7Hz,1H),4.19(d,J＝17.7Hz,1H),3.5.-3.53(m,4H),3.43(s,2H),2.82-2.94(m,1H),2.49-2.58(m,1H),2.36-2.41(m,1H),2.26-2.32(m,4H),1.91-1.98(m,1H).LCMS:469.2([M+1]+).
参照前述实施例67中的合成方法，用相应的底物替换4-(3-(氯甲基)-4-氟苯基)吗啉盐酸盐。就可以合成下列实施例68-69中的化合物。
实施例68化合物A404(S)-3-deuterium-3-(4-((2-fluoro-3-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A404.
Figure PCTCN2015088312-appb-000270
1H NMR(DMSO-d6,300MHz):δ10.94(s,1H),7.45-7.53(m,2H),7.31-7.42(m,3H),7.17-7.21(m,1H),5.28(s,2H),4.37(d,J＝18.0Hz,1H),4.21(d,J＝18.0Hz,1H),3.51-3.62(m,6H),2.82-2.95(m,1H),2.57-2.62(m,1H),2.28-2.42(m,5H),1.91-2.01(m,1H).LCMS:469.2([M+1]+).
实施例69化合物A406
(S)-3-deuterium-3-(4-((2-fluoro-4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A406.
Figure PCTCN2015088312-appb-000271
1H NMR(DMSO-d6,300MHz):δ10.98(s,1H),7.47-7.55(m,2H),7.31-7.38(m,2H),7.16-7.20(m,2H),5.24(s,2H),5.06-5.12(m,0.04H),4.35(d,J＝18.0Hz,1H),4.19(d,J＝18.0Hz,1H),3.55(br,4H),3.47(s,2H),2.82-2.94(m,1H),2.48-2.57(m,1H),2.33-2.42(m,5H),1.91-1.96(m,1H).LCMS:469.2([M+1]+).
实施例70化合物A400
(S)-3-deuterium-3-(4-((2-fluoro-3-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A400.
合成路线：
Figure PCTCN2015088312-appb-000272
实验部分
步骤A：向化合物A356C(400mg,1.44mmol)的MeOH溶液(30mL)中加入2-氟-3-(吗啉甲基)苯甲醛(481mg,2.16mmol)和HOAc(0.5mL)，30℃下搅拌过夜，将Pd/C(150mg,10％,50％water)加入到反应液中，氢气环境下剧烈搅拌3小时，过滤去除固体，减压浓缩滤液后得到产品A400A(580mg).
1H NMR(DMSO-d6,300MHz):δ7.57(br s,1H),7.06-7.31(m,5H),6.88-6.90(m,1H),6.58-6.60(m,1H),6.37(s,1H),4.26-4.54(m,4H),3.47-3.66(m,6H),2.23-2.37(m,4H),2.07-2.15(m,3H),1.85-1.97(m,1H).
步骤B：将A400A(480mg,0.99mmol)的DCM(20mL)溶液冷却到-40℃后滴加DMF(1mL)和SOCl2(589mg,4.95mmol)，搅拌2小时后加入吡啶(383mg,4.95mmol)，再搅拌30分钟后，将Et3N(501mg,4.95mmol)加入反应液，-40℃下继续搅拌1小时后将反应液倒入水(80mL)中淬灭反应，用DCM(80mL×3)萃取，合并有机相后，无水硫酸钠干燥，过滤、减压浓缩后经柱层析纯化(DCM/MeOH＝40/1)得到产品A400(251mg,54％).
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.20-7.31(m,3H),7.10(t,J＝7.8Hz,1H),6.95(d,J＝7.5Hz,1H),6.65(d,J＝7.8Hz,1H),6.29-6.32(m,1H),5.09-5.15(m,0.05H),4.43(d,J＝5.1Hz,2H),4.31(d,J＝17.1Hz,1H),4.19(d,J＝17.1Hz,1H),3.49-3.64(m,6H),2.87-2.99(m,1H),2.58-2.65(m,1H),2.25-2.44(m,5H),2.01-2.06(m,1H).LCMS:468.2([M+1]+).
参照前述实施例70中的合成方法，用相应的底物替换步骤A中的2-氟-3-(吗啉甲基)苯甲醛。就可以合成下列实施例71-72中的化合物。
实施例71化合物A401
(S)-3-deuterium-3-(4-((2-fluoro-5-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A401.
Figure PCTCN2015088312-appb-000273
1H NMR(DMSO-d6,400MHz):δ11.03(br s,1H),7.32(d,J＝6.8Hz,1H),7.12-7.23(m,3H),6.94(d,J＝7.6Hz,1H),6.62(d,J＝8.0Hz,1H),6.34(t,J＝6.0Hz,1H),5.11-5.16(m,0.4H),4.42(d,J＝5.6Hz,2H),4.31(d,J＝16.8Hz,1H),4.20(d,J＝17.2Hz,1H),3.42-3.49(m,4H),3.37(s,2H),2.89-2.98(m,1H),2.58-2.67(m,1H),2.28-2.35(m,1H),2.18-2.26(m, 4H),2.02-2.06(m,1H).LCMS:468.2[(M+1)+].
实施例72化合物A402
(S)-3-deuterium-3-(4-((2-fluoro-4-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A402.
Figure PCTCN2015088312-appb-000274
1H NMR(DMSO-d6,300MHz):δ11.01(s,1H),7.30-7.35(m,1H),7.22(t,J＝7.8Hz,1H),7.05-7.13(m,2H),6.92(d,J＝7.5Hz,1H),6.64(d,J＝8.1Hz,1H),6.27-6.31(m,1H),5.08-5.14(m,0.05H),4.38(d,J＝5.4Hz,2H),4.28(d,J＝17.4Hz,1H),4.16(d,J＝17.4Hz,1H),3.54(br s,4H),3.42(s,2H),2.85-2.97(m,1H),2.56-2.62(m,1H),2.24-2.31(m,5H),1.98-2.06(m,1H).LCMS:468.2([M+1]+).
实施例73化合物A405
3-(6-fluoro-4-((4-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A405.
合成路线：
Figure PCTCN2015088312-appb-000275
步骤A：-70℃氮气保护下将(COCl)2(152mg,1.2mmol)加入到DMSO(156mg,2.0mmol)的DCM溶液(10mL)中,维持温度-70℃继续搅拌30分钟，然后加入4-(吗啉甲基)-苯甲醇(207mg,1.0mmol)的3mL DCM溶液继续搅拌1小时。滴入Et3N(405mg,4.0mmol)，维持温度-70℃继续搅拌1小时后升至25℃，滴加水(10mL)淬灭反应，加入NaHCO3溶液(5mL)。分液，水相用10mL DCM萃取，合并有机相浓缩后柱层析(PE:EtOAc＝2:1)得浅黄色油状产品A405A(180mg，收率：88％)。
1H NMR(CDCl3,300MHz):δ9.99(s,1H),7.84(d,J＝7.8Hz,2H),7.51(d,J＝8.1Hz,2H),3.70-3.73(m,4H),3.57(s,2H),2.46(t,J＝4.2Hz,4H).
步骤B:25℃下将A405A(111mg,0.54mmol)和I-28(100mg,0.36mmol)溶解于HOAc(6mL)和DCM(6mL)的混合溶液中搅拌3小时后加入NaBH3CN(45mg,0.72mmol)， 室温反应过夜。补加A405A(40mg,0.14mmol)，40℃反应6小时。减压浓缩除去溶剂，加入NaHCO3(10mL)和DCM(25mL)，分液，水相用DCM萃取(20mL×2)，合并有机相，。减压浓缩除去溶剂Prep-HPLC纯化(含0.5％TFA)后，冷冻干燥所得固体加入5mL NaHCO3饱和溶液调pH值为8，用DCM萃取(5mL×5)蒸干得白色固体产物A405(50mg,收率：30％)。
1H NMR(DMSO-d6,300MHz):δ11.01(s,1H),7.23-7.33(m,4H),6.72(br s,1H),6.60(dd,J＝1.8Hz,7.5Hz,1H),6.42(dd,J＝2.1Hz,12.6Hz,1H),5.09(dd,J＝5.1Hz,13.2Hz,1H),4.35(d,J＝5.4Hz,2H),4.27(d,J＝17.4Hz,1H),4.14(d,J＝17.4Hz,1H),3.53(br s,4H),3.41(s,2H),2.84-2.96(m,1H),2.57-2.63(m,1H),2.21-2.31(m,5H),2.01-2.05(m,1H).LCMS:467.2([M+1]+).
实施例74化合物A386
3-(4-((2-fluoro-4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A386.
合成路线：
Figure PCTCN2015088312-appb-000276
实验部分：
步骤A.向2-氟-4-吗啉甲基苯甲醇(1.0g,4.4mmol)的氯仿溶液(25mL)中加入SOCl2(1.1g,9.2mmol)。加热回流反应2小时后蒸干溶剂，用25mL氯仿带蒸两次得白色固体产品A386A(1.2g，收率:97％)。
1H NMR(DMSO-d6,400MHz):δ11.98(br s,1H),7.70(d,J＝10.8Hz,1H),7.63(t,J＝8.0Hz,1H),7.70(d,J＝7.6Hz,1H),4.82(s,2H),4.37(d,J＝4.8Hz,2H),3.86-3.93(m,4H),3.07-3.21(m,4H).
步骤B：A386A、A386B(0.8g,2.4mmol)，K2CO3(1.3g,9.6mmol)的DMF(20mL)溶液氮气置换后加热至40℃反应18小时。反应液倒入100mL冰水中用EtOAc萃取(20mL×5)，合并有机相用水(20mL)，食盐水(20mL)洗，干燥后浓缩，硅胶柱层析纯化(PE:EtOAc＝2：1至1：1)得白色固体产品A386C(1.2g，收率:92％)。
1H NMR(CDCl3,300MHz):δ7.37-7.47(m,3H),7.10-7.16(m,3H),6.30(br s,1H),5.33 (br s,1H),5.18(s,2H),4.86-4.91(m,1H),4.36-4.51(m,2H),3.71-3.74(m,4H),3.51(s,2H),2.45-2.48(m,4H),2.09-2.40(m,4H),1.42(s,9H).
步骤C：向A386C(1.2g,2.2mmol)的DCM(30mL)溶液加入TFA(15mL)，35℃下搅拌反应2小时。反应液减压浓缩至干，剩余物经Prep-HPLC纯化得浅黄色固体产品A386E(1.4g,收率：64％)。
1H NMR(DMSO-d6,300MHz):δ12.05(br s,1H),7.56(br s,2H),7.47(t,J＝8.1Hz,1H),7.29-7.36(m,4H),7.15-7.22(m,1H),5.25(s,2H),4.68-4.73(m,1H),4.50(d,J＝17.7Hz,1H),4.36(d,J＝17.7Hz,1H),3.56-3.60(m,6H),2.26-2.45(m,2H),1.94-2.16(m,4H),1.72-1.77(m,2H).
步骤D：A386E(421mg,0.867mmol)溶于DCM/THF(50mL/5mL)后降温至-40℃加入SOCl2(516mg,4.33mmol)的DCM(10mL)溶液。-40至-20℃反应2小时后加入吡啶(339mg,4.33mmol)，-40℃搅拌半小时后加入Et3N(438mg,4.33mmol)。缓慢升至25℃，加入0.5mL水淬灭反应。过滤，滤饼用5mL CH3CN溶解，滤除不溶物蒸干得粗品；DCM用水(25mL×2)洗，食盐水(25mL)洗，蒸干。合并粗品用prep-HPLC纯化两次得白色固体产物A386(105mg，收率：26％)。
1H NMR(DMSO-d6,300MHz):δ10.95(s,1H),7.49-7.58(m,2H),7.34-7.40(m,2H),7.17-7.21(m,2H),5.26(s,2H),5.07-5.13(m,1H),4.38(d,J＝17.7Hz,1H),4.22(d,J＝17.7Hz,1H),3.58(br s,4H),3.49(br s,2H),2.84-2.96(m,1H),2.56-2.60(m,1H),2.30-2.43(m,5H),1.92-2.02(m,1H).
实施例75化合物A425
3-deuterium-3-(4-((2-fluoro-5-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A425.
Figure PCTCN2015088312-appb-000277
参照前述实施例67中的合成方法，用相应的外消旋混合物A403A为底物，就可以合成实施例75中的化合物A425。
1H NMR(DMSO-d6,300MHz):δ10.95(s,1H),7.49-7.57(m,2H),7.33-7.40(m,2H),7.18-7.22(m,2H),5.26(s,2H),4.37(d,J＝17.7Hz,2H),4.21(d,J＝17.7Hz,1H),3.58-3.62(m,4H),3.49(s,2H),2.84-2.96(m,1H),2.27-2.58(m,6H),1.93-1.99(m,1H).LCMS＝ 469.2([M+1]+).
实施例76化合物A427
3-deuterium-3-(4-((4-((2,6-dimethylmorpholino)methyl)-2-fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A427.
Figure PCTCN2015088312-appb-000278
参照前述实施例67中的合成方法，用相应的底物替换4-(3-(氯甲基)-4-氟苯基)吗啉盐酸盐[4-(3-(chloromethyl)-4-fluorobenzyl)morpholine hydrochloride]。就可以合成实施例76中的化合物,A427。
1H NMR(DMSO-d6,300MHz):δ10.97(s,1H),7.49-7.58(m,2H),7.34-7.41(m,2H),7.17-7.21(m,2H),5.26(s,2H),4.38(d,J＝17.7Hz,1H),4.21(d,J＝17.7Hz,1H),3.54-3.61(m,2H),3.47(s,2H),2.84-2.96(m,1H),2.53-2.68(m,3H),2.38-2.44(m,1H),1.93-1.99(m,1H),1.66(t,J＝10.5Hz,2H),1.02(d,J＝6.0Hz,6H).LCMS:497.2([M+1]+).
实施例77化合物A426
3-deuterium-3-(4-((2-fluoro-4-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A426.
Figure PCTCN2015088312-appb-000279
参照前述实施例70中的合成方法，用相应的外消旋混合物A400A为底物，就可以合成实施例77中的化合物A426。
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.32(t,J＝8.1Hz,1H),7.22(t,J＝7.8Hz,1H),7.05-7.13(m,2H),6.93(d,J＝7.5Hz,1H),6.64(d,J＝8.1Hz,1H),6.27(t,J＝6.0Hz,1H),5.07-5.13(m,0.01H),4.38(d,J＝5.4Hz,2H),4.28(d,J＝17.1Hz,1H),4.16(d,J＝17.1Hz,1H),3.52-3.55(m,4H),3.42(s,2H),2.85-2.97(m,1H),2.56-2.65(m,1H),2.23-2.35(m,5H),1.99-2.06(m,1H).LCMS:468.2([M+1]+).
实施例78化合物A428
3-deuterium-3-(4-((4-((2,6-dimethylmorpholino)methyl)-2-fluorobenzyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione,A428.
Figure PCTCN2015088312-appb-000280
参照前述实施例70中的合成方法，用相应的底物替换步骤A中的2-氟-3-(吗啉甲基)苯甲醛，就可以合成实施例78中的化合物,A428。
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.34(t,J＝7.8Hz,1H),7.24(t,J＝7.8Hz,1H)7.06-7.13(m,2H),6.95(d,J＝7.5Hz,1H),6.67(d,J＝7.8Hz,1H),6.28(t,J＝5.7Hz,1H),4.40(d,J＝5.1Hz,2H),4.30(d,J＝17.1Hz,1H),4.18(d,J＝17.1Hz,1H),3.52-3.61(m,2H),3.42(s,2H),2.87-2.99(m,1H),2.59-2.65(m,3H),2.35-2.25(m,1H),2.01-2.06(m,1H),1.63(t,J＝10.5Hz,2H),1.01(d,J＝6.0Hz,6H).LCMS:496.2([M+1]+).
效果实施例
TNF-α活性抑制实验方法
采集健康志愿者的外周血并用EDTA抗凝管收集。将血液用1640培养基(Gibco,产品目录号11875-093,USA)稀释5倍后加入到96孔细胞培养板中(Costar,产品目录号3599,USA)，然后用10μL本发明通式(I)化合物的DMSO(Sigma，产品目录号D2650,USA)溶液处理，化合物的终浓度为100nM，DMSO的终浓度为0.2％。在37℃，5％CO2培养箱中孵育60分钟后，于反应体系中加入10μL LPS(Sigma,产品目录号L-2880,USA)，终浓度10ng/mL，再在37℃，5％CO2条件下继续培养6小时后。收集上清液，TNF-α含量通过ELISA方法(BD Biosciences,产品目录号555212,USA)测定。用读板仪器检测吸收光强度,检测OD450nm值，以OD650nm值作为参考，以含0.2％DMSO培养基的溶液对照组作为0％抑制。记录原始数据和标准曲线。通过XL-fit软件，绘制四参数药物抑制曲线并计算每个化合物的抑制率，具体见表1。
表1
Figure PCTCN2015088312-appb-000281
Figure PCTCN2015088312-appb-000282
细胞增殖实验方法
将MM.1S细胞(骨髓瘤细胞)(ATCC,产品目录号CRL-2974)按每孔1.8×103个接种至含有RPMI-1964培养基(Gibco,产品目录号A10491-01)的96-孔培养板中，置于37℃,5％CO2培养箱内培养24小时。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(DMSO终浓度为0.5％)后加入各孔，在37℃,5％CO2培养箱内孵育72小时。之后，每孔加入20μl MTS(Promega,产品目录号G3581)，在37 ℃,5％CO2培养箱内再培养1-4小时。检测OD490nm，以OD650nm值作为参考，以含0.5％DMSO培养基的溶液对照组作为0％抑制。用GraphPad Prism 5软件，允许变斜率制作量效曲线并计算IC50值，具体见表2。
表2
Figure PCTCN2015088312-appb-000283
Figure PCTCN2015088312-appb-000284
注：A:<300nM；B::≥300nM。
CTG细胞增殖实验方法
将Rec-1细胞(套细胞淋巴瘤细胞)(ATCC,产品目录号CRL-3004)，Namalwa.CSN/70细胞(伯基特淋巴瘤细胞)(DSMZ，产品目录号ACC-70)，WSU-DLCL-2细胞(弥漫性大B细胞淋巴瘤细胞)(DSMZ，产品目录号ACC-575)，按每孔(5-15)×103个接种至含有特定培养基的底透壁白的96-孔培养板(Corning，产品目录号CLS3903)中，置于37℃，5％CO2培养箱内培养24小时。化合物用DMSO(Sigma，产品目录号276855)配成150mM的储备液，用培养基稀释至所需浓度(DMSO终浓度为0.2％)后加入各孔，在37℃，5％CO2培养箱内孵育72-120小时。之后，每孔加入100μl
Figure PCTCN2015088312-appb-000285
细胞活性检测试剂(Promega，产品目录号G7570)，在振板机上混匀10分钟，诱导细胞溶解。将96孔板在室温中放置10分钟，使其发光信号稳定。粘贴白色的底膜于培养板底部，使用EnSpire测板。通过XLfit软件进行数据处理，获得IC50值，具体见表3。
表3
Figure PCTCN2015088312-appb-000286
Figure PCTCN2015088312-appb-000287
注:A:<100nM；B:100-400nM；C:401nM-300μM；D:>300μM.
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (16)

  1. 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、立体异构体、同位素化合物、代谢物或前药：
    Figure PCTCN2015088312-appb-100001
    通式(I)中，n1选自0或1；
    Z为
    Figure PCTCN2015088312-appb-100002
    其中，用*标注的碳为不对称中心；
    R1、R3、R4、R5、R6、R7、R8和R9独立地选自H或D；
    R2选自H、D或卤素；
    L1和L2独立地选自CD2、CHD或CH2；
    X选自NH、ND或O；
    R10为H、D或
    Figure PCTCN2015088312-appb-100003
    其中R1’、R2’、R3’、R4’和R5’分别独立地选自H、D、卤素、氰基、羟基、
    Figure PCTCN2015088312-appb-100004
    取代或未取代的(C1-C12)烷基、取代或未取代的(C1-C12)烷氧基、(C2～C20)杂环烷基或氘代(C2～C20)杂环烷基；其中，Ra和Rb独立地为H、(C1-C12)烷基或(C1-C12)烷基酰基；Rc和Rd独立地为H或(C1～C12)烷基；Re为
    Figure PCTCN2015088312-appb-100005
    或(C2-C20)杂环烷基；Re1和Re2独立地为H或(C1-C12)烷基；
    所述的取代的(C1-C12)烷氧基中的取代基选自下列基团中的一个或多个：D、卤素、羟基、(C1-C12)烷氧基、(C2-C20)杂环烷基、(C1-C12)烷基取代的(C2-C20)杂环烷基、
    Figure PCTCN2015088312-appb-100006
    或
    Figure PCTCN2015088312-appb-100007
    其中Rf和Rg独立地为H或(C1-C12)烷基；Rh为(C2-C20)的杂环烷基；
    所述的取代的(C1-C12)烷基中的取代基选自下列基团中的一个或多个：D、(C2-C20)杂环烷基、氘代(C2-C20)杂环烷基、(C1-C12)烷基取代的(C2-C20)杂环烷基或氘代(C1-C12)烷基取代的(C2-C20)杂环烷基；
    当所述的取代的(C1-C12)烷氧基或所述的取代的(C1-C12)烷氧基中的取代基为多个时，所述的取代基相同或不同；
    上述各基团中，所述的(C2-C20)的杂环烷基、所述的氘代(C2-C20)杂环烷基、所述的(C1-C12)烷基取代的(C2-C20)杂环烷基或所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基中所述的(C2-C20)杂环烷基中的杂原子选自O、N和S中的一个或多个；
    条件是：通式(I)中，当n1为0时，R1、R3和R10为H或D，X为NH或ND，R2为卤素；
    条件是：通式(I)中，当n1为1，X为O，R2为H或D时，R10为
    Figure PCTCN2015088312-appb-100008
    或
    Figure PCTCN2015088312-appb-100009
    当R10为
    Figure PCTCN2015088312-appb-100010
    时，Re为(C2-C20)杂环烷基；
    条件是：通式(I)中，当n1为1，X为NH时，R10为
    Figure PCTCN2015088312-appb-100011
    条件是：通式(I)和Z中，当n1为1，X为NH，R1～R9均为H，L1和L2均为CH2时，R10不为
    Figure PCTCN2015088312-appb-100012
    或者
    Figure PCTCN2015088312-appb-100013
  2. 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、立体异构体、同位素化合物、代谢物或前药，其特征在于，
    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；
    和/或，通式(I)中，所述的Z为下列任一结构：
    Figure PCTCN2015088312-appb-100014
    Figure PCTCN2015088312-appb-100015
  3. 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、立体异构体、同位素化合物、代谢物或前药，其特征在于，
    通式(I)中，所述的(C2-C20)的杂环烷基、所述的氘代(C2-C20)杂环烷基、所述的(C1-C12)烷基取代的(C2-C20)杂环烷基或所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基中所述的(C2-C20)杂环烷基是指杂原子为N或O，杂原子数为1-2个的(C2-C6)杂环烷基；和/或，通式(I)中，当R10为
    Figure PCTCN2015088312-appb-100016
    R1’、R2’、R3’、R4’和R5’分别独立地选自
    Figure PCTCN2015088312-appb-100017
    Figure PCTCN2015088312-appb-100018
    或取代的(C1-C12)烷氧基，Ra和Rb独立地为(C1-C12)烷基或(C1-C12)烷基酰基，Rc和Rd独立地为(C1～C12)烷基，Re为
    Figure PCTCN2015088312-appb-100019
    Re1和Re2独立地为(C1-C12)烷基，所述的取代的(C1-C12)烷氧基中的取代基为
    Figure PCTCN2015088312-appb-100020
    Rf和Rg独立地为(C1-C12)烷基时，所述 的(C1-C12)烷基酰基的结构为
    Figure PCTCN2015088312-appb-100021
    Ra1为(C1-C12)烷基；Ra、Rb、Ra1、Rc、Rd、Re1、Re2、Rf或Rg中，所述的(C1-C12)烷基为(C1-C4)烷基；和/或，通式(I)中，当R10为
    Figure PCTCN2015088312-appb-100022
    R1’、R2’、R3’、R4’和R5’分别独立地选自取代的(C1-C12)烷氧基，所述的取代的(C1-C12)烷氧基中的取代基选自(C1-C12)烷氧基时，所述的(C1-C12)烷氧基为(C1-C4)烷氧基；和/或，通式(I)中，当R10为
    Figure PCTCN2015088312-appb-100023
    R1’、R2’、R3’、R4’和R5’分别独立地选自取代的(C1-C12)烷氧基，所述的取代的(C1-C12)烷氧基中的取代基选自
    Figure PCTCN2015088312-appb-100024
    时，所述的
    Figure PCTCN2015088312-appb-100025
    为
    Figure PCTCN2015088312-appb-100026
    或
    Figure PCTCN2015088312-appb-100027
    通式(I)中，当R10为
    Figure PCTCN2015088312-appb-100028
    R1’、R2’、R3’、R4’和R5’分别独立地选自取代的(C1-C12)烷氧基，所述的取代的(C1-C12)烷氧基中的取代基选自
    Figure PCTCN2015088312-appb-100029
    时，所述的
    Figure PCTCN2015088312-appb-100030
  4. 如权利要求3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、立体异构体、同位素化合物、代谢物或前药，其特征在于，
    所述的(C2-C6)杂环烷基为四氢吡咯、吗啉基或哌嗪基；所述的(C1-C12)烷基取代的(C2-C20)杂环烷基或所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基中所述的(C1-C12)烷基为(C1-C4)烷基；所述的氘代(C2-C20)杂环烷基为
    Figure PCTCN2015088312-appb-100031
    所述的(C1-C12)烷基取代的(C2-C20) 杂环烷基为
    Figure PCTCN2015088312-appb-100032
    所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基为
    Figure PCTCN2015088312-appb-100033
    和/或，Ra、Rb、Ra1、Rc、Rd、Re1、Re2、Rf或Rg中，所述的(C1-C12)烷基为(C1-C4)烷基；所述的(C1-C4)烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；
    和/或，通式(I)中，当R10为
    Figure PCTCN2015088312-appb-100034
    R1’、R2’、R3’、R4’和R5’分别独立地选自取代的(C1-C12)烷氧基，所述的取代的(C1-C12)烷氧基中的取代基选自(C1-C4)烷氧基时，所述的(C1-C4)烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基。
  5. 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、立体异构体、同位素化合物、代谢物或前药，其特征在于，
    通式(I)中，当R10为
    Figure PCTCN2015088312-appb-100035
    R1’、R2’、R3’、R4’和R5’分别独立地选自卤素时，所述的卤素为F、Cl、Br或I；
    和/或，通式(I)中，当R10为
    Figure PCTCN2015088312-appb-100036
    R1’、R2’、R3’、R4’和R5’分别独立地选自取代或未取代的(C1-C12)烷基时，所述的取代或未取代的(C1-C12)烷基为取代或未取代的(C1-C4)烷基；
    和/或，通式(I)中，当R10为
    Figure PCTCN2015088312-appb-100037
    R1’、R2’、R3’、R4’和R5’分别独立地选自取代或未取代的(C1-C12)烷氧基时，所述的取代或未取代的(C1-C12)烷氧基为取代或未取 代的(C1-C4)烷氧基；和/或，通式(I)中，当R10为
    Figure PCTCN2015088312-appb-100038
    R1’、R2’、R3’、R4’和R5’分别独立地选自
    Figure PCTCN2015088312-appb-100039
    时，所述的
    Figure PCTCN2015088312-appb-100040
    和/或，通式(I)中，当R10为
    Figure PCTCN2015088312-appb-100041
    R1’、R2’、R3’、R4’和R5’分别独立地选自
    Figure PCTCN2015088312-appb-100042
    时，所述的
    Figure PCTCN2015088312-appb-100043
    和/或，通式(I)中，当R10为
    Figure PCTCN2015088312-appb-100044
    R1’、R2’、R3’、R4’和R5’分别独立地选自
    Figure PCTCN2015088312-appb-100045
    时，所述的
    Figure PCTCN2015088312-appb-100046
  6. 如权利要求5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、立体异构体、同位素化合物、代谢物或前药，其特征在于，
    通式(I)中，当R10为
    Figure PCTCN2015088312-appb-100047
    R1’、R2’、R3’、R4’和R5’分别独立地选自取代或未取代的(C1-C4)烷基时，所述的取代或未取代的(C1-C4)烷基为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或者取代或未取代的叔丁基；所述的取代的(C1-C12)烷基为
    Figure PCTCN2015088312-appb-100048
    Figure PCTCN2015088312-appb-100049
    和/或，通式(I)中，当R10为
    Figure PCTCN2015088312-appb-100050
    R1’、R2’、R3’、R4’和R5’分别独立地选自取代或未取代的(C1-C4)烷氧基时，所述的取代或未取代的(C1-C4)烷氧基为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、取代或未取代的正丁氧基、取代或未取代的异丁氧基或者取代或未取代的叔丁氧基；所述的取代的(C1-C12)烷氧基为
    Figure PCTCN2015088312-appb-100051
    Figure PCTCN2015088312-appb-100052
  7. 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、立体异构体、同位素化合物、代谢物或前药，其特征在于，
    R10中，所述的
    Figure PCTCN2015088312-appb-100053
    Figure PCTCN2015088312-appb-100054
    Figure PCTCN2015088312-appb-100055
    Figure PCTCN2015088312-appb-100056
  8. 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、晶型、立体异构体、溶剂化物、同位素化合物、代谢物或前药，其特征在于，通式(I)化合物为下列任一化合物：
    Figure PCTCN2015088312-appb-100057
    Figure PCTCN2015088312-appb-100058
    Figure PCTCN2015088312-appb-100059
    Figure PCTCN2015088312-appb-100060
    Figure PCTCN2015088312-appb-100061
    Figure PCTCN2015088312-appb-100062
    Figure PCTCN2015088312-appb-100063
    Figure PCTCN2015088312-appb-100064
    Figure PCTCN2015088312-appb-100065
    Figure PCTCN2015088312-appb-100066
    Figure PCTCN2015088312-appb-100067
    Figure PCTCN2015088312-appb-100068
    Figure PCTCN2015088312-appb-100069
    Figure PCTCN2015088312-appb-100070
    Figure PCTCN2015088312-appb-100071
    Figure PCTCN2015088312-appb-100072
    Figure PCTCN2015088312-appb-100073
    Figure PCTCN2015088312-appb-100074
    Figure PCTCN2015088312-appb-100075
    Figure PCTCN2015088312-appb-100076
    Figure PCTCN2015088312-appb-100077
    Figure PCTCN2015088312-appb-100078
    Figure PCTCN2015088312-appb-100079
    Figure PCTCN2015088312-appb-100080
    Figure PCTCN2015088312-appb-100081
    Figure PCTCN2015088312-appb-100082
    Figure PCTCN2015088312-appb-100083
    Figure PCTCN2015088312-appb-100084
    Figure PCTCN2015088312-appb-100085
    Figure PCTCN2015088312-appb-100086
    Figure PCTCN2015088312-appb-100087
    Figure PCTCN2015088312-appb-100088
    Figure PCTCN2015088312-appb-100089
    Figure PCTCN2015088312-appb-100090
    Figure PCTCN2015088312-appb-100091
    Figure PCTCN2015088312-appb-100092
  9. 一种如权利要求1～8任一项中所述的通式(I)所示的异吲哚啉衍生物的制备方法，其特征在于其采用方法A制备：
    所述的方法A包括下列步骤：将化合物A-06(1)进行如下所示的脱保护反应，制得化合物A(06a1)；再将化合物A(06a1)进行如下所示的酰胺化反应，制得通式(I)化合物；
    Figure PCTCN2015088312-appb-100093
    方法A中，化合物A-06(1)、A-06(a1)或通式(I)中，L1、L2、X、Z、*、R1～R10、n1的定义均如权利要求1～8任一项所述；Ra和Rb一个为
    Figure PCTCN2015088312-appb-100094
    另一个为
    Figure PCTCN2015088312-appb-100095
    Figure PCTCN2015088312-appb-100096
    Ra1和Rb1其中一个为
    Figure PCTCN2015088312-appb-100097
    另一个为
    Figure PCTCN2015088312-appb-100098
    中，Ra”和Rb”独立地为H或D；
    通式(I)中，当n1为0时，所述的通式(I)化合物还可进一步采用方法B制备，所述的方法B包括下列步骤：将化合物I-RS进行如下所示的还原反应，制得通式(I)化合物；
    Figure PCTCN2015088312-appb-100099
    方法B中，化合物I-RS或通式(I)中，R2为卤素，n1为0，X为NH或ND，R10为H或D；L1、Z、R1和R3的定义均如权利要求1或2所述；
    当通式(I)中，n1为1，X为NH或ND时，所述的通式(I)化合物还可进一步采用方法C制备，所述的方法C包括下列步骤：将化合物P-01与
    Figure PCTCN2015088312-appb-100100
    进行如下所示的还原胺化反应，制得通式(I)化合物；
    Figure PCTCN2015088312-appb-100101
    方法C中，
    Figure PCTCN2015088312-appb-100102
    化合物P-01或通式(I)中，X为NH或ND，n1为1，Rp1、Rp2和Rp3独立地为H或D；L1、L2、Z、R1、R2和R3的定义均如权利要求1或2所述；
    Figure PCTCN2015088312-appb-100103
    中，R10为
    Figure PCTCN2015088312-appb-100104
    R1’、R2’、R3’、R4’和R5’的定义如权利要求1-8任一项所述。
  10. 如权利要求9所述的制备方法，其特征在于，
    方法A中，当通式(I)中，n1为0时，所述的通式(I)化合物的制备方法，其还进一步包含下列步骤：将化合物A-05(1)进行如下所示的还原反应，制得所述的化合物A-06(1)；即可；
    Figure PCTCN2015088312-appb-100105
    其中，化合物A-05(1)和A-06(1)中，L1、L2、R1～R8、R10、Ra和Rb的定义均如权利要求9所述；化合物A-06(1)中，X为NH或ND，n1为0；R10为H或D；
    或者，方法A中，当通式(I)中，X为NH或ND，n1为1时，所述的通式(I)化合物的制备方法，其还可进一步包含下列步骤：将化合物A-05(2)与
    Figure PCTCN2015088312-appb-100106
    进行如下所示的还原胺化反应，制得所述的化合物A-06(1)；即可；
    Figure PCTCN2015088312-appb-100107
    其中，化合物A-05(2)和A-06(1)中，L1、L2、R1～R9、Ra和Rb的定义均如权利要求9所述；化合物A-06(1)中，X为NH或ND，n1为1；
    Figure PCTCN2015088312-appb-100108
    中，Rp3为H或D；R10为
    Figure PCTCN2015088312-appb-100109
    R1’、R2’、R3’、R4’和R5’的定义如权利要求1-8任一项所述；
    或者，方法A中，当通式(I)中，X为O，n1为1时，所述的通式(I)化合物的制备方法，其还进一步包含下列步骤：将化合物A-05(3)与
    Figure PCTCN2015088312-appb-100110
    进行如下所示的亲核取代反应，制得所述的化合物A-06(1)；即可；
    Figure PCTCN2015088312-appb-100111
    其中，化合物A-05(3)和A-06(1)中，L1、L2、R1～R8、Ra和Rb的定义均如权利要求9所述；化合物A-06(1)中，X为O，n1为1；
    Figure PCTCN2015088312-appb-100112
    中，R10为
    Figure PCTCN2015088312-appb-100113
    R1’、R2’、R3’、R4’和R5’定义如权利要求1-8任一项所述；
    或者，方法B中，所述的通式(I)化合物的制备方法，其还进一步包含下列步骤：将化合物A-03，与化合物A-04(2)或其盐进行如下所示的偶合反应，制得所述的化合物I-RS；
    Figure PCTCN2015088312-appb-100114
    其中，化合物A-03、A-04(2)或I-RS中，L1、Z、*、R1～R9的定义如权利要求9所述；化合物A-03中，Hal为卤素；
    或者，方法B中，所述的通式(I)化合物的制备方法，其还进一步包含下列步骤：将化合物A-05(1)先后进行脱保护及酰胺化反应，制得所述的化合物I-RS；
    Figure PCTCN2015088312-appb-100115
    其中，A-05(1)、A-06(a2)或I-RS中，L1、Z、*、R1～R8、Ra和Rb的定义均如权利要求9所述；Ra2和Rb2其中一个为
    Figure PCTCN2015088312-appb-100116
    另一个为
    Figure PCTCN2015088312-appb-100117
    中，Ra”和Rb”独立地为H或D；
    或者，方法C中，所述的通式(I)化合物的制备方法，其还进一步包含下列步骤：将化合物I-RS进行还原反应，制得化合物P-01；
    Figure PCTCN2015088312-appb-100118
    化合物I-RS或化合物P-01中，R2为H、D或卤素；Rp1和Rp2独立地为H或D；L1、L2、Z、R1和R3的定义均如权利要求1或2所述。
  11. 一种制备通式(I)所示的异吲哚啉衍生物的中间体化合物A-06(1)、A-06(a1)、I-RS或P-01：
    Figure PCTCN2015088312-appb-100119
    化合物A-06(1)、A-06(a1)、I-RS或P-01中，L1、L2、n1、Z、*、R1～R10的定义均同权利要求1-8任一项所述；化合物A-06(1)中，Ra和Rb一个为
    Figure PCTCN2015088312-appb-100120
    另一个为
    Figure PCTCN2015088312-appb-100121
    Figure PCTCN2015088312-appb-100122
    化合物A-06(a1)中，Ra1和Rb1其中一个为
    Figure PCTCN2015088312-appb-100123
    另一个为
    Figure PCTCN2015088312-appb-100124
    Figure PCTCN2015088312-appb-100125
    中，Ra”和Rb”独立地为H或D；化合物P-01中，Rp1和Rp2独立地为H或D。
  12. 一种药物组合物，其特征在于，其包括治疗和/或预防有效量的如权利要求1～8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、立体异构体、同位素化合物、代谢物和前药中的一种或多种。
  13. 如权利要求12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，所述的其它治疗剂为elotuzumab、palbociclib、nivolumab、pembrolizumab、panobinostat、PD-1抑制剂、PDL-1抑制剂、培美曲塞、托泊替康、阿霉素、硼替佐米、吉西他滨、达卡巴嗪、地塞米松、克拉霉素、长春新碱、阿糖胞苷、利妥昔单抗、曲妥珠单抗、泼尼松、多西他赛、氯法拉滨注射液、Ublituximab、romidepsin、HDAC抑制剂、雄激素受体抑制剂、雄激素生物合成抑制剂、BTK抑制剂、红血球生长激素、eltrombopag、米诺四环素、CAR-T和美法仑中的一种或多种。
  14. 一种如权利要求1-8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、立体异构体、同位素化合物、代谢物或前药，在制备治疗或预防由TNF-α产生的、或由TNF-α活性调节异常相关的疾病、病症或病况的药物中的应 用。
  15. 如权利要求14所述的应用，其特征在于，所述的疾病、病症或病况包括：骨髓增生异常综合征、多发性骨髓瘤、套细胞淋巴瘤、非霍奇金淋巴瘤、乳头状和滤泡状甲状腺癌、乳腺癌、前列腺癌、慢性淋巴细胞白血病、淀粉样变性、I型复杂性局部疼痛综合征、恶性黑色素瘤、神经根病、骨髓纤维化、成胶质细胞瘤、胶质肉瘤、恶性胶质瘤、难治性浆细胞瘤、慢性粒单核细胞白血病、滤泡性淋巴瘤、睫状体和慢性黑色素瘤、虹膜黑色素瘤、复发性两眼间黑色素瘤、眼外延伸黑色素瘤、实体瘤、T细胞淋巴瘤、红系淋巴瘤、成单核细胞和单核细胞白血病、髓性白血病、中枢神经系统淋巴瘤、脑肿瘤、脑膜瘤、脊髓肿瘤、甲状腺癌、非小细胞肺癌、卵巢癌、皮肤癌、肾细胞癌、骨髓纤维化、伯基特淋巴瘤、霍奇金淋巴瘤、大细胞淋巴瘤、弥漫性大B细胞淋巴瘤、星状细胞瘤、肝细胞癌或原发性巨球蛋白血症。
  16. 一种治疗或预防由TNF-α产生的、或由TNF-α活性调节异常相关的疾病、病症或病况的方法，其特征在于，所述的方法通过给予受试者治疗或预防有效量的如权利要求1-8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、立体异构体、同位素化合物、代谢物和前药中的一种或多种。
PCT/CN2015/088312 2014-10-30 2015-08-27 异吲哚啉衍生物、其中间体、制备方法、药物组合物及应用 WO2016065980A1 (zh)

Priority Applications (14)

Application Number Priority Date Filing Date Title
RU2017118453A RU2695521C9 (ru) 2014-10-30 2015-08-27 Производное изоиндолина, промежуточный продукт, способ получения, фармацевтическая композиция и ее применение
PL15855986T PL3214081T3 (pl) 2014-10-30 2015-08-27 Pochodna izoindoliny, półprodukt, sposób wytwarzania, kompozycja farmaceutyczna i ich zastosowanie
JP2017542243A JP6546997B2 (ja) 2014-10-30 2015-08-27 イソインドリン誘導体、その中間体、製造方法、薬物組成物及び応用
KR1020177014411A KR102191256B1 (ko) 2014-10-30 2015-08-27 이소인돌린 유도체, 이의 중간체, 제조방법, 약물 조성물 및 응용
ES15855986T ES2812877T3 (es) 2014-10-30 2015-08-27 Derivado de isoindolina, producto intermedio, método de preparación, composición farmacéutica y uso del mismo
DK15855986.4T DK3214081T3 (da) 2014-10-30 2015-08-27 Isoindolinderivat, mellemprodukt, fremgangsmåde til fremstilling, farmaceutisk sammensætning og anvendelse deraf
US15/523,651 US10017492B2 (en) 2014-10-30 2015-08-27 Isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof
CA2966038A CA2966038C (en) 2014-10-30 2015-08-27 Isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof
NZ731789A NZ731789A (en) 2014-10-30 2015-08-27 Isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof
AU2015341301A AU2015341301B2 (en) 2014-10-30 2015-08-27 Isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof
EP19214472.3A EP3643709B1 (en) 2014-10-30 2015-08-27 Isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof
PL19214472T PL3643709T3 (pl) 2014-10-30 2015-08-27 Pochodna izoindoliny, jej związek pośredni, sposób wytwarzania, kompozycja farmaceutyczna i zastosowanie
EP15855986.4A EP3214081B1 (en) 2014-10-30 2015-08-27 Isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof
CY20201100896T CY1123361T1 (el) 2014-10-30 2020-09-23 Παραγωγο ισοϊνδολινης, ενδιαμεσο, μεθοδος παρασκευης, φαρμακευτικη συνθεση και χρηση αυτου

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201410605148 2014-10-30
CN201410605148.8 2014-10-30
CN201410632870.0 2014-11-11
CN201410632870 2014-11-11

Publications (1)

Publication Number Publication Date
WO2016065980A1 true WO2016065980A1 (zh) 2016-05-06

Family

ID=55856570

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/088312 WO2016065980A1 (zh) 2014-10-30 2015-08-27 异吲哚啉衍生物、其中间体、制备方法、药物组合物及应用

Country Status (15)

Country Link
US (1) US10017492B2 (zh)
EP (2) EP3643709B1 (zh)
JP (1) JP6546997B2 (zh)
KR (1) KR102191256B1 (zh)
CN (2) CN111205268B (zh)
AU (1) AU2015341301B2 (zh)
CA (1) CA2966038C (zh)
CY (1) CY1123361T1 (zh)
DK (2) DK3214081T3 (zh)
ES (2) ES2901509T3 (zh)
NZ (1) NZ731789A (zh)
PL (2) PL3643709T3 (zh)
PT (2) PT3643709T (zh)
RU (1) RU2695521C9 (zh)
WO (1) WO2016065980A1 (zh)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105968133A (zh) * 2016-05-18 2016-09-28 大连和田科技有限公司 一种磷酸酯季铵盐杀菌剂的制备方法
US9695145B2 (en) 2013-01-22 2017-07-04 Celgene Corporation Processes for the preparation of isotopologues of 3-(4-((4- morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and pharmaceutically acceptable salts thereof
US9822094B2 (en) 2010-02-11 2017-11-21 Celgene Corporation Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same
WO2018001270A1 (en) * 2016-06-30 2018-01-04 Noratech Pharmaceuticals, Inc. Palbociclib prodrugs and composition thereof
WO2018010637A1 (en) * 2016-07-14 2018-01-18 Shanghai Meton Pharmaceutical Co., Ltd Iso-citrate dehydrogenase (idh) inhibitor
WO2018108147A1 (zh) 2016-12-16 2018-06-21 康朴生物医药技术（上海）有限公司 一种组合、其应用及治疗方法
WO2019040274A1 (en) * 2017-08-25 2019-02-28 Biotheryx, Inc. ETHER COMPOUNDS AND USES THEREOF
JP2020506216A (ja) * 2017-02-13 2020-02-27 カング バイオファーマシューティカルズ リミテッド 前立腺癌を治療する組み合わせ、薬物組成物および治療方法
CN110914253A (zh) * 2017-05-22 2020-03-24 微境生物医药科技(上海)有限公司 一类异吲哚酮-酰亚胺环-1,3-二酮-2-烯化合物、其组合物和用途
WO2020064002A1 (zh) 2018-09-30 2020-04-02 中国科学院上海药物研究所 异吲哚啉类化合物、其制备方法、药物组合物及用途
WO2020114482A1 (zh) 2018-12-06 2020-06-11 中国科学院上海药物研究所 一类异吲哚啉类化合物、其制备方法、药物组合物及其应用
US10717703B2 (en) 2017-08-21 2020-07-21 Celgene Corporation Processes for the preparation of (S)-tert-butyl 4,5-diamino-5-oxopentanoate
US20210113577A1 (en) * 2019-10-21 2021-04-22 Celgene Corporation Methods of treating hematological malignancies using 2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione
WO2021147889A1 (zh) 2020-01-20 2021-07-29 康朴生物医药技术（上海）有限公司 一种异吲哚啉衍生物、其药物组合物及应用
CN113582980A (zh) * 2020-04-30 2021-11-02 上海科技大学 基于杂环和戊二酰亚胺骨架的化合物及其应用
US11236103B2 (en) 2018-07-27 2022-02-01 Biotheryx, Inc. Bifunctional compounds
US11897930B2 (en) 2020-04-28 2024-02-13 Anwita Biosciences, Inc. Interleukin-2 polypeptides and fusion proteins thereof, and their pharmaceutical compositions and therapeutic applications

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10017492B2 (en) 2014-10-30 2018-07-10 Kangpu Biopharmaceuticals, Ltd. Isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof
WO2017054739A1 (zh) * 2015-09-29 2017-04-06 康朴生物医药技术（上海）有限公司 一种药物组合物及其应用
WO2017176958A1 (en) * 2016-04-06 2017-10-12 The Regents Of The University Of Michigan Monofunctional intermediates for ligand-dependent target protein degradation
TWI808055B (zh) 2016-05-11 2023-07-11 美商滬亞生物國際有限公司 Hdac 抑制劑與 pd-1 抑制劑之組合治療
TWI794171B (zh) 2016-05-11 2023-03-01 美商滬亞生物國際有限公司 Ｈｄａｃ抑制劑與ｐｄ-ｌ１抑制劑之組合治療
JP6737967B1 (ja) * 2017-07-18 2020-08-12 ロンザ リミテッドＬｏｎｚａ Ｌｉｍｉｔｅｄ ５−フルオロ−２−メチル−３−ニトロ安息香酸およびそのメチルエステルを製造する方法
ES2959622T3 (es) * 2018-04-23 2024-02-27 Celgene Corp Compuestos de 4-aminoisoindolina-1,3-diona sustituidos y su uso para tratar el linfoma
BR122022012697B1 (pt) 2018-07-10 2023-04-04 Novartis Ag Usos de derivados de 3-(5-hidróxi-1-oxoisoindolin-2-il)piperidina-2,6- diona, e kit
AR116109A1 (es) * 2018-07-10 2021-03-31 Novartis Ag Derivados de 3-(5-amino-1-oxoisoindolin-2-il)piperidina-2,6-diona y usos de los mismos
WO2020102195A1 (en) * 2018-11-13 2020-05-22 Biotheryx, Inc. Substituted isoindolinones
CN109776377B (zh) * 2019-02-01 2021-08-24 沈阳药科大学 吲哚啉类化合物及其制备方法和应用
AR119715A1 (es) * 2019-04-12 2022-01-05 Celgene Corp Métodos para tratar linfoma no hodgkin con el uso de 2-(2,6-dioxopiperidin-3-il)-4-((2-fluoro-4-((3-morfolinoazetidin-1-il)metil)bencil)amino)isoindolin-1,3-diona
CN113121573A (zh) * 2019-12-31 2021-07-16 成都百裕制药股份有限公司 嘌呤衍生物及其在医药上的应用
KR20220145366A (ko) * 2020-02-25 2022-10-28 상하이테크 유니버시티 글루타르이미드 골격을 기초로 하는 화합물 및 그 응용
JP2024504932A (ja) 2021-01-13 2024-02-02 モンテ ローザ セラピューティクス， インコーポレイテッド イソインドリノン化合物
WO2024027694A1 (zh) * 2022-08-01 2024-02-08 苏州开拓药业股份有限公司 一种蛋白降解剂
WO2024051766A1 (zh) * 2022-09-08 2024-03-14 标新生物医药科技(上海)有限公司 基于cereblon蛋白设计的分子胶化合物及其应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998003502A1 (en) * 1996-07-24 1998-01-29 Celgene Corporation Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and method of reducing tnf-alpha levels
WO2002059106A1 (en) * 2000-12-27 2002-08-01 Celgene Corporation Isoindole-imide compounds, compositions, and uses thereof
WO2002094180A2 (en) * 2000-11-14 2002-11-28 Celgene Corporation Pharmaceutically active isoindoline derivatives
WO2010053732A1 (en) * 2008-10-29 2010-05-14 Celgene Corporation Isoindoline compounds for use in the treatment of cancer
WO2011100380A1 (en) * 2010-02-11 2011-08-18 Celgene Corporation Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same
WO2012079022A1 (en) * 2010-12-10 2012-06-14 Concert Pharmaceuticals, Inc. Substituted dioxopiperidinyl phthalimide derivatives

Family Cites Families (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4678500A (en) 1984-06-29 1987-07-07 E. I. Du Pont De Nemours And Company Herbicidal 2,6-disubstituted benzylsulfonamides and benzenesulfamates
US5629327A (en) 1993-03-01 1997-05-13 Childrens Hospital Medical Center Corp. Methods and compositions for inhibition of angiogenesis
HU228769B1 (en) 1996-07-24 2013-05-28 Celgene Corp Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and their use for production of pharmaceutical compositions for mammals to reduce the level of tnf-alpha
US5955476A (en) * 1997-11-18 1999-09-21 Celgene Corporation Substituted 2-(2,6-dioxo-3-fluoropiperidin-3-yl)-isoindolines and method of reducing inflammatory cytokine levels
DE60231989D1 (de) 2001-08-06 2009-05-28 Childrens Medical Center Antiangiogenese wirkung von stickstoffsubstituierten thalidomid-analoga
TW200404054A (en) 2002-07-26 2004-03-16 Wako Pure Chem Ind Ltd Method for deuteration of aromatic ring
JP4943845B2 (ja) 2003-09-17 2012-05-30 ザ ガバメント オブ ザ ユナイテッド ステイツ オブ アメリカ アズ リプレゼンティッド バイ ザ セクレタリー オブ ザ デパートメント オブ ヘルス アンド ヒューマン サービシーズ サリドマイド類似体
US20060058311A1 (en) 2004-08-14 2006-03-16 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation
BRPI0514865A (pt) 2004-09-03 2008-06-24 Celgene Corp processo para preparar um composto
MX2008002765A (es) * 2005-08-31 2008-04-07 Celgene Corp Compuestos de isoindol-imida y composiciones que la comprenden y metodos para usar los mismos.
NZ575689A (en) * 2006-09-15 2011-12-22 Celgene Corp N-methylaminomethyl isoindole compounds and compositions comprising and methods of using the same
NZ599199A (en) * 2007-03-20 2013-10-25 Celgene Corp 4'-o-substituted isoindoline derivatives and compositions comprising and methods of using the same
US8288414B2 (en) 2007-09-12 2012-10-16 Deuteria Pharmaceuticals, Inc. Deuterium-enriched lenalidomide
US9045453B2 (en) * 2008-11-14 2015-06-02 Concert Pharmaceuticals, Inc. Substituted dioxopiperidinyl phthalimide derivatives
JP5647615B2 (ja) 2008-11-14 2015-01-07 コンサート ファーマシューティカルズ インコーポレイテッド 置換ジオキソピペリジニルフタルイミド誘導体
US20120053159A1 (en) 2009-02-11 2012-03-01 Muller George W Isotopologues of lenalidomide
CN101580501B (zh) 2009-06-01 2011-03-09 南京卡文迪许生物工程技术有限公司 3-(取代二氢异吲哚酮-2-基)-2,6-哌啶二酮的合成方法及其中间体
BRPI1012313B1 (pt) * 2009-06-18 2020-03-24 Concert Pharmaceuticals, Inc. Compostos derivados de isoindolina-1,3-diona substituída, uso dos mesmos e composição farmacêutica
US8841325B2 (en) * 2009-11-24 2014-09-23 Celgene Corporation Immunomodulatory compounds for the restoration of vitamin D sensitivity in vitamin D resistant tumor cells
WO2011160042A2 (en) 2010-06-18 2011-12-22 Makoto Life Sciences, Inc. Prpk-tprkb modulators and uses thereof
JP2013543009A (ja) 2010-11-18 2013-11-28 デューテリア ファーマシューティカルズ， インコーポレイテッド ３−ジュウテロ−ポマリドマイド
US8927725B2 (en) 2011-12-02 2015-01-06 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Thio compounds
US9695145B2 (en) 2013-01-22 2017-07-04 Celgene Corporation Processes for the preparation of isotopologues of 3-(4-((4- morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and pharmaceutically acceptable salts thereof
WO2014180882A2 (en) 2013-05-07 2014-11-13 Universitat De Barcelona Treatment of brain metastasis from cancer
US10017492B2 (en) 2014-10-30 2018-07-10 Kangpu Biopharmaceuticals, Ltd. Isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998003502A1 (en) * 1996-07-24 1998-01-29 Celgene Corporation Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and method of reducing tnf-alpha levels
WO2002094180A2 (en) * 2000-11-14 2002-11-28 Celgene Corporation Pharmaceutically active isoindoline derivatives
WO2002059106A1 (en) * 2000-12-27 2002-08-01 Celgene Corporation Isoindole-imide compounds, compositions, and uses thereof
WO2010053732A1 (en) * 2008-10-29 2010-05-14 Celgene Corporation Isoindoline compounds for use in the treatment of cancer
WO2011100380A1 (en) * 2010-02-11 2011-08-18 Celgene Corporation Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same
WO2012079022A1 (en) * 2010-12-10 2012-06-14 Concert Pharmaceuticals, Inc. Substituted dioxopiperidinyl phthalimide derivatives

Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10669257B2 (en) 2010-02-11 2020-06-02 Celgene Corporation Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same
US10189814B2 (en) 2010-02-11 2019-01-29 Celgene Corporation Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same
US9822094B2 (en) 2010-02-11 2017-11-21 Celgene Corporation Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same
US9828361B2 (en) 2010-02-11 2017-11-28 Celgene Corporation Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same
US11414399B2 (en) 2010-02-11 2022-08-16 Celgene Corporation Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same
US9969712B2 (en) 2013-01-22 2018-05-15 Celgene Corporation Process for the preparation of isotopologues of 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and pharmaceutically acceptable salts thereof
US9695145B2 (en) 2013-01-22 2017-07-04 Celgene Corporation Processes for the preparation of isotopologues of 3-(4-((4- morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and pharmaceutically acceptable salts thereof
CN105968133A (zh) * 2016-05-18 2016-09-28 大连和田科技有限公司 一种磷酸酯季铵盐杀菌剂的制备方法
WO2018001270A1 (en) * 2016-06-30 2018-01-04 Noratech Pharmaceuticals, Inc. Palbociclib prodrugs and composition thereof
WO2018010637A1 (en) * 2016-07-14 2018-01-18 Shanghai Meton Pharmaceutical Co., Ltd Iso-citrate dehydrogenase (idh) inhibitor
CN109641890B (zh) * 2016-07-14 2022-04-26 浙江迈同生物医药有限公司 异柠檬酸脱氢酶(idh)抑制剂
CN109641890A (zh) * 2016-07-14 2019-04-16 上海迈同生物科技有限公司 异柠檬酸脱氢酶(idh)抑制剂
US10752626B2 (en) 2016-07-14 2020-08-25 Shanghai Meton Pharmaceutical Co., Ltd Iso-citrate dehydrogenase (IDH) inhibitor
CN110049765A (zh) * 2016-12-16 2019-07-23 康朴生物医药技术（上海）有限公司 一种组合、其应用及治疗方法
RU2731535C1 (ru) * 2016-12-16 2020-09-04 Канпу Биофармасьютикалз, Лтд. Комбинация, ее применение и способ лечения
US10933059B2 (en) 2016-12-16 2021-03-02 Kangpu Biopharmaceuticals. Ltd. Combination, application thereof and treatment method
CN110049765B (zh) * 2016-12-16 2022-02-01 康朴生物医药技术（上海）有限公司 一种组合、其应用及治疗方法
KR102368555B1 (ko) * 2016-12-16 2022-02-28 강푸 바이오파마슈티칼즈 리미티드 조성물, 이의 적용 및 치료 방법
JP2020510620A (ja) * 2016-12-16 2020-04-09 カンプ・バイオファーマスーティカルズ、リミテッドＫａｎｇｐｕ Ｂｉｏｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｌｔｄ 組み合わせ、その用途及び処置方法
US20190328722A1 (en) * 2016-12-16 2019-10-31 Kangpu Biopharmaceuticals, Ltd. Combination, application thereof and treatment method
WO2018108147A1 (zh) 2016-12-16 2018-06-21 康朴生物医药技术（上海）有限公司 一种组合、其应用及治疗方法
JP7048106B2 (ja) 2016-12-16 2022-04-05 カンプ・バイオファーマスーティカルズ、リミテッド 組み合わせ、その用途及び処置方法
KR20190097007A (ko) * 2016-12-16 2019-08-20 강푸 바이오파마슈티칼즈 리미티드 조성물, 이의 적용 및 치료 방법
AU2017376704B2 (en) * 2016-12-16 2021-08-05 Kangpu Biopharmaceuticals, Ltd. Composition, application thereof and treatment method
RU2733950C1 (ru) * 2017-02-13 2020-10-08 Канпу Биофармасьютикалс, Лтд. Комбинация для лечения рака предстательной железы, фармацевтическая композиция и способ лечения
JP2020506216A (ja) * 2017-02-13 2020-02-27 カング バイオファーマシューティカルズ リミテッド 前立腺癌を治療する組み合わせ、薬物組成物および治療方法
CN110914253B (zh) * 2017-05-22 2022-12-16 微境生物医药科技(上海)有限公司 一类异吲哚酮-酰亚胺环-1,3-二酮-2-烯化合物、其组合物和用途
CN110914253A (zh) * 2017-05-22 2020-03-24 微境生物医药科技(上海)有限公司 一类异吲哚酮-酰亚胺环-1,3-二酮-2-烯化合物、其组合物和用途
US10717703B2 (en) 2017-08-21 2020-07-21 Celgene Corporation Processes for the preparation of (S)-tert-butyl 4,5-diamino-5-oxopentanoate
US11912644B2 (en) 2017-08-21 2024-02-27 Celgene Corporation Processes for the preparation of (S)-tert-butyl 4,5-diamino-5-oxopentanoate
US11505522B2 (en) 2017-08-21 2022-11-22 Celgene Corporation Processes for the preparation of (S)-tert-butyl 4,5- diamino-5-oxopentanoate
JP2020531481A (ja) * 2017-08-25 2020-11-05 バイオセリックス， インコーポレイテッド エーテル化合物およびその使用
WO2019040274A1 (en) * 2017-08-25 2019-02-28 Biotheryx, Inc. ETHER COMPOUNDS AND USES THEREOF
US10513515B2 (en) 2017-08-25 2019-12-24 Biotheryx, Inc. Ether compounds and uses thereof
US10927104B2 (en) 2017-08-25 2021-02-23 Biotheryx, Inc. Ether compounds and uses thereof
US11236103B2 (en) 2018-07-27 2022-02-01 Biotheryx, Inc. Bifunctional compounds
WO2020064002A1 (zh) 2018-09-30 2020-04-02 中国科学院上海药物研究所 异吲哚啉类化合物、其制备方法、药物组合物及用途
WO2020114482A1 (zh) 2018-12-06 2020-06-11 中国科学院上海药物研究所 一类异吲哚啉类化合物、其制备方法、药物组合物及其应用
US11666579B2 (en) * 2019-10-21 2023-06-06 Celgene Corporation Methods of treating hematological malignancies using 2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione
US20210113577A1 (en) * 2019-10-21 2021-04-22 Celgene Corporation Methods of treating hematological malignancies using 2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione
WO2021147889A1 (zh) 2020-01-20 2021-07-29 康朴生物医药技术（上海）有限公司 一种异吲哚啉衍生物、其药物组合物及应用
US11897930B2 (en) 2020-04-28 2024-02-13 Anwita Biosciences, Inc. Interleukin-2 polypeptides and fusion proteins thereof, and their pharmaceutical compositions and therapeutic applications
WO2021219078A1 (zh) * 2020-04-30 2021-11-04 上海科技大学 基于杂环和戊二酰亚胺骨架的化合物及其应用
CN113582980A (zh) * 2020-04-30 2021-11-02 上海科技大学 基于杂环和戊二酰亚胺骨架的化合物及其应用
CN113582980B (zh) * 2020-04-30 2023-11-24 上海科技大学 基于杂环和戊二酰亚胺骨架的化合物及其应用

Also Published As

Publication number Publication date
JP2017533955A (ja) 2017-11-16
CN105566290A (zh) 2016-05-11
KR20170078740A (ko) 2017-07-07
AU2015341301A1 (en) 2017-06-01
RU2695521C9 (ru) 2019-08-19
EP3214081B1 (en) 2020-07-08
US10017492B2 (en) 2018-07-10
EP3214081A4 (en) 2018-08-15
ES2901509T3 (es) 2022-03-22
DK3214081T3 (da) 2020-09-28
EP3643709A1 (en) 2020-04-29
CA2966038A1 (en) 2016-05-06
RU2695521C2 (ru) 2019-07-23
JP6546997B2 (ja) 2019-07-17
AU2015341301B2 (en) 2019-05-16
CN111205268A (zh) 2020-05-29
NZ731789A (en) 2019-04-26
KR102191256B1 (ko) 2020-12-15
PT3643709T (pt) 2021-12-20
RU2017118453A (ru) 2018-12-04
EP3643709B1 (en) 2021-10-20
CN105566290B (zh) 2020-05-22
US20170313676A1 (en) 2017-11-02
PL3643709T3 (pl) 2022-02-21
CA2966038C (en) 2020-04-21
RU2017118453A3 (zh) 2019-01-17
DK3643709T3 (da) 2021-12-20
ES2812877T3 (es) 2021-03-18
CY1123361T1 (el) 2021-12-31
PT3214081T (pt) 2020-08-31
PL3214081T3 (pl) 2021-04-06
CN111205268B (zh) 2021-01-26
EP3214081A1 (en) 2017-09-06

Similar Documents

Publication Publication Date Title
CN111205268B (zh) 异吲哚啉衍生物、其中间体、制备方法、药物组合物及应用
TWI817929B (zh) 趨化介素受體調節劑及其用途
AU2022200946A1 (en) Modulators of the integrated stress pathway
US9969712B2 (en) Process for the preparation of isotopologues of 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and pharmaceutically acceptable salts thereof
CA3080801A1 (en) Modulators of the integrated stress pathway
CA3138144A1 (en) Substituted cyclolakyls as modulators of the integrated stress pathway
CA3080806A1 (en) Modulators of the integrated stress pathway
AU2023203860A1 (en) Modulators of the integrated stress pathway
US9682952B2 (en) Isotopologues of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl) piperidine-2-6-dione and methods of preparation thereof
CA3023164A1 (en) Modulators of the integrated stress pathway
CN104703978A (zh) (s)-3-(4-((4-(吗啉代甲基)苄基)氧基)-1-氧代异二氢吲哚-2-基)哌啶-2,6-二酮的盐和固体形式及包含所述盐和固体形式的组合物及其使用方法
CA2637245A1 (en) Inhibitors of tnf.alpha., pde4 and b-raf, compositions thereof and methods of use therewith
AU2015272560A1 (en) Novel anticancer agent
WO2011123937A1 (en) Kinase inhibitors and method of treating cancer with same
CA2595224A1 (en) Novel quinolinium salts and derivatives
TW202311262A (zh) Menin-mll交互作用之抑制劑
IL303492A (en) Adenosine A2A receptor antagonists
WO2020260857A1 (en) Hydroxamate compounds as antagonists of the adenosine a2a receptor

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15855986

Country of ref document: EP

Kind code of ref document: A1

DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
ENP Entry into the national phase

Ref document number: 2966038

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2017542243

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 15523651

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 20177014411

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2017118453

Country of ref document: RU

Kind code of ref document: A

REEP Request for entry into the european phase

Ref document number: 2015855986

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2015341301

Country of ref document: AU

Date of ref document: 20150827

Kind code of ref document: A