CN109422751A - One kind has the degradation active compound of tyrosine protein kinase JAK3 - Google Patents

One kind has the degradation active compound of tyrosine protein kinase JAK3 Download PDF

Info

Publication number
CN109422751A
CN109422751A CN201710783074.0A CN201710783074A CN109422751A CN 109422751 A CN109422751 A CN 109422751A CN 201710783074 A CN201710783074 A CN 201710783074A CN 109422751 A CN109422751 A CN 109422751A
Authority
CN
China
Prior art keywords
substituent group
alkyl
integer
compound
independently selected
Prior art date
Legal status (The legal status 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 status listed.)
Granted
Application number
CN201710783074.0A
Other languages
Chinese (zh)
Other versions
CN109422751B (en
Inventor
舒永志
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Zhi Zhi Medical Science And Technology Co Ltd
Original Assignee
Shanghai Zhi Zhi Medical Science And Technology Co Ltd
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
Application filed by Shanghai Zhi Zhi Medical Science And Technology Co Ltd filed Critical Shanghai Zhi Zhi Medical Science And Technology Co Ltd
Priority to CN201710783074.0A priority Critical patent/CN109422751B/en
Priority to CN201880004075.3A priority patent/CN109963853B/en
Priority to PCT/CN2018/103708 priority patent/WO2019042443A1/en
Publication of CN109422751A publication Critical patent/CN109422751A/en
Application granted granted Critical
Publication of CN109422751B publication Critical patent/CN109422751B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Dermatology (AREA)
  • Biomedical Technology (AREA)
  • Endocrinology (AREA)
  • Pulmonology (AREA)
  • Hematology (AREA)
  • Rheumatology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Oncology (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Emergency Medicine (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides one kind to have the degradation active compound of tyrosine protein kinase JAK3, and specifically, the present invention provides a kind of such as following formula I compound represented；Wherein, the definition of each group is as noted in the discussion.The compound of the present invention has good JAK3 degrading activity, can be used for preparing the drug of the relevant disease of JAK3 between treatment.

Description

One kind has the degradation active compound of tyrosine protein kinase JAK3
Technical field
The invention belongs to field of medicaments, have the degradation active chemical combination of tyrosine protein kinase JAK3 more particularly to one kind Object and its preparation and application.
Background technique
Janus kinases (JAKs) is to be present in intracellular non-receptor tyrosine protein kinase, to T cell growth, activation It is particularly significant with the multiple functions such as steady-state adjustment, it plays a crucial role in adjusting lymphohematological cell function.Mammal In, which contains 4 principal home's family members, i.e. JAK1, JAK2, JAK3 and Tyk2.Wherein, JAK1, JAK2 and Tyk2 The wide expression in various histocytes, the main high efficient expression in hematopoietic tissue of JAK3, the bone-marrow-derived lymphocyte, T lymph of such as activation Cell, bone marrow cell and thymocyte etc..
It is organ-graft refection, heterograft, lupus erythematosus, more due to the extensive adjustment effect of JAK3-STAT signal path Hair property hardening, rheumatoid arthritis, psoriasis (psoriasis), cancer, asthma, atopic dermatitis, type-1 diabetes mellitus and diabetes Complication, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer disease, leukaemia, lymph Many diseases such as tumor, Huppert's disease, alopecia areata, leucoderma also relate to JAK3, and JAK3 transmits member as signal It plays a crucial role in disease generation, becomes the drug targets that this kind of disease is treated in exploitation in medicine research and development.
Therefore, those skilled in the art, which are dedicated to developing, is able to suppress the active compound of JAK3.
Summary of the invention
It is able to suppress and the compound for the JAK3 that degrades it is an object of the invention to provide a kind of, and its preparation and application.
In the first aspect of the present invention, provides one kind such as following formula I compound represented or its is pharmaceutically acceptable Salt:
Wherein:
--- indicate singly-bound；
Indicate singly-bound or double bond；
A missing is selected from C (=O), C (=O) X1, SOX1, SO2The C of X1, with or without substituent group1-8Alkyl, band Have or without substituent group C1-8The C of cyclic hydrocarbon radical and with or without substituent group1-8Heterocyclic hydrocarbyl；Wherein X1 missing or choosing From (CR12R13)eO、(CR12R13)eS and NR14；Wherein R12、R13、R14It is independently selected from H, with or without substituent group C1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical and with or without substituent group C1-8Heterocyclic hydrocarbon Base, e are the integer (such as 1,2 or 3) between 0 to 3；
W missing is selected from O, NR17,-X2C (=O) X3 ,-X2S (=O)gX3；Wherein R17For H, with or without substituted The C of base1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbon Base；Wherein X2, X3 are independent lacks or is selected from O, S, NR18；The wherein integer that g is 0 to 2；Wherein R18For H, have or not C with substituent group1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8 Heterocyclic hydrocarbyl；
Y is (CR22R23)h、CHX4(CR22R23)h, CX4=CH (CR22R23)hOr (CR22R23)h；Wherein h is between 0 to 30 Integer；Wherein R22、R23It is independently selected from the C of H, cyano, hydroxyl, amino, with or without substituent group1-8Hydrocarbon The C of base, with or without substituent group1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl, have or not C with substituent group1-8Oxyl；Wherein X4=H, halogen, cyano, nitro, hydroxyl, with or without substituent group C1-8Hydrocarbon Oxygroup, with or without substituent group C1-8Hydrocarbon carbonyl oxygen, with or without substituent group C1-8Amido, with or without substituted Base C1-8Ester group, with or without substituent group C1-8Amino-carbonyl, with or without substituent group C1-8Alkyl, with or without Substituted base C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl；
Z is (CR24R25)i、CHX5(CR24R25)i, CX5=CH (CR24R25)iOr C ≡ C (CR24R25)i；Wherein i is 0 to 30 Between integer；Wherein R24、R25It is independently selected from the C of H, cyano, hydroxyl, amino, with or without substituent group1-8's Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl, with or without take For base C1-8Oxyl；Wherein X5=H, halogen, cyano, nitro, hydroxyl, with or without substituent group C1-8Oxyl, band Have or without substituent group C1-8Hydrocarbon carbonyl oxygen, with or without substituent group C1-8Amido, with or without substituent group C1-8Ester Base, with or without substituent group C1-8Amino-carbonyl, with or without substituent group C1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl；
B missing is selected from O, C=O, S, NR15、-NR15C (=O)-,-C (=O) NR15,-C (=O) O-, OC (=O) O-、-NR15C (=O) O- ,-OC (=O) NR15-、-NR15C (=O) NR16, with or without substituent group C1-12Alkyl, The C of with or without substituent group1-12Cyclic hydrocarbon radical and with or without substituent group C1-12Heterocyclic hydrocarbyl；Wherein R15、 R16It is independently selected from the C of H, with or without substituent group1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon The C of base and with or without substituent group1-8Heterocyclic hydrocarbyl；
X is selected from CR19R20, C (=O), S (=O), SO2、NR21；Wherein R19、R20Be independently selected from H, cyano, hydroxyl, The C of amino, with or without substituent group1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without The C of substituted base1-8Heterocyclic hydrocarbyl, with or without substituent group C1-8Oxyl；Wherein R21Selected from H, have or not C with substituent group1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8 Heterocyclic hydrocarbyl；
R1、R6、R10It is each independently selected from the C of H, with or without substituent group1-8Alkyl, with or without substituted The cyclic hydrocarbon radical of base, the heterocyclic hydrocarbyl of with or without substituent group, with or without substituent group C1-6Acyl group；
R2、R5It is independently selected from: hydrogen, OR33、NR34R35, cyano, halogen, with or without substituent group C1~8Hydrocarbon Base, the cyclic hydrocarbon radical of with or without substituent group, the heterocyclic hydrocarbyl of with or without substituent group, with or without substituent group C1-6The amide groups of acyl group, with or without substituent group；Wherein R33、R34、R35Be independently selected from H, with or without The C of substituted base1~8Alkyl, with or without substituent group cyclic hydrocarbon radical, the heterocyclic hydrocarbyl of with or without substituent group；
R3、R7、R8、R9It is independently selected from: H, OR27、NR28R29, cyano, halogen, nitro, with or without substituted The C of base1-8Alkyl, the cyclic hydrocarbon radical of with or without substituent group, the heterocyclic hydrocarbyl of with or without substituent group, X6S (=O)kR30, X6C (=O) R31；Wherein k is the integer between 0 to 2；Wherein R27, R28, R29, R30, R31It is independently selected from H, has Or the C without substituent group1~8Alkyl, cyclic hydrocarbon radical, heterocyclic hydrocarbyl；Wherein X6 lacks or is selected from O, S, NR32；Wherein R32For H, band Have or without substituent group C1-8Alkyl, with or without substituent group cyclic hydrocarbon radical and with or without substituent group Heterocyclic hydrocarbyl；
R4Selected from H, cyano, carboxyl, with or without substituent group C1-8Alkyl, with or without substituent group Hydrocarbon carbonyl oxygen；
A is the integer (such as 1,2,3,4,5) between 0 to 5；
B is the integer (such as 1,2,3) between 0 to 3；
C is the integer (such as 1,2,3,4,5,6,7,8,9) between 0 to 30；
D is the integer (such as 1,2,3,4,5,6,7,8,9) between 0 to 9.
In another preferred example, A is lacked；W is X2C (=O) X3, wherein X2 NR18And X3 missing or X3 are NR18And X2 is lacked；Y is (CR22R23)h, wherein R22、R23It is independently selected from H, hydroxyl, with or without substituent group C1-4Alkyl, h be 1 to 6 between integer；Z is (CR24R25)i, wherein R24、R25It is independently selected from H, hydroxyl, has Or the C without substituent group1-4Alkyl, i be 1 to 6 between integer；C is 0.
In another preferred example, A is lacked；W missing is O；Y is (CR22R23)h, wherein R22、R23It is independently selected from H, the C of hydroxyl, with or without substituent group1-4Alkyl, h be 0 to 3 between integer；B is O；Z is (CR24R25)i, wherein R24、R25It is independently selected from the C of H, hydroxyl, with or without substituent group1-4Alkyl, i be 0 to 3 between integer；c For the integer between 1 to 6.
In another preferred example, A is C (=O) X1, and wherein X1 lacks or be selected from (CR12R13)eAnd (CR O,12R13)eS, Middle e is the integer between 0 to 2, R12、R13、R14Independent is hydrogen or C1-4Alkyl；W is NR17, wherein R17For H or band Have or without substituent group C1-4Alkyl；Y is (CR22R23)h, wherein R22、R23Be independently selected from H, hydroxyl, have or Without the C of substituent group1-4Alkyl, h be 0 to 3 between integer；Z is (CR24R25)i, wherein R24、R25Choosing independent From H, hydroxyl, with or without substituent group C1-4Alkyl, i be 0 to 3 between integer；B is O；C is whole between 1 to 4 Number.
In another preferred example, A SO2X1, wherein X1 lacks or is selected from O and S；W is O；Y is (CR22R23)h, wherein R22、R23It is independently selected from the C of H, hydroxyl, with or without substituent group1-4Alkyl, h be 1 to 6 between integer；Z For (CR24R25)i, wherein R24、R25It is independently selected from the C of H, hydroxyl, with or without substituent group1-4Alkyl, i 0 Integer between to 3；C is 0.
In another preferred example, A is lacked；W is NR17, wherein R17For the H or C of with or without substituent group1-4Hydrocarbon Base；Y is (CR22R23)h, wherein R22、R23It is independently selected from the C of H, hydroxyl, with or without substituent group1-4Alkyl, h For the integer between 0 to 3；Z is (CR24R25)i, wherein R24、R25It is independently selected from H, hydroxyl, with or without substituted The C of base1-4Alkyl, i be 0 to 4 between integer；B is O；C is the integer between 1 to 6.
In another preferred example, A is lacked；W missing；Y is (CR22R23)h, wherein R22、R23It is independently selected from H, hydroxyl The C of base, with or without substituent group1-4Alkyl, h be 0 to 3 between integer；Z is (CR24R25)i, wherein R24、R25Respectively The independent C for being selected from H, hydroxyl, with or without substituent group1-4Alkyl, i be 0 to 3 between integer；B is O；C be 1 to Integer between 10 (between preferably 1 to 6).
In another preferred example, any substituent group is selected from the group: halogen, unsubstituted or halogenated C1-C6 alkyl, Unsubstituted or halogenated C1-C6 alkoxy, unsubstituted or halogenated C2-C6 alkoxyalkyl, unsubstituted or halogenated C3-C8 ring Alkyl, unsubstituted or halogenated C2-C6 alkyl-carbonyl, unsubstituted or halogenated C1-C6 alkylidene-hydroxyl, unsubstituted or C1-C6 Alkyl-substituted amido.
In another preferred example, in Formulas I,Indicate singly-bound.
In another preferred example, the X is C (=O).
In another preferred example, R1It is selected from: the C of H and with or without substituent group1-4Alkyl.
In another preferred example, R2、R5It is independently selected from: the C of hydrogen and with or without substituent group1-4Alkyl.
In another preferred example, R3It is selected from: the C of hydrogen and with or without substituent group1-4Alkyl.
In another preferred example, R6It is selected from: the C of hydrogen, with or without substituent group1-4Alkyl, OR29Wherein R29Selected from H, The C of with or without substituent group1-6Alkyl.
In another preferred example, R7It is selected from: the C of hydrogen, with or without substituent group1-4Alkyl and NR28R29, wherein R28R29For the H or C of with or without substituent group1-4Alkyl.
In another preferred example, R8It is selected from: the C of hydrogen, halogen and with or without substituent group1-4Alkyl.
In another preferred example, R9It is selected from: the C of hydrogen, halogen and with or without substituent group1-4Alkyl.
In another preferred example, R10Be selected from: hydrogen, halogen, cyano, nitro and with or without substituent group C1-4Alkane Base.
In another preferred example, R4Selected from H, cyano, with or without substituent group C1-6Alkyl.
The second aspect of the present invention, provides a kind of pharmaceutical composition, and the composition contains change described in first aspect Close object or its pharmaceutically acceptable salt, prodrug and pharmaceutically acceptable carrier.
In another preferred example, the effective quantity refers to therapeutically effective amount or inhibits effective quantity, preferably 0.01~ 99.99%.
In another preferred example, described pharmaceutical composition also includes another or a variety of antitumor agents.
In another preferred example, pharmaceutical composition degradation JAK3.
In another preferred example, the pharmaceutical composition is for treating JAK3 activity or the relevant disease of expression quantity.
The third aspect of the present invention provides the purposes of compound as described in the first aspect of the invention, is used for:
(a) drug of preparation treatment disease relevant to JAK3 activity or expression quantity；
(b) preparation JAK3 targets degradation agent；
(c) the external non-therapeutic ground JAK3 that degrades；
(d) inhibit tumor cell proliferation to external non-therapeutic；And/or
(e) treatment disease relevant to JAK3 activity or expression quantity.
In another preferred example, the disease relevant to JAK3 activity or expression quantity is tumour or autoimmune disease.
In another preferred example, the disease relevant to JAK3 activity or expression quantity is selected from the group: organ-graft refection, Xenograft rejection, lupus erythematosus, multiple sclerosis, rheumatoid arthritis, psoriasis (psoriasis), cancer, asthma, spy answer Property dermatitis, type-1 diabetes mellitus and diabetic complication, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer disease, leukaemia, lymthoma, Huppert's disease, alopecia areata and leucoderma etc..
The fourth aspect of the present invention provides a kind of preparation method of compound of formula I as described in the first aspect of the invention, Comprising steps of
(a) it in atent solvent, is reacted with formula IV compound and Formula II compound, obtains compound of formula I；
In the above formulas, each group is as defined above, M1For leaving group.
In another preferred example, the method also includes steps:
(b) it in atent solvent, is reacted with formula III compound and Formula V compound, obtains Formula II compound, M1、M2For from Remove group.
The fifth aspect of the present invention provides the method for JAK3 that degrades a kind of, comprising steps of applying to effective object effective The compound of formula I as described in the first aspect of the invention or its pharmaceutically acceptable salt of amount, or to inhibiting object application to inhibit A effective amount of pharmaceutical composition as described in the fourth aspect of the present invention.
In another preferred example, the degradation is external non-therapeutic.
In another preferred example, when applying a effective amount of Formulas I chemical combination as described in the first aspect of the invention to effective object When object or its pharmaceutically acceptable salt, the inhibition effective quantity is 0.001-500nmol/L, preferably 0.01- 200nmol/L。
The sixth aspect of the present invention provides a kind of method for treating disease relevant to JAK3 activity or expression quantity, institute The method of stating includes: the compound of formula I as described in the first aspect of the invention to treatment object application therapeutically effective amount, or such as this hair The bright 4th invention pharmaceutical composition.
In another preferred example, the object is mammal；Preferably, the mammal is behaved.
In another preferred example, the disease relevant to JAK3 activity or expression quantity is tumour or autoimmune disease.
In another preferred example, the disease relevant to JAK3 activity or expression quantity is selected from the group: organ-graft refection, Xenograft rejection, lupus erythematosus, multiple sclerosis, rheumatoid arthritis, psoriasis (psoriasis), cancer, asthma, spy answer Property dermatitis, type-1 diabetes mellitus and diabetic complication, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer disease, leukaemia, lymthoma, Huppert's disease, alopecia areata and leucoderma etc..
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist This no longer tires out one by one states.
Specific embodiment
The present inventor after extensive and in-depth study, is prepared for a kind of compound with structure shown in Formulas I, and find It is with JAK3 degrading activity.And the compound is at much lower concentrations, degradation can be generated to JAK3, activity is quite It is excellent, thus can be used for treating disease such as tumour relevant to JAK3 activity or expression quantity.This hair is completed on this basis It is bright.
The present invention provides the purposes of a kind of noval chemical compound and its tyrosine protein kinase JAK3 that degrades.Chemical combination of the invention Object can degrade JAK3, and can be used as JAK3 degradation agent two and wave immunoregulation effect, and the class for treating mammal Rheumatic arthritis, psoriasis, psoriasis arthropathica, ankylosing spondylitis, atopic dermatitis, keratoconjunctivitis sicca with And the diseases such as Crohn disease.
Term
In the present invention, term " C1-8Alkyl " refers to the functional group for containing only two kinds of carbon, hydrogen atoms, wherein of carbon atom Number is 1~8.Alkyl can be regarded as corresponding hydrocarbon and lose remaining free radical after a hydrogen atom, can be alkyl, cycloalkanes Base, alkenyl or alkynyl etc.；Its structure can be straight chain, branch or ring-type；It can be aliphatic, be also possible to aromatic.
Term " C1-6Alkyl " refers to the linear or branched alkyl group with 1~6 carbon atom, such as methyl, ethyl, propyl, different Propyl, butyl, isobutyl group, sec-butyl, tert-butyl, or similar group.
The term as used herein " alkoxy " includes O- alkyl, and " alkyl " therein is as defined above.
Term used herein " halogenated " unless otherwise directed, including fluoro, chloro, bromo or iodo.
The compound of the present invention can contain double bond.When containing this kind of double bond, the compound of the present invention is with cis-, trans- Or mixtures thereof exist.
Halogen described herein includes fluorine, chlorine, bromine and iodine.
Unless otherwise directed, the moieties of alkyl and alkoxy referred to herein can be straight chain, branch or ring-type 's.
In the present invention, term " cyclic hydrocarbon radical " refers to the functional group containing two kinds of carbon, hydrogen atoms.Including naphthenic base, cycloalkenyl (at least containing a carbon-carbon double bond) and aryl.They can be monocycle, bicyclic and polycyclic.They can be loop coil, can also be with It is condensed ring.
In the present invention, term " heterocyclic hydrocarbyl " refers to containing carbon, hydrogen and at least one heteroatomic function in addition to carbon, hydrogen Group.Including Heterocyclylalkyl, heterocycloalkenyl (at least containing a carbon-carbon double bond) and heteroaryl.One or more cyclization in ring is former Son is hetero atom.Hetero atom can be O, N and S atom and their various combinations.They can be monocycle, bicyclic and more Ring.They can be loop coil, be also possible to condensed ring.
In the present invention, term " substituent group " includes but is not limited to fluorine, chlorine, bromine, cyano, hydroxyl, amino, C1-6Oxyl, C1-6Halohydrocarbyl, C1-6Acyl group, C1-6Sulfonyl.
The term as used herein " oxyl " refers to O- alkyl, and " alkyl " therein is as defined above.
The term as used herein " hydrocarbon carbonyl oxygen " refers to C (=O) O- alkyl, and " alkyl " therein is as defined above.
The term as used herein " amido " refers to N (H or alkyl 1) (H or alkyl 2), and " alkyl " therein is as above to determine Justice.
The term as used herein " amino-carbonyl " refers to C (=O)-amido, and " amido " therein is as defined above.
The term as used herein " amide groups " refers to N (H or alkyl)-C (=O)-alkyl, and " alkyl " therein is institute as above Definition.
In the present invention, term " containing ", "comprising" or " comprising " indicate that various composition can be applied to of the invention mix together It closes in object or composition.Therefore, term " mainly by ... form " and " consist of " were included in term " containing ".
In the present invention, term " pharmaceutically acceptable " ingredient refers to suitable for people and/or animal and without excessive bad pair It reacts (such as toxicity, stimulation and allergy), that is, has the substance of reasonable benefit/risk ratio.
In the present invention, amount or table that term " effective quantity " refers to therapeutic agent treatment, alleviates or prevent target disease or situation Reveal the detectable amount for treating or preventing effect.The figure of the object is depended on for the accurate effective quantity of certain an object and is good for The combination of therapeutic agent and/or therapeutic agent that health situation, the property and degree of illness and selection are given.Therefore, standard is preassigned True effective quantity is useless.However, can determine the effective quantity with routine experiment for the situation that Mr. Yu gives, face Bed doctor can judge.
Herein, except place is illustrated, term " substitution " refers to that one or more hydrogen atoms on group are selected from down The substituent group of group replaces: halogen, unsubstituted or halogenated C1-6Alkyl, unsubstituted or halogenated C2-6It is acyl group, unsubstituted or halogenated C1-6Alkyl-hydroxyl.
Unless stated otherwise, in the present invention, the compound occurred is intended to including all possible optical isomer, Such as the compound of single chiral or the mixture (i.e. racemic modification) of various different chipal compounds.All chemical combination of the invention Among object, each asymmetric carbon atom can be optionally the mixture of R configuration or S configuration or R configuration and S configuration.
As used herein, term " the compounds of this invention " refers to Formulas I compound represented.The term further includes and Formulas I chemical combination Various crystalline forms, pharmaceutically acceptable salt, hydrate or the solvate of object.
As used herein, term " pharmaceutically acceptable salt " refers to that the compounds of this invention and acid or alkali are formed by suitable use Make the salt of drug.Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferred salt is the compounds of this invention and acid The salt of formation.The acid for suitably forming salt includes but is not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid etc. are inorganic Acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, Picric acid, methanesulfonic acid, benzene methanesulfonic acid, the organic acids such as benzene sulfonic acid；And the acidic amino acids such as aspartic acid, glutamic acid.
Compound and its pharmaceutically acceptable salt
The present invention relates to compounds of Formula I or its pharmaceutically acceptable salts；
Wherein:
--- indicate singly-bound；
Indicate singly-bound or double bond；
A missing is selected from C (=O), C (=O) X1, SOX1, SO2The C of X1, with or without substituent group1-8Alkyl, band Have or without substituent group C1-8The C of cyclic hydrocarbon radical and with or without substituent group1-8Heterocyclic hydrocarbyl；Wherein X1 missing or choosing From (CR12R13)eO、(CR12R13)eS and NR14；Wherein R12、R13、R14It is independently selected from H, with or without substituent group C1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical and with or without substituent group C1-8Heterocyclic hydrocarbon Base, e are the integer between 0 to 3；
W missing is selected from O, NR17,-X2C (=O) X3 ,-X2S (=O)gX3；Wherein R17For H, with or without substituted The C of base1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbon Base；Wherein X2, X3 are independent lacks or is selected from O, S, NR18；The wherein integer that g is 0 to 2；Wherein R18For H, have or not C with substituent group1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8 Heterocyclic hydrocarbyl；
Y is (CR22R23)h、CHX4(CR22R23)h, CX4=CH (CR22R23)hOr (CR22R23)h；Wherein h is between 0 to 30 Integer；Wherein R22、R23It is independently selected from the C of H, cyano, hydroxyl, amino, with or without substituent group1-8Hydrocarbon The C of base, with or without substituent group1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl, have or not C with substituent group1-8Oxyl；Wherein X4=H, halogen, cyano, nitro, hydroxyl, with or without substituent group C1-8Hydrocarbon Oxygroup, with or without substituent group C1-8Hydrocarbon carbonyl oxygen, with or without substituent group C1-8Amido, with or without substituted Base C1-8Ester group, with or without substituent group C1-8Amino-carbonyl, with or without substituent group C1-8Alkyl, with or without Substituted base C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl；
Z is (CR24R25)i、CHX5(CR24R25)i, CX5=CH (CR24R25)iOr C ≡ C (CR24R25)i；Wherein i is 0 to 30 Between integer；Wherein R24、R25It is independently selected from the C of H, cyano, hydroxyl, amino, with or without substituent group1-8's Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl, with or without take For base C1-8Oxyl；Wherein X5=H, halogen, cyano, nitro, hydroxyl, with or without substituent group C1-8Oxyl, band Have or without substituent group C1-8Hydrocarbon carbonyl oxygen, with or without substituent group C1-8Amido, with or without substituent group C1-8Ester Base, with or without substituent group C1-8Amino-carbonyl, with or without substituent group C1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl；
B missing is selected from O, C=O, S, NR15、-NR15C (=O)-,-C (=O) NR15,-C (=O) O-, OC (=O) O-、-NR15C (=O) O- ,-OC (=O) NR15-、-NR15C (=O) NR16, with or without substituent group C1-12Alkyl, The C of with or without substituent group1-12Cyclic hydrocarbon radical and with or without substituent group C1-12Heterocyclic hydrocarbyl；Wherein R15、 R16It is independently selected from the C of H, with or without substituent group1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon The C of base and with or without substituent group1-8Heterocyclic hydrocarbyl；
X is selected from CR19R20, C (=O), S (=O), SO2、NR21；Wherein R19、R20Be independently selected from H, cyano, hydroxyl, The C of amino, with or without substituent group1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without The C of substituted base1-8Heterocyclic hydrocarbyl, with or without substituent group C1-8Oxyl；Wherein R21Selected from H, have or not C with substituent group1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8 Heterocyclic hydrocarbyl；
R1、R6、R10It is each independently selected from the C of H, with or without substituent group1-8Alkyl, with or without substituted The cyclic hydrocarbon radical of base, the heterocyclic hydrocarbyl of with or without substituent group, with or without substituent group C1-6Acyl group；
R2、R5It is independently selected from: hydrogen, OR33、NR34R35, cyano, halogen, with or without substituent group C1~8Hydrocarbon Base, the cyclic hydrocarbon radical of with or without substituent group, the heterocyclic hydrocarbyl of with or without substituent group, with or without substituent group C1-6The amide groups of acyl group, with or without substituent group；Wherein R33、R34、R35Be independently selected from H, with or without The C of substituted base1~8Alkyl, with or without substituent group cyclic hydrocarbon radical, the heterocyclic hydrocarbyl of with or without substituent group；
R3、R7、R8、R9It is independently selected from: H, OR27、NR28R29, cyano, halogen, nitro, with or without substituted The C of base1-8Alkyl, the cyclic hydrocarbon radical of with or without substituent group, the heterocyclic hydrocarbyl of with or without substituent group, X6S (=O)kR30, X6C (=O) R31；Wherein k is the integer between 0 to 2；Wherein R27, R28, R29, R30, R31It is independently selected from H, has Or the C without substituent group1~8Alkyl, cyclic hydrocarbon radical, heterocyclic hydrocarbyl；Wherein X6 lacks or is selected from O, S, NR32；Wherein R32For H, band Have or without substituent group C1-8Alkyl, with or without substituent group cyclic hydrocarbon radical and with or without substituent group Heterocyclic hydrocarbyl；
R4Selected from H, cyano, carboxyl, with or without substituent group C1-8Alkyl, with or without substituent group Hydrocarbon carbonyl oxygen；
A is the integer (such as 1,2,3,4,5) between 0 to 5；
B is the integer (such as 1,2,3) between 0 to 3；
C is the integer (such as 1,2,3,4,5,6,7,8,9) between 0 to 30；
D is the integer (such as 1,2,3,4,5,6,7,8,9) between 0 to 9.
Unless otherwise instructed, integer described herein can be 0,1,2,3,4,5,6,7,8 or 9.
It is preferably carried out in mode at of the invention one, the compound is selected from the group:
The compound of the present invention packet can form pharmaceutically acceptable salt with inorganic acid, organic acid or alkali.The nothing Machine acid includes but is not limited to hydrochloric acid, hydrobromic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid etc.；The organic acid includes but is not limited to Methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzene sulfonic acid, p- toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, Lactic acid, tartaric acid, malonic acid, glycolic, succinic acid and propionic acid etc.；The alkali includes but is not limited to inorganic salts and amine.
Term pharmaceutically acceptable salt refers to according to medical judgment suitable for contacting the tissue of people and mammal and without mistake Spend those of toxicity, stimulation, allergic reaction etc. salt.Pharmaceutically acceptable salt is well known in the art.
Present invention also contemplates that the pharmaceutical composition of pro-drug containing a compound of formula I.Pro-drug includes suchization Object is closed, wherein precursor molecule passes through carbonic acid ester bond, urethane bond, amido bond, alkyl ester bond, phosphoric acid ester bond, phosphoramidic acid Ester bond is covalently bound on free carboxy, hydroxyl, amino or the amido of compound of formula I.
The preparation of compound
Preparation method
The preparation method of formula I structural compounds is described more particularly below, but these specific methods are not to this hair Bright composition any restrictions.The compounds of this invention can also be optionally by various conjunctions describing in the present specification or known in the art It combines at method and is easily made, such combination can readily be carried out by those skilled in the art in the invention.
Following reaction process illustrates the preparation of the compounds of this invention.Unless otherwise directed, reaction process and the discussion below In A, B, W, Y, Z, X, a, b, c, d, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10It is as defined above.
In general, the slave formula III as described in following proposal obtains the compound of Formulas I:
In compound II, when W is ether, formula III (W1=OH) can be used under alkali effect and containing leaving group Intermediate direct nucleophilic displacement of fluorine preparation, or reaction prolonged using light react with alcohol and prepare；When W is ester, carbamate (NHCO2) When, formula III (W1=OH) can be used and react preparation with acyl chlorides, Acibenzolar (amide), carboxylic acid, isocyanates under alkali effect；Work as W When for amine, formula III (W1=NH can be used2) prepared under alkali effect with the direct nucleophilic displacement of fluorine of the intermediate containing leaving group, Formula III (W1=NH can also be used2) with aldehyde/ketone reductive amination process is carried out to prepare；When W is amide, alkoxy carbonyl group amine (OCONH) and when urea formula III (W1=NH, can be used2) alkali effect under with corresponding acyl chlorides, Acibenzolar (amide), carboxylic acid, isocyanide Acid esters reaction preparation.
It, can be with directly replacing or prepared by reduction amination when A and nitrogen-atoms are keyed with C-N in compound I；When A with When nitrogen-atoms is connected in a manner of amide, urea, carbamate, sulfonamide, sulphamide, corresponding acyl chlorides, Acibenzolar (acyl can be used Amine), carboxylic acid, isocyanates, sulfonic acid chloride, chlorosulfuric acid preparation.
In general, the case where according to connection structure A and W, compound I can also connect formula IV and intermediate chain by elder generation It connects, then reacts to obtain with formula III.Chemical synthesis process used is same as above.
Formula III, IV compound can be obtained by known synthetic method or be easy through commercially available acquisition.
The application of compound of formula I
The compound of formula I can be used for one or more purposes below:
(a) drug of preparation treatment disease relevant to JAK3 activity or expression quantity；
(b) preparation JAK3 targets degradation agent；
(c) the external non-therapeutic ground JAK3 that degrades；
(d) inhibit tumor cell proliferation to external non-therapeutic；And/or
(e) treatment disease (such as autoimmune disease) relevant to JAK3 activity or expression quantity.
In another preferred example, the disease relevant to JAK3 activity or expression quantity is organ-graft refection, xenogenesis shifting Plant, lupus erythematosus, multiple sclerosis, rheumatoid arthritis, psoriasis (psoriasis), cancer, asthma, atopic dermatitis, I type Diabetes and diabetic complication, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer Disease, leukaemia, lymthoma, Huppert's disease, alopecia areata, leucoderma etc..
Compound of formula I of the invention can be used for preparing a kind of pharmaceutical composition, and the pharmaceutical composition includes: that (i) has The compound of formula I of effect amount or its pharmaceutically acceptable salt；(ii) pharmaceutically acceptable carrier.
In another preferred example, the effective quantity refers to therapeutically effective amount or inhibits effective quantity.
Compound of formula I of the invention can be also used for inhibiting or the method for degradation cloth JAK3, the inhibition are external non- Therapeutic inhibition is also possible to therapeutic inhibition.
In another preferred example, when to inhibition object application a effective amount of compound of formula I of the invention of inhibition or its pharmacy When upper acceptable salt, the inhibition effective quantity is 0.001-500nmol/L, preferably 0.01-200nmol/L.
Particularly, described the present invention also provides a kind of method for the treatment of disease relevant to JAK3 activity or expression quantity Method includes: to the compound of formula I for the treatment of object application therapeutically effective amount or the compound of formula I that contains as effective component Pharmaceutical composition.
Pharmaceutical composition and method of administration
Since the compounds of this invention can degrade JAK3 significantly to play to JAK3 inhibitory activity, the compounds of this invention And its various crystal forms, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and contain the compounds of this invention For main active pharmaceutical composition can be used for treating, prevent and alleviate by JAK3 activity or the relevant disease of expression quantity Disease.According to the prior art, the compounds of this invention can be used for treating the disease including tumour etc..
Pharmaceutical composition of the invention include safe and effective amount within the scope of the compounds of this invention or its be pharmacologically subjected to Salt and pharmacologically acceptable excipient or carrier.Wherein " safe and effective amount " refers to: the amount of compound is enough obviously Improve the state of an illness, and is unlikely to generate serious side effect.In general, pharmaceutical composition contains 1-2000mg the compounds of this invention/agent, More preferably, containing 5-200mg the compounds of this invention/agent.Preferably, described is " one " for a capsule or tablet.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solids or liquid filler or jello Matter, they are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " referred to herein as combines In object each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the drug effect of compound.Medicine Acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, fibre on Tie up plain acetic acid esters etc.), gelatin, talcum, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame Sesame oil, peanut oil, olive oil etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbierite), emulsifier (such as)、 Wetting agent (such as lauryl sodium sulfate), colorant, flavoring agent, stabilizer, antioxidant, preservative, apirogen water.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representative method of application includes (but being not limited to): in oral, tumor, rectum, parenteral (intravenous, intramuscular or subcutaneous) and local administration.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations In type, reactive compound is mixed at least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with Following compositions mixing: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) it bonds Agent, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；(c) moisturizer, example Such as, glycerol；(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates, And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti Pure and mild glycerin monostearate；(h) adsorbent, for example, kaolin；(i) lubricant, for example, talcum, calcium stearate, tristearin Or mixtures thereof sour magnesium, solid polyethylene glycol, lauryl sodium sulfate,.In capsule, tablet and pill, dosage form also may include Buffer.
Coating and shell material preparation can be used in solid dosage forms such as tablet, sugar-pill, capsule, pill and granule, such as casing and Other materials well known in the art.They may include opacifying agent, also, reactive compound or compound in this composition Release can discharge in certain a part in the digestive tract in a delayed fashion.The example of adoptable embedding component is polymeric material And wax material.When necessary, reactive compound can also be with one of above-mentioned excipient or a variety of formation microencapsulation forms.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture. In addition to active compounds, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, increase Solvent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethyl formyl The mixture of amine and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances Deng.
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste Agent, tender taste agent and fragrance.
In addition to active compounds, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene Sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or the mixture of these substances etc..
Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, Suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.It is suitable aqueous and Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
The dosage form of the compounds of this invention for local administration includes ointment, powder, patch, stock solution and inhalant. Active constituent aseptically with physiologically acceptable carrier and any preservative, buffer, or when necessary may need Propellant be mixed together.
The compounds of this invention can be administered alone, or be administered in combination with other pharmaceutically acceptable compounds.
It is the mammal that the compounds of this invention of safe and effective amount is applicable to treatment when using pharmaceutical composition (such as people), wherein dosage is the effective dosage pharmaceutically thought when application, for the people of 60kg weight, day is to medicament Amount is usually 1~2000mg, preferably 5~500mg.Certainly, specific dosage be also contemplated that administration route, patient health situation etc. because Element, within the scope of these are all skilled practitioners technical ability.
Main advantages of the present invention include:
1. providing a kind of compound shown in formula I.
2. providing JAK3 degradation agent and its preparation and the application of a kind of structure novel, the inhibitor is in extremely low concentration It is down degradable JAK3.
3. providing the pharmaceutical composition of a kind for the treatment of and JAK3 activity related diseases.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are weight percent and weight Number.
The preparation of 1 compound 3 of embodiment
Step 1:
2.14g 6- bromine caproyl chloride and 1.37g pomalidomide are dissolved in 50ml THF (tetrahydrofuran), 8h is stirred at reflux, It is down to room temperature, is dried in vacuo to obtain compound (1) 2.19g for 40 DEG C after concentration.MS(ESI):450[M+H]+。
Step 2:
1g compound (1), 1.28g compound (2) and 2.6g DIPEA (n,N-diisopropylethylamine) are dissolved in 50ml In DMF (n,N-Dimethylformamide), 80 DEG C of stirring 6h are down to room temperature, chromatograph to obtain compound (3) 810mg through column after concentration, receive Rate: 65.6%.MS(ESI):615[M+H]+。1H NMR(400MHz,CD3OD) δ 8.61 (d, J=8Hz, 1H), 8.11 (s, 1H), 7.72 (m, 1H), 7.54 (d, J=8Hz, 1H), 7.10 (d, J=4Hz, 1H), 6.63 (s, 1H), 5.14 (dd, J=12,4Hz, 1H),3.48(br,3H),3.37(s,1H),2.50-3.10(m,10H),2.32(m,1H),2.16(m,1H),1.25-2.00 (m, 9H), 1.03 (d, J=8Hz, 3H).
The preparation of 2 compound 7 of embodiment
Step 1:
4- hydroxyl Thalidomide 100mg, triethylene glycol list benzyl oxide 96mg, triphenylphosphine 100mg are dissolved in the anhydrous THF of 10ml In, DIAD (diisopropyl azodiformate) 95mg is added dropwise, reacts at room temperature 2h.Decompression removes THF, obtains chemical combination after column chromatographic purifying Object (4) 110mg.MS(ESI):497[M+H]+。
Step 2:
100mg compound (4) and 10%Pd-C 100mg are added in methanol 10ml, room temperature hydrogenated over night.Filtering, filtrate Concentration, residue obtain compound (5) 40mg after column chromatographic purifying.MS(ESI):407[M+H]+。
Step 3:
Compound (5) 30mg is dissolved in methylene chloride 5ml, Dess-martin oxidant 47mg, room temperature reaction is added 3h.NaHCO is added3Saturated aqueous solution and Na2S2O3Saturated aqueous solution stirs 5min, organic layer is separated, through anhydrous Na2S2O3It is dry It is dry, it is concentrated to dryness, obtains compound (6) and be directly used in the next step.
After compound (6) are dissolved with methylene chloride 7ml, it is added raw material (2) 36mg and NaBH (OAc)323mg, room temperature Reaction overnight, removes methylene chloride under reduced pressure, obtains compound (7) after column chromatographic purifying, and 20mg.MS (ESI): 634 [M+H]+。1H NMR (hydrochloride, 400MHz, D2O) δ 8.09 (d, J=1.6Hz, 1H), 7.45-7.62 (m, 1H), 7.18 (dd, J=12.0, 7.2Hz,1H),7.07(m,2H),6.54-6.70(m,1H),4.90-5.08(m,2H),4.12(m,2H),3.30-3.85(m, 14H), 3.20 (s, 3H), 2.73 (m, 2H), 2.42 (m, 2H), 2.09 (m, 2H), 1.73 (m, 1H), 1.00 (d, J=8.0Hz, 3H)。
The preparation of 3 compound 10 of embodiment
Step 1:
By 2- (2- (2- bromine oxethyl) ethyoxyl) benzyl acetate 174mg, potassium carbonate 100mg, potassium iodide 20mg and pool horse It spends amine 100mg to be added in 20ml DMF (n,N-Dimethylformamide), 80 DEG C of reactions are overnight.Reaction solution obtains after column chromatographic purifying Compound (8) 113mg.MS(ESI):510[M+H]+。
Step 2:
100mg compound (8) and 10%Pd-C100mg are added in 10ml methanol, room temperature hydrogenated over night.Filtering, filtrate Concentration, residue obtain compound (9) 73mg after column chromatographic purifying.MS (ESI anion): 418 [M-H]-。
Step 3:
Compound (9) 50mg and raw material (2) 30mg are dissolved in methylene chloride 5ml, HOBt (1- hydroxy benzo three is added Azoles) 20mg and EDC (1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride) 40mg, room temperature reaction is overnight.Decompression is steamed Except methylene chloride, compound (10) are obtained after column chromatographic purifying, 50mg.MS (ESI): 647 [M+H]+。1H NMR(400MHz, CDCl3) δ 10.63 (br, 1H), 9.84 (br, 1H), 8.22 (d, J=1.2Hz, 1H), 7.43 (t, J=7.6Hz, 1H), 7.06 (dd, J=7.2,1.2Hz, 1H), 6.97 (d, J=2.8Hz, 1H), 6.82 (d, J=8.4Hz, 1H), 6.51 (d, J=3.6Hz, 1H),6.42(m,1H),5.12(br,1H),4.91(m,1H),4.55(br,2H),3.89(m,4H),3.64(s,3H),3.51 (br,2H),3.38(m,3H),2.50-3.01(m,6H),2.25(br,1H),2.10(m,1H),1.86(br,1H),1.64 (br, 1H), 0.96 (d, J=6.8Hz, 3H).
The preparation of 4 compound 13 of embodiment
Step 1:
Raw material (2) 200mg is dissolved in methylene chloride 20ml, triethylamine 100mg and 5- benzyloxy pentane sulfonic acid chloride is added 180mg, room temperature reaction is overnight.Evaporating solvent under reduced pressure, after column chromatographic purifying compound (11) 187mg.MS(ESI):486[M+ H]+。
Step 2:
180mg compound (11) and 10%Pd-C 180mg are added in methanol 20ml, room temperature hydrogenation is stayed overnight.It crosses Filter, filtrate are concentrated, and obtain compound (12) 134mg.MS (ESI): 396 [M+H] after column chromatographic purifying+。
Step 3:
4- hydroxyl Thalidomide 50mg, triphenylphosphine 50mg and compound (12) 50mg are dissolved in the anhydrous tetrahydro furan of 5ml In muttering, DIAD (diisopropyl azodiformate) 50mg is added dropwise, reacts at room temperature 3h.Decompression removal tetrahydrofuran, column chromatographic purifying Compound (13) 33mg is obtained afterwards.MS(ESI):652[M+H]+。1H NMR (hydrochloride, 400MHz, D2O) 8.11 (d, J=of δ 2.0Hz, 1H), 7.43-7.61 (m, 1H), 7.20 (dd, J=11.6,6.8Hz, 1H), 7.08 (m, 2H), 6.60-6.71 (m, 1H),5.02(m,2H),4.54(m,1H),4.02(m,2H),3.85(m,2H),3.18(s,3H),2.72-3.12(m,4H), 2.15-2.50 (m, 4H), 1.28-2.06 (m, 9H), 0.96 (d, J=7.6Hz, 3H).
Following compound is prepared by the method for similar embodiment 2,3:
Following compound is prepared by the method for similar embodiment 2:
The activity of the Western blot detection compound degradation JAK3 albumen of embodiment 4
Cell strain: Jurkat cell strain uses the RPMI1640 culture containing 10% calf serum to be based on 37 DEG C, 5%CO2, saturation Culture in humidified incubator.
DMSO control group, compound intervention group (10 μM) are set, handles and 100 μ L pre-cooling is added after collecting within 6 hours cell Cell pyrolysis liquid cracks 30min on ice, extracts total protein of cell, and bicinchoninic acid (BCA) method measurement protein concentration is simultaneously determined Amount.Conventional glue, loading, electrophoresis, then transferring film, closing are separately added into rabbit-anti people JAK3 (1: 500), 4 DEG C of overnight incubations, drift The goat anti-rabbit igg (1: 5000) of horseradish peroxidase-labeled is added after washing, ECL developer solution develops the color after rinsing, and Bio-Rad is solidifying Glue imaging system scanning imagery, software processing analysis.With the control of glyceraldehyde phosphate dehydrogenase (GAPDH) internal reference.
Gray analysis is carried out to each band using Image J software, calculates the degradation rate of degradation JAK3 albumen.Meter It is as follows to calculate formula:
Compound see the table below the degradation rate of JAK3 albumen in Jurkat cell:
Embodiment 5CCK8 method detects formula compound and makees to the inhibition that Jurkat cell (human leukemia T lymphocyte) is proliferated With
In vitro with CCK8 method measuring compound to the inhibited proliferation of Jurkat cell.Specific step is as follows:
It takes Jurkat cell to be incubated in 1640 culture mediums of 10% calf serum, is inoculated in 96 orifice plates, 2 × 105Cell/ Hole is placed in 37 DEG C, 5%CO2In incubator.Compound is dissolved in dimethyl sulfoxide (DMSO), obtaining concentration is the molten of 10mM Liquid, then it is diluted to required concentration with phosphate buffer, it is separately added into above-mentioned 96 orifice plate, each 2 hole of concentration, every 10 μ l of hole, often A concentration makees two parallel testings.It is added in plate after DMSO accordingly to be made to gradient dilution, as control.
By above-mentioned 96 orifice plate in 37 DEG C, 5%CO2After cultivating 48 hours in cell incubator, 10 μ l CCK8 are added in every hole Solution continues to keep the temperature 1~4 hour in the incubator.Measure 465nm absorbance value.
Comparative survival rate of cells after compound is handled is calculated according to absorbance value.Calculation formula is as follows:
Compound is calculated to the IC of Jurkat cell by software50。
The compound of synthesis is shown in Table 1 to the in-vitro multiplication inhibiting effect of Jurkat cell:
Table 1
The above result shows that the compound of synthesis has the good activity for inhibiting Jurkat cell.
The internal resisting rheumatoid arthritis activity of 6 compound of embodiment (15)
In vivo using full Freund's adjuvant induction Wistar rat rheumatoid arthritis as model, measurement compound (15) Resisting rheumatoid arthritis effect.Specific step is as follows:
1) test specimen
Sample: compound (15).
2) preparation method
Sample: compound (15), when preparation, are dissolved with normal saline solution
3) animal and adjuvant
Wistar rat 18, male, weight 170-200g.
Adjuvant: full Freund's adjuvant (CFA), Sigma.
4) test method
Wistar rat is divided into 3 groups, every group 6 at random.Respectively blank control group, model group, compound (15) Group (20mg/kg ip administration).Rheumatoid arthritis is induced in the left back vola pedis intracutaneous injection CFA 0.1mL of rat.After rat modeling 11st day beginning drug treatment, once a day, the 22nd day treatment end.Left back sufficient volume is measured after treatment end, and it is swollen to calculate foot Swollen inhibiting rate.
5) test result
Compound (15) is shown in Table 2 to the foot swelling inhibiting rate of full Freund's adjuvant induced rat rheumatoid arthritis:
Table 2
Group Foot swelling inhibiting rate (%)
Blank control group -
Model group -
Compound (15) 87
Above experiment in vivo is the result shows that compound (15) has good resisting rheumatoid arthritis activity in vivo.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims (10)

1. a kind of such as following formula I compound represented or its pharmaceutically acceptable salt:
Wherein:
--- indicate singly-bound；
Indicate singly-bound or double bond；
A missing is selected from C (=O), C (=O) X1, SOX1, SO2The C of X1, with or without substituent group1-8Alkyl has or not C with substituent group1-8The C of cyclic hydrocarbon radical and with or without substituent group1-8Heterocyclic hydrocarbyl；Wherein X1 is lacked or is selected from (CR12R13)eO、(CR12R13)eS and NR14；Wherein R12、R13、R14Independent is the C of H, with or without substituent group1-8 Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical and with or without substituent group C1-8Heterocyclic hydrocarbyl, e For the integer between 0 to 3；
W missing is selected from O, NR17, X2C (=O) X3, X2S (=O)gX3；Wherein R17For H, the C of with or without substituent group1-8 Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl；Wherein X2, X3 missing independent are selected from O, S, NR18；The wherein integer that g is 0 to 2；Wherein R18It is taken for H, with or without The C of Dai Ji1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocycle Alkyl；
Y is (CR22R23)h、CHX4(CR22R23)h, CX4=CH (CR22R23)hOr (CR22R23)h；Wherein h is whole between 0 to 30 Number；Wherein R22、R23It is independently selected from the C of H, cyano, hydroxyl, amino, with or without substituent group1-8Alkyl, band Have or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl, with or without The C of substituent group1-8Oxyl；Wherein X4=H, halogen, cyano, nitro, hydroxyl, with or without substituent group C1-8Hydrocarbon oxygen Base, with or without substituent group C1-8Hydrocarbon carbonyl oxygen, with or without substituent group C1-8Amido, with or without substituent group C1-8Ester group, with or without substituent group C1-8Amino-carbonyl, with or without substituent group C1-8Alkyl, with or without Substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl；
Z is (CR24R25)i、CHX5(CR24R25)i, CX5=CH (CR24R25)iOr C ≡ C (CR24R25)i；Wherein i is between 0 to 30 Integer；Wherein R24、R25It is independently selected from the C of H, cyano, hydroxyl, amino, with or without substituent group1-8Hydrocarbon Base, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl, with or without substituted Base C1-8Oxyl；Wherein X5=H, halogen, cyano, nitro, hydroxyl, with or without substituent group C1-8Oxyl, have Or without substituent group C1-8Hydrocarbon carbonyl oxygen, with or without substituent group C1-8Amido, with or without substituent group C1-8Ester Base, with or without substituent group C1-8Amino-carbonyl, with or without substituent group C1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl；
B missing is selected from O, C=O, S, NR15、NR15C (=O), C (=O) NR15, C (=O) O, OC (=O) O, NR15C (=O) O, OC (=O) NR15、NR15C (=O) NR16, with or without substituent group C1-12Alkyl, with or without substituent group C1-12Cyclic hydrocarbon radical and with or without substituent group C1-12Heterocyclic hydrocarbyl；Wherein R15、R16It is independently selected from H, band Have or without substituent group C1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical and with or without take The C of Dai Ji1-8Heterocyclic hydrocarbyl；
X is selected from CR19R20, C (=O), S (=O), SO2、NR21；Wherein R19、R20It is independently selected from H, cyano, hydroxyl, ammonia The C of base, with or without substituent group1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without The C of substituent group1-8Heterocyclic hydrocarbyl, with or without substituent group C1-8Oxyl；Wherein R21Selected from H, with or without The C of substituted base1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8's Heterocyclic hydrocarbyl；
R1、R6、R10It is each independently selected from the C of H, with or without substituent group1-8The ring of alkyl, with or without substituent group Alkyl, the heterocyclic hydrocarbyl of with or without substituent group, with or without substituent group C1-6Acyl group；
R2、R5It is independently selected from: hydrogen, OR33、NR34R35, cyano, halogen, with or without substituent group C1~8Alkyl, band Have or without the cyclic hydrocarbon radical of substituent group, the heterocyclic hydrocarbyl of with or without substituent group, with or without substituent group C1-6 The amide groups of acyl group, with or without substituent group；Wherein R33、R34、R35It is independently selected from H, with or without substituted The C of base1~8Alkyl, with or without substituent group cyclic hydrocarbon radical, the heterocyclic hydrocarbyl of with or without substituent group；
R3、R7、R8、R9It is independently selected from: H, OR27、NR28R29, cyano, halogen, nitro, with or without substituent group C1-8Alkyl, the cyclic hydrocarbon radical of with or without substituent group, the heterocyclic hydrocarbyl of with or without substituent group, X6S (=O)kR30、 X6C (=O) R31；Wherein k is the integer between 0 to 2；Wherein R27, R28, R29, R30, R31It is independently selected from H, has or not C with substituent group1~8Alkyl, cyclic hydrocarbon radical, heterocyclic hydrocarbyl；Wherein X6 lacks or is selected from O, S, NR32；Wherein R32For H, have or Without the C of substituent group1-8Alkyl, the cyclic hydrocarbon radical of with or without substituent group and the heterocycle of with or without substituent group Alkyl；
R4Selected from H, cyano, carboxyl, with or without substituent group C1-8Alkyl, with or without substituent group hydrocarbon oxygen carbonyl Base；
A is the integer between 0 to 5；
B is the integer between 0 to 3；
C is the integer between 0 to 30；
D is the integer between 0 to 9.
2. compound as described in claim 1 or its pharmaceutically acceptable salt, it is characterised in that:
In the Formulas I, A missing；W is X2C (=O) X3, wherein X3 NR18And X2 missing or X2 are NR18And X3 Missing；Y is (CR22R23)h, wherein R22、R23It is independently selected from the C of H, hydroxyl, with or without substituent group1-4Hydrocarbon Base, h are the integer between 1 to 6；Z is (CR24R25)i, wherein R24、R25It is independently selected from H, hydroxyl, with or without The C of substituent group1-4Alkyl, i be 1 to 6 between integer；C is 0；Or
In the Formulas I, A missing；W missing is O；Y is (CR22R23)h, wherein R22、R23It is independently selected from H, hydroxyl, band Have or without substituent group C1-4Alkyl, h be 0 to 3 between integer；B is O；Z is (CR24R25)i, wherein R24、R25Respectively The independent C for being selected from H, hydroxyl, with or without substituent group1-4Alkyl, i be 0 to 3 between integer；C is between 1 to 6 Integer；Or
In the Formulas I, A is C (=O) X1, and wherein X1 lacks or be selected from (CR12R13)eAnd (CR O,12R13)eS, wherein e be 0 to 2 it Between integer, R12、R13、R14Independent is hydrogen or C1-4Alkyl；W is NR17, wherein R17For H or with or without The C of substituent group1-4Alkyl；Y is (CR22R23)h, wherein R22、R23It is independently selected from H, hydroxyl, with or without substituted The C of base1-4Alkyl, h be 0 to 3 between integer；Z is (CR24R25)i, wherein R24、R25It is independently selected from H, hydroxyl, band Have or without substituent group C1-4Alkyl, i be 0 to 3 between integer；B is O；C is the integer between 1 to 4；Or
In the Formulas I, A SO2X1, wherein X1 lacks or is selected from O and S；W is O；Y is (CR22R23)h, wherein R22、R23Respectively solely The vertical C for being selected from H, hydroxyl, with or without substituent group1-4Alkyl, h be 1 to 6 between integer；Z is (CR24R25)i, Middle R24、R25It is independently selected from the C of H, hydroxyl, with or without substituent group1-4Alkyl, i be 0 to 3 between integer； C is 0；Or
In the Formulas I, A missing；W is NR17, wherein R17For the H or C of with or without substituent group1-4Alkyl；Y is (CR22R23)h, wherein R22、R23It is independently selected from the C of H, hydroxyl, with or without substituent group1-4Alkyl, h be 0 to 3 Between integer；Z is (CR24R25)i, wherein R24、R25It is independently selected from the C of H, hydroxyl, with or without substituent group1-4 Alkyl, i be 0 to 4 between integer；B is O；C is the integer between 1 to 6；Or
In the Formulas I, A missing；W missing；Y is (CR22R23)h, wherein R22、R23It is independently selected from H, hydroxyl, has or not C with substituent group1-4Alkyl, h be 0 to 3 between integer；Z is (CR24R25)i, wherein R24、R25It is independently selected from H, the C of hydroxyl, with or without substituent group1-4Alkyl, i be 0 to 3 between integer；B is O；C be 1 to 10 between (preferably Between 1 to 6) integer.
3. compound as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that in Formulas I, X be C (= O)。
4. compound as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that R1It is selected from: H and having Or the C without substituent group1-4Alkyl.
5. compound as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that R4Selected from H, cyano, band Have or without substituent group C1-6Alkyl.
6. compound as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that the compound is selected from The following group:
7. a kind of pharmaceutical composition, which is characterized in that the composition contains compound described in claim 1 or its pharmacy Upper acceptable salt, prodrug and pharmaceutically acceptable carrier.
8. the purposes of a kind of compound as described in claim 1 or its pharmaceutically acceptable salt, is used for:
(a) drug of preparation treatment disease relevant to JAK3 activity or expression quantity；
(b) preparation JAK3 targets degradation agent；
(c) the external non-therapeutic ground JAK3 that degrades；
(d) inhibit tumor cell proliferation to external non-therapeutic；And/or
(e) treatment disease relevant to JAK3 activity or expression quantity.
9. purposes as claimed in claim 8, which is characterized in that the disease relevant to JAK3 activity or expression quantity is tumour Or autoimmune disease.
10. a kind of method of external degradation JAK3, which comprises a effective amount of to effective object application such as claim 1 The compound of formula I or its pharmaceutically acceptable salt, or inhibit a effective amount of such as claim 7 institute to inhibiting object to apply The pharmaceutical composition stated.
CN201710783074.0A 2017-09-03 2017-09-03 Compound with activity of degrading tyrosine protein kinase JAK3 Active CN109422751B (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN201710783074.0A CN109422751B (en) 2017-09-03 2017-09-03 Compound with activity of degrading tyrosine protein kinase JAK3
CN201880004075.3A CN109963853B (en) 2017-09-03 2018-09-02 Compound with activity of degrading tyrosine protein kinase JAK3
PCT/CN2018/103708 WO2019042443A1 (en) 2017-09-03 2018-09-02 Compound having tyrosine protein kinase jak3-degradation activity

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710783074.0A CN109422751B (en) 2017-09-03 2017-09-03 Compound with activity of degrading tyrosine protein kinase JAK3

Publications (2)

Publication Number Publication Date
CN109422751A true CN109422751A (en) 2019-03-05
CN109422751B CN109422751B (en) 2022-04-22

Family

ID=65512838

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201710783074.0A Active CN109422751B (en) 2017-09-03 2017-09-03 Compound with activity of degrading tyrosine protein kinase JAK3
CN201880004075.3A Active CN109963853B (en) 2017-09-03 2018-09-02 Compound with activity of degrading tyrosine protein kinase JAK3

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN201880004075.3A Active CN109963853B (en) 2017-09-03 2018-09-02 Compound with activity of degrading tyrosine protein kinase JAK3

Country Status (2)

Country Link
CN (2) CN109422751B (en)
WO (1) WO2019042443A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109963853A (en) * 2017-09-03 2019-07-02 上海美志医药科技有限公司 One kind has the degradation active compound of tyrosine protein kinase JAK3
WO2022089400A1 (en) * 2020-10-26 2022-05-05 上海美志医药科技有限公司 Compound for targeted degradation of btk and anti-tumour use thereof

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1767533A1 (en) * 2000-12-27 2007-03-28 Celgene Corporation N-{(2-(2,6-dioxo(3-piperidyl)-1,3-dioxo-2,3-dihydro-1H-isoindolin-4-yl)methyl}cyclopropylcarboxamide as TNF inhibitor
CN102372717A (en) * 2010-08-20 2012-03-14 和记黄埔医药（上海）有限公司 Pyrrolopyrimidine compound and use thereof
CN103119045A (en) * 2010-08-20 2013-05-22 和记黄埔医药（上海）有限公司 Pyrrolopyrimidine compounds and uses thereof
CN103502249A (en) * 2011-05-17 2014-01-08 普林斯匹亚生物制药公司 Azaindole derivatives as tyrosine kinase inhibitors
CN103748096A (en) * 2012-08-06 2014-04-23 美国艾森生物科学公司 Novel pyrrolopyrimidine compounds as inhibitors of protein kinases
CN104736569A (en) * 2012-01-12 2015-06-24 耶鲁大学 Compounds & methods for the enhanced degradation of targeted proteins & other polypeptides by an e3 ubiquitin ligase
CN104853754A (en) * 2012-11-20 2015-08-19 普林斯匹亚生物制药公司 Azaindole derivatives as jak3 inhibitors
CN104910161A (en) * 2009-07-02 2015-09-16 健泰科生物技术公司 Pyrazolopyrimidine JAK inhibitor compounds and methods
CN105712998A (en) * 2014-12-05 2016-06-29 上海润诺生物科技有限公司 Azaindole derivatives, preparation method and applications thereof in medicine
CN106458993A (en) * 2014-04-14 2017-02-22 阿尔维纳斯股份有限公司 Imide-based modulators of proteolysis and associated methods of use

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3440082A1 (en) * 2016-04-06 2019-02-13 The Regents of The University of Michigan Monofunctional intermediates for ligand-dependent target protein degradation
RU2752677C2 (en) * 2016-04-12 2021-07-29 Дзе Риджентс Оф Дзе Юниверсити Оф Мичиган Vet protein decomposers
JP2020505327A (en) * 2016-12-23 2020-02-20 アルビナス・オペレーションズ・インコーポレイテッドＡｒｖｉｎａｓ Ｏｐｅｒａｔｉｏｎｓ， Ｉｎｃ． EGFR proteolytic targeting chimeric molecules and related methods of use
CN109422751B (en) * 2017-09-03 2022-04-22 上海美志医药科技有限公司 Compound with activity of degrading tyrosine protein kinase JAK3

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1767533A1 (en) * 2000-12-27 2007-03-28 Celgene Corporation N-{(2-(2,6-dioxo(3-piperidyl)-1,3-dioxo-2,3-dihydro-1H-isoindolin-4-yl)methyl}cyclopropylcarboxamide as TNF inhibitor
CN104910161A (en) * 2009-07-02 2015-09-16 健泰科生物技术公司 Pyrazolopyrimidine JAK inhibitor compounds and methods
CN102372717A (en) * 2010-08-20 2012-03-14 和记黄埔医药（上海）有限公司 Pyrrolopyrimidine compound and use thereof
CN103119045A (en) * 2010-08-20 2013-05-22 和记黄埔医药（上海）有限公司 Pyrrolopyrimidine compounds and uses thereof
CN103502249A (en) * 2011-05-17 2014-01-08 普林斯匹亚生物制药公司 Azaindole derivatives as tyrosine kinase inhibitors
CN104736569A (en) * 2012-01-12 2015-06-24 耶鲁大学 Compounds & methods for the enhanced degradation of targeted proteins & other polypeptides by an e3 ubiquitin ligase
CN103748096A (en) * 2012-08-06 2014-04-23 美国艾森生物科学公司 Novel pyrrolopyrimidine compounds as inhibitors of protein kinases
CN104853754A (en) * 2012-11-20 2015-08-19 普林斯匹亚生物制药公司 Azaindole derivatives as jak3 inhibitors
CN106458993A (en) * 2014-04-14 2017-02-22 阿尔维纳斯股份有限公司 Imide-based modulators of proteolysis and associated methods of use
CN105712998A (en) * 2014-12-05 2016-06-29 上海润诺生物科技有限公司 Azaindole derivatives, preparation method and applications thereof in medicine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BING ZHOU等: "Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression", 《J. MED. CHEM.》 *
LONGCHUAN BAI等: "Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer", 《CANCER RES.》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109963853A (en) * 2017-09-03 2019-07-02 上海美志医药科技有限公司 One kind has the degradation active compound of tyrosine protein kinase JAK3
CN109963853B (en) * 2017-09-03 2022-04-22 上海美志医药科技有限公司 Compound with activity of degrading tyrosine protein kinase JAK3
WO2022089400A1 (en) * 2020-10-26 2022-05-05 上海美志医药科技有限公司 Compound for targeted degradation of btk and anti-tumour use thereof

Also Published As

Publication number Publication date
CN109422751B (en) 2022-04-22
WO2019042443A1 (en) 2019-03-07
CN109963853B (en) 2022-04-22
CN109963853A (en) 2019-07-02

Similar Documents

Publication Publication Date Title
CN109422752A (en) One kind has inhibition and the active compound of bruton's tyrosine protein kinase B tk of degrading
CN109422733A (en) One kind inhibits and the compound for the tyrosine protein kinase ALK that degrades
CN109516989A (en) One kind inhibits and the compound for the CDK that degrades
CN110317192A (en) One kind has the compound of degradation estrogen receptor activity
JP5897566B2 (en) Cyclic N, N'-diarylthiourea and N, N'-diarylurea-androgen receptor antagonists, anticancer agents, methods for their preparation and uses
WO2018175311A1 (en) Crystalline forms of 4-(1-(1,1-di(pyridin-2-yl)ethyl)-6-(3,5-dimethylisoxazol-4-yl)-1h- pyrrolo[3,2-b]pyridin-3-yl)benzoic acid that inhibits bromodomain
WO2004022538A1 (en) Crystal for oral solid drug and oral solid drug for dysuria treatment containing the same
JP2009545594A (en) Pseudo-base benzo [c] phenanthridine with improved efficacy, stability and safety
EP3746421B1 (en) Antagonists of the muscarinic acetylcholine receptor m4
JP2011527704A (en) Oral anticancer drug
DE10323345A1 (en) New pyridopyrazines and their use as kinase inhibitors
JP2020526557A (en) Antagonist of muscarinic acetylcholine receptor M4
JP2020537667A (en) Antagonist of muscarinic acetylcholine receptor M4
CN111662294A (en) Compound with activity of degrading Btk
CN109422751A (en) One kind has the degradation active compound of tyrosine protein kinase JAK3
CN109422753A (en) One kind has inhibition and the active compound of tyrosine protein kinase JAK1 or JAK2 of degrading
US10538491B2 (en) 4,5-substituted picolinamide and picolinonitrile metabotropic glutamate receptor 2 negative allosteric modulators
AU2010277947B2 (en) R-7-(3-aminomethyl-4-methoxyimino-3-methyl-pyrrolidin-1-yl)-1-cyclopropyl- 6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid and L-aspartic acid salt, process for the preparation thereof and pharmaceutical composition comprising the same for antimicrobial
JP2019089822A (en) New crystal form of topiroxostat, and preparation method therefor
CN108558869B (en) For treating the compound and its preparation of liver cancer
KR101812128B1 (en) 3-Isoxazol-3-yl)-pyrazolo[3,4-d]pyrimidine-4-amine derivatives as protein kinase inhibitors
CN116120327A (en) Beta-elemene 13, 14-position symmetrical disubstituted derivative and preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant