CN110407915A - One kind has inhibition and Janus kinases of degrading (JAK1 or JAK2) active compound - Google Patents

One kind has inhibition and Janus kinases of degrading (JAK1 or JAK2) active compound Download PDF

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CN110407915A
CN110407915A CN201810395389.2A CN201810395389A CN110407915A CN 110407915 A CN110407915 A CN 110407915A CN 201810395389 A CN201810395389 A CN 201810395389A CN 110407915 A CN110407915 A CN 110407915A
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substituent group
alkyl
hydrocarbon radical
cyclic hydrocarbon
jak1
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舒永志
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Shanghai Zhi Zhi Medical Science And Technology Co Ltd
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Abstract

The present invention provides one kind inhibition and Janus kinases of degrading (JAK1 or JAK2) active compounds, 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 to be inhibited and Janus kinases of degrading (JAK1 or JAK2) activity well, can be used for preparing the drug of the relevant disease for the treatment of JAK1 or JAK2 activity.

Description

One kind has inhibition and Janus kinases of degrading (JAK1 or JAK2) active compound
Technical field
The invention belongs to field of medicaments, have more particularly to one kind inhibit and degrade tyrosine protein kinase JAK1 or The active compound of JAK2 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, mainly the high efficient expression in hematopoietic tissue, the bone-marrow-derived lymphocyte, T of such as activation drench JAK3 Bar cell, bone marrow cell and thymocyte etc..
JAK1 can be with IL-10, IL-19, IL-20, IL-22, IL-26, IL-28, IFN-α, IFN-γ, in gp130 family IL-6 and other receptors etc. of the c containing γ combine.JAK1 gene knockout experiment on mouse model shows the enzyme in adjusting It states in the biological effect of cytokine profiles receptor and plays key effect.JAK1 has become the diseases such as immune, inflammation and cancer The novel target spot in field.
JAK2 is including EPO, GH, PRL, the IL-3 in IFN-γ and β c family, a variety of receptors such as IL-5, GM-CSF It plays a significant role during Signal Regulation.JAK2 is knocked out in mouse model can lead to animal dead caused by anaemia.Human body In JAK2 gene on a base mutation JAK2V617F, with the polycythemia vera in myeloproliferative disease (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), chronic myelocytic leukemia (CML) etc. Occur closely related.Therefore, JAK2 has become the definite action target spot of such disease treatment and prevention.
It is organ-graft refection, heterograft, lupus erythematosus, more due to the extensive adjustment effect of JAK-STAT signal path Hair property hardening, rheumatoid arthritis, psoriasis (psoriasis), cancer, asthma, atopic dermatitis, type-1 diabetes mellitus and glycosuria Sick complication, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer disease, leukaemia, leaching Many diseases such as bar tumor, Huppert's disease, alopecia areata, leucoderma also relate to JAK1/2, and JAK1/2 is as signal biography It passs member to play 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 exploitation, to be closed by inhibiting JAK1/2 activity to treat rheumatoid Save the drug of the diseases such as inflammation.
Summary of the invention
It is an object of the invention to provide a kind of compounds being able to suppress and degrade JAK1 and/or JAK2, 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 (CR11R12)fO、(CR11R12)fS and NR13；Wherein R11、R12、R13It is independent for 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, f are the integer between 0 to 3；
W missing is selected from NR14, X2C (=O) X3, X2S (=O)gX3；Wherein R14For H, with or without substituent group C1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl； Wherein X2, X3 are independent lacks or is selected from O, S, NR15；The wherein integer that g is 0 to 2；Wherein R15For 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 Heterocyclic hydrocarbyl；
X is O or S；
Y is (CR16R17)h、CHX4(CR16R17)h, CX4=CH (CR16R17)hOr (CR16R17)h；Wherein h is between 0 to 30 Integer；Wherein R16、R17It 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 C1-8 Oxyl, 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, have or Without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl；
Z is (CR18R19)i、CHX5(CR18R19)i, CX5=CH (CR18R19)iOr C ≡ C (CR18R19)i；Wherein i is 0 to 30 Between integer；Wherein R18、R19It is independently selected from the C of H, cyano, hydroxyl, amino, with or without substituent group1-8 Alkyl, 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 C1-8Hydrocarbon 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；
B missing is selected from O, C=O, S, NR20、NR20C (=O), C (=O) NR20, C (=O) O, OC (=O) O, NR20C (=O) O, OC (=O) NR20、NR20C (=O) NR21, with or without substituent group C1-12Alkyl, with or without The C of substituent group1-12Cyclic hydrocarbon radical and with or without substituent group C1-12Heterocyclic hydrocarbyl；Wherein R20、 R21It is respectively independent Selected from H, with or without substituent group C1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical and have Or the C without substituent group1-8Heterocyclic hydrocarbyl；
X is selected from CR22R23, C (=O), S (=O), SO2、NR24；Wherein R22、R23It is independently selected from H, cyano, hydroxyl Base, amino, with or without substituent group C1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, have or Without the C of substituent group1-8Heterocyclic hydrocarbyl, with or without substituent group C1-8Oxyl；Wherein R24Selected from H, have Or the C without substituent group1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl；
R1、R2、R6、R7、R9、R10It is independently selected from: H, OR25、NR26R27, cyano, halogen, nitro, have or not C with substituent group1-8Alkyl, the cyclic hydrocarbon radical of with or without substituent group, the heterocyclic hydrocarbyl of with or without substituent group, X6S (=O)jR28, X6C (=O) R29；Wherein j is the integer between 0 to 2；Wherein R25, R26, R27, R28, R29It is independent C selected from H, with or without substituent group1~8Alkyl, cyclic hydrocarbon radical, heterocyclic hydrocarbyl；Wherein X6 lacks or is selected from O, S, NR30； Wherein R30For H, the C of with or without substituent group1-8Alkyl, with or without substituent group cyclic hydrocarbon radical and have or Without the heterocyclic hydrocarbyl of substituent group；
R3、R5It is selected from from independent: hydrogen, OR31、NR32R33, cyano, halogen, cyanogen methyl, halogenated methyl, with or without The C of substituted base1~8Alkyl, the cyclic hydrocarbon radical of with or without substituent group, the heterocyclic hydrocarbyl of with or without substituent group, band Have or without substituent group C1-6The amide groups of acyl group, with or without substituent group；Wherein R31、R32、 R33It is independent C selected from H, with or without substituent group1~8Alkyl, with or without substituent group cyclic hydrocarbon radical, with or without The heterocyclic hydrocarbyl of substituent group；
R4Selected from H, cyano, carboxyl, with or without substituent group C1-8Alkyl, with or without substituent group Hydrocarbon carbonyl oxygen；
R8C selected from H, with or without substituent group1-8Alkyl, with or without substituent group cyclic hydrocarbon radical, have Or without the heterocyclic hydrocarbyl of substituent group, the C of with or without substituent group1-6Acyl group；
A is the integer between 0 to 4；
B is the integer between 0 to 4；
C is the integer between 0 to 30；
D is the integer between 0 to 5；
E is the integer between 0 to 2；
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, the pharmaceutical composition inhibits or degrades JAK1 and/or JAK2.
In another preferred example, the pharmaceutical composition is related for treating JAK1 and/or JAK2 activity or expression quantity Disease.
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 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 JAK1 and/or JAK2 activity or expression quantity；
(b) agent of JAK1 and/or JAK2 targeted inhibition or degradation agent are prepared；
(c) inhibit to external non-therapeutic or the JAK1 and/or JAK2 that degrades；
(d) inhibit tumor cell proliferation to external non-therapeutic；And/or
(e) treatment disease relevant to JAK1 and/or JAK2 activity or expression quantity.
In another preferred example, it is described to JAK1 and/or JAK2 activity or the relevant disease of expression quantity be tumour or itself Immunological diseases.
In another preferred example, the disease relevant to JAK1 and/or JAK2 activity or expression quantity is selected from the group: organ Graft rejection, xenograft rejection, lupus erythematosus, multiple sclerosis, rheumatoid arthritis, psoriasis (psoriasis), cancer Disease, asthma, atopic dermatitis, type-1 diabetes mellitus and diabetic complication, autoimmune thyroid disorders, ulcerative colitis Inflammation, 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 a kind of inhibition or the method for the JAK1 and/or JAK2 that degrades, comprising steps of right Effective object applies a effective amount of compound of formula I or its pharmaceutically acceptable salt or right as described in the first aspect of the invention Object application is inhibited to inhibit a effective amount of pharmaceutical composition as described in the fourth aspect of the present invention.
In another preferred example, the inhibition or degradation are external non-therapeutics.
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 that a kind for the treatment of and JAK1 and/or JAK2 are active or the relevant disease of expression quantity Method, which comprises to treatment object application therapeutically effective amount Formulas I chemical combination as described in the first aspect of the invention Object, or the pharmaceutical composition as described in the 4th invention of the invention.
In another preferred example, the object is mammal；Preferably, the mammal is behaved.
In another preferred example, it is described to JAK1 and/or JAK2 activity or the relevant disease of expression quantity be tumour or itself Immunological diseases.
In another preferred example, the disease relevant to JAK1 and/or JAK2 activity or expression quantity is selected from the group: organ Graft rejection, xenograft rejection, lupus erythematosus, multiple sclerosis, rheumatoid arthritis, psoriasis (psoriasis), cancer Disease, asthma, atopic dermatitis, type-1 diabetes mellitus and diabetic complication, autoimmune thyroid disorders, ulcerative colitis Inflammation, 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, Not repeated them here.
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 inhibits with JAK1 and/or JAK2 and degrading activity.And the compound is at much lower concentrations, can to JAK1 and/ Or JAK2 generate inhibit and degradation, activity it is quite excellent, thus can be used for treat with JAK1 and/or JAK2 activity or The relevant disease of expression quantity such as tumour.The present invention is completed on this basis.
The present invention provides the purposes of a kind of noval chemical compound and its degrade tyrosine protein kinase JAK1 and/or JAK2.This The compound of invention is able to suppress or degrades JAK1 and/or JAK2, and can be used as JAK1 and/or JAK2 inhibitor or degradation Agent and wave immunoregulation effect, and the rheumatoid arthritis for treating mammal, psoriasis, psoriatic joint The diseases such as inflammation, ankylosing spondylitis, atopic dermatitis, keratoconjunctivitis sicca and 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 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, ring Alkyl, 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, for example, methyl, ethyl, propyl, Isopropyl, 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 Atom is hetero atom.Hetero atom can be O, N and S atom and their various combinations.They can be monocycle, bicyclic With it is polycyclic.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, it preassigns Accurate effective quantity is useless.However, the effective quantity can be determined with routine experiment for the situation that Mr. Yu gives, Clinician 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 C2-6Acyl group, unsubstituted or halogen The C in generation1-6Alkyl-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: the nothings such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid Machine acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, lemon 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 (CR11R12)fO、(CR11R12)fS and NR13；Wherein R11、R12、R13It is independent for 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, f are the integer between 0 to 3；
W missing is selected from NR14, X2C (=O) X3, X2S (=O)gX3；Wherein R14For H, with or without substituent group C1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl； Wherein X2, X3 are independent lacks or is selected from O, S, NR15；The wherein integer that g is 0 to 2；Wherein R15For 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 Heterocyclic hydrocarbyl；
X is O or S；
Y is (CR16R17)h、CHX4(CR16R17)h, CX4=CH (CR16R17)hOr (CR16R17)h；Wherein h is between 0 to 30 Integer；Wherein R16、R17It 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 C1-8 Oxyl, 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, have or Without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl；
Z is (CR18R19)i、CHX5(CR18R19)i, CX5=CH (CR18R19)iOr C ≡ C (CR18R19)i；Wherein i is 0 to 30 Between integer；Wherein R18、R19It is independently selected from the C of H, cyano, hydroxyl, amino, with or without substituent group1-8 Alkyl, 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 C1-8Hydrocarbon 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；
B missing is selected from O, C=O, S, NR20、NR20C (=O), C (=O) NR20, C (=O) O, OC (=O) O, NR20C (=O) O, OC (=O) NR20、NR20C (=O) NR21, with or without substituent group C1-12Alkyl, with or without The C of substituent group1-12Cyclic hydrocarbon radical and with or without substituent group C1-12Heterocyclic hydrocarbyl；Wherein R20、 R21It is respectively independent Selected from H, with or without substituent group C1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical and have Or the C without substituent group1-8Heterocyclic hydrocarbyl；
X is selected from CR22R23, C (=O), S (=O), SO2、NR24；Wherein R22、R23It is independently selected from H, cyano, hydroxyl Base, amino, with or without substituent group C1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, have or Without the C of substituent group1-8Heterocyclic hydrocarbyl, with or without substituent group C1-8Oxyl；Wherein R24Selected from H, have Or the C without substituent group1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl；
R1、R2、R6、R7、R9、R10It is independently selected from: H, OR25、NR26R27, cyano, halogen, nitro, have or not C with substituent group1-8Alkyl, the cyclic hydrocarbon radical of with or without substituent group, the heterocyclic hydrocarbyl of with or without substituent group, X6S (=O)jR28, X6C (=O) R29；Wherein j is the integer between 0 to 2；Wherein R25, R26, R27, R28, R29It is independent C selected from H, with or without substituent group1~8Alkyl, cyclic hydrocarbon radical, heterocyclic hydrocarbyl；Wherein X6 lacks or is selected from O, S, NR30； Wherein R30For H, the C of with or without substituent group1-8Alkyl, with or without substituent group cyclic hydrocarbon radical and have or Without the heterocyclic hydrocarbyl of substituent group；
R3、R5It is selected from from independent: hydrogen, OR31、NR32R33, cyano, halogen, cyanogen methyl, halogenated methyl, with or without The C of substituted base1~8Alkyl, the cyclic hydrocarbon radical of with or without substituent group, the heterocyclic hydrocarbyl of with or without substituent group, band Have or without substituent group C1-6The amide groups of acyl group, with or without substituent group；Wherein R31、R32、 R33It is independent C selected from H, with or without substituent group1~8Alkyl, with or without substituent group cyclic hydrocarbon radical, with or without The heterocyclic hydrocarbyl of substituent group；
R4Selected from H, cyano, carboxyl, with or without substituent group C1-8Alkyl, with or without substituent group Hydrocarbon carbonyl oxygen；
R8C selected from H, with or without substituent group1-8Alkyl, with or without substituent group cyclic hydrocarbon radical, have Or without the heterocyclic hydrocarbyl of substituent group, the C of with or without substituent group1-6Acyl group；
A is the integer between 0 to 4；
B is the integer between 0 to 4；
C is the integer between 0 to 30；
D is the integer between 0 to 5；
E is the integer between 0 to 2；
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 unlimited In methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzene sulfonic acid, p- toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, anti-bad Hematic 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 Class.
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 optionally will be describing or known in the art various in the present specification Synthetic method combines and is easily made, such combination can by those skilled in the art in the invention readily into Row.
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, X, Y, Z, a, b, c, d, e, 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 be amine, formula III (W1=NH can be used2) alkali effect under with contain leaving group The direct nucleophilic displacement of fluorine preparation of intermediate, can also be used formula III (W1=NH2) with aldehyde/ketone reductive amination process is carried out to prepare； When W is amide, alkoxy carbonyl group amine (OCONH) and urea, formula III (W1=NH can be used2) alkali effect under with corresponding acyl chlorides, Acibenzolar (amide), carboxylic acid, isocyanates 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；Work as A When connecting in a manner of amide, urea, carbamate, sulfonamide, sulphamide with nitrogen-atoms, corresponding acyl chlorides, Acibenzolar can be used (amide), 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 V 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 JAK1 and/or JAK2 activity or expression quantity；
(b) agent of JAK1 and/or JAK2 targeted inhibition or degradation agent are prepared；
(c) inhibit to external non-therapeutic or the JAK1 and/or JAK2 that degrades；
(d) inhibit tumor cell proliferation to external non-therapeutic；And/or
(e) treatment disease (such as autoimmune disease) relevant to JAK1 and/or JAK2 activity or expression quantity.
In another preferred example, the disease relevant to JAK1 and/or JAK2 activity or expression quantity is organ transplant row Reprimand, heterograft, lupus erythematosus, multiple sclerosis, rheumatoid arthritis, psoriasis (psoriasis), cancer, asthma, spy Answering property dermatitis, type-1 diabetes mellitus and diabetic complication, autoimmune thyroid disorders, ulcerative colitis, Chron 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 JAK1 and/or JAK2, the inhibition are The inhibition of external non-therapeutic 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, the present invention also provides a kind for the treatment of diseases relevant to JAK1 and/or JAK2 activity or expression quantity Method, which comprises the compound of formula I of therapeutically effective amount is applied to treatment object or the compound of formula I that contains is made For the pharmaceutical composition of effective component.
Pharmaceutical composition and method of administration
Due to the compounds of this invention can significantly inhibit and degrade JAK1 and/or JAK2 activity, the compounds of this invention and Its various crystal form, 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 with JAK1 and/or JAK2 activity or expression Measure relevant 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 contain 1-2000mg the compounds of this invention/ Agent more preferably contains 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 group Close 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. Pharmaceutically acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose Sodium, cellulose ethanoate etc.), gelatin, talcum, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as Soya-bean oil, 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, apyrogeneity Water etc..
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 It is mixed with following compositions: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid； (b) Adhesive, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；(c) moisturizing Agent, for example, glycerol；(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain comprehensive silicons Hydrochlorate and sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, example Such as cetanol and glycerin monostearate；(h) adsorbent, for example, kaolin；(i) lubricant, for example, talcum, stearic acid Or mixtures thereof calcium, magnesium stearate, solid polyethylene glycol, lauryl sodium sulfate,.In capsule, tablet and pill, dosage form It 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 be discharged in certain a part in the digestive tract in a delayed fashion.The example of adoptable embedding component is polymerization Substance and wax material.When necessary, reactive compound can also be with one of above-mentioned excipient or a variety of formation microcapsules shapes Formula.
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, Solubilizer and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethyl Formamide and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances Mixture etc..
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 administration Dosage is usually 1~2000mg, preferably 5~500mg.Certainly, specific dosage is also contemplated that administration route, patient health situation Etc. factors, 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 JAK1 and/or JAK2 degradation agent and its preparation and the application of a kind of structure novel, the degradation agent It is at much lower concentrations degradable JAK1 and/or JAK2.
3. providing the pharmaceutical composition of a kind for the treatment of and JAK1 and/or JAK2 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 again Measure number.
The preparation of 1 compound 4 of embodiment
VHL ligand hydrochloride 1 (200mg) and n,N-diisopropylethylamine (0.2mL) are dissolved in methylene chloride (5ml), Cooling lower dropwise addition 6- bromine caproyl chloride (100mg) of ice-water bath, room temperature reaction.2 crude product of the compound dissolution obtained after reaction solution concentration In n,N-Dimethylformamide (3ml), compound 3 (200mg) and n,N-diisopropylethylamine (0.3mL) are added at room temperature, 80 DEG C of stirring 16h.Compound 4 (52mg) is chromatographed to obtain through column after reaction solution concentration.MS(ESI): 806[M+H]+。1H NMR (400MHz, DMSO-d6) δ 9.55 (s, 1H), 8.96 (br, 1H), 8.72 (s, 1H), 8.53 (d, J=8.0Hz, 1H), 7.96- 8.11 (br, 2H), 7.62 (d, J=8.0Hz, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 7.32 (d, 2H, J=7.6Hz), 7.15 (d, 2H, J=7.6Hz), 4.51-4.71 (m, 2H), 4.45 (s, 2H), 3.45-3.92 (m, 7H), 2.85 (s, 2H), 2.50-2.58(m,1H),2.49(s,3H),2.08-2.44(m,6H),1.24-1.65(m,6H),1.07(s,9H)。
The preparation of 2 compound 6 of embodiment
The synthesis of compound 5:
At room temperature by the bromo- 2- of 1- (2- (2- bromine oxethyl) ethyoxyl) ethane (2.76g), compound 3 (2.79g) and carbonic acid Potassium (4.14g) is added in n,N-Dimethylformamide (60ml), and overnight, reaction solution is concentrated under reduced pressure, residue for 80 DEG C of heating reactions With silica gel column purification, compound 5 (1.31g) is obtained.MS(ESI):474[M+H]+。
The synthesis of compound 6:
Acetonitrile is added in intermediate 5 (200mg), VHL ligand hydrochloride 1 (200mg) and potassium carbonate (400mg) at room temperature In (15ml), back flow reaction is overnight.Reaction solution is concentrated under reduced pressure, and residue silica gel column purification obtains compound 6 (32mg).MS (ESI):824[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.53(s,1H),8.95(br, 1H),8.73(s,1H), 8.51 (d, J=8.0Hz, 1H), 7.96 (br, 1H), 7.60 (d, J=8.0Hz, 1H), 7.52 (s, 1H), 7.43 (s, 1H), 7.35 (d, 2H, J=8.0Hz), 7.15 (d, 2H, J=7.6Hz), 4.53 (m, 1H), 4.43 (s, 2H), 3.40-3.93 (m, 16H),2.82(s,2H),2.50-2.78(m,5H),2.48(s,3H),2.05-2.41(m,3H),1.06(s,9H)。
The preparation of 3 compound 8 of embodiment
The synthesis of compound 7:
By compound 3 (1.00g), 6 hydroxycaproic acid (375mg), I-hydroxybenzotriazole (460mg), triethylamine (1.00g) and 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (817g) are added in methylene chloride, and room temperature is stirred It mixes overnight.Reaction solution concentration, residue silica gel column purification obtain compound 7 (637mg).MS(ESI):394[M+H]+。
The synthesis of compound 8:
At -78 DEG C, in the anhydrous methylene chloride (10ml) dissolved with intermediate 7 (393mg) and dimethyl sulfoxide (100mg) Oxalyl chloride (130mg) is added dropwise in solution, triethylamine (300mg) is added at low temperature in low-temp reaction 1h, continues low-temp reaction 2h. Reaction solution is concentrated under reduced pressure, and residue is dissolved in 1,2- dichloroethanes (5ml), and VHL ligand hydrochloride 1 (400mg) and ice vinegar is added Sour (1ml) is stirred at room temperature 1h, acetic acid sodium borohydride (636mg) is added under ice-water bath, 4h is stirred at room temperature.Reaction solution decompression is dense Contracting, residue silica gel column purification obtain compound 8 (65mg).MS(ESI):806 [M+H]+。1H NMR(400MHz, DMSO-d6) δ 9.45 (s, 1H), 8.96 (br, 1H), 8.71 (s, 1H), 8.56 (d, J=8.0Hz, 1H), 7.89 (br, 1H), 7.67 (d, J=8.0Hz, 1H), 7.55 (s, 1H), 7.47 (s, 1H), 7.36 (d, 2H, J=7.6Hz), 7.16 (d, 2H, J= 7.6Hz),4.35-4.68(m,7H),3.42-3.85(m,4H),2.86(s,2H), 2.08-2.59(m,11H),1.22-1.62 (m,6H),1.05(s,9H)。
Embodiment 4 tests compound to the inhibitory activity of JAK1/2 with Caliper assay method
Experimental procedure is as follows:
Configure 1 × kinase reaction buffer (50mM HEPES, PH 7.5；0.0015%Brij-35) and kinase reaction is whole Only liquid (100mM HEPES, PH 7.5；0.0015%Brij-35；0.2%Coating Reagent；50mM EDTA)；
Configuration laboratory sample: the sample solution (100%DMSO dissolution) of 5 μM of 100 μ L is added in 96 orifice plates, obtains 50 × sample solution.Two are arranged on same plate and contains only the hole of 100 μ L 100%DMSO as control.One as not Add sample controls, another is used as not enzyme control.10 μ L samples and 90 μ 1 × kinase reactions of L buffering are added in 96 orifice plates Liquid, as transit plate.This transit plate is shaken 10 minutes.
Prepare breadboard: taking in 96 hole transit plates configured each 5 μ L of sample into 384 orifice plates.
Kinase reaction: the 2.5 of 10 μ L are added in 55 × compound solutions of μ L (being dissolved with DMSO, be diluted with water 10 times) × JAK1/2 kinase solution (kinases with 1 × kinase reaction buffer dilute), add 10 μ L's after being incubated at room temperature 10min 2.5 × substrate peptide solution (in the diluted FAM label peptide of 1 × kinase reaction buffer and ATP).
It terminates kinase reaction: 25 μ L kinase reaction terminate liquids is added after reacting a period of time at 28 DEG C.
Fluorescence (F) is tested on Caliper, and collects data.
Calculate kinase activity inhibiting rate: to percent inhibition=(F of kinase activityDMSO control-FSample)/(FDMSO control-FNegative control) × 100, using DMSO as solution control, kinases is not added as negative control.
The results show that the inhibitory activity of 4,6,8 couples of JAK1/2 of compound is all larger than 80% under 100nM concentration.
The activity of the Western blot detection compound degradation JAK1 and JAK2 albumen of embodiment 5
Cell strain: Jurkat cell strain uses the RPMI1640 culture containing 10% calf serum to be based on 37 DEG C, 5%CO2, it is full It is cultivated in humidified incubator.
DMSO control group, compound intervention group (10 μM) are set, handles and 100 μ L pre-cooling is added within 6 hours after collection cell Cell pyrolysis liquid, crack 30min on ice, extract total protein of cell, bicinchoninic acid (BCA) method measurement protein concentration is gone forward side by side Row is quantitative.Conventional glue, loading, electrophoresis, then transferring film, closing are separately added into rabbit-anti people JAK1 (1: 500) and rabbit-anti people JAK2 (1: 500), 4 DEG C of overnight incubations, is added the goat anti-rabbit igg (1: 5 000) of horseradish peroxidase-labeled after rinsing, ECL developer solution develops the color after rinsing, Bio-Rad gel imaging system scanning imagery, software processing analysis.It is sweet with phosphoric acid Oily aldehyde dehydrogenase (GAPDH) internal reference control.
Gray analysis is carried out to each band using Image J software, calculates the drop of degradation JAK1 or JAK2 albumen Solution rate.Calculation formula is as follows:
The results show that the degradation rate of JAK1/2 albumen is big in 4,6,8 pairs of Jurkat cells of compound under 10 μM of concentration In 70%.
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 The present invention can be made various changes or modifications, such equivalent forms equally fall within the application the appended claims and limited Range.

Claims (7)

1. a kind of such as following formula I compound represented or its pharmaceutically acceptable salt:
,I
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, with or without The C of substituted base1-8The C of cyclic hydrocarbon radical and with or without substituent group1-8Heterocyclic hydrocarbyl；Wherein X1 is lacked or is selected from (CR11R12)fO、(CR11R12)fS and NR13；Wherein R11、R12、R13Independent 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, f For the integer between 0 to 3；
W missing is selected from NR14、X2C(=O)X3、X2S(=O)gX3；Wherein R14For H, the C of 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；Wherein X2, X3 missing independent is selected from O, S, NR15；The wherein integer that g is 0 to 2；Wherein R15For H, with or without substituent group C1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbon Base；
X is O or S；
Y is (CR16R17)h、CHX4(CR16R17)h、CX4=CH(CR16R17)hOr (CR16R17)h；Wherein h is whole between 0 to 30 Number；Wherein R16、R17It 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 C1-8Oxyl, With or without substituent group C1-8Hydrocarbon carbonyl oxygen, with or without substituent group C1-8Amido, with or without substituent group C1-8 Ester 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 (CR18R19)i、CHX5(CR18R19)i、CX5=CH(CR18R19)iOr C ≡ C (CR18R19)i；Wherein i is between 0 to 30 Integer；Wherein R18、R19It is independently selected from the C of H, cyano, hydroxyl, amino, with or without substituent group1-8Alkyl, With or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8Heterocyclic hydrocarbyl, with or without substituent group C1-8Oxyl；Wherein X5=H, halogen, cyano, nitro, hydroxyl, with or without substituent group C1-8Oxyl, have or not With substituent group C1-8Hydrocarbon carbonyl oxygen, with or without substituent group C1-8Amido, with or without substituent group C1-8Ester group, band Have or without substituent group C1-8Amino-carbonyl, with or without substituent group C1-8Alkyl, with or without substituent group C1-8Ring Alkyl, with or without substituent group C1-8Heterocyclic hydrocarbyl；
B missing is selected from O, C=O, S, NR20、NR20C(=O)、C(=O) NR20、C(=O)O、OC(=O)O、NR20C(=O)O、OC(= O)NR20、NR20C(=O)NR21, with or without substituent group C1-12Alkyl, with or without substituent group C1-12Ring The C of alkyl and with or without substituent group1-12Heterocyclic hydrocarbyl；Wherein R20、R21Be independently selected from H, with or without The C of substituted base1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical and with or without substituent group C1-8 Heterocyclic hydrocarbyl；
X is selected from CR22R23、C(=O)、S(=O)、SO2、NR24；Wherein R22、R23Be independently selected from H, cyano, hydroxyl, amino, The C of with or without substituent group1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without takes The C of Dai Ji1-8Heterocyclic hydrocarbyl, with or without substituent group C1-8Oxyl；Wherein R24Selected from H, with or without The C of substituent group1-8Alkyl, with or without substituent group C1-8Cyclic hydrocarbon radical, with or without substituent group C1-8It is miscellaneous Cyclic hydrocarbon radical；
R1、R2、R6、R7、R9、R10It is independently selected from: H, OR25、NR26R27, cyano, halogen, nitro, with or without take The C of Dai Ji1-8Alkyl, the cyclic hydrocarbon radical of with or without substituent group, the heterocyclic hydrocarbyl of with or without substituent group, X6S (= O)jR28、X6C(=O)R29；Wherein j is the integer between 0 to 2；Wherein R25, R26, R27, R28, R29It is independently selected from H, band Have or without substituent group C1~8Alkyl, cyclic hydrocarbon radical, heterocyclic hydrocarbyl；Wherein X6 lacks or is selected from O, S, NR30；Wherein R30For H, The C of with or without substituent group1-8Alkyl, with or without substituent group cyclic hydrocarbon radical and with or without substituent group Heterocyclic hydrocarbyl；
R3、R5It is selected from from independent: hydrogen, OR31、NR32R33, cyano, halogen, cyanogen methyl, halogenated methyl, with or without substituted The C of base1~8Alkyl, the heterocyclic hydrocarbyl of with or without substituent group, has or not the cyclic hydrocarbon radical of with or without substituent group C with substituent group1-6The amide groups of acyl group, with or without substituent group；Wherein R31、R32、R33Be independently selected from H, The C of with or without substituent group1~8Alkyl, the cyclic hydrocarbon radical of with or without substituent group, 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 oxygen carbonyl Base；
R8C selected from H, with or without substituent group1-8Alkyl, with or without substituent group cyclic hydrocarbon radical, with or without The C of the heterocyclic hydrocarbyl of substituted base, with or without substituent group1-6Acyl group；
A is the integer between 0 to 4；
B is the integer between 0 to 4；
C is the integer between 0 to 30；
D is the integer between 0 to 5；
E is the integer between 0 to 2.
2. compound as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that the compound is selected from The following group:
Structure
。
3. 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.
4. 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 JAK1 and/or JAK2 activity or expression quantity；
(b) agent of JAK1 and/or JAK2 targeted inhibition or degradation agent are prepared；
(c) inhibit to external non-therapeutic or the JAK1 and/or JAK2 that degrades；
(d) inhibit tumor cell proliferation to external non-therapeutic；And/or
(e) treatment disease relevant to JAK1 and/or JAK2 activity or expression quantity.
5. purposes as claimed in claim 4, which is characterized in that described relevant to JAK1 and/or JAK2 activity or expression quantity Disease is tumour or autoimmune disease.
6. purposes as claimed in claim 4, including but not limited to following disease: organ-graft refection, xenograft rejection, red Yabbi sore, multiple sclerosis, rheumatoid arthritis, psoriasis (psoriasis), cancer, asthma, atopic dermatitis, I type glycosuria It is disease and diabetic complication, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer disease, white Blood disease, lymthoma, Huppert's disease, alopecia areata and leucoderma etc..
7. the method for a kind of inhibition or degradation JAK1 and/or JAK2, which is characterized in that comprising steps of having to effective object application The compound of formula I as described in claim 1 or its pharmaceutically acceptable salt of effect amount, or inhibit effective to inhibiting object to apply The pharmaceutical composition as claimed in claim 7 of amount.
CN201810395389.2A 2018-04-27 2018-04-27 One kind has inhibition and Janus kinases of degrading (JAK1 or JAK2) active compound Withdrawn CN110407915A (en)

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Application publication date: 20191105