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CN109311824A - Kinase inhibitor - Google Patents

Kinase inhibitor Download PDF

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Publication number
CN109311824A
CN109311824A CN201780029397.9A CN201780029397A CN109311824A CN 109311824 A CN109311824 A CN 109311824A CN 201780029397 A CN201780029397 A CN 201780029397A CN 109311824 A CN109311824 A CN 109311824A
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compound
alkyl
triazole
room temperature
acid
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黄牛
齐湘兵
王艳丽
孙毓泽
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National Institute of Biological Sciences Beijin
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National Institute of Biological Sciences Beijin
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The invention discloses the compound for inhibiting kinases Lck or Btk, pharmaceutically acceptable salt, hydride, stereoisomer and pharmaceutical compositions.

Description

Kinase inhibitor
Inventor: ox, Qi Xiangbing, Wang Yanli, Sun Yuze
Applicant: Beijing Life Sciences Institute
Background of invention
Autoimmune disease, also known as autoimmune conditions, it is characterized in that immune response overacfivity or mistakenly For autologous tissue1.Traditionally, autoimmune disease is T cell and/or the damage that autoantibody mediates.According to recent Research, T and bone-marrow-derived lymphocyte and congenital immunity play an important role in pathogenesis2.On a molecular scale, T and B leaching The activation of bar cell is depended on through immunity receptor, for example, T- cell antigen receptor (TCR) and B- cell antigen receptor (BCR) into Capable signal cascade.These immunity receptors can be activated by ligand binding, then lead to the activation of downstream kinase target spot.Egg The complex network of white tyrosine kinase (PTKs) is related to important access.The PTKs of activation then makes receptor correlation cross-film be connected egg In the white cytoplasm face (receptor-associated transmembrane adaptors) based on immunity receptor tyrosine Activation motifs (ITAMs) phosphorylation.By a series of posttranslational modification, such as phosphorylation, starts downstream effect object, such as adjust The transcription factor of the gene expression of various inflammatory cytokines3,4。
Protein kinase plays an important role in the activation of B and T cell.As the sound to extracellular medium and environmental change It answers, protein kinase takes part in the signal event of control T and B cell activation, growth and differentiation.Some small molecule kinase inhibitors are There are the potentiality of the diseases such as treatment rheumatoid arthritis, psoriasis through showing5-9。
In the T lymphocyte of overacfivity, the signal path that TCR is mediated results in inflammatory cytokine, as stimulation is exempted from The IL-2 of epidemic disease reaction and the interferon gamma (up-regulation of (IFN-γ).At present it has been determined that the crucial starting event of T cell activation is The increase of the phosphorylation of activation motifs (ITAM) based on immunity receptor tyrosine in TCR-CD3 compound, the Phosphorylation events It is completed by Src family PTKs.Src family is made of 8 kinds of different members: Src, Lck, Fyn, Lyn, Hck, Fgr, Blk and Yes. Wherein, Lymphocyte-specific protein kinases (Lck) and proto-oncogenic tyrosine protein kinase (Fyn) are expressed in T cell, and And it is located at the initial phase for the signal cascade reaction that TCR is mediated3,10,11。
Lck is mainly expressed in T cell, related to the cytoplasmic compartment of CD4 and CD8 surface receptor in composition.? In mature periphery T cell, Lck makes TCR phosphorylation, and starts signal transduction (the TCR-linked signal of TCR link transduction).Lck is also expressed in all stages of thymic cell development, is risen in the selection and maturation of development T cell To key effect10,11。
Specifically, Lck plays the role of making ITAM phosphorylation in the starting of the TCR signal path mediated, this is Syk family The series connection SH2 structural domain of race kinases ZAP-70 provides binding site.Once ZAP-70 is i.e. by Lck in its activation ring by raising Tyr493 on phosphorylation and activation12, which results in the autophosphorylations of ZAP-70.The ZAP-70 of activation then makes adaptor protein, If the effect of LAT phosphorylation, the adaptor protein acts as bracket, to raise downstream signaling molecule.It is this cascade with start with carefully Intracellular cytokine discharges (especially IL-2) relevant genetic transcription and comes to an end, and finally promotes the proliferation of T cell13.Interfere Lck kinases Activity can produce strong immunosuppressive action.For example, Imatinib reduces the increasing of TCR induction by the inhibiting effect to LCK It grows and activates14, selectivity Lck inhibitor A-770041 (IC is administered orally50=147nM) it can inhibit in whole blood by sword bean egg The generation of the IL-2 of white A stimulation, the EC of the effect50About 80nM15.When dosage is 10mg/kg/d, A-770041 is shown The rejection for preventing heterotopic transplantation heart from passing through ajor histocompatibility barrier reaches at least 65 days15,16.By targeting SH2 structure Domain inhibits the Rosmarinic acid (RosA) of LCK to also show that the inhibiting effect to T cell activation and proliferation17.When dosage is 50mg/ When kg/d, the RosA synovitis that can inhibit collagen-induced arthritis mouse model is given daily within continuous 15 days18.Methyl ester derivation (RosA-Me) inhibit IL-2 gene expression and the effect of T cell proliferation much stronger than its counterpart RosA.Compared with RosA and MTX, The oral RosA-Me for giving mouse 50mg/kg/d dosage greatly reduces inflammation and arthritis index19。
As another member of Src family, the function and Lck of Fyn has part in terms of the tyrosine phosphorylation of starting TCR It is overlapped.Two kinds of kinases all interact with TCR, and increase the generation of interleukin 2 (IL-2)20,21.Genetic evidence It proves, Fyn activation is directly related with the Lck indexing that TCR is induced, and Fyn is prompted to take part in the activation process of T cell.However, Lck The research of deficient mice and Fyn deficient mice shows that effect of these kinases in growth course is limited22-24.Lck defect T The research of cell line (JCaM1) confirms that on specific tyrosine residue, TCR still can be phosphorylation, and this facilitate ZAP-70 The recruitment of kinases.In contrast, the modified phoshorylation pattern of TCR is changed, and defect occurs in the activation of ZAP-70.Herein In the process, the expression of molecular marked compound CD69 increases, and NFAT activation and the generation of interleukin 2 then substantially reduce. These results indicate that Fyn can be catalyzed the phosphorylation of ITAM in the presence of no Lck, but can not be largely Compensate the missing of Lck.In addition, the result of TCR signal transduction can according to which kind of kinase members of Src family come enabling signal The selection of cascade reaction determines25。
During Fyn and Lck starting TCR signal path, myristylated and palm is acidified dual fatty acylated process It is very crucial.2- bromine palmitinic acid can effectively block the palmitoylation of Fyn.In Jurkat T cell, 2- bromine palmitinic acid is blocked Endogenous palmitoylation Fyn and Lck then inhibits TCR signal path and T cell activation in the positioning of anti-detergent film26.This Outside, it was found that unsaturated fatty acid (PUFAs), especially n-3 series can also inhibit that Fyn's is fatty acylated26,27, clinically As immunosuppressor.Glucocorticoid (GC) is a kind of effective immunosuppressor, can promptly inhibit Fyn and Lck Recruitment to tcr complex.These results specify that Lck and Fyn kinases is used as and are situated between by GC receptor-independent access The molecular target of the GC led28.Inhibit Fyn and Lck that can inhibit autoimmune disease simultaneously.
B cell removes the success of therapy (BCDT), such as Rituximab (MabThera/Rituxan；Biogen Idec/ Genentech) clinical application in treatment rheumatoid arthritis has prompted B cell in certain autoimmune diseases Important function29.Tec family kinase BTK is limited to B cell, monocyte, macrophage, neutrophil leucocyte and mast cell Middle expression does not find its expression then in T cell or natural kill (NK) cell.Btk is B cell development, activation, issues signal With the key modulator of survival.B cell after B-cell receptor (BCR) participates in activates especially needed Btk30.Under the stimulation of BCR, BTK is activated by Src family kinase Blk, Lyn and Fyn of upstream.The BTK of activation then makes phospholipase C γ 2 (PLC γ 2) phosphoric acid Change and activation, PLC γ 2 are catalyzed the generation of DAG and IP3, downstream signaling molecule are resulted in, such as transcription factor NF-KB and NFAT Stimulation.Btk Functional mutations cause the chain immune deficiency (X-linked of X that feature is the decline of serum I g level in mouse Immunodeficiency, Xid)31.The nonsense mutation of Btk functionality results in periphery B cell in the mankind and lacks and sero-immunity ball The horizontal extremely low primary immunodeficiency disease of albumen (Ig).
The covalent conjunct agent of specific residue (Cys481) in some targeting Btk, as her cloth replaces Buddhist nun (PCI-32765) and AVL- 292 show IC in the CIA mouse model of foundation50High binding affinity and Oral Availability lower than 0.5nM, this meaning To clinical arthritis scoring and anti-collagen albumen autoantibody generate dose-dependent inhibition6.In addition, in MRL-Fas (lpr) in lupus model, PCI-32765 also inhibits autoantibody generation and development of renal disease6.Another Btk inhibitor RN486 (IC50=4.0nM) progression of disease of NZB × NZW systemic loupus erythematosus (SLE) mouse model can be prevent completely.RN486 gives Medicine can significantly inhibit the inflammatory reaction of PCA (I type allergy) or rPCA (type III allergy) mouse model.For RA model, RN486 Oral administration can reduce foot swelling and marker of inflammation by inhibiting joint and systemic inflammatorome32。
Other than the kinases of above-mentioned participation TCR and BCR near end signal access, accumulation research is also prompted, and p38 MAPK exists Several immunologically mediated diseases, including it is rheumatoid arthritis (RA), Sjogren syndrome, systemic loupus erythematosus (SLE), inflammatory It plays an important role in enteropathy (IBD) and the pathogenesis of psoriasis.In TCR and BCR signal path, MAPK cascade is swashed by Vav It is living.As downstream effect, Rac1 plays the role of MAPKK kinases (MAPKKK), and is located at the upstream p38 MAPK.p38 MAPK After activation, by transcription and post-transcriptional mechanism adjust tumor necrosis factor (TNF) α, interferon (IFN) γ and other cells because Son, such as the expression of IL-1, TL-6 and IL-1733,34.The success of antibody therapy has prompted cell factor and p38 MAPK itself exempting from The developing key effect of epidemic disease disease.Some small p38 inhibitor are shown in preclinical and early stage clinical research Promising feedback result.It all being had failed however, next clinical test is most of, reason either validity is poor, or Person is that toxicity is serious.Although occupying the p38 MAPK inhibitor VX-745 of ATP capsule in the II clinical trial phase that indication is RA Promising test result has been obtained, but has had ceased test because of hepatotoxicity wind agitation35.It is induced at dextran sulfate sodium salt (DSS) Colitis model in, SB203580 processing improves clinic and comments by reducing the mRNA level in-site of internal pro-inflammatory cytokine Point36.In addition, some highly selective non ATP competitive inhibitors, as VX-702, SCIO469, BIRB796 are also shown to proinflammatory The of short duration inhibiting effect of property disease marker, and disease progression or progress can not be fully controlled37。
Unacceptable toxicity and low effectiveness prompt p38 MAPK inhibitor administration may not be anti-inflammatory in clinical test The best solution for the treatment of.It is more that patulous research prompts p38 MAPK to have in adjusting many cell processes in addition to inflammation Aspect effect.The diversity of function is the reason of generating high toxicity and high inhibition effect.Moreover, existing compensation mechanism seems Seem the validity for further weakening treatment.These researchs, which all highlight, targets more pathomechanisms correlations while developing new The necessity of the medicament of property upstream kinases.For limited toxicity and lasting clinical response, have more targeting properties and The inhibitor of moderate but the affinity balanced represents better therapeutic choice.
Summary of the invention
The present invention provides the compounds of Formulas I:
Wherein:
R1–R5It is each independently H, halogen, hydroxyl, methyl, trifluoromethyl or methoxyl group, especially, wherein R1And R5Respectively solely It is on the spot halogen, hydroxyl, methyl, trifluoromethyl；And
R6It is optionally substituted Cn cyclic hydrocarbon radical, wherein n=3-18, and include most n-1 and be each independently selected from N, O, S With the hetero atom of P, especially, wherein the alkyl be selected from naphthenic base, aryl, heteroaryl or heterocycle；
Or its stereoisomer or pharmaceutically acceptable salt.
In specific embodiments:
- n is 3,4,5,6,8,9 or 10；Or n is 3,5,6 or 9；
-R6It is substituted or unsubstituted 5 or 6 yuan of homoatomic rings or heterocycle or 9 or 10 membered bicyclic aryl；
-R6It is optionally substituted: cyclopropyl；Selected from pyrroles, azoles (for example, pyrazoles, imidazoles, triazole, tetrazolium, pentazole, evil Azoles, isoxazole, thiazole or isothiazole), furans, dioxole thiophene, dithiole or oxygen sulphur Polymorphs two Alkene and its 5 yuan of aryl for restoring form (for example, dihydrofuran, glyoxalidine)；Preferably 2- replaces part, such as 2- azoles, 2- pyrrole It coughs up, 2- azoles (for example, 2- pyrazoles, 2- imidazoles, 2- oxazole, 2- isoxazole, 2- thiazole or 2- isothiazole), 2- furans, 2- thiophene, 2- Oxole, dioxole or 2- dithiole (2- thiophene)；6 yuan of aryl selected from phenyl and pyridine； Or 9 yuan of aryl are benzimidazoles；
-R6It is phenyl, 3- substituted-phenyl, 3,4- substituted-phenyl, 3,4,5- substituted-phenyl；
-R6Substituent group be selected from: halogen ,-OR' ,-OC (O) R' ,-NR'R " ,-SR' ,-R' ,-CN ,-NO2、-CO2R'、- CONR'R"、-C(O)R'、-OC(O)NR'R"、-NR"C(O)R'、-NR"CO2R'、-NR'-C(O)NR"R'"、-NR'-SO2NR" R'"、-NH-C(NH2)=NH ,-NR'C (NH2)=NH ,-NH-C (NH2)=NR' ,-S (O) R' ,-SO2R'、-SO2NR'R"、-NR" SO2R、-N3、-CH(Ph)2, perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl, the number of substituent group is 0 to aromatic ring The sum of opening chemical valence in system；Wherein R', R " and R' " be each independently selected from hydrogen, (C1-C8) alkyl and miscellaneous alkyl, Unsubstituting aromatic yl and heteroaryl, (unsubstituting aromatic yl)-(C1-C4) alkyl and (unsubstituting aromatic yl) oxygroup-(C1-C4) alkyl；
-R2-R4For H, and R1And R5In at least one be halogen, hydroxyl, methyl, trifluoromethyl or methoxyl group；
-R2-R4For H, R1And R5It is halogen, hydroxyl, methyl, trifluoromethyl or methoxyl group；
Its all combination, such as, in which:
R2-R4For H, R1And R5It is halogen, hydroxyl, methyl, trifluoromethyl or methoxyl group；
R6It is substituted or unsubstituted 5- or 6-membered homoatomic ring or heterocycle or 9 or 10 membered bicyclic aryl；And
R6Substituent group be selected from: halogen ,-OR' ,-OC (O) R' ,-NR'R " ,-SR' ,-R' ,-CN ,-NO2、-CO2R'、-CONR' R"、-C(O)R'、-OC(O)NR'R"、-NR"C(O)R'、-NR"CO2R'、-NR'-C(O)NR"R'"、-NR'-SO2NR"R'"、- NH-C(NH2)=NH ,-NR'C (NH2)=NH ,-NH-C (NH2)=NR' ,-S (O) R' ,-SO2R'、-SO2NR'R"、-NR" SO2R、-N3、-CH(Ph)2, perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl, the number of substituent group is 0 to aromatic ring Opening chemical valence sum in system；Wherein R', R " and R' " are each independently selected from hydrogen, (C1-C8) alkyl and miscellaneous alkyl, not Substituted aryl and heteroaryl, (unsubstituting aromatic yl)-(C1-C4) alkyl and (unsubstituting aromatic yl) oxygroup-(C1-C4) alkyl；And/or
These compounds have in kinase activity assay test is equivalent to IC50Press down for 10uM or Lck below or Btk System activity.
Representative, illustrative compound includes with flowering structure or its stereoisomer or its is pharmaceutically acceptable Salt:
The present invention provides the pharmaceutical compositions comprising motif compound.In some respects, the present invention provides comprising controlling Treat the motif compound of a effective amount of unit dosage form and the pharmaceutical composition of one or more pharmaceutically acceptable excipient Object.In some respects, the present invention provides composition, the composition includes the motif compound of therapeutically effective amount and exempts to itself Epidemic disease and/or diseases associated with inflammation or cancer have the different therapeutic agents of therapeutic activity.
The present invention also provides the methods of manufacture and use motif compound, the method including inhibiting kinase activity.One A little aspects, the present invention provides the method for the treatment of and unexpected kinase activity related diseases, including to needing its people to give The motif compound of effect amount or its prodrug, wherein the disease be anaphylactia, autoimmune disease, diseases associated with inflammation or Cancer, wherein the method may further include leading diagnose the illness or the step of cancer or subsequent detection disease Or cancer improves the step of situation.
The present invention contains all combinations of specific embodiment of the present invention.
The description of invention specific embodiment
Specific embodiment and embodiment are described in a manner of illustrating and noting limit below.Art technology Personnel will be easily identified out a variety of non-key parameters, and changing or modify these parameters can produce substantially similar knot Fruit.The present invention provides countless embodiments.
The present invention includes all possible combination, just as being respectively expressly recited；Therefore, aspect and reality of the invention The scheme of applying includes, for example, wherein R1For phenyl substituted or unsubstituted；R2For H, hydroxyl, C1-C4 alkyl or C1-C4 alkoxy, R3 It is H or methyl, and R4It is the combination of 1- dimethyl propyl.
Unless show it is improper or otherwise noted, these description and the whole instruction in, indefinite article indicate one Or it is multiple, term "or" indicate and/or, polynucleotide sequence be interpreted as comprising reverse strand and it is described herein other substitution bones Frame.In addition, this specification describes type with shorthand way, to enumerate all members of the type, for example, being abbreviated as (C1-C3) The narration expression of alkyl lists all C1-C3 alkyl: methyl, ethyl and propyl, including its isomers.
Unless being otherwise noted in applied context, following word, phrase and symbol are generally intended to indicate following meanings.
Term used herein " hetero atom " is commonly referred to as any atom in addition to carbon or hydrogen.It is preferred that hetero atom includes Oxygen (O), phosphorus (P), sulphur (S), nitrogen (N) and halogen, preferably heteroatom functional group are haloformyl, hydroxyl, aldehyde radical, amido, idol Nitrogen base, carboxyl, cyano, sulphur cyanato (thiocyanyl), carbonyl, halogen, hydroperoxy (hydroperoxyl), imido grpup, Aldimine groups, isonitrile base (isocyanide), isocyanate group (iscyante), nitrato, itrile group, nitrito-, nitro, nitrous Base, phosphate, phosphono, sulphur, sulfonyl, sulfo group and sulfydryl.
Unless otherwise indicated, term " alkyl " itself or a part as another substituent group, indicate fully saturated, contain There are the linear chain or branched chain or cyclic hydrocarbon group of specified quantity carbon atom (that is, C1-C8 indicates 1-8 carbon atom), or combinations thereof.Alkane The example of base includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, tert-butyl, isobutyl group, sec-butyl, cyclohexyl, (hexamethylene Base) methyl, Cvclopropvlmethvl, homologue and isomers, for example, the homologue of n-pentyl, n-hexyl, n-heptyl, n-octyl etc. And isomers.
Term " alkenyl " itself or a part as another substituent group indicate single insatiable hunger and/or how unsaturated, contain The linear chain or branched chain of carbon atom (that is, C2-C8 indicates 2-8 carbon atom) and one or more double bonds of specified quantity, or it is cyclic annular Alkyl, or combinations thereof object.The example of alkenyl include vinyl, 2- acrylic, crotyl, 2- isopentene group, 2- (butadienyl), 2,4- pentadienyl, 3- (1,4- pentadienyl) and its higher homologue and isomers.
Term " alkynyl " itself or a part as another substituent group indicate single insatiable hunger and/or how unsaturated, contain The linear chain or branched chain alkyl of carbon atom (that is, C2-C8 indicates 2-8 carbon atom) and one or more three keys of specified quantity, or A combination thereof.The example of alkynyl includes acetenyl, 1- propinyl and 3- propinyl, 3- butynyl and its higher homologue and isomery Body.
Term " alkylidene " itself or a part as another substituent group are indicated with-CH2-CH2-CH2-CH2For, Bilvalent radical from alkyl derivative.In general, alkyl (or alkylene) base has 1-24 carbon atom, the present invention preferably has 10 Or the group of following carbon atom." low alkyl group " or " low-grade alkylidene " is the shorter alkyl or alkylidene of chain, usually has 8 A or 8 or less carbon atoms.
Term " alkoxy ", " alkylamino radical " and " alkylthio group (alkylthio) " (or thio alkoxy (thioalkoxy)) With the use of its conventional meaning, refer to that those alkyl pass through the remainder split-phase of oxygen atom, amino or sulphur atom and molecule respectively Even.
Unless otherwise indicated, term " miscellaneous alkyl " itself or when combining with another term, indicates former by the carbon of the quantity The stable linear chain or branched chain or cyclic hydrocarbon group that son and 1 to 3 hetero atom selected from O, N, P, Si and S form, or combinations thereof, Wherein nitrogen, sulphur and phosphorus atoms can be optionally oxidized, and nitrogen heteroatom can be optionally quaternized.Hetero atom O, N, P and S can To be located at any position inside miscellaneous alkyl.Hetero atom Si can be located at any position of miscellaneous alkyl, including alkyl and molecule remain The position of remaining part split-phase even.Example includes-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2- S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3,-CH=CH-O-CH3、-Si(CH3)3、-CH2- CH= N-OCH3With-CH=CH-N (CH3)2.Up to 2 hetero atoms can be continuously, e.g., for example,-CH2-NH-OCH3With-CH2-O- Si(CH3)3。
Similarly, term " miscellaneous alkylidene " itself or a part as another substituent group are indicated with-CH2-CH2-S- CH2-CH2And-CH2-S-CH2-CH2-NH-CH2For, the bilvalent radical that is derived by miscellaneous alkyl.For miscellaneous alkylidene, Hetero atom can also occupy one or two end of the chains of the end of the chain (for example, alkylene oxide group (alkyleneoxy), alkylene dioxo base (alkylenedioxy), alkylene amino (alkyleneamino), alkylene diamino (alkylenediamino) etc.).More into one Step ground, for the linking group of alkylidene and miscellaneous alkylidene, is not implied by the orientation of linking group.
Unless otherwise indicated, term " naphthenic base " and " Heterocyclylalkyl " itself or when combining with other terms, respectively represents Be annular form " alkyl " and " miscellaneous alkyl ".Therefore, naphthenic base has the carbon atom of specified quantity (that is, C3-C8 indicates 3- 8 carbon), one or two double bond can also be contained.Heterocyclylalkyl has the carbon atom of specified quantity and 1-3 a selected from O, N, Si With the hetero atom of S, wherein nitrogen and sulphur atom can be optionally oxidized, and nitrogen heteroatom can be optionally quaternized.In addition, right For Heterocyclylalkyl, hetero atom can take up the position that heterocycle is connected with molecule remainder.The example of naphthenic base includes ring Amyl, cyclohexyl, 1- cyclohexenyl group, 3- cyclohexenyl group, suberyl etc..The example of Heterocyclylalkyl includes 1- (1,2,5,6- tetrahydro Pyridin-2-yl), 1- piperidyl, 2- piperidyl, 3- piperidyl, 4- morpholinyl, morpholinyl, tetrahydrofuran -2- base, tetrahydrofuran - 3- base, thiophane -2- base, thiophane -3- base, 1- piperazinyl, 2- piperazinyl etc..
Unless otherwise indicated, term " halogenated " and " halogen " itself or as another substituent group a part when, indicate fluorine, Chlorine, bromine or iodine atom.In addition, term such as " halogenated alkyl " is intended to include by 1 to (2m'+1) a halogen that can be identical or different The alkyl that atom replaces, wherein m' is the total number of carbon atoms in alkyl.For example, term " halogenated (C1-C4) alkyl " be intended to include Trifluoromethyl, 2,2,2- trifluoroethyl, 4- chlorobutyl, 3- bromopropyl etc..Therefore, term " halogenated alkyl " includes a halogenated alkyl (by the alkyl that a halogen atom replaces) and multi-haloalkyl (alkyl replaced by 2 to (2m'+1) a halogen atom, wherein M' is the total number of carbon atoms in alkyl).Unless otherwise indicated, term " whole haloalkyl " is indicated by (2m'+1) a halogen atom Substituted alkyl, wherein m' is the total number of carbon atoms in alkyl.Such as term " perhalogeno (C1-C4) alkyl " is intended to include trifluoro Methyl, five chloroethyls, the bromo- 2- chloroethyl of the fluoro- 2- of 1,1,1- tri- etc..
Term " acyl group " those of refers to going organic acid obtaining after the hydroxylic moiety of deacidification group.Therefore, acyl group is anticipated Finger includes, for example, acetyl group, propiono, bytyry, capryl, pivaloyl group, benzoyl etc..
Unless otherwise indicated, term " aryl " means how unsaturated hydrocarbon substituents, and usually arene replaces Base can be monocycle, or polycyclic (up to 3 rings) be fused together or to be covalently keyed.Aryl it is unrestricted Property example includes phenyl, 1- naphthalene, 2- naphthalene, 4- xenyl and 1,2,3,4- naphthane.
Term " heteroaryl " refers to the heteroatomic aryl (or ring) that N, O and S are selected from containing 0-4, wherein nitrogen and sulphur Atom is optionally oxidized, and nitrogen heteroatom is optionally quaternized.Heteroaryl can pass through the remainder of hetero atom and molecule Connection.The non-limitative example of heteroaryl includes 1- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 3- pyrazolyl, 2- imidazole radicals, 4- Imidazole radicals, pyrazinyl, 2- oxazolyl, 4- oxazolyl, 2- phenyl -4- oxazolyl, 5- oxazolyl, 3- isoxazolyl, 4- isoxazole Base, 5- isoxazolyl, 2- thiazolyl, 4- thiazolyl, 5- thiazolyl, 2- furyl, 3- furyl, 2- thienyl, 3- thienyl, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- benzothiazolyl, purine radicals, 2- benzimidazole Base, 5- indyl, 1- isoquinolyl, 5- isoquinolyl, 2- quinoxalinyl, 5- quinoxalinyl, 3- quinolyl and 6- quinolyl.
For brevity, (for example, aryloxy group, arylthio when term " aryl " and other terms are applied in combination (arylthioxy), aralkyl), including above-mentioned aryl and heteroaryl ring.Therefore, term " aralkyl " means to include aryl and alkane Those of base phase company group (for example, phenyl, phenethyl, pyridylmethyl etc.), the alkyl include carbon atom (for example, methylene Base) by for example, oxygen atom substitution those of alkyl (for example, Phenoxymethyl, 2- pyridyloxymethyl, 3- (1- naphthoxy) third Base etc.).
Above-mentioned each term (for example, " alkyl ", " miscellaneous alkyl ", " aryl " and " heteroaryl ") means to include the base The substitution and unsubstituted form of group.Provided hereinafter the preferred substituents of each type of group.
Alkyl and miscellaneous alkyl (and it is referred to as alkylidene, alkenyl, miscellaneous alkylidene, miscellaneous thiazolinyl, alkynyl, naphthenic base, heterocycle alkane Those of base, cycloalkenyl and heterocycloalkenyl group) substituent group can be varied group, be selected from :-OR' ,=O ,=NR', =N-OR' ,-NR'R " ,-SR', halogen ,-SiR'R " R' " ,-OC (O) R' ,-C (O) R' ,-CO2R'、-CONR'R"、-OC(O) NR'R"、-NR"C(O)R'、-NR'-C(O)NR"R'"、-NR'-SO2NR'"、-NR"CO2R'、-NH-C(NH2)=NH ,-NR'C (NH2)=NH ,-NH-C (NH2)=NR' ,-S (O) R' ,-SO2R'、-SO2NR'R"、-NR"SO2R ,-CN and-NO2, substituent group Number is 0-3, and it is especially preferred for having those of 0,1 or 2 substituent group group.R', R " and R' " refer to each independently Hydrogen, unsubstituted (C1-C8) alkyl and miscellaneous alkyl, unsubstituting aromatic yl, the aryl replaced by 1-3 halogen, unsubstituted alkyl, alcoxyl Base or thio alkoxy or aryl-(C1-C4) alkyl.It, can be with nitrogen-atoms knot when R' and R " are connected with same nitrogen-atoms It closes and forms 5,6 or 7 member rings." mean to include 1- pyrrolidinyl and 4- morpholinyl for example,-NR'R.In general, alkyl or miscellaneous alkyl tool There is 0-3 substituent group, it is currently preferred for having those of 2 or less substituent groups group.It is further preferred that alkyl or miscellaneous Alkyl is unsubstituted or mono-substituted.Most preferably, alkyl or miscellaneous alkyl are unsubstituted.From the above-mentioned discussion about substituent group In, it will be understood by the skilled person that term " alkyl " means to include if tri haloalkyl is (for example,-CF3With-CH2CF3) Group.
The preferred substituents of alkyl and miscellaneous alkyl are selected from :-OR' ,=O ,-NR'R " ,-SR', halogen ,-SiR'R " R' " ,-OC (O)R'、-C(O)R'、-CO2R'、-CONR'R"、-OC(O)NR'R"、-NR"C(O)R'、-NR"CO2R'、-NR'-SO2NR" R'"、-S(O)R'、-SO2R'、-SO2NR'R"、-NR"SO2R ,-CN and-NO2, wherein R' and R " are as defined above.It is further excellent The substituent group of choosing is selected from :-OR' ,=O ,-NR'R ", halogen ,-OC (O) R' ,-CO2R'、-CONR'R"、-OC(O)NR'R"、-NR" C(O)R'、-NR"CO2R'、-NR'-SO2NR"R'"、-SO2R'、-SO2NR'R"、-NR"SO2R ,-CN and-NO2。
Similarly, the substituent group of aryl and heteroaryl is also various, is selected from: halogen ,-OR' ,-OC (O) R' ,- NR'R",-SR'、-R'、-CN、-NO2、-CO2R'、-CONR'R"、-C(O)R'、-OC(O)NR'R"、-NR"C(O)R'、-NR" CO2R'、-NR'-C(O)NR"R'"、-NR'-SO2NR"R'"、-NH-C(NH2)=NH ,-NR'C (NH2)=NH ,-NH-C (NH2)= NR'、-S(O)R'、-SO2R'、-SO2NR'R"、-NR"SO2R、-N3、-CH(Ph)2, perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl, the number of substituent group are the sum of the 0 opening chemical valence (open valences) for arriving aromatic rings system；Wherein R', R " and R' " are each independently selected from hydrogen, (C1-C8) alkyl and miscellaneous alkyl, unsubstituting aromatic yl and heteroaryl, (unsubstituted virtue Base)-(C1-C4) alkyl and (unsubstituting aromatic yl) oxygroup-(C1-C4) alkyl.It, can be with when aryl is 1, when 2,3,4- naphthane (C3-C7) spiro cycloalkyl group being substituted or unsubstituted replaces.(C3-C7) spiro cycloalkyl group can " cycloalkanes as defined herein Base " is substituted in the same way like that.In general, aryl or heteroaryl have 0-3 substituent group, there are 2 or less substitutions Those of base group is currently preferred.In one embodiment of the invention, aryl or heteroaryl are unsubstituted or single Replace.In another embodiment, aryl or heteroaryl are unsubstituted.
The preferred substituents of aryl and heteroaryl are selected from: halogen ,-OR' ,-OC (O) R' ,-NR'R " ,-SR' ,-R' ,-CN ,- NO2、-CO2R'、-CONR'R"、-C(O)R'、-OC(O)NR'R"、-NR"C(O)R'、-S(O)R'、-SO2R'、-SO2NR'R"、- NR"SO2R、-N3、-CH(Ph)2, perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl, wherein the definition of R' and R " is such as On.Further preferred substituent group is selected from: halogen ,-OR' ,-OC (O) R' ,-NR'R " ,-R' ,-CN ,-NO2、-CO2R'、-CONR' R"、-NR"C(O)R'、-SO2R'、-SO2NR'R"、-NR"SO2R, perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkane Base.
Substituent group-CO used in the present invention2H includes the displacement of its bioisostere；See, e.g., The Practice of Medicinal Chemistry；Wermuth,C.G.,Ed.；Academic Press:New York,1996；p.203.
Two substituent groups on the adjacent atom of aromatic ring or hetero-aromatic ring can be optionally by formula-T-C (O)-(CH2)q-U- Substituent group displacement, wherein T and U are each independently-NH- ,-O- ,-CH2Or singly-bound, q are 0 to 2 integers.Alternatively, in virtue Two substituent groups on the adjacent atom of ring or hetero-aromatic ring can be optionally by formula-A- (CH2) r-B- substituent group displacement, wherein A and B are each independently-CH2-、-O-、-NH-、-S-、-S(O)-、-S(O)2-、-S(O)2NR'- or singly-bound, r be 1 to 3 it is whole Number.One singly-bound of the new ring formed in this way can be substituted optionally by double bond.Alternatively, in aromatic ring or the adjacent atom of hetero-aromatic ring On two substituent groups can be optionally by formula-(CH2)s-X-(CH2) t- substituent group displacement, wherein s and t are each independently 0 to 3 integer, X are-O- ,-NR'- ,-S- ,-S (O)-,-S (O)2Or-S (O)2NR'-.- NR'- and-S (O)2Taking in NR'- Hydrogen or unsubstituted (C1-C6) alkyl are selected from for base R'.
The invention discloses preferred substituents, and to preferred substituents in table, structure, embodiment and claims It has carried out for example, preferred substituents can be with cross-application in different compounds of the invention, that is, any appointed compound Substituent group can be used with other compound combinations.
In specific embodiments, applicable substituent group be each independently substituted or unsubstituted hetero atom, substitution or It is unsubstituted to contain 0-3 heteroatomic C1-C6 alkyl, is substituted or unsubstituted containing 0-3 heteroatomic C2-C6 alkenyls, substitution Or it is unsubstituted containing 0-3 heteroatomic C2-C6 alkynyls or substituted or unsubstituted containing 0-3 heteroatomic C6-C14 aryl, Wherein each hetero atom independently is oxygen, phosphorus, sulphur or nitrogen.
In a more particular embodiment, applicable substituent group be each independently aldehyde radical, aldimine groups, alkanoyloxy, Alkoxy, alkoxy carbonyl, alkoxy, alkyl, amido, azo group, halogen, carbamyl, carbonyl, formamido, carboxyl, cyanogen Base, ester group, halogen, haloformyl, hydroperoxy (hydroperoxyl), hydroxyl, imido grpup, isonitrile base (isocyanide), isocyanate group (iscyante), N- tertbutyloxycarbonyl, nitrato, itrile group, nitrito-, nitro, nitrous Base, phosphate, phosphono, sulfide (sulfide), sulfonyl, sulfo group, sulfydryl, mercapto (thiol), thiocyanogen, fluoroform Base or trifluoromethoxy (trifluromethyl ether, OCF3)。
Term " pharmaceutically acceptable salt " be intended to include the compound according to the present invention specified substituent, with opposite The salt of nontoxic acid or the reactive compound of alkali preparation.It, can be with when the compound of the present invention contains relatively acid functional group It obtains alkali by contacting the compound of neutral form with enough pure or in appropriate atent solvent expection alkali and adds At salt.The example of pharmaceutically acceptable base addition salts includes sodium salt, sylvite, calcium salt, ammonium salt, organic amine salt or magnesium salts or class As salt.When the compound of the present invention contains relatively alkaline functional group, can by by the compound of neutral form with Enough pure or in appropriate atent solvent expected acid contacts to obtain acid-addition salts.Pharmaceutically acceptable acid-addition salts Example include by inorganic acid, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, a hydrogen carbonic acid (monohydrogencarbonic), phosphorus Acid, a hydrogen phosphoric acid (monohydrogenphosphoric), dihydrogen phosphoric acid (dihydrogenphosphoric), sulfuric acid, a hydrogen The salt that sulfuric acid (monohydrogensulfuric), hydroiodic acid or phosphorous acid etc. are derived, and by the organic of relative nontoxic Acid, as acetic acid, propionic acid, isobutyric acid, oxalic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, The salt that phthalic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid etc. are derived.It further include amino acid, The salt and organic acid of such as arginine, such as the salt of glucuronic acid or galacturonic acid (galactunoric acids). Certain particular compounds of the invention contain simultaneously alkalinity and acidic functionality, this allow these compounds be converted into alkali or Acid-addition salts.
The compound of neutral form can regenerate by the following method: first contact salt with alkali or acid, then with conventional side Method isolates parent compound.The compound of the compound of parent fo and various salt forms is in certain physical properties, such as in pole Property solvent in solubility in terms of it is different, however in other respects, for the purposes of the present invention, these salt are equivalent In the compound of parent fo.
Other than salt form, the present invention also provides the compounds of prodrug forms.The prodrug of compound of the present invention It is to provide those of the compound of the present invention compound after undergoing chemical change in physiological conditions.In addition, in an in vitro environment, Prodrug can be converted into the compound of the present invention by chemistry or biochemical method.For example, with enzyme appropriate or chemical reagent When be placed in the storage cavern of transdermal patch together, prodrug can slowly be converted into the compound of the present invention.Prodrug is usually to have , because in some cases, prodrug can be easier to be administered than parent drug.For example, prodrug can have when oral administration There is bioavilability more higher than parent drug.Prodrug can also have more higher than parent drug molten in pharmacological composition Xie Du.Diversified prodrug derivant be it is known in the art, such as dependent on prodrug hydrolytic rupture or oxidized activating that A bit.The non-limitative example of prodrug is with ester (" prodrug ") administration, and then hydrolysis is metabolized as the of the invention of active entities carboxylic acid Compound.Other examples include the peptide radical derivative of the compound of the present invention.
Certain compounds of the invention can exist with nonsolvated forms and solvation form, including hydrated form.Generally For, solvation form is equal to nonsolvated forms, is comprised in the scope of the present invention.Certain compounds of the invention Can by polycrystalline or it is unbodied in the form of exist.For the purposes covered typically for the present invention, all physical forms are all With, it is intended to be included within.
Certain compounds of the invention have asymmetric carbon atom (optical centre) or double bond；It is racemic modification, diastereomeric different Structure body, geometric isomer and individual isomers individual are intended to be included within.
Non-enantiomer mixture can be according to the difference in physicochemical property, by well-known to those skilled in the art Method, as chromatography and/or fractional crystallization isolate diastereoisomer individual.Enantiomter can be by the following method Separation: first make enantiomeric mixture and optically active compound appropriate (for example, chiral auxiliary, such as chiral alcohol or Mosher acid chloride (Mosher's acid chloride)) reaction, it is translated into non-enantiomer mixture, then Diastereoisomer is isolated, then it is corresponding pure enantiomter that each diastereoisomer, which is converted (for example, hydrolysis),.It is right Reflecting isomers can also be separated with chiral HPLC column.
Single stereoisomer, for example, substantially pure enantiomter can be by using such as being split with optical activity Dosage form at diastereoisomer method, resolving racemic mixtures come obtain (Eliel, E. and Wilen, S.Stereochemistry of Organic Compounds.New York:John Wiley&Sons,Inc.,1994； Lochmuller,C.H.,et al."Chromatographic resolution of enantiomers:Selective review."J.Chromatogr.,113(3)(1975):pp.283-302).The racemic of chipal compounds of the invention mixes Object can be separated by any suitable method and isolation, comprising: (1) forms diastereoisomer ion with chipal compounds Then salt forms diastereomeric compound by separation crystallization or other methods separation, (2) and chiral derivatizing agent, will Diastereoisomer separation, is then converted to pure stereoisomer, and (3) directly separated under chiral conditions it is substantially pure or The stereoisomer of enrichment.Referring to: Wainer, Irving W., Ed.Drug Stereochemistry:Analytical Methods and Pharmacology.New York:Marcel Dekker,Inc.,1993。
The compound of the present invention can also contain the same position of non-natural on the one or more atoms for constituting these compounds Plain atomic component.For example, compound can use radioactive isotope, e.g., for example, tritium (3H), I125 (125I) or carbon 14 (14C) into Row radioactive label.All isotopic variations of the compound of the present invention are included in this hair in spite of with radioactivity In bright range.
Term " therapeutically effective amount " refer to being explored by researcher, animal doctor, doctor or other clinicians obtain will be The amount of the motif compound of tissue, whole body, the biology of animals or humans or medical response is caused e.g. to be given on certain significance degree Medicine metapedes is to prevent the development of one or more symptoms of disease being treated or illness to a certain extent or mitigate treated disease The amount of one or more symptoms of disease or illness.Therapeutically effective amount will be according to compound, disease and its severity and to be treated The difference of age, the weight of mammal etc. and change.
The present invention also provides the pharmaceutical compositions including motif compound and pharmaceutically acceptable excipient, especially wrap These compositions of the motif compound of unit dose are included, the purposes of disease or illness is especially applicable in description composition treatment These compositions that the specification of (present invention) is packed together.
Composition for being administered can be using the form of bulk liquids solution or suspension or bulk powder.However, more For commonly, composition is presented in a unit, to facilitate accurate administration.Term " unit dosage form " refers to object It is discrete in reason, it is suitable as the unit of the single dose for human experimenter or other mammals, each unit contains There are the active material and pharmaceutical excipient appropriate for being computed the predetermined amount that can generate expected response to treatment.Representative list Position dosage form include the pill of the pre-filled of liquid composition, predetermined amount ampoule or syringe or solid composite, tablet, Capsule, dragee (losenges) etc..In these compositions, compound is usually from micro constitutent (by weight about 0.1% To about 50%, or preferably by weight about 1% to about 40%), remainder is various media or carrier and contributes to form pre- The processing aid of phase form of medication.
Excipient or carrier appropriate, and preparation can administration composition method be it is known to one of skill in the art or It will be apparent that in publication such as Remington's Pharmaceutical Science, Mack Publishing Co, NJ (1991) this is described in more detail in.In addition, compound can also be advantageously public with of the present invention or this field institute The other therapeutic agents known, especially other anti-autoimmunity agent are used in conjunction with.Therefore, composition can independent, joint or combination It is administered in single dose unit.
Dosage depends on preparation, the administration route etc. of compound, usually in routine test based on practical experience Determining, and change it is necessary to the difference according to administration target, host and approach etc..In general, unit dose formulations In the amount of reactive compound can be changed in about 1,3,10 or 30 to about 30,100,300 or 1000mg according to specific application Or adjustment.In a specific embodiment, unit dosage form is packed with the multi-pack that sequence uses is suitable for, e.g., packet The blister package of the bubble cap tray containing at least 6,9 or 12 unit dosage forms is included.Actually using dosage can be according to patient's The difference of the severity of demand and condition being treated and change.The determination of correct dose under particular condition is in art technology model In enclosing.In general, the predose for the treatment of is smaller dose, less than the optimal dosage of compound.Later, gradually marginally dose Amount, until reaching optimum effect in this case.For convenience, if it is desired, daily accumulated dose can be separated into It is administered after several parts in one day.
Compound can be administered by various methods, including but not limited to parenteral, surface, oral or topical administration, such as It is administered by aerosol or with transdermal means, is used for preventative and/or therapeutic treatment.Also, therapeutic scheme is (for example, administration Dosage and number) can also according to the cognition of skilled clinician, based on observed drug treatment agent to the effect of patient, And observed disease changes the difference of the response condition of drug treatment agent.
To treat patient, during effective therapeutic scheme, therapeutic agent of the invention can treat effective dosage It is administered with amount.Although optimal dosage is compound specificity for each compound, generally according to practical experience Determine, however, the amount of per kilogram patient's microgram (μ g) is enough for more effective compound, for example, about 1,10 or In the range of 100ug/kg to about 0.01,0.1,1,10 or 100mg/kg patient's weight.
In general, routine experiment in clinical test is by each therapeutic agent of determination, the optimum treatment of each dosage regimen The specific range of effect, to specific patient administration also can the situation according to patient and the reaction to initial administration and be adjusted to In the range of effect and safety.However, final dosage regimen will be based on factor according to the clinician for participating in test, such as the year of patient Age, situation and size and compound potency, disease being treated severity and the judgement made be adjusted.For example, chemical combination The dosage regimen of object can be that point 2 to 4 times (preferably 2 times) are oral to give 10mg to 2000mg/ days, preferably 10 to 1000mg/ days, More preferable 50 to 600mg/ days.Can also using intermittent treatment (for example, one week in every three weeks or three weeks in every four weeks into Row treatment).
The present invention provides new solution for the autoimmune disease and cancer of T cell and B cell mediation.It is certain Autoimmune disease, if diseases associated with inflammation is (for example, inflammatory bowel disease, rheumatoid arthritis, glomerulonephritis and lung fiber Change, psoriasis, cutaneous anaphylaxis, atherosclerosis, restenosis, allergic asthma, multiple sclerosis and 1 type glycosuria Disease) it is improper related (J.H.Hanke et al., Inflamm.Res., 1995,357) with T cell activation.In addition, transplant organ Acute rejection and allogenic bone marrow and stem cell transplantation after graft versus host disease(GVH disease) (GvHD) T can also be construed to Cell activation improperly result.Bone-marrow-derived lymphocyte activate it is improper be many autoimmune diseases mark, such as this thyroid gland of bridge Inflammation, autoimmune hemolytic anemia, the autoimmune atrophic gastritis for causing pernicious anaemia, autoimmune myelencephalon Inflammation, autoimmune orchitis, Goodpasture disease, the autoimmune blood including Idiopathic Thrombocytopenic Purpura are small Plate is reduced, sympathetic ophthalmia, myasthenia gravis, Graves disease, primary biliary cirrhosis, chronic active hepatitis, ulcer Property colitis and membranous nephropathy, those are specified disease relevant to systemic autoimmune disease disease, such as systemic erythema Lupus, immunologic thrombocytopenic purpura, rheumatoid arthritis, Sjogren syndrome, Reiter syndrome, polymyositis With dermatomyositis, systemic sclerosis, nodular polyarteritis, multiple sclerosis and bullous pemphigoid.The present invention may be used also To be used to treat other autoimmune diseases based on B cell (body fluid) or based on T cell, including it is Cogan syndrome, tetanic Property rachitis, Wegener granulomatosis, autoimmune alopecia, I type or young onset diabetes and thyroiditis.T cell and B Cellular malfunction is malignant tumour in the other diseases wherein to play an important role, such as alimentary canal/gastrointestinal cancer, colon cancer, liver Cancer, cutaneum carcinoma, including mastocytoma and squamous cell carcinoma, breast cancer (breast and mammary cancer), ovary Cancer, prostate cancer, lymthoma and leukaemia (including but not limited to acute myelocytic leukemia, chronic granulocytic leukemia, Lymphoma mantle cell, non-Hodgkin's (NHL) B cell lymphoma are (for example, precursor B-ALL, marginal zone B-cell lymphoma, chronic leaching Bar cell leukemia, diffusivity large B cell lymphoid tumor, Burkitt lymthoma, vertical diaphragm large B cell lymphoid tumor), Huo Qijin leaching Bar tumor, natural kill and t cell lymphoma；Myeloma (including Huppert's disease), bone marrow proliferative illness, kidney, lung cancer, Muscle cancer, osteocarcinoma, bladder cancer, the cancer of the brain, melanoma (including oral cavity melanoma and metastasis melanin tumor), Kaposi meat Tumor, Proliferative diabetic retinopathy and angiogenesis associated disease (including solid tumor) and cancer of pancreas [Lim et al, Haematologica,95(2010)pp 135-143].We by focusing on a batch it is relevant to above-mentioned indication have it is bright It determines opinion and the kinases target spot with high correlation, including but not limited to Lck, Fyn, Btk, p38 MAPK, provides one Serial more targeting small molecule kinase inhibitors.
It should be understood that embodiment and embodiment of the present invention are for illustrative purposes only, according to its progress Various modifications or alterations will be suggested to those skilled in the art, and spirit herein and permission and appended will be included in In the range of claims.For all purposes, all publications, patents and patent applications cited in the present invention, including Quotation therein, it is all incorporated herein as reference in its entirety.
Embodiment
Reagent and chemicals
Chromatographic column for protein purification: NI-NTA- agarose, MonoQ HP chromatographic column and Superdex 75 are purchased from GE Healthcare.Reagent for crystallization is obtained from Hampton Research.Encoding human mitogen-activated protein kinase 14 (hMAPK14) and the DNA sequence dna of people's mitogen-activated protein kinase kinases 6 (MKK6) is purchased from OpenBiosystems.Unless another It is described, all reactions all carry out in inert nitrogen or argon gas.DMF, DMSO (99.9%, extremely dry) are straight by when receiving Connect use.Unless otherwise indicated, other all reagents are all bought from market, and are directly used as when receiving.NMR light Spectrum is recorded with Bruker spectrometer.1H (400MHz) and nmr chemical displacement are relative to TMS internal standard (δ=0.00ppm) or remnants The value of protonated solvent (protiated solvent) is reported.Data are presented in the following manner: chemical shift (ppm), multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, sept=heptet, m=multiplet, br=broad peak), coupling It closes constant J (Hz) and integrates.
Synthesis:
I) aminoguanidine nitrate, NaOH, H2O, reflux；
Ii) a) the chloro- 6- fluorobenzaldehyde of 2-, toluene flow back；B) NaBH3CN, acetic acid, room temperature.
The synthesis of step 1:3- (furans -2- base) -1H-1,2,4- triazole -5- amine (1):
Suspension of the aminoguanidine nitrate (22.0g, 160.5mmol) in acetonitrile (200mL) is cooled to 0 DEG C, by several times It is added NaOH (20.0g, 500.0mmol), 3h is stirred at room temperature in gained mixture.Then, 2- furans first is added dropwise at 0 DEG C Acyl chlorides (20.0g, 153.2mmol).After the completion of charging, 6h is stirred at room temperature in gained mixture.Then through rotary evaporation Solvent is removed, gained residue is dissolved in water (200mL), and is heated to reflux 5h.Decompression removal solvent, obtained crude product is through column Chromatographic purifying (silica gel, methylene chloride/methanol=50:1 to 10:1) obtain 3- (furans -2- base) -1H-1 for white solid, 2,4- triazole -5- amine (1) (8.5g, yield 37%).Mass spectrum (ESI) m/z C6H6N4O[M+H]+Calculated value 151.05, measured value 151.10。1H NMR(400MHz,d6-DMSO)δ(ppm)12.07(s,1H),7.68(s,1H),6.71-6.61(m,1H),6.54 (s,1H),6.08(s,2H)。
The synthesis of step 2:N- (the chloro- 6- benzyl of 2-) -3- (furans -2- base) -1H-1,2,4- triazole -5- amine (a):
By 3- (furans -2- base) -1H-1,2,4- triazole -5- amine (1) (8.5g, 56.6mmol) and the chloro- 6- fluorobenzaldehyde of 2- The mixture of (17g, 107.2mmol) in dry toluene (100mL) is heated to reflux 8h.After being cooled to room temperature, NaBH is added3CN (5.0g, 79.6mmol) and acetic acid (20mL).Then, 3h is stirred at room temperature in gained mixture.By reaction mixture water (10mL) is quenched, then depressurizes removal solvent.Residue passes through reversed rapid column chromatography (C18) purifying, obtain the N- for white solid (the chloro- 6- benzyl of 2-) -3- (furans -2- base) -1H-1,2,4- triazole -5- amine (a) (3.2g, yield 19.3%).Mass spectrum (ESI)m/z C13H10ClFN4O[M+H]+Calculated value 293.05,295.05, measured value 293.2,295.3.1H NMR(400MHz, d6- DMSO) δ 12.22 (s, 1H), 7.70 (s, 1H), 7.37 (dd, J=20.6,7.3Hz, 2H), 7.24 (t, J=8.7Hz, 1H),6.94(s,1H),6.73(s,1H),6.55(s,1H),4.50(s,2H)。
The conjunction of step 2:N- (the chloro- 6- methylbenzyl of 2-) -3- (furans -2- base) -1H-1,2,4- triazole -5- amine (b) At:
By 3- (furans -2- base) -1H-1,2,4- triazole -5- amine (1) (50mg, 0.33mmol) and the chloro- 6- methylbenzene first of 2- Mixture of the aldehyde (97.3mg, 0.63mmol) in dry toluene (5mL) is heated to reflux 8h.After being cooled to room temperature, it is added NaBH3CN (29.5mg, 0.47mmol) and acetic acid (0.5mL).Then, 3h is stirred at room temperature in gained mixture.Reaction is mixed It closes object to be quenched with water (1mL), then depressurizes removal solvent.Residue passes through reversed rapid column chromatography (C18) purifying, it obtains as white N- (the chloro- 6- methylbenzyl of 2-) -3- (furans -2- base) -1H-1 of color solid, 2,4- triazole -5- amine (b) (12mg, yield 12.3%).Mass spectrum (ESI) m/z C14H13ClFN4O[M+H]+Calculated value 289.08,291.07, measured value 289.40,291.40.1H NMR(400MHz,d6- DMSO/ methanol) δ 12.17 (s, 1H), 7.70 (s, 1H), 7.31 (d, J=7.5Hz, 1H), 7.22 (dd, J =17.4,7.1Hz, 2H), 6.82 (s, 1H), 6.73 (s, 1H), 6.56 (s, 1H), 4.48 (d, J=4.9Hz, 2H), 2.44 (s, 3H)。
The synthesis of step 1:3- (5- amino -1H-1,2,4- triazole -3- base) phenol (intermediate 1):
Aminoguanidine nitrate (5.46g, 39.82mmol) and K2CO3(5.5g, 39.82mmol) is in N,N-dimethylformamide (DMF) 1h is stirred at room temperature in the suspension in (50mL).3- hydroxybenzoic acid (5.0g, 36.2mmol) is in N, N- dimethyl methyl Solution in amide (DMF) (30mL) is at 0 DEG C with N, N'- carbonyl dimidazoles (CDI) (6.46g, 39.82mmol) processing.Later, 1h is stirred at room temperature in acquired solution.Then, which is added dropwise in suspension.After the completion of charging, reaction mixture 3h is stirred at room temperature.100 DEG C are heated the mixture to again and keep 5h.After being cooled to room temperature, filtering, decompression removal solvent. Through column chromatography, (silica gel, methylene chloride/methanol=100:1 to 10:1) purifying, obtains 3- (the 5- ammonia for white solid to residue Base -1H-1,2,4- triazole -3- bases) phenol (1) (2.67g, yield 41.9%).Mass spectrum (ESI) m/z C8H8N4O [M-H]-is calculated Value 175.07, measured value 175.10.1H NMR(400MHz,d6-DMSO)δ12.06(s,1H),9.47(s,1H),7.36-7.29 (m, 2H), 7.17 (t, J=8.0Hz, 1H), 6.77-6.67 (m, 1H), 6.00 (s, 2H).
The synthesis of step 2:3- (5- ((the chloro- 6- benzyl of 2-) amino) -1H-1,2,4- triazole -3- base) phenol:
By 3- (5- amino -1H-1,2,4- triazole -3- base) phenol (1) (5.0g, 28.38mmol), the chloro- 6- fluorobenzene first of 2- Aldehyde (5.0g, 31.53mmol) and the mixture of p-methyl benzenesulfonic acid (500mg, 2.90mmol) in isopropanol (50mL) heat back Flow through night.Solution is cooled to room temperature, NaBH is added3CN (4.0g, 63.65mmol) and acetic acid (2mL).Then, gained is mixed It closes object and 10h is stirred at room temperature, be quenched with water.Decompression removal solvent.Residue through column chromatograph (silica gel, methylene chloride/methanol= 100:1 to 10:1) purifying, obtains 3- (5- ((the chloro- 6- benzyl of 2-) amino) -1H-1,2, the 4- triazoles-for white solid 3- yl) phenol (1.2g, yield 13.3%), and recycle compound 31 (1.8g).Mass spectrum (ESI) m/z C15H12ClFN4O[M+H]+ Calculated value 319.07,321.07, measured value 319.40,321.20.1H NMR(400MHz,d6-DMSO)δ12.15(s,1H), 9.43(s,1H),7.35(s,4H),7.13-7.27(m,2H),6.90(s,1H),6.75(s,1H),4.51(s,2H)。
(i) a) aminoguanidine nitrate, NaOH, DMF, 0 DEG C；B) CDI, DMF, 0 DEG C to room temperature；c)H2O, reflux；
(ii) a) the chloro- 6- fluorobenzaldehyde of 2-, toluene, reflux；b)NaBH3CN, acetic acid, room temperature；
(iii)BBr3, cyclohexene, DCM, 0 DEG C.
The synthesis of step 1:3- (3,5- Dimethoxyphenyl) -1H-1,2,4- triazole -5- amine (intermediate 1):
By aminoguanidine nitrate (824.7mg, 6.02mmol) and NaOH (240.6mg, 6.02mmol) in N, N- dimethyl Suspension in formamide (DMF) (10mL) is cooled to 0 DEG C.3,5- dimethoxybenzoic acid (1.0g, 5.49mmol) and N, N- Solution of the diisopropylethylamine (DIPEA) (780mg, 6.03mmol) in N,N-dimethylformamide (DMF) (10mL) is at 0 DEG C With N, N'- carbonyl dimidazoles (CDI) (890mg, 5.49mmol) processing.Later, 3h is stirred at room temperature in acquired solution.Then, will This solution is added dropwise in suspension.After the completion of charging, 3h is stirred at room temperature in gained reaction mixture.It is steamed again by rotation Hair removal solvent, gained residue is dissolved in water (70mL), and be heated to reflux 18h.After being cooled to room temperature, filtering, gained Solid recrystallizing methanol, obtains 3- (3,5- Dimethoxyphenyl) -1H-1 for beige solid, 2,4- triazole -5- amine (in Mesosome 1) (260mg, yield 21.5%).Mass spectrum (ESI) m/z C10H12N4O2[M+H]+Calculated value 221.10, measured value 221.40。1H NMR(400MHz,d6- DMSO) δ 12.08 (s, 1H), 7.05 (dd, J=10.8,2.3Hz, 2H), 6.46 (s, 1H),6.08(s,2H),3.71(s,6H)。
Step 2:N- (the chloro- 6- benzyl of 2-) -3- (3,5- Dimethoxyphenyl) -1H-1,2,4- triazole -5- amine (12) Synthesis:
By 3- (3,5- Dimethoxyphenyl) -1H-1,2,4- triazole -5- amine (intermediate 1) (50mg, 0.23mmol) and 2- Mixture of the chloro- 6- fluorobenzaldehyde (36mg, 0.23mmol) in dry toluene (10mL)/DMSO (0.1mL) is heated to reflux 3h. It is cooled to room temperature solution, NaBH is added3CN (42.8mg, 0.68mmol) and acetic acid (1mL).Then, gained mixture room temperature 10h is stirred, is quenched with water.Decompression removal solvent.Residue is washed with water (25mL), obtained solid ethyl acetate/petroleum ether Solution recrystallization, obtains N- (the chloro- 6- benzyl of 2-) -3- (3,5- Dimethoxyphenyl) -1H-1 for white solid, and 2,4- Triazole -5- amine (12) (30mg, yield 36.4%).Mass spectrum (ESI) m/z C17H16ClFN4O2[M+H]+Calculated value 363.09, 365.09, measured value 363.20,365.20.1H NMR(400MHz,d6- DMSO) δ 7.97 (s, 1H), 7.51 (d, J=8.0Hz, 1H), 7.41 (t, J=8.0Hz, 1H), 7.31 (d, J=8.2Hz, 1H), 7.12 (s, 2H), 6.57 (s, 1H), 4.67 (s, 2H), 3.80(s,6H)。
Step 3:5- (5- ((the chloro- 6- benzyl of 2-) amino) -1H-1,2,4- triazole -3- base) benzene -1,3- glycol (9) Synthesis:
By compound 12 (18mg, 0.05mmol) and the mixture of cyclohexene (2mL) in methylene chloride (DCM) (10mL) It is cooled to 0 DEG C.Solution of the BBr3 (220mg, 0.88mmol) in methylene chloride (DCM) (1mL) is added dropwise into mixture. After the completion of charging, gained reaction mixture is in 0 DEG C of stirring 18h.Then solvent is removed by rotary evaporation, residue is inverted HPLC(C18) purifying, obtain the 5- (5- ((the chloro- 6- benzyl of 2-) amino) -1H-1,2,4- triazole -3- bases) for white solid Benzene -1,3- glycol (9) (3mg, yield 18.1%).Mass spectrum (ESI) m/z C15H12ClFN4O2[M+H]+Calculated value 335.06, 337.06, measured value 335.05,337.10.1H NMR(400MHz,CD3OD) δ 7.32 (dt, J=11.3,8.1Hz, 2H), 7.12 (t, J=8.6Hz, 1H), 6.85 (s, 2H), 6.32 (s, 1H), 4.64 (s, 2H).
(i) a) aminoguanidine nitrate, NaOH, methanol, 0 DEG C；B) CDI, DMF, 0 DEG C to room temperature；c)H2O,
Reflux；
(ii) a) the chloro- 6- fluorobenzaldehyde of 2-, toluene, reflux；b)NaBH3CN, acetic acid, room temperature.
The synthesis of step 1:3- (3,4- Dimethoxyphenyl) -1H-1,2,4- triazole -5- amine (intermediate 1):
By aminoguanidine nitrate (13.55g, 98.83mmol) and NaOH (240.6mg, 6.02mmol) at methanol (100mL) In suspension be stirred at room temperature 3h, evaporative removal solvent, residue is again molten with n,N-Dimethylformamide (DMF) (100mL) Solution.3,4- dimethoxybenzoic acid (15.0g, 82.34mmol) is molten in N,N-dimethylformamide (DMF) (150mL) Liquid at 0 DEG C with N, N'- carbonyl dimidazoles (CDI) (14.69g, 90.59mmol) processing.Later, 3h is stirred at room temperature in solution.So Solution is added dropwise in suspension afterwards.After the completion of charging, 3h is stirred at room temperature in reaction mixture.Then, it is steamed by rotation Hair removal solvent；Residue is dissolved in water (150mL), and is heated to reflux 18h.After being cooled to room temperature, filtering, obtained solid With recrystallizing methanol, 3- (3,4- Dimethoxyphenyl) -1H-1 for beige solid, 2,4- triazole -5- amine (intermediates are obtained 1) (9.38g, yield 51.7%).Mass spectrum (ESI) m/z C10H12N4O2[M+H]+Calculated value 221.10, measured value 221.40.1H NMR(400MHz,d6- DMSO) δ 11.95 (s, 1H), 7.46-7.39 (m, 2H), 6.98 (d, J=8.8Hz, 1H), 5.93 (s, 2H), 3.77 (d, J=3.4Hz, 6H).
Step 2:N- (the chloro- 6- fluorophenyl of 2-) -3- (3,4- Dimethoxyphenyl) -1H-1,2,4- triazole -5- amine (11) Synthesis:
By 3- (3,4- Dimethoxyphenyl) -1H-1,2,4- triazole -5- amine (intermediate 1) (8g, 36.33mmol), 2- Chloro- 6- fluorobenzaldehyde (8g, 50.46mmol) and p-methyl benzenesulfonic acid (625.5mg, 3.63mmol) are mixed in isopropanol (40mL) Close object heated overnight at reflux.After being cooled to room temperature solution, NaBH is added3CN (5.0g, 79.56mmol) and acetic acid (1mL).So Afterwards, 5h is stirred at room temperature in gained mixture, then is quenched with water.Decompression removal solvent.Residue through column chromatograph (silica gel, methylene chloride/ Methanol=50:1 to 10:1) purifying, obtains N- (the chloro- 6- benzyl of 2-) -3- (3,4- dimethoxy benzenes for white solid Base) -1H-1,2,4- triazole -5- amine (11) (4.5g, yield 34.1%).Mass spectrum (ESI) m/z C17H16ClFN4O2[M+H]+Meter Calculation value 363.09,365.09, measured value 363.40,365.40.1H NMR(400MHz,d6- DMSO, rotational isomer 2:1 mixing Object) δ 13.13 (s, 0.5H), 12.06 (s, 1H), 7.50-7.41 (m, 3H), 7.40-7.29 (m, 3H), 7.28-7.15 (m, 2H), 7.05 (d, J=8.2Hz, 0.5H), 6.98 (d, J=8.8Hz, 1H), 6.87 (t, J=5.4Hz, 1H), 6.12 (t, J= 6Hz, 0.5H), 4.53 (d, J=4.9Hz, 2H), 4.45 (d, J=5.2Hz, 1H), 3.78 (d, J=6.9Hz, 9H).
The synthesis of step 1:3- (3- nitrobenzophenone) -1H-1,2,4- triazole -5- amine (intermediate 1):
By aminoguanidine nitrate (2.58g, 18.82mmol) and NaOH (789.79mg, 19.75mmol) at methanol (30mL) In suspension 3h is stirred at room temperature, evaporate solvent, residue is re-dissolved with n,N-Dimethylformamide (DMF) (30mL). 3- nitrobenzoic acid (3.0g, 17.95mmol) and N, N- diisopropylethylamine (DIPEA) (2.55g, 19.73mmol) are in N, N- Solution in dimethylformamide (DMF) (30mL) at 0 DEG C with N, at N'- carbonyl dimidazoles (CDI) (3.2g, 19.73mmol) Reason.3h is stirred at room temperature in acquired solution.Then solution is added dropwise in suspension.After the completion of charging, reaction mixture exists 3h is stirred at room temperature.Solvent is removed by rotary evaporation, residue is dissolved in water (100mL), and be heated to reflux 18h.It is cooling To room temperature, filtering, obtained solid recrystallizing methanol obtains 3- (3- nitrobenzophenone) -1H-1 for yellow solid, and 2,4- tri- Azoles -5- amine (1) (3.0g, yield 81.5%).Mass spectrum (ESI) m/z C8H7N5O2[M+H]+Calculated value 206.06, measured value 206.20。1H NMR(400MHz,d6- DMSO) δ 12.38 (s, 1H), 8.65-8.60 (m, 1H), 8.28 (d, J=7.8Hz, 1H), 8.22-8.16 (m, 1H), 7.71 (t, J=8.0Hz, 1H), 6.22 (s, 2H).
The conjunction of step 2:N- (the chloro- 6- benzyl of 2-) -3- (3- nitrobenzophenone) -1H-1,2,4- triazole -5- amine (13) At:
By 3- (3- nitrobenzophenone) -1H-1,2,4- triazole -5- amine (1) (300mg, 1.46mmol) and the chloro- 6- fluorobenzene first of 2- Mixture of the aldehyde (300mg, 1.89mmol) in dry toluene (10mL)/DMSO (0.1mL) is heated to reflux 15h.Keep solution cold But to after room temperature, NaBH is added3CN (200mg, 3.18mmol) and acetic acid (1mL).Then, 3h is stirred at room temperature in gained mixture, It is quenched with water again.Decompression removal solvent, through column chromatography, (silica gel, methylene chloride/methanol=50:1 to 10:1) purifying, obtains residue To N- (the chloro- 6- benzyl of 2-) -3- (3- nitrobenzophenone) -1H-1,2,4- triazole -5- amine (2a) for faint yellow solid (150mg, yield 29.5%).Mass spectrum (ESI) m/z C15H11ClFN5O2[M+H]+Calculated value 348.06,350.06, measured value 348.10,350.10.1H NMR(400MHz,CD3OD) δ 8.82 (s, 1H), 8.34 (d, J=7.8Hz, 1H), 8.29-8.22 (m, 1H), 7.69 (t, J=8.0Hz, 1H), 7.40-7.27 (m, 2H), 7.14 (t, J=8.8Hz, 1H), 4.70 (s, 2H).
The conjunction of step 3:3- (3- aminophenyl)-N- (the chloro- 6- benzyl of 2-) -1H-1,2,4- triazole -5- amine (16) At:
By N- (the chloro- 6- fluorophenyl of 2-) -3- (3- nitrobenzene methyl) -1H-1,2,4- triazole -5- amine (2a) (50mg, 0.14mmol) and the mixture of hydrazine hydrate (0.5mL, 80% aqueous solution) in ethyl alcohol (10mL) is heated to 60 DEG C.Then it is added Raney-Ni(10mg).Gained mixture stirs 3h at this temperature.After being cooled to room temperature, filtering, decompression removal solvent.Residual Through column chromatography, (silica gel, methylene chloride/methanol=50:1 to 10:1) purifying, obtains 3- (the 3- aminobenzene for white solid to object Base)-N- (the chloro- 6- benzyl of 2-) -1H-1,2,4- triazole -5- amine (3a) (36mg, yield 78.8%).Mass spectrum (ESI) m/z C15H13ClFN5[M+H]+Calculated value 318.08,320.08, measured value 318.10,320.10.1H NMR(400MHz,CD3OD)δ 7.33 (ddd, J=19.0,9.5,6.9Hz, 2H), 7.27-7.19 (m, 2H), 7.19-7.08 (m, 2H), 6.78 (d, J= 7.8Hz,1H),4.64(s,2H)。
The synthesis of N- (the chloro- 6- methylbenzyl of 2-) -3- (3- nitrobenzophenone) -1H-1,2,4- triazole -5- amine (15)
To 3- (3- nitrobenzophenone) -1H-1,2,4- triazole -5- amine (1) (100mg, 0.49mmol) and the chloro- 6- of 2- of stirring Mixture of the tolyl aldehyde (150.69mg, 0.97mmol) in dry toluene (6mL)/ethyl alcohol (0.5mL) is heated to reflux 15h.After being cooled to room temperature, in 0 DEG C of addition NaBH3CN (100mg, 1.59mmol) and acetic acid (1mL).Then, gained mixture 3h is stirred at room temperature.Decompression removal solvent.(silica gel, methylene chloride/methanol=50:1 are pure to 10:1) through column chromatography for residue Change, obtains N- (the chloro- 6- methylbenzyl of 2-) -3- (3- nitrobenzophenone) -1H-1 for faint yellow solid, 2,4- triazole -5- amine (2b) (34mg, yield 20.3%), and 3- (3- nitrobenzophenone) -1H-1 is recycled, 2,4- triazole -5- amine (1) (40mg).Mass spectrum (ESI)m/zC16H14ClN5O2[M+H]+Calculated value 344.08,346.08, measured value 344.40,346.40.1H NMR(400MHz, CD3OD) δ 8.84-8.81 (m, 1H), 8.37-8.33 (m, 1H), 8.29-8.24 (m, 1H), 7.70 (t, J=8.0Hz, 1H), 7.30(m,1H),7.22–7.19(m,2H),4.68(s,2H),2.52(s,3H)。
The synthesis of step 3:3- (3- aminophenyl)-N- (the chloro- 6- aminomethyl phenyl of 2-) -1H-1,2,4- triazole -5- amine (19)
By compound N-(the chloro- 6- methylbenzyl of 2-) -3- (3- nitrobenzophenone) -1H-1,2,4- triazole -5- amine (2b) The mixture of (30mg, 0.087mmol) and hydrazine hydrate (0.3mL, 80% aqueous solution) in ethyl alcohol (5mL) is heated to 60 DEG C.So Raney-Ni (10mg) is added afterwards.Gained mixture stirs 3h in this temperature.After being cooled to room temperature, filtering, decompression removal solvent. Residue passes through reversed rapid column chromatography (C18) purifying, obtain 3- (3- aminophenyl)-N- (chloro- 6-first of 2- for white solid Base phenyl) -1H-1,2,4- triazole -5- amine (3b) (20mg, yield 73%).Mass spectrum (ESI) m/z C16H16ClN5[M+H]+It calculates Value 314.11,316.11, measured value 314.40,316.40.1H NMR(400MHz,CD3OD)δ7.28(m,3H),7.19(m, 3H),6.79(s,1H),4.62(s,2H),2.50(s,3H)。
Step 4:N- (3- (5- ((the chloro- 6- benzyl of 2-) amino) -1H-1,2,4- triazole -3- base) phenyl) acryloyl The synthesis of amine (17):
By compound 3a (12.0mg, 0.038mmol) and triethylamine (5.0mg, 0.049mmol) at tetrahydrofuran (THF) Mixture in (0.5mL) is cooled to 0 DEG C, is added acryloyl chloride (3.45mg, 0.038mmol).Then by gained mixture room Temperature stirring 3h, then be quenched with water.Decompression removal solvent, the inverted HPLC (C of residue18) purifying, obtain the N- for white solid (3- (5- ((the chloro- 6- benzyl of 2-) amino) -1H-1,2,4- triazole -3- bases) phenyl) acrylamide (a) (2.6mg, yield 18.5%).Mass spectrum (ESI) m/z C18H15ClFN5O[M+H]+Calculated value 372.09,374.09, measured value 372.30,374.20.1H NMR(400MHz,CD3OD)δ8.12(s,1H),7.77(s,1H),7.73–7.63(m,1H),7.40(s,1H),7.37–7.27 (m, 2H), 7.14 (t, J=8.1Hz, 1H), 6.46 (dd, J=17.0,9.6Hz, 1H), 6.38 (dd, J=17.0,2.3Hz, 1H), 5.79 (dd, J=9.6,2.3Hz, 1H), 4.67 (s, 2H).
Step 4:N- (3- (5- ((the chloro- 6- methylbenzyl of 2-) amino) -1H-1,2,4- triazole -3- base) phenyl) propylene The synthesis of amide (20):
By compound 3b (4.0mg, 0.013mmol) and triethylamine (30.0mg, 0.3mmol) at tetrahydrofuran (THF) Mixture in (0.5mL) is cooled to 0 DEG C, is added acryloyl chloride (2.0mg, 0.022mmol).Then, by gained mixture room Temperature stirring 3h, then be quenched with water.Decompression removal solvent.Inverted HPLC (the C of residue18) purifying, obtain the N- for white solid (3- (5- ((the chloro- 6- methylbenzyl of 2-) amino) -1H-1,2,4- triazole -3- bases) phenyl) acrylamide (b (3.1mg, yield 66.1%).Mass spectrum (ESI) m/z C19H18ClN5O[M+H]+Calculated value 368.12,370.12, measured value 368.40,370.40.1H NMR(400MHz,d6- DMSO) δ 10.25 (s, 1H), 8.19 (s, 1H), 7.75 (d, J=9.0Hz, 1H), 7.62 (d, J= 7.9Hz, 1H), 7.36 (d, J=7.9Hz, 1H), 7.32 (dd, J=6.8,4.8Hz, 1H), 7.22 (dd, J=12.1,4.7Hz, 2H), 6.46 (dd, J=17.0,10.1Hz, 1H), 6.27 (dd, J=17.0,2.0Hz, 1H), 5.76 (dd, J=10.1, 2.0Hz, 1H), 4.52 (d, J=5.4Hz, 2H), 2.48 (s, 3H).
Step 4:N- (3- (5- ((the chloro- 6- benzyl of 2-) amino) -1H-1,2,4- triazole -3- base) phenyl) -2- cyanogen The synthesis of base -4,4- dimethyl-penten -2- acrylamide (42):
By neovaleraldehyde (pivalaldehyde) (solution of 202.5mg, 1.79mmol, 75% in n-butanol), 2- cyano The suspension of acetic acid (150.0mg, 1.74mmol) and KOH (200.0mg, 3.56mmol) in methanol (2mL) is heated to 40 DEG C 5h.After TLC analysis shows that after starting material is consumed, the pH value for adjusting mixture with 3M HCl uses ethyl acetate to 3~4 (50ml) extraction.Gained ethyl acetate solution is dry, and concentration obtains 2- cyano -4,4- dimethyl-penten -2- alkene for white solid Sour (100mg, yield 37.3%).Mass spectrum (ESI) m/z C8H11NO2[M-H]-Calculated value 152.08, measured value 152.20.1H NMR(400MHz,CDCl3) (Z) -2- cyano -4,4- dimethyl-penten -2- olefin(e) acid δ 4.35 (s, 1H), 0.90 (s, 9H)；(E)-2- Cyano -4,4- dimethyl-penten -2- olefin(e) acid δ 7.73 (s, 1H), 1.33 (s, 9H).
By compound 3a (30.0mg, 0.094mmol), 2- cyano -4,4- dimethyl-penten -2- olefin(e) acid (15.0mg, 0.098mmol) and N, N- lutidines -4- amine (DMAP) (2mg, 0.016mmol) are at N,N-dimethylformamide (DMF) Mixture in (2mL) is cooled to 0 DEG C, is added EDCI (40.0mg, 0.209mmol).Then gained mixture is stirred at room temperature 20h, then be quenched with water.Decompression removal solvent.(silica gel, methylene chloride/methanol=50:1 are pure to 10:1) through column chromatography for residue Change, obtains N- (3- (5- ((the chloro- 6- benzyl of 2-) amino) -1H-1,2,4- triazole -3- bases) phenyl) -2- for white solid Cyano -4,4- dimethyl-penten -2- acrylamide (c) (14mg, yield 32.7%).Mass spectrum (ESI) m/z C23H22ClFN6O[M+H]+ Calculated value 453.15,455.15, measured value 453.20,455.30.
Step 4:N- (3- (5- ((the chloro- 6- methylbenzyl of 2-) amino) -1H-1,2,4- triazole -3- base) phenyl) -2- cyanogen The synthesis of base -4,4- dimethyl-penten -2- acrylamide (23):
By compound 3b (10.0mg, 0.032mmol), 2- cyano -4,4- dimethyl-penten -2- olefin(e) acid (5.0mg, 0.033mmol) and N, N- lutidines -4- amine (DMAP) (0.4mg, 0.0032mmol) are in N,N-dimethylformamide (DMF) mixture in (2mL) is cooled to 0 DEG C, is added EDCI (15.0mg, 0.078mmol).Then by gained mixture room temperature 20h is stirred, then is quenched with water.Decompression removal solvent.Residue through column chromatograph (silica gel, methylene chloride/methanol=50:1 to 10: 1) it purifies, obtains the N- (3- (5- ((the chloro- 6- methylbenzyl of 2-) amino) -1H-1,2,4- triazole -3- bases) for white solid Phenyl) -2- cyano -4,4- dimethyl-penten -2- acrylamide (d) (5.0mg, yield 35%).Mass spectrum (ESI) m/z C24H25ClN6O [M+H]+Calculated value 449.18,451.18, measured value 449.50,451.30.1H NMR(400MHz,CDCl3, rotational isomer is mixed Close object) δ 7.94 (s, 1H), 7.84 (d, J=7.7Hz, 1H), 7.79 (s, 0.2H), 7.42 (t, J=7.8Hz, 1H), 7.32 (d, J=8.7Hz, 1H), 7.23 (d, J=7.3Hz, 1H), 7.15-7.09 (m, 2H), 5.05 (s, 1H), 4.67 (s, 2H), 4.35 (d, J=2.8Hz, 1H), 3.81 (d, J=2.9Hz, 1H), 2.51 (s, 3H), 1.33 (s, 1.3H), 1.03 (s, 9H).
Step 4:N- (3- (5- ((the chloro- 6- benzyl of 2-) amino) -1H-1,2,4- triazole -3- base) phenyl) butyl- 2- alkynes The synthesis of amide (37):
By compound 3a (15.0mg, 0.047mmol), 2- tetrolic acid (10.0mg, 0.118mmol) and N, N- dimethyl pyrazole Mixture of the pyridine -4- amine (DMAP) (2mg, 0.016mmol) in n,N-Dimethylformamide (DMF) (2mL) is cooled to 0 DEG C, It is added EDCI (40.0mg, 0.209mmol).Then 20h is stirred at room temperature in gained mixture, then be quenched with water.Decompression removal is molten Agent.Through column chromatography, (silica gel, methylene chloride/methanol=50:1 to 10:1) purifying, obtains the N- (3- for white solid to residue (5- ((the chloro- 6- benzyl of 2-) amino) -1H-1,2,4- triazole -3- bases) phenyl) butyl- 2- alkynyl amide (5mg, yield 27.6%).Mass spectrum (ESI) m/z C19H15ClFN5O[M+H]+Calculated value 384.09,386.09, measured value 384.30,86.43.1H NMR(400MHz,CD3OD)δ8.05(s,1H),7.68-7.66(m,2H),7.38-7.29(m,3H),7.20-7.13(m, 1H),4.67(s,2H),2.04(s,3H)。
The synthesis of step 1:3- ((tert-butoxycarbonyl) amino) benzoic acid (intermediate 1):
By 3- aminobenzoic acid (500mg, 3.65mmol) and triethylamine (1.11g, 10.97mmol) in methanol (6mL) Mixture be cooled to 0 DEG C, be added di-tert-butyl dicarbonate (880mg, 4.03mmol).Then gained mixture is stirred at room temperature 10h, then be quenched with water.Decompression removal solvent.(silica gel, methylene chloride/methanol=100:1 are pure to 10:1) through column chromatography for residue Change, obtains 3- ((tert-butoxycarbonyl) amino) benzoic acid (1) (800mg, yield 92.5%) for white solid.Mass spectrum (ESI)m/z C12H15NO4[M-H]-Calculated value 236.10, measured value 236.10.1H NMR(400MHz,d6-DMSO)δ12.90 (s, 1H), 9.55 (s, 1H), 8.14 (s, 1H), 7.62 (d, J=8.5Hz, 1H), 7.53 (d, J=7.8Hz, 1H), 7.36 (t, J =7.9Hz, 1H), 1.48 (s, 9H).
The synthesis of step 2:3- ((tert-butoxycarbonyl) (methyl) amino) benzoic acid (intermediate 2):
By 3- ((tert-butoxycarbonyl) amino) benzoic acid (1) (1.0g, 4.21mmol) in N,N-dimethylformamide (DMF) mixture in (10mL) is cooled to 0 DEG C, and sodium hydride is added, and (505.7mg, 12.64mmol, 60% are dispersed in mineral oil In).Mixture stirs 1h at this temperature, is added iodomethane (1.26g, 8.80mmol).5h is stirred at room temperature in gained mixture, It is quenched with water again.Decompression removal solvent, residue methanol (10mL)/water (1mL) dissolve, addition sodium hydroxide (337.2mg, 8.43mmol).After TLC analysis shows that after starting material is consumed, the pH value of mixture is adjusted to 3~4 with 3M HCl, then use second Acetoacetic ester (50ml) extraction.Gained ethyl acetate solution is dry, and concentration obtains 3- ((the tert-butoxy carbonyl for white solid Base) (methyl) amino) benzoic acid (2) (950mg, yield 89.7%).Mass spectrum (ESI) m/z C13H17NO4[M-H]-Calculated value 250.12 measured value 250.10.1H NMR(400MHz,d6- DMSO) δ 13.06 (s, 1H), 7.83 (t, J=1.8Hz, 1H), 7.75-7.72 (m, 1H), 7.53 (ddd, J=8.0,2.3,1.2Hz, 1H), 7.49-7.43 (m, 1H), 3.20 (s, 3H), 1.40 (s,9H)。
Step 3:(3- (5- amino -1H-1,2,4- triazole -3- base) phenyl) (methyl) t-butyl carbamate (intermediate 3) synthesis:
By aminoguanidine nitrate (360mg, 2.63mmol) and K2CO3(660mg, 4.78mmol) is in N, N- dimethyl formyl 1h is stirred at room temperature in suspension in amine (DMF) (3mL).3- ((tert-butoxycarbonyl) (methyl) amino) benzoic acid (2) (600mg, 2.39mmol) solution in N,N-dimethylformamide (DMF) (30mL) is at 0 DEG C with N, N'- carbonyl dimidazoles (CDI) (426mg, 2.63mmol) processing.1h is stirred at room temperature in solution.It is then added in suspension.Gained mixture is stirred at room temperature 3h is then heated to 100 DEG C and maintains 3h.It is cooled to room temperature mixture, is filtered, concentration.Residue through column chromatograph (silica gel, Methylene chloride/methanol=100:1 to 10:1) purifying, obtains (3- (5- the amino -1H-1,2,4- triazole -3- for yellow oil Base) phenyl) (methyl) t-butyl carbamate (3) (220g, yield 31.8%).Mass spectrum (ESI) m/z C14H19N5O2[M+H]+ Calculated value 290.15, measured value 290.20.1H NMR(400MHz,CDCl3)δ7.85–7.80(m,1H),7.73–7.67(m, 1H), 7.61 (s, 1H), 7.29 (t, J=7.9Hz, 1H), 7.23-7.18 (m, 1H), 7.04 (s, 2H), 3.23 (s, 3H), 1.46 (s,9H)。
Step 4:(3- (5- ((the chloro- 6- benzyl of 2-) amino) -1H-1,2,4- triazole -3- base) phenyl) (methyl) ammonia The synthesis of base t-butyl formate (intermediate 4):
By (3- (5- amino -1H-1,2,4- triazole -3- base) phenyl) (methyl) t-butyl carbamate (3) (200mg, 0.69mmol), the chloro- 6- fluorobenzaldehyde (200mg, 1.26mmol) of 2- and p-methyl benzenesulfonic acid (11.9mg, 0.069mmol) are in isopropyl Mixture heated overnight at reflux in alcohol (5mL).After being cooled to room temperature solution, NaBH is added3CN(120mg,1.91mmol) With acetic acid (0.5mL).Then 5h is stirred at room temperature in gained mixture, then be quenched with water.Decompression removal solvent.(3-(5-((2- Chloro- 6- fluorophenyl) amino) -1H-1,2,4- triazole -3- base) phenyl) (methyl) t-butyl carbamate (4) crude product is further It purifies and directly uses.
Step 5:N- (the chloro- 6- benzyl of 2-) -3- (3- (methylamino) phenyl) -1H-1,2,4- triazole -5- amine (18) Synthesis:
By (3- (5- ((the chloro- 6- benzyl of 2-) amino) -1H-1,2,4- triazole -3- base) phenyl) (methyl) amino first Mixture of tert-butyl acrylate (4) (100mg) crude product in tetrahydrofuran (THF) (5mL) is cooled to 0 DEG C, and trifluoroacetic acid is added (10mL).Then 5h is stirred at room temperature in gained mixture.Decompression removal solvent.Residue through column chromatograph (silica gel, methylene chloride/ Methanol=100:1 to 10:1) purifying, obtains N- (the chloro- 6- benzyl of 2-) -3- (3- (methylamino) benzene for white solid Base) -1H-1,2,4- triazole -5- amine (5) (45mg, yield 19.6%, two steps).Mass spectrum (ESI) m/z C16H15ClFN5[M+H]+ Calculated value 332.10,334.10, measured value 332.40,334.30.1H NMR(400MHz,d6- DMSO, rotational isomer 2:1 are mixed Close object) δ 13.17 (s, 0.5H), 12.07 (s, 1H), 7.35 (s, 3H), 7.23 (s, 1.5H), 7.12 (s, 4.5H), 6.85 (s, 1H),6.48-6.52(m,1.5H),6.13(s,0.6H),5.71-5.75(m,1.5H),4.51(s,3H),2.69(s,4.5H)。
Step 6:N- (3- (5- ((the chloro- 6- fluorophenyl of 2-) amino) -1H-1,2,4- triazole -3- base) phenyl)-N- methyl-prop The synthesis of acrylamide (21)
By compound 29 (32mg, 0.096mmol) and N- ethyl-N-iospropyl -2- propylamine (DIPEA) (50mg, 0.39mmol) mixture in tetrahydrofuran (THF) (0.5mL) is cooled to 0 DEG C, be added acryloyl chloride (20mg, 0.22mmol).Then 3h is stirred at room temperature in gained mixture.Decompression removal solvent.Residue methanol (2mL)/water (0.5mL) Dissolution is added NaOH (10mg, 0.25mmol), and 5h is stirred at room temperature in reaction mixture, is concentrated.Residue through column chromatograph (silica gel, Methylene chloride/methanol=100:1 to 10:1) purifying, obtains N- (3- (5- ((the chloro- 6- benzyl of 2-) ammonia for white solid Base) -1H-1,2,4- triazole -3- bases) phenyl)-N methacrylamide (6.3mg, yield 17%).Mass spectrum (ESI) m/z C19H17ClFN5O[M+H]+Calculated value 386.11,388.11, measured value 386.50,388.40.1H NMR(400MHz,CDCl3)δ 7.95 (d, J=7.9Hz, 1H), 7.83 (t, J=1.7Hz, 1H), 7.43 (t, J=7.8Hz, 1H), 7.25-7.19 (m, 2H), 7.18-7.14 (m, 1H), 7.00-7.05 (m, 1H), 6.34 (dd, J=16.8,1.9Hz, 1H), 6.09 (dd, J=16.5, 10.3Hz, 1H), 5.50 (dd, J=10.3,1.6Hz, 1H), 5.37 (s, 1H), 4.68 (d, J=5.3Hz, 2H), 3.36 (s, 3H)。
The synthesis of step 1:3- (4- methoxyl group -3- nitrobenzophenone) -1H-1,2,4- triazole -5- amine (intermediate 1):
By the suspension of aminoguanidine nitrate (139mg, 1.01mmol) and KOH (57mg, 1.02mmol) in methanol (2mL) 1.5h is stirred at room temperature in liquid, concentration.Residue is diluted with N,N-dimethylformamide (DMF) (2mL).4- methoxyl group -3- nitrobenzene Solution N, N'- carbonyl dimidazoles (CDI) of the formic acid (197mg, 1.0mmol) in N,N-dimethylformamide (DMF) (5mL) (190mg, 1.17mmol) is handled at 0 DEG C.1.5h is stirred at room temperature in solution.Then it is added dropwise in suspension.After the completion of charging, 2h is stirred at room temperature in reaction mixture.Solvent, residue water (50mL), dissolution are removed by rotary evaporation, and is heated to reflux 5h.After being cooled to room temperature, filtering, obtained solid recrystallizing methanol obtains the 3- (4- methoxyl group -3- nitre for faint yellow solid Base phenyl) -1H-1,2,4- triazole -5- amine (1) (110mg, yield 46.8%).Mass spectrum (ESI) m/z C9H9N5O3[M+H]+It calculates Value 236.07, measured value 236.20.1H NMR(400MHz,d6- DMSO) δ 12.15 (s, 1H), 8.26 (d, J=1.4Hz, 1H), 8.11 (dd, J=8.8,2.1Hz, 1H), 7.42 (d, J=8.9Hz, 1H), 6.14 (s, 2H), 3.95 (s, 3H).
Step 2:N- (the chloro- 6- benzyl of 2-) -3- (4- methoxyl group -3- nitrobenzophenone) -1H-1,2,4- triazole -5- amine The synthesis of (intermediate 2):
By 3- (4- methoxyl group -3- nitrobenzophenone) -1H-1,2,4- triazole -5- amine (1) (100mg, 0.43mmol) and 2- Mixture of the chloro- 6- fluorobenzaldehyde (150mg, 0.95mmol) in dry toluene (10mL) is heated to reflux 15h.Keep solution cooling To room temperature, NaBH is added3CN (45mg, 0.72mmol) and acetic acid (1mL).Then 3h is stirred at room temperature in gained mixture, then It is quenched with water.Decompression removal solvent.Through column chromatography, (silica gel, methylene chloride/methanol=50:1 to 10:1) purifying, obtains residue For N- (the chloro- 6- fluorophenyl of 2-) -3- (4- methoxyl group -3- nitrobenzophenone) -1H-1,2,4- triazole -5- amine (2) of faint yellow solid (70mg, yield 43.6%), is directly used in next step.Mass spectrum (ESI) m/z C16H13ClFN5O3[M+H]+Calculated value 378.07,380.07, measured value 378.30,380.30.
Step 3:3- (3- amino-4-methoxyl phenyl)-N- (the chloro- 6- benzyl of 2-) -1H-1,2,4- triazole -5- amine (24) synthesis:
By N- (the chloro- 6- benzyl of 2-) -3- (4- methoxyl group -3- nitrobenzophenone) -1H-1,2,4- triazole -5- amine (2) The mixture of (70mg, 0.19mmol) and hydrazine hydrate (1.0mL, 80% aqueous solution) in ethyl alcohol (10mL) is heated to 60 DEG C.So Raney-Ni (10mg) is added afterwards.3h is stirred at room temperature in gained mixture.After being cooled to room temperature, filtering, decompression removal solvent.Residual Through column chromatography, (silica gel, methylene chloride/methanol=50:1 to 10:1) purifying, obtains the 3- (3- amino -4- first for white solid to object Phenyl)-N- (the chloro- 6- fluorophenyl of 2-) -1H-1,2,4- triazole -5- amine (3) (50mg, yield 77.6%).Mass spectrum (ESI) m/z C16H15ClFN5O[M+H]+Calculated value 348.09,350.09, measured value 348.50,350.60.1H NMR(400MHz, CD3OD) δ 7.36-7.23 (m, 4H), 7.11 (t, J=8.3Hz, 1H), 6.89 (d, J=8.2Hz, 1H), 4.63 (s, 2H), 3.88(s,3H)。
Step 4:N- (5- (5- ((the chloro- 6- benzyl of 2-) amino) -1H-1,2,4- triazole -3- base) -2- methoxybenzene Base) acrylamide (22) synthesis:
By compound 3 (8.0mg, 0.023mmol) and N- ethyl-N-iospropyl -2- propylamine (DIPEA) (12.0mg, 0.093mmol) after the mixture in tetrahydrofuran (THF) (0.5mL) is cooled to 0 DEG C, addition acryloyl chloride (5.0mg, 0.055mmol).30min is stirred at room temperature in gained mixture, then is quenched with water.Decompression removal solvent.Residue with methanol (2mL)/ Water (0.5mL) dissolution, is then added NaOH (5.0mg, 0.13mmol), 1h is stirred at room temperature in reaction mixture.Concentration, residue Through column chromatography, (silica gel, methylene chloride/methanol=100:1 to 10:1) purifying, ((((2- is chloro- by 5- by 5- by the N- for obtaining as white solid 6- benzyl) amino) -1H-1,2,4- triazole -3- bases) -2- methoxyphenyl)-acrylamide (5.1mg, yield 55.2%).Mass spectrum (ESI) m/z C19H17ClFN5O2[M-H]-Calculated value 400.11,401.11, measured value 400.40, 402.40。1H NMR(400MHz,CDCl3) δ 8.94 (s, 1H), 7.91 (s, 1H), 7.73 (dd, J=8.5,2.1Hz, 1H), 7.21-7.16 (m, 2H), 7.03-6.97 (m, 1H), 6.94 (d, J=8.6Hz, 1H), 6.42 (dd, J=16.9,1.4Hz, 1H), 6.30 (dd, J=16.9,10.1Hz, 1H), 5.77 (dd, J=10.0,1.4Hz, 1H), 5.09 (s, 1H), 4.68 (d, J =5.0Hz, 2H), 3.94 (s, 3H).
The synthesis of step 1:3- (3,4,5- trimethoxyphenyl) -1H-1,2,4- triazole -5- amine (intermediate 1):
By aminoguanidine nitrate (137mg, 1.0mmol) and K2CO3(276mg, 2.0mmol) is in N,N-dimethylformamide (DMF) 1h is stirred at room temperature in the suspension in (3mL).3,4,5- trimethoxybenzoic acid (212mg, 1.0mmol) is in N, N- diformazan Solution N, N'- carbonyl dimidazoles (CDI) (162mg, 1.0mmol) in base formamide (DMF) (5mL) are handled at 0 DEG C.Solution 1h is stirred at room temperature.It is then added in suspension.3h is stirred at room temperature in gained mixture, is again heated to 100 DEG C and maintains 3h.Mixing Object is cooled to room temperature, and is filtered, and concentration obtains 3- (3,4,5- trimethoxyphenyl) -1H-1 for white solid, 2,4- triazoles - 5- amine (intermediate 1) crude product (180mg), is directly used in next step.Mass spectrum (ESI) m/z C11H14N4O3[M+H]+Calculated value 251.11 measured value 241.20.
Step 2:N- (the chloro- 6- benzyl of 2-) -3- (3,4,5- trimethoxyphenyl) -1H-1,2,4- triazole -5- amine (36) synthesis:
By 3- (3,4,5- trimethoxyphenyl) -1H-1,2,4- triazole -5- amine (intermediate 1) (180mg, 0.72mmol), The chloro- 6- fluorobenzaldehyde (180mg, 1.14mmol) of 2- and p-methyl benzenesulfonic acid (20.00mg, 0.12mmol) are in isopropanol (5mL) Mixture heated overnight at reflux.After being cooled to room temperature solution, NaBH is added3CN (180mg, 2.86mmol) and acetic acid (1.5mL).Then, 5h is stirred at room temperature in gained mixture, then is quenched with water.Decompression removal solvent, residue chromatograph (silicon through column Glue, methylene chloride/methanol=100:1 to 10:1) purifying, obtain for white solid N- (the chloro- 6- fluorophenyl of 2-) -3- (3,4, 5- trimethoxyphenyl) -1H-1,2,4- triazole -5- amine (65mg, yield 16.6%, 2 steps).Mass spectrum (ESI) m/z C18H18ClFN4O3[M+H]+Calculated value 393.11,395.11, measured value 393.33,395.27.1H NMR(400MHz,CDCl3)δ 7.96(s,1H),7.25-7.22(m,1H),7.18(s,2H),7.15-7.11(m,1H),7.06-7.02(m,1H),5.22(t, J=5.6Hz, 1H), 4.65 (d, J=5.6Hz, 2H), 3.89 (s, 6H), 3.87 (s, 3H)
The synthesis of step 1:3- (1H- benzo [d] imidazoles -2- base) -1H-1,2,4- triazole -5- amine (intermediate 1):
By aminoguanidine nitrate (150mg, 1.09mmol) and K2CO3(150mg, 1.09mmol) is in N, N- dimethyl formyl 1h is stirred at room temperature in suspension in amine (DMF) (3mL).1H- benzo [d] imidazoles -2- carboxylic acid (162mg, 1.0mmol) is in N, N- bis- Solution in methylformamide (DMF) (5mL) is in 0 DEG C of processing N, N'- carbonyl dimidazoles (CDI) (180mg, 1.1mmol).It is molten 1h is stirred at room temperature in liquid.It is then added in suspension.3h is stirred at room temperature in gained mixture, is then heated to 100 DEG C and maintains 3h. Mixture is cooled to room temperature, and is filtered, and concentration obtains 3- (1H- benzo [d] imidazoles -2- base) -1H-1 for white solid, and 2,4- (290mg, purity about 40%) crude product, is directly used in next step to triazole -5- amine (intermediate 1).Mass spectrum (ESI) m/z C9H8N6[M+H]+Calculated value 201.08, measured value 201.20.
Step 2:3- (1H- benzo [d] imidazoles -2- base)-N- (the chloro- 6- benzyl of 2-) -1H-1,2,4- triazole -5- amine (31) synthesis:
By 3- (1H- benzo [d] imidazoles -2- base) -1H-1,2,4- triazole -5- amine (intermediate 1) (50mg, 0.25mmol, 40% purity), the chloro- 6- fluorobenzaldehyde (50mg, 0.32mmol) of 2- and p-methyl benzenesulfonic acid (5.00mg, 0.03mmol) be in ethyl alcohol Mixture heated overnight at reflux in (5mL).After being cooled to room temperature solution, NaBH is added3CN (50mg, 0.80mmol) and second Sour (1.5mL).Then, 5h is stirred at room temperature in gained mixture, then is quenched with water.Decompression removal solvent, residue chromatograph (silicon through column Glue, methylene chloride/methanol=100:1 to 10:1) purifying, obtains 3- (1H- benzo [d] imidazoles -2- base)-N- for white solid (the chloro- 6- benzyl of 2-) -1H-1,2,4- triazole -5- amine (1.4mg).Mass spectrum (ESI) m/z C16H12ClFN6[M+H]+It calculates Value 343.08,345.08, measured value 343.33,345.27.1H NMR(400MHz,CD3OD)δ7.62(s,2H),7.32-7.27 (m,4H),7.20-7.14(m,1H),4.72(s,2H).
The synthesis of bis- (2- methoxy ethoxy) benzoic acid (intermediate 1) of step 1:3,4-:
By 3,4- dihydroxy-benzoic acid (1.0g, 6.49mmol), TBAI (239.67mg, 0.65mmol) and K2CO3 The suspension of (3.59g, 25.98mmol) in N,N-dimethylformamide (DMF) (10mL) is heated to 100 DEG C and maintains 1h. After so that mixture is cooled to 50 DEG C, the chloro- 2- Ethyl Methyl Ether (2.45g, 25.92mmol) of 1- is added.Gained mixture is at 85 DEG C 15h is stirred, room temperature is cooled to.Filtering, concentration, residue THF (40mL)/H2O (10mL) dissolution, addition KOH (1.09g, 19.5mmol).5h is stirred at room temperature in acquired solution, is then quenched with 1N HCl.It is extracted again with ethyl acetate (30mL, 3 times), it is organic It is mutually washed with salt water (15mL), in Na2SO4On dry, filter, be concentrated, obtain bis- (the 2- methoxyl groups of 3,4- for clear oily matter Ethyoxyl) benzoic acid (intermediate 1) (1.32g, yield 75.33%).1H NMR(400MHz,CDCl3) δ 7.48 (d, J= 8.4Hz 1H), 7.65 (s, 1H), 6.94 (d, J=8.4Hz, 1H), 4.24-4.16 (m, 4H), 3.82-3.76 (m, 4H), 3.47 (s,6H)。
The conjunction of step 2:3- (bis- (2- methoxy ethoxy) phenyl of 3,4-) -1H-1,2,4- triazole -5- amine (intermediate 2) At:
By aminoguanidine nitrate (737.08mg, 5.38mmol) and K2CO3(743.02mg, 5.38mmol) is in N, N- diformazan 1h is stirred at room temperature in suspension in base formamide (DMF) (5mL).Bis- (2- methoxy ethoxy) benzoic acid (intermediate 1) of 3,4- The solution of (1.32g, 4.89mmol) in N,N-dimethylformamide (DMF) (10mL) is at 0 DEG C with N, N'- carbonyl dimidazoles (CDI) (871.77mg, 5.38mmol) is handled.1h is stirred at room temperature in solution.It is then added in suspension.Gained mixture room temperature 3h is stirred, 100 DEG C is again heated to and maintains 10h.Mixture is cooled to room temperature, and is filtered, concentration.Residue passes through reversed-phase HPLC (C18) purifying, obtain 3- (3,4- bis- (2- methoxy ethoxy) phenyl) -1H-1 for white solid, 2,4- triazole -5- amine (in Mesosome 2) (800mg, yield 53.09%).1H NMR(400MHz,d6-DMSO)δ11.93(s,1H),7.43-7.40(m,2H), 6.99-6.97(m,1H),6.01(s,2H),4.12-4.09(m,4H),3.69-3.64(m,4H),3.33(s,6H).
Step 3:3- (bis- (2- methoxy ethoxy) phenyl of 3,4-)-N- (the chloro- 6- benzyl of 2-) -1H-1,2,4- three The synthesis of azoles -5- amine (34):
By 3- (bis- (2- methoxy ethoxy) phenyl of 3,4-) -1H-1,2,4- triazole -5- amine (intermediate 2) (800mg, 2.59mmol), the chloro- 6- fluorobenzaldehyde (1.03g, 6.49mmol) of 2- and p-methyl benzenesulfonic acid (44.7mg, 0.26mmol) are in isopropyl Mixture heated overnight at reflux in alcohol (10mL).After being cooled to room temperature solution, NaBH is added3CN(652.2mg, 10.38mmol) and acetic acid (1.5mL).Then, 5h is stirred at room temperature in gained mixture, then is quenched with water.Decompression removal solvent, it is residual Staying object through column chromatography, (silica gel, methylene chloride/methanol=100:1 to 10:1) purifying, (3,4- is bis- by the 3- for obtaining as white solid (2- methoxy ethoxy) phenyl)-N- (the chloro- 6- fluorophenyl of 2-) -1H-1,2,4- triazole -5- amine (120mg, yields 10.26%).Mass spectrum (ESI) m/z C21H24ClFN4O4[M+H]+Calculated value 451.15,453.15, measured value 451.44, 453.37。1H NMR(400MHz,CDCl3) δ 7.46 (s, 1H), 7.45-7.43 (d, J=8Hz, 1H), 7.25-7.22 (m, 2H), 7.03-7.0 (m, 1H), 6.92-6.90 (d, J=8Hz, 1H), 5.18 (t, J=6.8Hz, 1H), 4.65 (d, J=6.8Hz, 2H),4.19-4.16(m,4H),3.79-3.75(m,4H),3.44(s,6H).
The synthesis of step 1:3- methoxyl group -4- (morpholinyl propoxyl group) benzoic acid (intermediate 1):
By vanillic acid methyl esters (914.2mg, 5.02mmol), TBAI (185.4mg, 0.50mmol) And K2CO3The suspension of (763mg, 5.52mmol) in N,N-dimethylformamide (DMF) (10mL) is heated to 100 DEG C and ties up Hold 1h.After so that mixture is cooled to 50 DEG C, 4- (3- chloropropyl) morpholine (903.3mg, 5.52mmol) is added.Gained mixture exists 85 DEG C of stirring 15h, are cooled to room temperature.Filtering, concentration, residue THF (40mL)/H2O (10mL) dissolution, is added KOH (1.09g,19.5mmol).5h is stirred at room temperature in acquired solution, is quenched with 1N HCl.It is extracted, is had with ethyl acetate (30mL, 3 times) Machine is mutually washed with salt water (15mL), in Na2SO4On dry, filter, be concentrated, obtain the 3- methoxyl group -4- (3- for clear oily matter Morpholinopropoxy) benzoic acid (intermediate 1) (1.30g, yield 87.72%), it is not further purified and is directly used in down One step.
Step 2:3- (3- methoxyl group -4- (morpholinyl propoxyl group) phenyl) -1H-1,2,4- triazole -5- amine (intermediate 2) Synthesis:
By aminoguanidine nitrate (1.40g, 10.21mmol) and K2CO3(1.41g, 10.21mmol) is in N, N- dimethyl methyl 1h is stirred at room temperature in suspension in amide (DMF) (10mL).3- methoxyl group -4- (morpholinyl propoxyl group) benzoic acid (intermediate 1) solution of (0.90g, 3.05mmol) in N,N-dimethylformamide (DMF) (10mL) is at 0 DEG C with N, N'- carbonyl dimidazoles (CDI) (1.10g, 6.78mmol) is handled.1h is stirred at room temperature in solution.It is then added in suspension.Gained mixture room temperature is stirred 3h is mixed, be then heated to 100 DEG C and maintains 10h.Mixture is cooled to room temperature, and is filtered, concentration.Residue passes through reversed-phase HPLC (C18) purifying, obtain 3- (3- methoxyl group -4- (morpholinyl propoxyl group) phenyl) -1H-1,2,4- triazole -5- for white solid Amine (intermediate 2) (520mg, purity 80%), is directly used in next step.Mass spectrum (ESI) m/z C16H23N5O3[M+H]+Meter Calculation value 334.18, measured value 334.31.
Step 3:N- (the chloro- 6- benzyl of 2-) -3- (3- methoxyl group -4- (morpholinyl propoxyl group) phenyl) -1H-1,2, The synthesis of 4- triazole -5- amine (32):
By 3- (3- methoxyl group -4- (morpholinyl propoxyl group) phenyl) -1H-1,2,4- triazole -5- amine (intermediate 2) The chloro- 6- fluorobenzaldehyde (913.12mg, 5.76mmol) of (480mg, 1.15mmol, purity 80%), 2- and p-methyl benzenesulfonic acid The mixture heated overnight at reflux of (19.83mg, 0.12mmol) in isopropanol (10mL).After being cooled to room temperature solution, add Enter NaBH3CN (723.81mg, 11.52mmol) and acetic acid (1.5mL).Then, 5h is stirred at room temperature in gained mixture, then uses water quenching It goes out.Decompression removal solvent, through column chromatography, (silica gel, methylene chloride/methanol=100:1 to 10:1) purifying, obtains being white residue N- (the chloro- 6- fluorophenyl of 2-) -3- (3- methoxyl group -4- (morpholinyl propoxyl group) phenyl) -1H-1,2,4- triazole-of color solid 5- amine (85mg, yield 15.51%).Mass spectrum (ESI) m/z C23H27ClFN5O3[M+H]+Calculated value 476.18,478.18, actual measurement Value 476.39,478.27.1H NMR(400MHz,CDCl3) δ 7.46 (s, 1H), 7.45-7.43 (d, J=8.4Hz, 1H), 7.25- 7.22 (m, 2H), 7.03-7.0 (m, 1H), 6.92-6.90 (d, J=8.4Hz, 1H), 5.08 (brs, 1H), 4.65 (dd, J= 6.8,1.2Hz,2H),4.15-4.10(m,2H),3.90(s,3H),3.75-3.72(m,4H),2.61-2.58(m,2H),2.54 (brs,4H),2.08-2.04(m,2H).
Plasmid construction
People p38MAPK and MKK6 pet28a is cloned into Nco I/Not I, Nde I and Sal I restriction site respectively to carry On body.Then make pet28a-hMKK6 that S207D/T211D mutation occur with the site-directed mutagenesis kit from Transgen.To slotting Enter gene sequencing, to ensure that sequence is correct.
The purifying of fusion protein
Protein expression is carried out using E.coli BL21DE3 and LB culture medium.Culture grows to OD600nm at 37 DEG C 1.2,1h is cooled down when then at 18 DEG C in shaking, then induce 16h with 0.2mM IPTG at 16 DEG C.Protein carries out pure as previously described Change.In brief, cell is harvested, with Ni resin and MonoQ HP column purification.Then combined protein peak fraction is further adopted With Superdex-75 column, with 50mM Tris-HCl (pH 7.4), 150mM NaCl, 5% glycerol, 10mM MgCl2,5mM DTT It is purified for eluant, eluent.All purification steps are all carried out at 4 DEG C.
The detection of P38MAPK kinase activity
The hMKK6DD of 1000ng inactive hMAPK14 100ng constitutively activated (constitutively active) In 30 DEG C of activation 30min in the reaction volume that 15ul contains 50uM ATP.With Z '-LYTE kinase activity detection kit Ser/ 15 peptide of Thr (Invitrogen, Carlsbad, CA) carries out kinase activity detection.The standard reaction of screening compound contains 100nM hMAPK14,1mM peptide substrates, 100uM ATP, 50m MHEPES (pH 7.4), 10mM MgCl2,0.01%Brij-35 And 0.5%DMSO.
Cell culture
Jurkat T and Ramos B cell is used supplemented with 10%FBS, every milliliter of 100 μ g penicillin and streptomysin It is cultivated in RPMI1640 culture medium.
Antibody
For the anti-BTK (Tyr223) of western blot, anti-ZAP-70, anti-PLC γ -2, anti-p-BTK (Y223), anti-p- PLC γ -2 (Y1217), anti-p-ZAP-70 (Y319) and anti-GAPDH are bought from Cell Signaling Technology (Danvers,MA,USA)。
B and T cell activation and phosphorylation immunoblotting assay (Phospho-Blots)
At 37 DEG C in 5% carbon dioxide incubator, Ramos B is cultivated under conditions of with or without various concentration compound Cell or Jurkat T cell (2 × 106)1.5h.Then goat-anti people IgM F (ab ') 2 (10 μ g/mL are added；Invitrogen) Or Dynabeads Human T-activactor CD3/CD28, to stimulate Ramos B cell or Jurkat T respectively at 37 DEG C Cell 5min.Cell is centrifuged, is washed 1 time with cold DPBS, then with contain inhibitor of phospholipase enzymes cocktail 2 and protease The RIPA buffer (Sigma-Aldrich) of inhibitor C ocktail (being all from Sigma-Aldrich) dissolves on ice 20min.Then sample is centrifuged 20min in 4 DEG C of revolving speeds with 20,000g.Supernatant is collected, after diluting 5 times with sample-loading buffer, SDS-PAGE electrophoresis is carried out, then carries out immunoblotting assay.
Inhibitory activity of the compound to some autoimmune disease associated kinase target spots.
* N.A.: non-availability.
We also measured were the protein target in the signal path of use or the processed Ramos B cell of unused compound Phosphorylation level.With or unused compound processing 1.5h Ramos B cell with IgM F (ab ') 2 activate (+) or unactivated (-)5min.SDS-PAGE electrophoresis and immunoblotting assay experiment are carried out to the lysate of harvested cell.With goat-anti people IgM After F (ab ') 2 activates the BCR access of Ramos cell, exemplary compounds 1,6,11,17 and 20 are shown with dose-dependent Mode inhibits the phosphoric acid of the autophosphorylation of BTK and physiologic substrate (physiological substrate) PLC γ of BTK Change.The cell activity of above compound is consistent with the performance in enzymatic experiment.
We also measured were the protein target in the signal path of use or the processed Jurkat T cell of unused compound The phosphorylation level of point.With or unused compound processing 1.5h Jurkat T cell Dynabeads Human T- activator CD3/CD28 activates (+) or unactivated (-) 5 minutes.SDS-PAGE electrophoresis and Diagnosis of Sghistosomiasis are carried out to the lysate of harvested cell Mark analysis experiment.After the TCR access with Dynabeads Human T- activator CD3/CD28 activation Jurkat cell, example Property compound 1,6,11,17 and 20 shows the phosphorus for inhibiting the physiologic substrate ZAP-70 and LAT of LCK in a manner of dose-dependent Acidification.The cell activity of above compound is consistent with the performance in enzymatic experiment.
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Claims (15)

1. the compound of Formulas I:
Wherein:
R1–R5It is each independently H, halogen, hydroxyl, methyl, trifluoromethyl or methoxyl group, especially wherein R1And R5It is respectively independent Ground is halogen, hydroxyl, methyl, trifluoromethyl；And
R6It is optionally substituted Cn cyclic hydrocarbon radical, wherein n=3-18, and include most n-1 independently selected from N, O, S and P Hetero atom, especially wherein the alkyl is selected from naphthenic base, aryl, heteroaryl or heterocycle；
Or its stereoisomer or pharmaceutically acceptable salt.
2. the compound of claim 1, wherein n is 3,5,6 or 9.
3. the compound of claim 1, wherein R6It is substituted or unsubstituted 5- or 6-membered homoatomic ring or heterocycle or 9 yuan or 10 yuan Bicyclic aryl.
4. the compound of claim 1, wherein R6It is optionally substituted:
Cyclopropyl；
It is selected from pyrroles, pyrazoles, imidazoles, triazole, tetrazolium, pentazole, oxazole, isoxazole, thiazole or isothiazole, furans, dioxa Cyclopentene, thiophene, dithiole or oxygen dithiole and its reduction form, including dihydrofuran and glyoxalidine 5 yuan of aryl；
It is selected from 6 yuan of aryl of phenyl and pyridine；Or
- 9 yuan of aryl are benzimidazoles.
5. the compound of claim 1, wherein R6It is phenyl, 3- substituted-phenyl, 3,4- substituted-phenyl or 3,4,5- substituted-phenyl.
6. the compound of claim 1, wherein R6Substituent group be selected from: halogen ,-OR' ,-OC (O) R' ,-NR'R " ,-SR' ,- R'、-CN、-NO2、-CO2R'、-CONR'R"、-C(O)R'、-OC(O)NR'R"、-NR"C(O)R'、-NR"CO2R'、-NR'-C(O) NR"R'"、-NR'-SO2NR"R'"、-NH-C(NH2)=NH ,-NR'C (NH2)=NH ,-NH-C (NH2)=NR' ,-S (O) R' ,- SO2R'、-SO2NR'R"、-NR"SO2R、-N3、-CH(Ph)2, perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl, take The number of Dai Ji is the sum of the opening chemical valence on 0 to aromatic ring system；Wherein R', R " and R' " be each independently selected from hydrogen, (C1-C8) alkyl and miscellaneous alkyl, unsubstituting aromatic yl and heteroaryl, (unsubstituting aromatic yl)-(C1-C4) alkyl and (unsubstituting aromatic yl) Oxygroup-(C1-C4) alkyl.
7. the compound of claim 1, wherein R2-R4It is halogen, hydroxyl, methyl, fluoroform at least one in H, R1 and R5 Base or methoxyl group.
8. the compound of claim 1, wherein R2-R4It is halogen, hydroxyl, methyl, trifluoromethyl or methoxyl group for H, R1 and R5.
9. the compound of claim 1, in which:
R2-R4For H, R1And R5It is halogen, hydroxyl, methyl, trifluoromethyl or methoxyl group；
R6It is substituted or unsubstituted 5- or 6-membered homoatomic ring or heterocycle or 9 yuan or 10 membered bicyclic aryl；And
R6Substituent group be selected from: halogen ,-OR' ,-OC (O) R' ,-NR'R " ,-SR' ,-R' ,-CN ,-NO2、-CO2R'、-CONR' R"、-C(O)R'、-OC(O)NR'R"、-NR"C(O)R'、-NR"CO2R'、-NR'-C(O)NR"R'"、-NR'-SO2NR"R'"、- NH-C(NH2)=NH ,-NR'C (NH2)=NH ,-NH-C (NH2)=NR' ,-S (O) R' ,-SO2R'、-SO2NR'R"、-NR" SO2R、-N3、-CH(Ph)2, perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl, the number of substituent group is 0 to aromatic ring Opening chemical valence sum in system；Wherein R', R " and R' " are each independently selected from hydrogen, (C1-C8) alkyl and miscellaneous alkyl, not Substituted aryl and heteroaryl, (unsubstituting aromatic yl)-(C1-C4) alkyl and (unsubstituting aromatic yl) oxygroup-(C1-C4) alkyl.
10. the compound for the claim 1 having following structure or its stereoisomer or its pharmaceutically acceptable salt:
11. the compound of claim 1 has in kinase assays and is equivalent to IC50 as 10 μM or Lck below or Btk inhibition Activity.
12. a kind of pharmaceutical composition, it includes the compound of the claim 1 of the unit dosage form of therapeutically effective amount and one kind Or a variety of pharmaceutically acceptable excipient.
13. a kind of composition, it includes the compound of the claim 1 of therapeutically effective amount and to autoimmune and/or inflammation Property disease or cancer have therapeutic activity different therapeutic agents.
14. a kind of method for the treatment of and unexpected kinase activity related diseases comprising a effective amount of to needing its people to give The compound of claim 1 or its prodrug, wherein the disease is anaphylactia, autoimmune disease, diseases associated with inflammation Or cancer.
15. the method for claim 14, further include the steps that leading diagnose the illness or cancer or subsequent detection disease Or cancer finally improves the step of situation.
CN201780029397.9A 2016-03-10 2017-03-08 Kinase inhibitor Pending CN109311824A (en)

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