CN110483521A - A kind of reversible covalent bruton's tyrosine kinase inhibitor, pharmaceutical composition and its application - Google Patents

A kind of reversible covalent bruton's tyrosine kinase inhibitor, pharmaceutical composition and its application Download PDF

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CN110483521A
CN110483521A CN201810454713.3A CN201810454713A CN110483521A CN 110483521 A CN110483521 A CN 110483521A CN 201810454713 A CN201810454713 A CN 201810454713A CN 110483521 A CN110483521 A CN 110483521A
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CN110483521B (en
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周星露
刘兴国
胡苗
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HANGZHOU HERTZ PHARMACEUTICAL Co Ltd
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Abstract

The invention discloses a kind of bruton's tyrosine kinase of reversible covalent (BTK) inhibitor compound, pharmaceutical composition and and its in preparation treatment from the disease benefited in the active inhibition of bruton's tyrosine kinase, the application in obstruction and illness drug.The compounds of this invention has potent external BTK kinase inhibiting activity, it can be applied to individually or with other drugs use in conjunction treating disease, the obstruction and illness, including B cell lymphoma, autoimmune disease, inflammatory disease etc. benefited from the active inhibition of bruton's tyrosine kinase.

Description

A kind of reversible covalent bruton's tyrosine kinase inhibitor, pharmaceutical composition and its Using
Technical field
The invention belongs to field of medicaments, be specifically related to a kind of reversible covalent bruton's tyrosine kinase inhibiting compound, Pharmaceutical composition and its application.
Background technique
Bruton's tyrosine kinase (Bruton's tyrosine kinase, Btk), a kind of nonreceptor tyrosine kinase The member of Tec family is the pass expressed in all hematopoetic cell types other than T lymphocyte and natural killer cells Key signals enzyme.Btk is in connection cell surface B-cell receptor (B-cell receptor, BCR) stimulation to response in downstream cellular B cell signal transduction path in play the part of vital role.Btk is B cell development, activation, signal transduction and survival Key regulators.In addition, Btk works in other numerous hematopoietic cell signal transduction paths, such as in macrophage The TNF-α that Toll-like receptor (Toll likereceptor, TLR) and cytokine receptor mediate generates, in mast cell Immunoglobulin E receptor (Fc ε R1) signal transduction, the letter for inhibiting Fas/APO-1 Apoptosis in B- pedigree lymphoid cell The platelet aggregation of number conduction and collagen stimulation, see, for example, J.Bio.Chem., 2003,278:26258-26264, J.Exp.Med.,2003,197:1603-1611.Recent study shows that Btk signal path is current non-Hodgkin lymphoma (NHL), especially in chronic lymphocytic leukemia (CLL), B cell lymphoma and the research of autoimmune disease clinical treatment New hot spot.In addition to this, BTK signal path also take part in rheumatoid arthritis and as systemic loupus erythematosus other itself Immunity disease.
Her cloth of Btk inhibitor replaces the listing of Buddhist nun, is set to " breakthrough " new drug by FDA, research and development have a extensive future, granted Indication include lymphoma mantle cell, chronic lymphocytic leukemia, small lymphocyte lymthoma, follicular lymphoma, side Edge area lymthoma, Waldenstrom macroglobulinemia, chronic graft host disease, and in the orphan for obtaining gastric cancer in the recent period Medicine status.But gradually find that she replaces Buddhist nun to have the relevant side effect of bleeding by cloth in treatment in recent years, literature research thinks that it can Can be bad related for the Kinase Selectivity of Buddhist nun with her cloth, it is especially poor to the selectivity of TEC kinases.In addition, her cloth replaces Buddhist nun's In FDA declaration material, expert's proposition, the IC of hERG channel blocking activity are evaluated50Lower (IC50=1 μM or so), exist The risk of Cardiotoxity.Therefore, the highly efficient BTK inhibitor of a kind of selectivity of development development is needed for related disease Treatment.
Studies have shown that small molecule reversible covalent inhibitor (reversible covalent inhibitors) can be with target The disactivation area sulfhydryl residue of albumen forms reversible covalent bond, improves the residence time of compound and target protein, and presses down in BTK Certain progress is shown in the research and development of preparation, referring to Nat Chem Biol., 2015,11 (7): 525-531.Patent Research and disclosure in CN103534258B, CN104822681B etc. have also further demonstrated that the important of such compound exploitation Property.Small molecule covalency inhibitor (covalent inhibitors), also referred to as irreversible inhibitor (irreversible It inhibitors), is that Irreversible binding is occurred by covalent bond and target protein residue, to play one kind of its biological function Inhibitor.But irreversible covalency inhibitor can be with non-target protein (such as the non-target egg highly relevant with homologous sulfhydryl residue It is white) and active higher sulfydryl irrelevant target protein occur can covalent addition, some not expected side effects occur. And covalent reversible inhibitor can reduce the Irreversible binding with non-target protein, and reduce its security risk, while can be with BTK It is lasting to combine, improve the residence time with target protein, and there is good Kinase Selectivity, can application range it is wider.
Summary of the invention
The purpose of the present invention is to provide it is a kind of it is novel, have no reported in the literature there is efficient BTK inhibitory activity, specifically Property high (Kinase Selectivity is good) reversible covalent BTK inhibiting compound and its stereoisomer or stereoisomer mixture or its Pharmaceutically acceptable salt or solvate.
The present invention also provides one kind include above compound and its stereoisomer or stereoisomer mixture or its The pharmaceutical composition of pharmaceutically acceptable salt or solvate.
Invention also provides a kind of above compound and its stereoisomers or stereoisomer mixture or its medicine On acceptable salt or solvate be used to prepare treatment benefit from the active inhibition of bruton's tyrosine kinase disease, Application in obstruction and illness drug.
The present invention adopts the following technical scheme that:
Bruton's tyrosine kinase inhibitor provided by the present invention, the structure with general formula I:
Or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt or solvate；
Wherein:
A is selected from CRaOr N, wherein RaSelected from hydrogen, halogen, substituted or unsubstituted alkyl；
B be selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted naphthenic base, substituted or unsubstituted heterocycle, Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl；
R1Selected from substituted or non-substituted alkyl, substituted or non-substituted alkoxy, substituted or non-substituted naphthenic base, take Generation or non-substituted heterocycle；N is selected from 0,1,2；
X is selected from O, S ,-S (=O) ,-S (=O)2, NH, C (=O), CH2,-NHC (=O) O ,-NHC (=O) or-C (=O) NH；
Y1, Y2, Y3, Y4It is independently selected from C (Rd), N, and at least one be N, RdSelect hydrogen, halogen, alkyl, halogenated alkyl, hydroxyl Alkyl, halohydroxyalkyl, alkoxy, halogenated alkoxy or cyano；
Z is selected from C (=O) ,-S (=O)2,-S (=O).
Further, wherein A is selected from CH, CF, CCl or N.
Further, currently preferred compound has the structure of general formula II:
Or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt or solvate；
Wherein: A, R1、n、Y1、Y2、Y3、Y4Definition as defined in general formula I；
In general formula II, multiple R2It may be the same or different；Each R2It is independently hydrogen, halogen, alkyl, alkyl halide Base, hydroxyalkyl, halohydroxyalkyl, alkoxy, halogenated alkoxy or cyano.
Further, currently preferred compound has the structure of general formula III-A, III-B, III-C or III-D:
Or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt or solvate；
Wherein: R1、n、Y1、Y2、Y3、Y4、R2Definition as defined in formula (II)；R3Selected from hydrogen, halogen, alkyl, halogenated Alkyl, hydroxyalkyl, halohydroxyalkyl, alkoxy, halogenated alkoxy or cyano.
Preferably, the R1It is preferred that are as follows: cyclopropyl,Propyl, 2- propyl, Deng.
Preferably, the R2Preferably H or one, two, three mutually indepedent halogen, methyl, ethyl, methoxies Base, ethyoxyl, trifluoromethyl.
Preferably, the R3Preferably H, halogen, methyl etc..
Preferably, the bruton's tyrosine kinase inhibitor preferably compound in detail below:
And the stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt or molten of above formula compound Object is closed in agent.Preferably, the compound is following compound:
(R) -2- (3- (4- amino -3- (6- phenoxypyridines -3- base) -1H- pyrazoles [3,4-d] pyrimidine -1- base) piperidines - 1- carbonyl) -3- cyclopropylacrylonitrile 20a
(R) -2- (3- (4- amino -3- (6- (4- fluorophenoxy) pyridin-3-yl) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Piperidines -1- carbonyl) -3- cyclopropylacrylonitrile 20b
(R) -2- (3- (4- amino -3- (6- (2- fluorophenoxy) pyridin-3-yl) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Piperidines -1- carbonyl) -3- cyclopropylacrylonitrile 20c
(R) -2- (3- (4- amino -3- (6- (3,4- difluoro phenoxy group) pyridin-3-yl) -1H- pyrazoles [3,4-d] pyrimidine - 1- yl) piperidines -1- carbonyl) -3- cyclopropylacrylonitrile 20d
(R) -2- (3- (4- amino -3- (6- (2,6- difluoro phenoxy group) pyridin-3-yl) -1H- pyrazoles [3,4-d] pyrimidine - 1- yl) piperidines -1- carbonyl) -3- cyclopropylacrylonitrile 20e
(R) -2- (3- (4- amino -3- (6- (4- chlorophenoxy) pyridin-3-yl) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Piperidines -1- carbonyl) -3- cyclopropylacrylonitrile 20f
(R) -2- (3- (4- amino -3- (6- (to toloxyl) pyridin-3-yl) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Piperidines -1- carbonyl) -3- cyclopropylacrylonitrile 20g
(R) -2- (3- (4- amino -3- (6- (4- methoxyphenoxy) pyridin-3-yl) -1H- pyrazoles [3,4-d] pyrimidine - 1- yl) piperidines -1- carbonyl) -3- cyclopropylacrylonitrile 20h
(R) ((4- amino -3- (6- (4- (trifluoromethyl) phenoxy group) pyridin-3-yl) -1H- pyrazoles [3,4-d] is phonetic by 3- by -2- Pyridine -1- base) piperidines -1- carbonyl) -3- cyclopropylacrylonitrile 20i
(R) -2- (3- (- 1 base of 4- amino -3- (6- phenoxypyridines -3- base) -1H- pyrazoles [3,4-d] pyrimidine) piperidines -1- Carbonyl) -3- (3- methyl oxa- ring butyl- 3- yl) acrylonitrile 21a
(R) -2- (3- (4- amino -3- (6- phenoxypyridines -3- base) -1H- pyrazoles [3,4-d] pyrimidine -1- base) piperidines - 1- carbonyl) -4- methyl -4- (4- methylpiperazine-1-yl)-amyl- 2- alkene nitrile 21b
(R) -2- (3- (4- amino -3- (the fluoro- 6- benzene oxy picolinate -3- base of 5-) -1H- pyrazoles [3,4-d] pyrimidine -1- base) piperazine Pyridine -1- carbonyl) -3- cyclopropylacrylonitrile 22a
(R) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 4-) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Piperidines -1- carbonyl) -3- cyclopropylacrylonitrile 22b
(R) -2- (3- (4- amino -3- (4- methyl -6- phenoxypyridines -3- base) -1H- pyrazoles [3,4-d] pyrimidine -1- Base) piperidines -1- carbonyl) -3- cyclopropylacrylonitrile 22c
(R) -2- (3- (4- amino -3- (2- methyl -6- phenoxypyridines -3- base) -1H- pyrazoles [3,4-d] pyrimidine -1- Base) piperidines -1- carbonyl) -3- cyclopropylacrylonitrile 22d
(R) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Piperidines -1- carbonyl) -3- cyclopropylacrylonitrile 23a
(R, E) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- Base) piperidines -1- carbonyl) -3- cyclopropylacrylonitrile (E) -23a
(R, Z) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- Base) piperidines -1- carbonyl) -3- cyclopropylacrylonitrile (Z) -23a
(R) -2- (3- (4- amino -3- (the fluoro- 6- of 2- (4- fluorophenoxy) pyridin-3-yl) -1H- pyrazoles [3,4-d] pyrimidine - 1- yl) piperidines -1- carbonyl) -3- cyclopropylacrylonitrile 23b
(R) -2- (3- (4- amino -3- (6- (2,3- difluoro phenoxy group) -2- fluorine pyridin-3-yl) -1H- pyrazoles [3,4-d] Pyrimidine -1- base) piperidines -1- carbonyl) -3- cyclopropylacrylonitrile 23c
(R) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Piperidines -1- carbonyl) the amyl- 2- alkene nitrile 23d of -4- methyl
(R) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Piperidines -1- carbonyl) -5- methyl hex- 2- alkene nitrile 23e
(R) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Piperidines -1- carbonyl) -5,5- dimethyl hex- 2- alkene nitrile 23f
(R) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Piperidines -1- carbonyl) -4,4- dimethyl-penten -2- alkene nitrile 24a
(R, E) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- Base) piperidines -1- carbonyl) -4,4- dimethyl-penten -2- alkene nitrile (E) -24a
(R, Z) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- Base) piperidines -1- carbonyl) -4,4- dimethyl-penten -2- alkene nitrile (Z) -24a
(R) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Piperidines -1- carbonyl) -3- (3- methyl oxa- ring butyl- 3- yl) acrylonitrile 24b
(R) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Piperidines -1- carbonyl) the amyl- 2- alkene nitrile 24c of -4- (azetidin -1- base) -4- methyl
(R) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Piperidines -1- carbonyl) the amyl- 2- alkene nitrile 24d of -4- ethyoxyl -4- methyl
(R) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Piperidines -1- carbonyl) -4- methyl -4- morpholine-amyl- 2- alkene nitrile 24e
(R) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Piperidines -1- carbonyl) -4- methyl -4- (methyl (oxa- ring butyl- 3- yl) amino) amyl- 2- alkene nitrile 24f
(R) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Piperidines -1- carbonyl) -4- methyl -4- (2- oxa- -6- azaspiro [3.3] hept- 6- yl) amyl- 2- alkene nitrile 24g
(R) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Piperidines -1- carbonyl) -4- methyl -4- (4- (oxa- ring butyl- 3- yl) piperazine -1- base) amyl- 2- alkene nitrile is for 24 hours
(R, E) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- Base) piperidines -1- carbonyl) -4- methyl -4- (4- (oxa- ring butyl- 3- yl) piperazine -1- base) amyl- 2- alkene nitrile (E)-is for 24 hours
(R, Z) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- Base) piperidines -1- carbonyl) -4- methyl -4- (4- (oxa- ring butyl- 3- yl) piperazine -1- base) amyl- 2- alkene nitrile (Z)-is for 24 hours
(R) -2- (3- (4- amino -3- (2- phenoxy pyrimidine -5- base) -1H- pyrazoles [3,4-d] pyrimidine -1- base) piperidines - 1- carbonyl) -3- cyclopropylacrylonitrile 25a
(R) -2- (3- (4- amino -3- (5- phenoxypyridines -2- base) -1H- pyrazoles [3,4-d] pyrimidine -1- base) piperidines - 1- carbonyl) -3- cyclopropylacrylonitrile 25b
(R) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Pyrroles -1- carbonyl) -4- methyl -4- (4- (oxa- ring butyl- 3- yl) piperazine -1- base) amyl- 2- alkene nitrile 26a
(R, E) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- Base) pyrroles -1- carbonyl) -4- methyl -4- (4- (oxa- ring butyl- 3- yl) piperazine -1- base) amyl- 2- alkene nitrile (E) -26a
(R, Z) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- Base) pyrroles -1- carbonyl) -4- methyl -4- (4- (oxa- ring butyl- 3- yl) piperazine -1- base) amyl- 2- alkene nitrile (Z) -26a
(R) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Pyrroles -1- carbonyl) -4,4- dimethyl-penten -2- alkene nitrile 26b
(R) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Pyrroles -1- carbonyl) -3- (1- amino cyclopropyl) acrylonitrile 26c
(S) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Piperidines -1- carbonyl -3- cyclopropylacrylonitrile 27
(S) -2- (3- (4- amino -3- (the fluoro- 6- phenoxypyridines -3- base of 2-) -1H- pyrazoles [3,4-d] pyrimidine -1- base) Pyrroles -1- carbonyl) -4,4- dimethyl-penten -2- alkene nitrile 28
And the stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt or molten of above formula compound Object is closed in agent.
Term explanation:
Term used herein " aryl " is to remove a H by aromatic ring to obtain, and the aromatic ring refers to 5 to 12 carbon atoms Full carbon monocycle or fused polycycle group, the pi-electron system with total conjugated.The non-limiting example of aromatic ring has: phenyl ring, naphthalene nucleus And anthracene nucleus.Aromatic ring can be unsubstituted or substitution.The substituent group of aromatic ring be selected from halogen (preferably fluorine, chlorine, bromine, iodine), nitro, Amino, hydroxyl, C1-C6Alkyl (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, sec-butyl, tert-butyl, penta Base, isopentyl, neopentyl etc.), C1-C6Hydroxyalkyl (preferably methylol, ethoxy, hydroxypropyl, hydroxyl isopropyl etc.), C1-C6Alkane Oxygroup (preferably methoxyl group, ethyoxyl, propoxyl group, isopropyl oxygroup, butoxy, isobutyl group oxygroup, sec-butyl oxygroup, tertiary fourth Base oxygroup etc.), halogenated C1-C6Alkyl (preferably halogenated methyl, halogenated ethyl, halopropyl, haloisopropyl, halogenated butyl, Halogenated isobutyl group, halogenated sec-butyl, halogenated tert-butyl etc.), halogenated C1-C6Hydroxyalkyl (preferably halogenated methylol, halogenated hydroxyl second Base, halogenated hydroxypropyl, halogenated hydroxyl isopropyl etc.), halogenated C1-C6Alcoxyl (preferably halogenated methoxy, halo ethyoxyl, halogenated third Oxygroup, haloisopropyl oxygroup, halogenated butoxy, halogenated isobutyl group oxygroup, halogenated sec-butyl oxygroup, halogenated tert-butyl oxygroup Deng) base, C3-C6Naphthenic base (preferably cyclopropyl, cyclopenta, cyclohexyl etc.), halogenated C3-C6Naphthenic base (preferably halogenated cyclopropyl Base, halogenated cyclopenta, halocyclohexylmethyl etc.)；The substitution of aromatic ring can be monosubstituted (such as ortho position, meta position, contraposition substitution), It is also possible to disubstituted or three replace etc..
Term used herein " heteroaryl " refers to the unsaturated cyclic group of 5 to 12 annular atoms, the π with total conjugated Electronic system is equivalent in above-mentioned " aryl " one or more carbon and is replaced by hetero atom such as oxygen, nitrogen, sulphur etc..Hetero-aromatic ring can be with It is monocycle, is also possible to bicyclic, i.e., is formed by the way that two rings are condensed.Specific heterocyclic aryl (heteroaryl) may is that pyridyl group, Pyrimidine radicals, pyrazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl and imidazole radicals etc..Heterocyclic aryl can be It is unsubstituted or substitution.The substituent group of heterocyclic aryl is selected from halogen, nitro, amino, hydroxyl, C1-C6Alkyl, C1-C6Hydroxyalkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl, halogenated C1-C6Hydroxyalkyl, halogenated C1-C6Alkoxy, C3-C6Naphthenic base, halogenated C3-C6Ring Alkyl.
Term used herein " alkyl " refers to the linear saturation univalence hydrocarbyl or one with one to six carbon atom It is the univalence hydrocarbyl of a branch saturation with three to six carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, different Butyl, sec-butyl, tert-butyl, amyl, isopentyl, neopentyl etc..Alkyl can be unsubstituted monosubstituted or polysubstituted, takes more For when substituent group can be the same or different；The substituent group of alkyl is selected from halogen, nitro, hydroxyl, C1-C6Alkyl, C1-C6Alkane Oxygroup, C3-C10Naphthenic base, alkoxy carbonyl, alkylthio group, alkyl sulphonyl, alkylamidoalkyl, hydroxyalkylamide groups, sulfonamide Base, 3 to 10 circle heterocyclic ring bases or amino is monosubstituted or polysubstituted amino, wherein the substituent group of amino can it is identical can also be with Difference is selected from hydrogen, C1-C6Alkyl, C1-C6Hydroxyalkyl, C1-C6Alkoxy, C3-C10Naphthenic base, 3 to 10 circle heterocyclic ring bases.
Term used herein " hydroxyalkyl " refers to-alkyl-OH, and wherein alkyl is as defined above." hydroxyl alkane used in the present invention The example of base " includes but is not limited to methylol, ethoxy, hydroxypropyl, hydroxyl isopropyl etc.." hydroxyalkyl " further includes replacing hydroxyl alkane Base, substituent group can be halogen, amino, hydroxyl, C1-C6Alkyl, C1-C6Hydroxyalkyl, C1-C6Alkoxy, C1-C6Naphthenic base.
Term used herein " alkoxy " refers to-O- alkyl group, and wherein alkyl is as defined above.Used in the present invention The example of " alkoxy " includes but is not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy and tert-butoxy. " alkoxy " further includes substituted alkoxy, and substituent group can be halogen, amino, hydroxyl, C1-C6Alkyl, C1-C6Hydroxyalkyl, C1-C6 Alkoxy, C1-C6Naphthenic base.
Term used herein " naphthenic base " refers to tool, and there are three the ring filling univalence hydrocarbyls to ten carbon atoms, preferably Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc., wherein one or two carbon atom can be substituted by an oxo group.The ring Alkyl can be it is unsubstituted or replace, substituent group be selected from halogen, nitro, hydroxyl, C1-C6Alkyl, C1-C6Hydroxyalkyl, C1-C6 Alkoxy, halogenated C1-C6Alkyl, halogenated C1-C6Hydroxyalkyl, halogenated C1-C6Alkoxy, C3-C6Naphthenic base, halogenated C3-C6Cycloalkanes Base, alkoxy carbonyl, alkylthio group, alkyl sulphonyl, alkylamidoalkyl, hydroxyalkylamide groups, sulfoamido, 3 to 10 circle heterocyclic rings Base or amino is monosubstituted or polysubstituted amino, wherein the substituent group of amino can be the same or different, and be selected from hydrogen, C1- C6Alkyl, C1-C6Hydroxyalkyl, C1-C6Alkoxy, C3-C10Naphthenic base, 3 to 10 circle heterocyclic ring bases.
Term used herein " heterocycle " refer to tool there are three to ten annular atoms monocycle or it is polycyclic (two monocycles it Between with chemistry key connection or bridged ring or loop coil or condensed) ring group wrapped with one or more the hetero atom selected from N, O, S It includes but is not limited only to The heterocycle can be it is unsubstituted or replace, substituent group be selected from halogen, nitro, hydroxyl, C1-C6Alkyl, C1-C6Hydroxyalkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl, halogenated C1-C6Hydroxyalkyl, halogenated C1-C6Alkoxy, C3-C6Naphthenic base, halogenated C3-C6Naphthenic base, alkoxy carbonyl, alkylthio group, alkyl sulphonyl, alkylamidoalkyl, hydroxyalkyl amide Base, sulfoamido, 3 to 10 circle heterocyclic ring bases or amino is monosubstituted or polysubstituted amino, wherein the substituent group of amino can phase With can also be different, it is selected from hydrogen, C1-C6Alkyl, C1-C6Hydroxyalkyl, C1-C6Alkoxy, C3-C10Naphthenic base, 3 to 10 circle heterocyclic rings Base.
Term used herein " halogen " refers to fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine or bromine.
Term used herein " halogenated " refers to by the same atom or homoatomic is not optionally substituted by halogen, and can replace primary It can replace repeatedly, such as two substitutions or three substitutions.
Term used herein " halogenated alkyl " refers to the alkyl group replaced by halogen (preferably fluorine, chlorine, bromine, iodine), Wherein alkyl is as defined above." halogenated alkyl " can be optionally substituted by halogen one or many.
Term used herein " halohydroxyalkyl " refers to the hydroxyalkyl base replaced by halogen (preferably fluorine, chlorine, bromine, iodine) Group, wherein hydroxyalkyl is as defined above." halohydroxyalkyl " can be optionally substituted by halogen one or many.
Term used herein " halogenated alkoxy " refers to the alkoxy base replaced by halogen (preferably fluorine, chlorine, bromine, iodine) Group, wherein alkoxy is as defined above." halogenated alkoxy " can be optionally substituted by halogen one or many.
Term used herein " halogenated cycloalkyl " refers to the naphthenic base base replaced by halogen (preferably fluorine, chlorine, bromine, iodine) Group, wherein naphthenic base is as defined above." halogenated cycloalkyl " can be optionally substituted by halogen one or many.
Term used herein " n " preferably 1,2.
Formula I, Formula II, compound described in formula III A~IIID, * C have chirality, and configuration is R- configuration or S- structure The mixture of type or R- configuration and S- configuration.As further preferred, it is configured as R type.
Formula I, Formula II, formula III A~IIID or formula 20a~28 compound, in double bondIt indicates These compounds can be the mixing of individual E-isomer or Z-type isomers or E-isomer and Z-type isomer Object.
Term used herein " solvate " refers to by solute (such as: general formula I~compound of formula III of the invention) The compound of the varying chemical metering formed with solvent.For the purposes of the present invention, the solvent cannot interfere the biology of solute Learn activity.The example of suitable solvent includes but is not limited to water, methanol, ethyl alcohol and acetic acid.It is preferable to use solvent be pharmacy can Receive solvent.Suitable pharmaceutical acceptable solvents include but is not limited to water, ethyl alcohol and acetic acid.It is highly preferred that solvent for use is water.
The present invention can prepare the salt of compound of the present invention using method well-known to those skilled in the art.It is described Salt can be acylate, inorganic acid salt etc., the acylate includes citrate, fumarate, oxalates, apple Hydrochlorate, lactate, camsilate, tosilate, mesylate etc.；The inorganic acid salt includes halogen acid salt, sulphur Hydrochlorate, phosphate, nitrate etc..For example, and lower alkanesulfonic acid, such as methanesulfonic acid, trifluoromethanesulfonic acid etc. can be formed mesylate, Fluoroform sulphonate；Tosilate, benzene sulfonate can be formed with aryl sulfonic acid, such as benzene sulfonic acid or p-methyl benzenesulfonic acid；With Organic carboxyl acid, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid etc. can be formed accordingly Salt；Glutamate or aspartate can be formed with amino acid, such as glutamic acid or aspartic acid.With inorganic acid, (such as such as halogen acids Hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid), nitric acid, carbonic acid, sulfuric acid or phosphoric acid etc. can also form corresponding salt.
A second object of the present invention is to provide a kind of pharmaceutical compositions, including described in above-mentioned any one technical solution One of compound is a variety of.Pharmaceutical composition of the present invention can be change described in above-mentioned any one technical solution Close one of object or a variety of one with compound described in other compounds composition or above-mentioned any one technical solution Kind or a variety of compositions.
On the other hand, the present invention is to provide use general formula I~general formula III-A~D disclosed herein or formula 20a~28 The compound and its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt or solvate To inhibit bruton's tyrosine kinase (Btk) activity or treatment to obtain from bruton's tyrosine kinase (Btk) active inhibition Disease, the obstruction and illness of benefit.
In further preferred scheme, the present invention is to provide contain treatment by giving curer's one kind in need The composition of a effective amount of at least one compound, to inhibiting the active side of the bruton's tyrosine kinase of the subject Method, wherein the structural formula of the compound is general formula I~general formula III-A~D.In some embodiments, in need to be controlled Treatment person suffers from cancer, and the cancer is B cell proliferative disease, for example, diffusivity large B cell lymphoid tumor, follicular lymphoma, Chronic lymphocytic leukemia, chronic lymphocytic leukemia, B cell pre-lymphocytic leukemia, lymphoplasmacytic lymph Tumor/macroglobulinemia Waldenstron (Macroglobulinemia), splenic marginal zone lymthoma, slurry are thin Born of the same parents' property myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, lymphoma nodal marginal zone B cell, Mantle Cell leaching Bar tumor, vertical diaphragm (thymus gland) large B cell lymphoid tumor, intravascular large B cell lymphoma, lymphoma primary effusion, Hugh Burkitt leaching Bar tumor (Burkittlymphoma)/leukaemia or lymphomatoid granulomatosis.
In further embodiment, subject's suffering from autoimmune disease and inflammatory disease in need, example Such as inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriasis arthropathica, osteoarthritis, Still disease (Still ' S disease), adolescent arthritis, diabetes, myasthenia gravis, Hashimoto thyroiditis (Hashimoto ' s Thyroiditis), Order thyroiditis (Ord ' s thyroiditis), Graves' disease (Graves ' disease), class Rheumatic arthritis syndrome (Syndrome), multiple sclerosis, Guillain-Barre syndrome (Guillain- Barr é syndrome), acute diseminated encephalomyelitis, Addision's disease (Addison ' s disease), opsoclonus-flesh battle array Contraction syndrome, mandatory spondylitis, antiphospholipid antibody syndrome, alpastic anemia, oneself immunity hepatitis, chylous diarrhea (coeliac disease), goodpasture's syndrome (Goodpasture ' ssyndrome), idiopathic thrombocytopenic Purpura, optic neuritis, chorionitis, primary biliary cirrhosis, Reiter syndrome (Reiter ' s syndrome), Gao An Arteritis (Takayasu ' s arteritis), temporal arteritis, warm type autoimmune hemolytic anemia, Wegner's granulomatosis (Wegener ' s granulomatosis), psoriasis, alopecia universalis, behcet disease (Disease), chronic tired Labor, familial dysautonomia, mullerianosis, interstitial cystitis, neuromyotonia, chorionitis or vulva Bitterly, multiple sclerosis and chronic graft versus host disease.
The present invention also provides compound or pharmaceutically acceptable salt thereofs of the present invention to prepare the application in BTK inhibitor, special It is not the application in preparation treatment cell proliferative diseases.The cell proliferative diseases include cancer.In other words, the present invention is gone back Compound, stereoisomer or its stereoisomer mixture or its medicine described in formula I~general formula III-A~D are provided Acceptable salt or solvate individually or with other drugs are used in combination in treatment proliferative diseases (such as cancer) on Using.Can and the antineoplastic that be used in combination of compound or pharmaceutically acceptable salt thereof provided by the present invention include but and it is non-limiting at least A kind of following type: mitotic inhibitor (such as vincaleukoblastinum, eldisine and Vinorelbine)；Tubulin decomposing inhibitor (such as taxol))；Alkylating reagent (such as cis-platinum, carboplatin and cyclophosphamide)；Antimetabolite (such as 5 FU 5 fluorouracil, Tegafur, first ammonia Pterin, cytarabine and hydroxycarbamide)；It can be inserted into antibiotic (such as A Leisu, mitomycin and bleomycin))；Enzyme (such as lucid asparagus Adnosine deaminase)；Topoisomerase inhibitors (as relied on primary glycosides and camptothecine)；Biological response modifiers (such as interferon).
Inventor experiments prove that, the compounds of this invention have potent external BTK kinase inhibiting activity, can Applied to individually or with other drugs use in conjunction treatment benefit from the active inhibition of bruton's tyrosine kinase disease, Obstruction and illness, including B cell lymphoma, autoimmune disease, inflammatory disease etc..
Inventor experiments prove that, the compounds of this invention be reversible covalent inhibitor, be expected to reduce irreversible The security risk of inhibitor.
Therefore, the BTK inhibitor of reversible covalent of the invention will be suitable for treatment B cell lymphoma, autoimmune type disease Disease and inflammatory disease are expected to reduce the security risk of irreversible inhibitor.
Specific embodiment
Illustrate exploitativeness of the invention below by embodiment, it will be understood by those of skill in the art that according to existing There is the introduction of technology, corresponding technical characteristic is modified or replaced, the scope of protection of present invention is still fallen within.With Lower compound, on double key carbonIndicate that these compounds are separated into the indefinite mixture of (E) and (Z) isomer.
The preparation of 1. intermediate 1a of embodiment
Operating procedure: iodo- 4- amino -1H- pyrazolo [3, the 4-d] pyrimidine (6.45g, 24.7mmol) of 3-, (S) -1-Boc- 3- hydroxy piperidine (9.93g, 49.4mmol), triphenyl phosphorus PPh3(9.73g, 37.1mmol) is placed in 250mL round-bottomed flask, is put Enter magneton, 130mL THF is added, is stirred at room temperature under nitrogen protection；Take diisopropyl azodiformate DIAD (7.5g, It 37.1mmol) is dissolved in about 30mLTHF, and is slowly added dropwise into reaction system, the reaction was continued about 12 hours after being added dropwise to complete, according to For TLC (thin-layered chromatography) as a result, stopping reaction, reduced pressure is elution with petroleum ether-ethyl acetate using silica gel column chromatography Agent carries out purifying to obtain white solid 1a, yield 70%, 1H NMR (δ, CDCl3): 1.45 (s, 9H), 1.54~1.76 (m, 1H), 181~1.97 (m, 1H), 2.05~2.26 (m, 1H), 2.75~2.96 (m, 1H), 3.48~3.61 (m, 1H), 4.13 (q, J= 7.0Hz, 2H), 4.65~4.88 (m, 1H), 6.45 (brs, 2H), 8.31 (s, 1H) .LC-ESI-MS:445 [M+H] .Chiral HPLC:99%ee.
The preparation of 2. intermediate 1b of embodiment
Operating procedure: iodo- 4- amino -1H- pyrazolo [3, the 4-d] pyrimidine (6.45g, 24.7mmol) of 3-, (R) -1-Boc- 3- hydroxy piperidine (9.93g, 49.4mmol), triphenyl phosphorus PPh3(9.73g, 37.1mmol) is placed in 250mL round-bottomed flask, is put Enter magneton, 130mL THF is added, is stirred at room temperature under nitrogen protection；Take diisopropyl azodiformate DIAD (7.5g, It 37.1mmol) is dissolved in about 30mLTHF, and is slowly added dropwise into reaction system, the reaction was continued about 12 hours after being added dropwise to complete, according to For TLC (thin-layered chromatography) as a result, stopping reaction, reduced pressure is elution with petroleum ether-ethyl acetate using silica gel column chromatography Agent carries out purifying to obtain white solid 1b, yield 68%.LC-ESI-MS:445 [M+H] .Chiral HPLC:99%ee.
The preparation of 3. intermediate 2a of embodiment
Operating procedure: iodo- 4- amino -1H- pyrazolo [3, the 4-d] pyrimidine (5.1g, 19.5mmol) of 3-, (S) -1-Boc-3- Hydroxy-pyrrolidine (7.3g, 39mmol), triphenyl phosphorus PPh3(7.7g, 29.3mmol) is placed in 250mL round-bottomed flask, is put into Magneton is added 100mL THF, is stirred at room temperature under nitrogen protection；Take diisopropyl azodiformate DIAD (5.9g, It 29.3mmol) is dissolved in about 25mL THF, and is slowly added dropwise into reaction system, the reaction was continued about 12 hours after being added dropwise to complete, root According to TLC as a result, stopping reaction, it is concentrated under reduced pressure, using silica gel column chromatography, is purified by eluant, eluent of petroleum ether-ethyl acetate Obtain white solid, 2a, yield 35%, LC-ESI-MS:431 [M+H] .Chiral HPLC:98%ee.
The preparation of 4. intermediate 2b of embodiment
Operating procedure: iodo- 4- amino -1H- pyrazolo [3, the 4-d] pyrimidine (5.1g, 19.5mmol) of 3-, (R) -1-Boc-3- Hydroxy-pyrrolidine (7.3g, 39mmol), triphenyl phosphorus PPh3(7.7g, 29.3mmol) is placed in 250mL round-bottomed flask, is put into Magneton is added 100mL THF, is stirred at room temperature under nitrogen protection；Take diisopropyl azodiformate DIAD (5.9g, It 29.3mmol) is dissolved in about 25mL THF, and is slowly added dropwise into reaction system, the reaction was continued about 12 hours after being added dropwise to complete, root According to TLC as a result, stopping reaction, it is concentrated under reduced pressure, using silica gel column chromatography, is purified by eluant, eluent of petroleum ether-ethyl acetate Obtain white solid 2b, yield 32%, LC-ESI-MS:431 [M+H] .Chiral HPLC:98%ee.
The preparation of 5. key intermediate 3a~3i of embodiment
Operating procedure (by taking intermediate 3a as an example): 2,5- dibromo pyridines (61.5mmol), phenol (64.6mmol), iodate are sub- Copper (6.15mmol), Cs2CO3(92mmol) is placed in the dried flask of 250mL, and 150mL DMSO is added, is then being added (unless otherwise specified, originally TMEDA (6.15mmol) (tetramethylethylenediamine) is heated to 110 degree under Ar protection The unit of temperature is degree Celsius DEG C in invention), it reacts about 20 hours, TLC monitoring conversion is complete.It is down to room temperature, is added a large amount of Ethyl acetate is washed 4 times, and ethyl acetate extracts 2 times, is merged EA (ethyl acetate) and is mutually washed with saturated common salt, dry organic phase, Filtering, revolving is dry, obtains brown oil product.
The bromo- 2- phenoxypyridines 3a (R of intermediate 5-1=H), yield 92%,1H NMR(400MHz,CDCl3):δ8.22 (d, J=2.4Hz, 1H), 7.76 (dd, J=8.7,2.5Hz, 1H), 7.41 (t, J=7.9Hz, 2H), 7.22 (t, J=7.4Hz, 1H), 7.12 (d, J=7.7Hz, 2H), 6.83 (d, J=8.7Hz, 1H) .LC-ESI-MS:251 [M+H].
Intermediate 3b (the bromo- 2- of 5- (the fluoro- phenoxy group of 4-) pyridine, R1=4- fluorine): reagent: 2,5- dibromo pyridine (6.15mmol), 4- fluorophenol (6.46mmol), cuprous iodide (0.62mmol), Cs2CO3(9.2mmol), TMEDA (0.62mmol), yield 82%, LC-ESI-MS:269 [M+H].
Intermediate 3c (the bromo- 2- of 5- (the fluoro- phenoxy group of 2-) pyridine, R1=2- fluorine): reagent: 2,5- dibromo pyridine (6.15mmol), 2- fluorophenol (6.46mmol), cuprous iodide (0.61mmol), Cs2CO3(9.2mmol), TMEDA (0.62mmol), yield 65%, LC-ESI-MS:269 [M+H].
Intermediate 3d (the bromo- 2- of 5- (3,4- dilquoro-phenogy) pyridine, R1=3,4- difluoro): reagent: 2,5- dibromo pyridine (6.15mmol), 3,4- difluorophenols (6.46mmol), cuprous iodide (0.61mmol), Cs2CO3(9.2mmol), TMEDA (0.62mmol), yield 82%, LC-ESI-MS:287 [M+H].
Intermediate 3e (bromo- (2, the 6- dilquoro-phenogy) pyridine of 5-, R1=2,6- difluoro): reagent: 2,5- dibromo pyridine (6.15mmol), 2,6- difluorophenols (6.46mmol), cuprous iodide (0.61mmol), Cs2CO3(9.2mmol), TMEDA (0.62mmol), yield 82%, LC-ESI-MS:287 [M+H].
Intermediate 3f (bromo- (the chloro- phenoxy group of the 4-) pyridine of 5-, R1=4- chlorine): reagent: 2,5- dibromo pyridine (6.15mmol), 4- chlorophenol (6.46mmol), cuprous iodide (0.61mmol), Cs2CO3(9.2mmol), TMEDA (0.62mmol), yield 72%.1H NMR(400MHz,CDCl3): δ 8.25 (d, J=2.5Hz, 1H), 7.79 (dd, J=8.7, 2.5Hz, 1H), 7.35 (d, J=9.2Hz, 2H), 7.08 (d, J=9.2Hz, 2H), 6.85 (d, J=8.5Hz, 1H) .LC-ESI- MS:285[M+H]。
Intermediate 3g (bromo- (4- methyl-phenoxv) pyridine of 5-, R1=4- methyl): reagent: 2,5- dibromo pyridine (6.15mmol), 4- methylphenol (6.46mmol), cuprous iodide (0.61mmol), Cs2CO3(9.2mmol), TMEDA (0.62mmol), yield 61%, LC-ESI-MS:265 [M+H].
Intermediate 3h (bromo- (4- Difluoro-phenoxy) pyridine of 5-, R1=4- methoxyl group): reagent: 2,5- dibromo pyridine (6.15mmol), 4- metoxyphenol (6.46mmol), cuprous iodide (0.61mmol), Cs2CO3(9.2mmol), TMEDA (0.62mmol), yield 59%,1H NMR(400MHz,CDCl3): δ 8.22 (d, J=2.4Hz, 1H), 7.76 (dd, J=8.4, 2.4Hz, 1H), 6.93 (d, J=8.4Hz, 1H), 6.75 (m, 4H), 3.68 (s, 3H) .LC-ESI-MS:281 [M+H].
Intermediate 3i (bromo- (4- tri fluoromethy I-phenoxy) pyridine of 5-, R1=4- trifluoromethyl): reagent: 2,5- dibromo pyrrole Pyridine (6.15mmol), 4- trifloro methyl phenol ((6.46mmol), cuprous iodide (0.61mmol), Cs2CO3(9.2mmol), TMEDA (0.62mmol), yield 66%, LC-ESI-MS:319 [M+H].
The preparation of 6. intermediate 4a~4d of embodiment
Operating procedure: substituted 2,5- dibromo pyridine (6.15mmol), phenol (6.46mmol), cuprous iodide CuI (0.62mmol), Cs2CO3(9.2mmol) is placed in the dried flask of 25mL, and 15mL DMSO is added, and TMEDA then is being added (0.62mmol) is heated to 110 degree under Ar protection, reacts about 20 hours, and TLC conversion is complete.It is down to room temperature, a large amount of second are added Acetoacetic ester is washed 4 times, and ethyl acetate extracts 2 times, is merged EA phase and is washed with saturated common salt, and dry organic phase, filtering, revolving is dry, Obtain brown oil product.
The fluoro- 2- phenoxypyridines 4a (R of the bromo- 4- of intermediate 5-2=4- fluorine), reagent: 2,5- bis- bromo- 4- fluorine pyridines (6.15mmol), phenol (6.46mmol), remaining reagent and dosage are same as above, yield 78%, LC-ESI-MS:269 [M+H].
The fluoro- 2- phenoxypyridines 4b (R of the bromo- 3- of intermediate 5-2=3- fluorine), reagent: 2,5- bis- bromo- 3- fluorine pyridines (6.15mmol), phenol (6.46mmol), remaining reagent and dosage are same as above, yield 80%, LC-ESI-MS:269 [M+H].
The bromo- 4- methyl -2- phenoxypyridines 4c (R of intermediate 5-2=4- methyl), reagent: 2,5- bis- bromo- 4- picolines (6.15mmol), phenol (6.46mmol), remaining reagent and dosage are same as above, yield 85%, LC-ESI-MS:265 [M+H].
The bromo- 6- methyl -2- phenoxypyridines 4d (R of intermediate 5-2=6- methyl), reagent: 2,5- bis- bromo- 6- picolines (6.15mmol), phenol (6.46mmol), remaining reagent and dosage are same as above, yield 51%, LC-ESI-MS:265 [M+H].
The preparation of 7. intermediate 5a~5h of embodiment
Operating procedure: 2,6- difluoro pyridines (6.15mmol), it is dried that substituted phenol (6.46mmol) is placed in 25mL In flask, 15mL DMSO is added, NaH (6.77mmol) then is added, is heated to 30 degree under Ar protection, reacts about 20 hours, TLC conversion is complete.It is down to room temperature, a large amount of ethyl acetate are added, is washed 4 times, ethyl acetate extracts 2 times, merges EA phase saturation Salt washing, dry organic phase, filtering, revolving is dry, obtains brown oil product.
The fluoro- 6- benzene oxy picolinate 5a (R of intermediate 2-1=H), reagent: 2,6- Difluoro-pyridins (6.15mmol), phenol (6.46mmol), remaining reagent and dosage are same as above, yield 65%, LC-ESI-MS:190 [M+H].
The fluoro- 6- of intermediate 2- (2- fluorobenzene oxy picolinate) 5b (R1=4- fluorine), reagent: 2,6- Difluoro-pyridins (6.15mmol), 4- fluorophenol (6.46mmol), remaining reagent and dosage are same as above, yield 55%, LC-ESI-MS:208 [M+H].
Intermediate 2- (2,3- difluorobenzene oxygen) -6- fluorine pyridine 5c (R1=2,3- difluoro), reagent: 2,6- Difluoro-pyridins (6.15mmol), 2,3- bis- fluorine-based phenol (6.46mmol), remaining reagent and dosage are same as above, yield 52%, LC-ESI-MS:226 [M+H]。
The preparation of 8. intermediate 6 of embodiment
Operating procedure: the bromo- 2- iodine pyrimidine (3mmol) of 5-, phenol (3.2mmol), 2- pyridine carboxylic acid (0.3mmol), iodate Cuprous CuI (0.3mmol), potassium phosphate (4.5mmol) are placed in the dried flask of 25mL, and 15mL DMSO is added, and are protected in Ar Under be heated to 100 degree, react about 20 hours, TLC conversion is complete.It is down to room temperature, a large amount of ethyl acetate are added, is washed 4 times, acetic acid Ethyl ester extracts 2 times, merges EA phase, is washed with saturated common salt, and dry organic phase, filtering, revolving is dry, and silica gel column chromatography purifies white Color product 1.1g, yield 87%.1H NMR(400MHz,CDCl3): δ 8.56 (s, 2H), 7.48-7.39 (m, 2H), 7.31-7.25 (m,1H),7.22–7.14(m,2H).LC-ESI-MS:251[M+H]。
The preparation of 9. intermediate 7 of embodiment
Operating procedure: it under Ar protection, is placed in ice-water bath in 15mL DMF solution, is carefully added into sodium hydride (5.1mmol), phenol (4.6mmol).It is stirred at room temperature after adding about 1 hour, the bromo- 5- fluorine pyridine of 2- is then added (4.6mmol) continues reaction at room temperature overnight.Extract reaction of going out with saturated aqueous ammonium chloride after TLC detection reaction completion, Ethyl acetate extracts 3 times.Merge organic phase anhydrous sodium sulfate to dry, filter, oil product is concentrated under reduced pressure to obtain, is directly used in next Step.LC-ESI-MS:251[M+H].
The preparation of 10. intermediate 8 of embodiment
Operating procedure:
Step 1: corresponding compound 3a~3i is dissolved in dried tetrahydrofuran, -78 are cooled under Ar protection Degree, is gradually added dropwise n-BuLi.Reaction system continues to be stirred to react 1 hour at this temperature, and triisopropyl borate ester is then added, In -78 degree reaction 1 hour after adding, then it is allowed to be to slowly warm up to room temperature, extracts reaction of going out with aqueous ammonium chloride solution.Use acetic acid Ethyl ester extracts three times, merges organic phase and the reduced pressure after anhydrous sodium sulfate dries, filters with saturated common salt washing is washed with water. Ethyl acetate and petroleum ether are recrystallized to give white solid boric acid product, are directly used in and react in next step.
Step 2: the boric acid product of previous step, compound 1a, four or three are added in the 70mL DMF being just bubbled with Ar Phenyl phosphorus palladium stirs under Ar protection, and 2N aq.K is then added2CO3Aqueous solution.Reaction system is heated to 85 degree under Ar protection, Overnight, TLC tracks fully reacting for reaction.It is down to room temperature, is filtered with diatomite, ethyl acetate washs several times.Washing 3 times, saturation Salt washing, dries, filters, and is concentrated under reduced pressure, and using petroleum ether-ethyl acetate as eluant, eluent, carries out silica gel column chromatography purifying.
Chemical reagent and data characterization:
Intermediate 8a (R1=H), reagent: compound 3a (30mmol), n-BuLi (33.3mmol), triisopropyl borate ester (39.4mmol), compound 1a (17.3mmol), four triphenyl phosphorus palladiums (0.78mmol), 2N aq.K2CO3(26mL), product are White solid, yield 60% (two steps), 1H NMR (400MHz, CDCl3): δ 8.51 (d, J=2.1Hz, 1H), 8.37 (s, 1H), 8.04 (dd, J=8.5,2.4Hz, 1H), 7.44 (t, J=7.9Hz, 2H), 7.29-7.22 (m, 1H), 7.19 (d, J=7.7Hz, 2H), 7.08 (d, J=8.5Hz, 1H), 5.75 (brs, 2H), 4.91-4.82 (m, 1H), 4.25 (brs, 1H), 4.12 (dd, J= 14.2,7.0Hz, 1H), 3.43 (brs, 1H), 2.87 (dd, J=13.0,10.0Hz, 1H), 2.33-2.10 (m, 2H), 1.90 (brs,1H),1.76–1.66(m,1H),1.44(s,9H).LC-ESI-MS:488[M+H]。
Intermediate 8b (R1=4- fluorine), reagent: compound 3b (3mmol), n-BuLi (3.33mmol), three isopropyl of boric acid Ester (3.94mmol), compound 1a (1.73mmol), four triphenyl phosphorus palladiums (0.078mmol), 2N aq.K2CO3(2.6mL) is produced Object is white solid, yield 45% (two steps), LC-ESI-MS:506 [M+H].
Intermediate 8c (R1=2- fluorine), reagent: compound 3c (3mmol), n-BuLi (3.33mmol), three isopropyl of boric acid Ester (3.94mmol), compound 1a (1.73mmol), four triphenyl phosphorus palladiums (0.078mmol), 2N aq.K2CO3(2.6mL) is produced Object is white solid, yield 52% (two steps), LC-ESI-MS:506 [M+H].
Intermediate 8d (R1=3,4- difluoro), reagent: compound 3d (3mmol), n-BuLi (3.33mmol), boric acid three Isopropyl ester (3.94mmol), compound 1a (1.73mmol), four triphenyl phosphorus palladiums (0.078mmol), 2N aq.K2CO3 (2.6mL), product are white solid, yield 26% (two steps), LC-ESI-MS:524 [M+H].
Intermediate 8e (R1=2,6- difluoro), reagent: compound 3e (3mmol), n-BuLi (3.33mmol), boric acid three Isopropyl ester (3.94mmol), compound 1a (1.73mmol), four triphenyl phosphorus palladiums (0.078mmol), 2N aq.K2CO3 (2.6mL), product are white solid, 36% (two steps), LC-ESI-MS:524 [M+H].
Intermediate 8f (R1=4- chlorine), reagent: compound 3f (3mmol), n-BuLi (3.33mmol), three isopropyl of boric acid Ester (3.94mmol), compound 1a (1.73mmol), four triphenyl phosphorus palladiums (0.078mmol), 2N aq.K2CO3(2.6mL) is produced Object is white solid, yield 41% (two steps), LC-ESI-MS:523 [M+H].
Intermediate 8g (R1=4- methyl), reagent: compound 3g (3mmol), n-BuLi (3.33mmol), boric acid three are different Propyl ester (3.94mmol), compound 1a (1.73mmol), four triphenyl phosphorus palladiums (0.078mmol), 2N aq.K2CO3(2.6mL), Product is white solid, yield 57% (two steps),1H NMR(400MHz,CDCl3): δ 8.48 (d, J=2.3Hz, 1H), 8.33 (s, 1H), 8.02 (dd, J=8.5,2.3Hz, 1H), 7.15-7.03 (m, 3H), 6.96-6.90 (m, 2H), 5.71 (brs, 2H), 4.92-4.80 (m, 1H), 4.19 (brs, 1H), 4.08 (dd, J=13.9,6.9Hz, 1H), 3.41 (brs, 1H), 2.90-2.81 (m,1H),2.32–2.11(m,2H),2.27(s,3H),1.88(brs,1H),1.77–1.65(m,1H),1.45(s,9H).LC- ESI-MS:502[M+H]。
Intermediate 8h (R1=4- methoxyl group), reagent: compound 3h (3mmol), n-BuLi (3.33mmol), boric acid three Isopropyl ester (3.94mmol), compound 1a (1.73mmol), four triphenyl phosphorus palladiums (0.078mmol), 2N aq.K2CO3 (2.6mL), product are white solid, 38% (two steps), LC-ESI-MS:518 [M+H].
Intermediate 8i (R1=4- trifluoromethyl), reagent: compound 3i (3mmol), n-BuLi (3.33mmol), boric acid Three isopropyl esters (3.94mmol), compound 1a (1.73mmol), four triphenyl phosphorus palladiums (0.078mmol), 2N aq.K2CO3 (2.6mL), product are white solid, 35% (two steps), LC-ESI-MS:556 [M+H].
The preparation of 11. intermediate 9 of embodiment
Operating procedure:
Step 1: corresponding compound 4a~4d is dissolved in the dried tetrahydrofuran of 15mL, be cooled under Ar protection- 78 degree, n-BuLi is gradually added dropwise.Reaction system continues to be stirred to react 1 hour at this temperature, and three isopropyl of boric acid is then added Then ester allows it to be to slowly warm up to room temperature in -78 degree reaction 1 hour after adding, extract reaction of going out with aqueous ammonium chloride solution.With Ethyl acetate extracts three times, and merging organic phase is washed with water washes with saturated common salt, and anhydrous sodium sulfate depressurizes dense after drying, filtering Contracting.Ethyl acetate and petroleum ether are recrystallized to give white solid boric acid product, are directly used in and react in next step.
Step 2: the boric acid product of previous step is added in the 7mL DMF being just bubbled with Ar, and compound 1a, four or three Phenyl phosphorus palladium stirs under Ar protection, 2N aq.K is then added2CO3Aqueous solution.Reaction system is heated to 85 under Ar protection Degree, overnight, TLC tracks fully reacting for reaction.It is down to room temperature, is filtered with diatomite, EA is washed several times.Then extracted with ethyl acetate It takes, washes 3 times, saturated common salt washing is dried, filtered, is concentrated under reduced pressure, and using petroleum ether-ethyl acetate as eluant, eluent, carries out silica gel Column chromatographic purifying.
Chemical reagent and data characterization:
Intermediate 9a (R2=4- fluorine), reagent: compound 4a (3mmol), n-BuLi (3.33mmol), three isopropyl of boric acid Ester (3.94mmol), compound 1a (1.73mmol), four triphenyl phosphorus palladiums (0.078mmol), 2N aq.K2CO3(2.6mL) is produced Object is white solid, yield 33% (two steps), LC-ESI-MS:506 [M+H].
Intermediate 9b (R2=3- fluorine), reagent: compound 4b (3mmol), n-BuLi (3.33mmol), three isopropyl of boric acid Ester (3.94mmol), compound 1a (1.73mmol), four triphenyl phosphorus palladiums (0.078mmol), 2N aq.K2CO3(2.6mL) product For white solid, yield 52% (two steps), LC-ESI-MS:506 [M+H].
Intermediate 9c (R2=4- methyl), reagent: compound 4c (3mmol), n-BuLi (3.33mmol), boric acid three are different Propyl ester (3.94mmol), compound 1a (1.73mmol), four triphenyl phosphorus palladiums (0.078mmol), 2N aq.K2CO3(2.6mL) is produced Object is white solid, yield 45% (two steps), LC-ESI-MS:502 [M+H].
Intermediate 9d (R2=6- methyl), reagent: compound 4d (3mmol), n-BuLi (3.33mmol), boric acid three are different Propyl ester (3.94mmol), compound 1a (1.73mmol), four triphenyl phosphorus palladiums (0.078mmol), 2N aq.K2CO3(2.6mL) is produced Object is white solid, yield 66% (two steps), LC-ESI-MS:502 [M+H].
The preparation of 12. intermediate 10a~10c of embodiment
Operating procedure:
Step 1: corresponding compound is dissolved in dried tetrahydrofuran in compound 5a~5c, it is cold under Ar protection But to -78 degree, n-BuLi is gradually added dropwise.Reaction system continues to be stirred to react 1 hour at this temperature, and boric acid three is then added Then isopropyl ester allows it to be to slowly warm up to room temperature in -78 degree reaction 1 hour after adding, gone out with aqueous ammonium chloride solution extraction anti- It answers.It is extracted with ethyl acetate three times, merging organic phase is washed with water washes with saturated common salt, after anhydrous sodium sulfate dries, filters It is concentrated under reduced pressure.Ethyl acetate and petroleum ether are recrystallized to give white solid boric acid product, are directly used in and react in next step.
Step 2: the boric acid product of previous step, compound 1a, four or three are added in the 70mL DMF being just bubbled with Ar Phenyl phosphorus palladium stirs under Ar protection, and 2N aq.K is then added2CO3Aqueous solution.Reaction system is heated to 85 degree under Ar protection, Overnight, TLC tracks fully reacting for reaction.It is down to room temperature, is filtered with diatomite, ethyl acetate washs several times.Washing 3 times, saturation Salt washing, dries, filters, and is concentrated under reduced pressure, and using petroleum ether-ethyl acetate as eluant, eluent, carries out silica gel column chromatography purifying, obtains White solid.
Intermediate 10a (R1=H), reagent: compound 5a (3mmol), n-BuLi (3.33mmol), triisopropyl borate ester (3.94mmol), compound 1a (1.73mmol), four triphenyl phosphorus palladiums (0.078mmol), 2N aq.K2CO3(2.6mL) product is White solid, yield 30% (two steps).1H NMR(500MHz,CDCl3) δ 8.29 (s, 1H), 7.97 (t, J=8.8Hz, 1H), 7.38 (t, J=7.8Hz, 2H), 7.25-7.17 (m, 1H), 7.12 (d, J=8.5Hz, 2H), 6.85 (d, J=8.1Hz, 1H), 5.56 (brs, 2H), 4.78 (ddd, J=14.9,10.2,4.6Hz, 1H), 4.46-4.09 (m, 1H), 4.03 (d, J= 11.2Hz,1H),3.47–3.15(m,1H),2.87–2.75(m,1H),2.22–2.06(m,2H),1.96–1.77(m,1H), 1.69–1.59(m,1H),1.36(s,9H).LC-ESI-MS:506[M+H]。
Intermediate 10b (R1=4- fluorine), reagent: compound 5b (3mmol), n-BuLi (3.33mmol), boric acid three are different Propyl ester (3.94mmol), compound 1a (1.73mmol), four triphenyl phosphorus palladiums (0.078mmol), 2N aq.K2CO3(2.6mL) is produced Object is white solid, yield 25% (two steps), LC-ESI-MS:524 [M+H].
Intermediate 10c (R1=2,3- difluoro), reagent: compound 5c (3mmol), n-BuLi (3.33mmol), boric acid Three isopropyl esters (3.94mmol), compound 1a (1.73mmol), four triphenyl phosphorus palladiums (0.078mmol), 2N aq.K2CO3 (2.6mL) product is white solid, yield 21% (two steps), LC-ESI-MS:542 [M+H].
The preparation of 13. intermediate 10d of embodiment
Operating procedure:
Step 1: compound 5a (3mmol) is dissolved in dried tetrahydrofuran, -78 degree are cooled under Ar protection, by N-BuLi (3.33mmol) is added dropwise in step.Reaction system continues to be stirred to react 1 hour at this temperature, and it is different that boric acid three is then added Then propyl ester (3.94mmol) allows it to be to slowly warm up to room temperature, uses aqueous ammonium chloride solution in -78 degree reaction 1 hour after adding Extract reaction of going out.It is extracted with ethyl acetate three times, merges organic phase and be washed with water and saturated common salt washing, anhydrous sodium sulfate drying, mistake It is concentrated under reduced pressure after filter.Ethyl acetate and petroleum ether are recrystallized to give white solid boric acid product, are directly used in and react in next step.
Step 2: the boric acid product of previous step, compound 1b are added in the 70mL DMF being just bubbled with Ar (1.73mmol), four triphenyl phosphorus palladiums (0.078mmol) stir under Ar protection, and 2N aq.K is then added2CO3Aqueous solution (2.6mL).Reaction system is heated to 85 degree under Ar protection, and overnight, TLC tracks fully reacting for reaction.It is down to room temperature, uses diatom Soil filtering, ethyl acetate wash several times.Washing 3 times, saturated common salt washing, dries, filters, and is concentrated under reduced pressure, with petroleum ether-acetic acid Ethyl ester is eluant, eluent, carries out silica gel column chromatography purifying, obtains white solid 10d (R1=H), yield 28% (two steps), LC-ESI- MS:506[M+H]。
The preparation of 14. intermediate 11 of embodiment
Operating procedure:
Step 1: compound 6 (3mmol) is dissolved in the dried tetrahydrofuran of 15mL, -78 are cooled under Ar protection Gradually n-BuLi (1.3mL, 3.3mmol, 2.5M in THF) is added dropwise in degree.Reaction system continues to be stirred to react at this temperature 1 hour, triisopropyl borate ester (0.74g, 3.94mmol) then is added, in -78 degree reaction 1 hour after adding, then allows it It is to slowly warm up to room temperature, extracts reaction of going out with aqueous ammonium chloride solution.It is extracted with ethyl acetate three times, merges organic phase and be washed with water and satisfy It is washed with salt, anhydrous sodium sulfate is concentrated under reduced pressure after drying, filtering.Ethyl acetate and petroleum ether are recrystallized to give white solid Boric acid product is directly used in and reacts in next step.
Step 2: the boric acid product (2.3mmol) of previous step, chemical combination are added in the 7mL DMF being just bubbled with Ar Four triphenyl phosphorus palladium (0.078mmol) of object 1a (1.73mmol) stirs under Ar protection, 2.6mL 2N aq.K is then added2CO3 Aqueous solution.Reaction system is heated to 85 degree under Ar protection, and overnight, TLC tracks fully reacting for reaction.It is down to room temperature, uses diatom Soil filtering, EA are washed several times.Then it being extracted with ethyl acetate, washes 3 times, saturated common salt washing is dried, filtered, is concentrated under reduced pressure, Using petroleum ether-ethyl acetate as eluant, eluent, carries out silica gel column chromatography and purify to obtain white solid 11, yield 25%,1HNMR (400MHz,CDCl3): δ 8.90 (s, 2H), 8.38 (s, 1H), 7.46 (dd, J=10.8,5.1Hz, 2H), 7.29 (dd, J= 10.1,4.7Hz,1H),7.26–7.18(m,2H),5.91(brs,2H),4.94–4.77(m,1H),4.29(brs,1H), 4.18-4.04 (m, 1H), 3.53-3.22 (m, 1H), 2.88 (t, J=11.7Hz, 1H), 2.33-2.13 (m, 2H), 1.97- 1.84(m,1H),1.77–1.64(m,1H),1.44(s,9H).LC-ESI-MS:489[M+H]。
The preparation of 15. intermediate 12 of embodiment
Operating procedure:
Step 1: compound 7 (3mmol) is dissolved in the dried tetrahydrofuran of 15mL, -78 are cooled under Ar protection Gradually n-BuLi (1.3mL, 3.3mmol, 2.5M in THF) is added dropwise in degree.Reaction system continues to be stirred to react at this temperature 1 hour, triisopropyl borate ester (0.74g, 3.94mmol) then is added, in -78 degree reaction 1 hour after adding, then allows it It is to slowly warm up to room temperature, extracts reaction of going out with aqueous ammonium chloride solution.It is extracted with ethyl acetate three times, merges organic phase and be washed with water and satisfy It is washed with salt, anhydrous sodium sulfate is concentrated under reduced pressure after drying, filtering.Ethyl acetate and petroleum ether are recrystallized to give white solid Boric acid product is directly used in and reacts in next step.
Step 2: the boric acid product (1.5mmol) of previous step, chemical combination are added in the 5mL DMF being just bubbled with Ar Four triphenyl phosphorus palladium (0.06mmol) of object 1a (1.1mmol) stirs under Ar protection, 1.5mL 2N aq.K is then added2CO3Water Solution.Reaction system is heated to 85 degree under Ar protection, and overnight, TLC tracks fully reacting for reaction.It is down to room temperature, uses diatomite Filtering, EA are washed several times.Then it being extracted with ethyl acetate, washes 3 times, saturated common salt washing is dried, filtered, is concentrated under reduced pressure, with Petroleum ether-ethyl acetate is eluant, eluent, carries out silica gel column chromatography and purifies to obtain white solid 12, yield 15%, LC-ESI-MS:488 [M+H]。
The preparation of 16. intermediate 13a of embodiment
Operating procedure:
Step 1: compound 5a is dissolved in dried tetrahydrofuran, it is cooled to -78 degree under Ar protection, is gradually added dropwise N-BuLi.Reaction system continues to be stirred to react 1 hour at this temperature, and triisopropyl borate ester is then added, after adding- 78 degree are reacted 1 hour, then it are allowed to be to slowly warm up to room temperature, extract reaction of going out with aqueous ammonium chloride solution.It is extracted with ethyl acetate three It is secondary, merge organic phase and the reduced pressure after anhydrous sodium sulfate dries, filters with saturated common salt washing is washed with water.Ethyl acetate and Petroleum ether is recrystallized to give white solid boric acid product, is directly used in and reacts in next step.
Step 2: the boric acid product of previous step, compound 2a, four or three are added in the 70mL DMF being just bubbled with Ar Phenyl phosphorus palladium stirs under Ar protection, and 2N aq.K is then added2CO3Aqueous solution.Reaction system is heated to 85 degree under Ar protection, Overnight, TLC tracks fully reacting for reaction.It is down to room temperature, is filtered with diatomite, ethyl acetate washs several times.Washing 3 times, saturation Salt washing, dries, filters, and is concentrated under reduced pressure, and using petroleum ether-ethyl acetate as eluant, eluent, carries out silica gel column chromatography purifying, obtains White solid 13a: reagent: compound 5a (3mmol), n-BuLi (3.33mmol), triisopropyl borate ester (3.94mmol) are changed It closes object 2a (3mmol), four triphenyl phosphorus palladiums (0.15mmol), 2N aq.K2CO3(4.5mL), product are white solid, yield 24% (two steps).1H NMR(400MHz,CDCl3) δ 8.35 (s, 1H), 8.06-8.02 (m, 1H), 7.45 (t, J=7.6Hz, 2H), 7.30-7.27 (m, 1H), 7.20 (d, J=8.4Hz, 2H), 6.92 (d, J=8.0Hz, 1H), 5.69 (s, 2H), 5.54- 5.50(m,1H),3.89(brs,1H),3.79-3.75(m,2H),3.59-3.52(m,1H),2.59-2.52(m,1H),2.43- 2.38(1,1H),1.48-1.45(m,9H).LC-ESI-MS:492[M+H]。
The preparation of 17. intermediate 13b of embodiment
Operating procedure:
Step 1: compound 5a (3mmol) is dissolved in dried tetrahydrofuran, -78 degree are cooled under Ar protection, by N-BuLi (3.33mmol) is added dropwise in step.Reaction system continues to be stirred to react 1 hour at this temperature, and it is different that boric acid three is then added Then propyl ester (3.94mmol) allows it to be to slowly warm up to room temperature, uses aqueous ammonium chloride solution in -78 degree reaction 1 hour after adding Extract reaction of going out.It is extracted with ethyl acetate three times, merges organic phase and be washed with water and saturated common salt washing, anhydrous sodium sulfate drying, mistake It is concentrated under reduced pressure after filter.Ethyl acetate and petroleum ether are recrystallized to give white solid boric acid product, are directly used in and react in next step.
Step 2: the boric acid product of previous step, compound 2b are added in the 70mL DMF being just bubbled with Ar (3mmol), four triphenyl phosphorus palladiums (0.15mmol) stir under Ar protection, and 2N aq.K is then added2CO3Aqueous solution (4.5mL). Reaction system is heated to 85 degree under Ar protection, and overnight, TLC tracks fully reacting for reaction.It is down to room temperature, is filtered with diatomite, Ethyl acetate washs several times.Washing 3 times, saturated common salt washing, dries, filters, and is concentrated under reduced pressure, is with petroleum ether-ethyl acetate Eluant, eluent carries out silica gel column chromatography purifying, obtains white solid 13b, yield 22% (two steps), LC-ESI-MS:492 [M+H].
The preparation of 18. intermediate 14a~14i of embodiment
Operating procedure:
1) corresponding compound in compound 8a~8i (1.3mmol) is taken to be dissolved in 15mL1,4- dioxane, in ice bath Under the conditions of, 5mL 2N HCl is added dropwise, is stirred overnight at room temperature.The crude product that solvent obtains is recovered under reduced pressure and obtains class with recrystallizing methanol White solid is directly used in and reacts in next step.
2) obtained solid is dissolved in 10mLN, 2- cyanoacetic acid (1.3mmol), contracting is added in N- dimethyl acetamide (DMF) Mixture HATU (1.95mmol) and triethylamine (TEA, 3.9mmol) react 1 hour at room temperature, reaction are then quenched with water, and use Ethyl acetate extraction is multiple and merges organic layer.Organic layer is washed with saturated sodium-chloride, organic layer is dense after anhydrous sodium sulfate is dry Contracting, residue obtain intermediate 14 using methylene chloride/methanol as eluant, eluent, using column chromatography for separation.
Chemical reagent and data characterization:
Intermediate 14a (R1=H), reagent: compound 8a (1.3mmol), 2- cyanoacetic acid (1.3mmol), HATU (1.95mmol), TEA (3.9mmol), product are white solid, yield 56% (two steps),1H NMR(400MHz,CDCl3)δ 8.50-8.49 (m, 1H), 8.35 (d, J=8.4Hz, 1H), 8.05-8.01 (m, 1H), 7.44 (t, J=7.6Hz, 2H), 7.26- 7.24 (m, 1H), 7.19 (d, J=8.4Hz, 2H), 7.10 (dd, J=5.6Hz, 8.4Hz, 1H), 5.78 (s, 2H), 4.94- 5.87 (m, 1H), 4.67 (dd, J=4.0Hz, 12.8Hz, 0.5H), 4.31-4.27 (m, 0.5H), 3.91-3.81 (m, 1H), 3.76-3.73(m,0.5H),3.64-3.55(m,2H),3.52-3.45(m,0.5H),3.37-3.31(m,0.5H),3.18- 3.12(m,0.5H),3.35-3.25(m,2H),2.01-1.95(m,1H),1.88-1.70(m,1H).LC-ESI-MS:455[M+ H]。
Intermediate 14b (R1=4- fluorine), reagent: compound 8b (1.3mmol), 2- cyanoacetic acid (1.3mmol), HATU (1.95mmol), TEA (3.9mmol), product are white solid, yield 60% (two steps), LC-ESI-MS:473 [M+H].
Intermediate 14c (R1=2- fluorine), reagent: compound 8c (1.3mmol), 2- cyanoacetic acid (1.3mmol), HATU (1.95mmol), TEA (3.9mmol), product are white solid, yield 58% (two steps), LC-ESI-MS:473 [M+H].
Intermediate 14d (R1=3,4- difluoro), reagent: compound 8d (1.3mmol), 2- cyanoacetic acid (1.3mmol), HATU (1.95mmol), TEA (3.9mmol), product are white solid, yield 50% (two steps), LC-ESI-MS:491 [M+H].
Intermediate 14e (R1=2,6- difluoro), reagent: compound 8e (1.3mmol), 2- cyanoacetic acid (1.3mmol), HATU (1.95mmol), TEA (3.9mmol), product are white solid, 48% (two steps), LC-ESI-MS:491 [M+H].
Intermediate 14f (R1=4- chlorine), reagent: compound 8f (1.3mmol), 2- cyanoacetic acid (1.3mmol), HATU (1.95mmol), TEA (3.9mmol), product are white solid, yield 41% (two steps), LC-ESI-MS:489 [M+H].
Intermediate 14g (R1=4- methyl), reagent: compound 8g (1.3mmol), 2- cyanoacetic acid (1.3mmol), HATU (1.95mmol), TEA (3.9mmol), product are white solid, yield 42% (two steps), LC-ESI-MS:469 [M+H].
Intermediate 14h (R1=4- methoxyl group), reagent: compound 8h (1.3mmol), 2- cyanoacetic acid (1.3mmol), HATU (1.95mmol), TEA (3.9mmol), product are white solid, 40% (two steps), LC-ESI-MS:485 [M+H].
Intermediate 14i (R1=4- trifluoromethyl), reagent: compound 8i (1.3mmol), 2- cyanoacetic acid (1.3mmol), HATU (1.95mmol), TEA (3.9mmol), product are white solid, 45% (two steps), LC-ESI-MS:523 [M+H].
The preparation of 19. intermediate 15a~15d of embodiment
Operating procedure:
1) corresponding compound in compound 9a~9d (1.3mmol) is taken to be dissolved in 15mL1,4- dioxane, in ice bath Under the conditions of, 5mL 2N HCl is added dropwise, is stirred overnight at room temperature.The crude product that solvent obtains is recovered under reduced pressure and obtains class with recrystallizing methanol White solid is directly used in and reacts in next step.
2) obtained solid is dissolved in 10mL n,N-dimethylacetamide (DMF), 2- cyanoacetic acid (1.3mmol), contracting is added Mixture HATU (1.95mmol) and triethylamine (TEA, 3.9mmol) react 1 hour at room temperature, reaction are then quenched with water, and use Ethyl acetate extraction is multiple and merges organic layer.Organic layer is washed with saturated sodium-chloride, organic layer is dense after anhydrous sodium sulfate is dry Contracting, residue obtain intermediate 15 using methylene chloride/methanol as eluant, eluent, using column chromatography for separation.
Chemical reagent and data characterization:
Intermediate 15a (R2=4- fluorine), reagent: compound 9a (1.3mmol), 2- cyanoacetic acid (1.3mmol), HATU (1.95mmol), TEA (3.9mmol), product are white solid, yield 42% (two steps), LC-ESI-MS:473 [M+H].
Intermediate 15b (R2=3- fluorine), reagent: compound 9b (1.3mmol), 2- cyanoacetic acid (1.3mmol), HATU (1.95mmol), TEA (3.9mmol), product are white solid, yield 45% (two steps), LC-ESI-MS:473 [M+H].
Intermediate 15c (R2=4- methyl), reagent: compound 9c (1.3mmol), 2- cyanoacetic acid (1.3mmol), HATU (1.95mmol), TEA (3.9mmol), product are white solid, yield 38% (two steps), LC-ESI-MS:469 [M+H].
Intermediate 15d (R2=6- methyl), reagent: compound 9d (1.3mmol), 2- cyanoacetic acid (1.3mmol), HATU (1.95mmol), TEA (3.9mmol), product are white solid, yield 40% (two steps), LC-ESI-MS:469 [M+H].
The preparation of 20. intermediate 16a~16c of embodiment
Operating procedure:
1) corresponding compound in compound 10a~10c (1.3mmol) is taken to be dissolved in 15mL1,4- dioxane, Yu Bing Under the conditions of bath, 5mL 2N HCl is added dropwise, is stirred overnight at room temperature.The crude product that solvent obtains is recovered under reduced pressure to be obtained with recrystallizing methanol Off-white powder is directly used in and reacts in next step.
2) obtained solid is dissolved in 10mL n,N-dimethylacetamide (DMF), 2- cyanoacetic acid (1.3mmol), contracting is added Mixture HATU (1.95mmol) and triethylamine (TEA, 3.9mmol) react 1 hour at room temperature, reaction are then quenched with water, and use Ethyl acetate extraction is multiple and merges organic layer.Organic layer is washed with saturated sodium-chloride, organic layer is dense after anhydrous sodium sulfate is dry Contracting, residue obtain intermediate 16a~16c using methylene chloride/methanol as eluant, eluent, using column chromatography for separation.
Chemical reagent and data characterization:
Intermediate 16a (R1=H), reagent: compound 10a (1.3mmol), 2- cyanoacetic acid (1.3mmol), HATU (1.95mmol), TEA (3.9mmol), product are white solid, yield 50% (two steps).1H NMR(400MHz,DMSO)δ 8.27 (d, J=7.2Hz, 1H), 8.15-8.08 (m, 1H), 7.52 (t, J=7.6Hz, 2H), 7.34-7.28 (m, 3H), 7.10- 7.07(m,1H),4.92-4.85(m,0.5H),4.76-4.68(m,0.5H),4.49-4.45(m,0.5H),4.14-4.12(m, 2H),4.09-4.01(m,1H),3.96-3.91(m,0.5H),3.76-3.69(m,1H),3.25-3.16(m,1H),2.28- 2.13(m,2H),1.93-1.56(m,2H).LC-ESI-MS:473[M+H]。
Intermediate 16b (R1=4- fluorine), reagent: compound 10b (1.3mmol), 2- cyanoacetic acid (1.3mmol), HATU (1.95mmol), TEA (3.9mmol), product are white solid, yield 48% (two steps), LC-ESI-MS:491 [M+H].
Intermediate 16c (R1=2,3- difluoro), reagent: compound 10c (1.3mmol), 2- cyanoacetic acid (1.3mmol), HATU (1.95mmol), TEA (3.9mmol), product are white solid, yield 45% (two steps), LC-ESI-MS:509 [M+H].
The preparation of 21. intermediate 16d of embodiment
Operating procedure:
1) corresponding compound in compound 10d (1.3mmol) is taken to be dissolved in 15mL1,4- dioxane, in condition of ice bath Under, 5mL 2N HCl is added dropwise, is stirred overnight at room temperature.The crude product that solvent obtains is recovered under reduced pressure and obtains off-white color with recrystallizing methanol Solid is directly used in and reacts in next step.
2) obtained solid is dissolved in 10mL n,N-dimethylacetamide (DMF), 2- cyanoacetic acid (1.3mmol), contracting is added Mixture HATU (1.95mmol) and triethylamine (TEA, 3.9mmol) react 1 hour at room temperature, reaction are then quenched with water, and use Ethyl acetate extraction is multiple and merges organic layer.Organic layer is washed with saturated sodium-chloride, organic layer is dense after anhydrous sodium sulfate is dry Contracting, residue obtain white solid 16d using methylene chloride/methanol as eluant, eluent, using column chromatography for separation, yield 50% (two steps), LC-ESI-MS:473[M+H]。
The preparation of 22. intermediate 17 of embodiment
Operating procedure:
1) corresponding compound in compound 11 (1.3mmol) is taken to be dissolved in 15mL1,4- dioxane, in condition of ice bath Under, 5mL 2N HCl is added dropwise, is stirred overnight at room temperature.The crude product that solvent obtains is recovered under reduced pressure and obtains off-white color with recrystallizing methanol Solid is directly used in and reacts in next step.
2) obtained solid is dissolved in 10mL n,N-dimethylacetamide (DMF), 2- cyanoacetic acid (1.3mmol), contracting is added Mixture HATU (1.95mmol) and triethylamine (TEA, 3.9mmol) react 1 hour at room temperature, reaction are then quenched with water, and use Ethyl acetate extraction is multiple and merges organic layer.Organic layer is washed with saturated sodium-chloride, organic layer is dense after anhydrous sodium sulfate is dry Contracting, residue obtain white solid 17 using methylene chloride/methanol as eluant, eluent, using column chromatography for separation, yield 43% (two steps), LC-ESI-MS:456[M+H]。
The preparation of 23. intermediate 18 of embodiment
Operating procedure:
1) corresponding compound in compound 12 (1.3mmol) is taken to be dissolved in 15mL1,4- dioxane, in condition of ice bath Under, 5mL 2N HCl is added dropwise, is stirred overnight at room temperature.The crude product that solvent obtains is recovered under reduced pressure and obtains off-white color with recrystallizing methanol Solid is directly used in and reacts in next step.
2) obtained solid is dissolved in 10mL n,N-dimethylacetamide (DMF), 2- cyanoacetic acid (1.3mmol), contracting is added Mixture HATU (1.95mmol) and triethylamine (TEA, 3.9mmol) react 1 hour at room temperature, reaction are then quenched with water, and use Ethyl acetate extraction is multiple and merges organic layer.Organic layer is washed with saturated sodium-chloride, organic layer is dense after anhydrous sodium sulfate is dry Contracting, residue obtain white solid 18 using methylene chloride/methanol as eluant, eluent, using column chromatography for separation, yield 32% (two steps), LC-ESI-MS:455[M+H]。
The preparation of 24. intermediate 19a of embodiment
Operating procedure:
1) corresponding compound in compound 13a (1.3mmol) is taken to be dissolved in 15mL1,4- dioxane, in condition of ice bath Under, 5mL 2N HCl is added dropwise, is stirred overnight at room temperature.The crude product that solvent obtains is recovered under reduced pressure and obtains off-white color with recrystallizing methanol Solid is directly used in and reacts in next step.
2) obtained solid is dissolved in 10mL n,N-dimethylacetamide (DMF), 2- cyanoacetic acid (1.3mmol), contracting is added Mixture HATU (1.95mmol) and triethylamine (TEA, 3.9mmol) react 1 hour at room temperature, reaction are then quenched with water, and use Ethyl acetate extraction is multiple and merges organic layer.Organic layer is washed with saturated sodium-chloride, organic layer is dense after anhydrous sodium sulfate is dry Contracting, residue obtain white solid 19a using methylene chloride/methanol as eluant, eluent, using column chromatography for separation, yield 50% (two steps), LC-ESI-MS:459[M+H]。
The preparation of 25. intermediate 19b of embodiment
Operating procedure:
1) corresponding compound in compound 13b (1.3mmol) is taken to be dissolved in 15mL1,4- dioxane, in condition of ice bath Under, 5mL 2N HCl is added dropwise, is stirred overnight at room temperature.The crude product that solvent obtains is recovered under reduced pressure and obtains off-white color with recrystallizing methanol Solid is directly used in and reacts in next step.
2) obtained solid is dissolved in 10mL n,N-dimethylacetamide (DMF), 2- cyanoacetic acid (1.3mmol), contracting is added Mixture HATU (1.95mmol) and triethylamine (TEA, 3.9mmol) react 1 hour at room temperature, reaction are then quenched with water, and use Ethyl acetate extraction is multiple and merges organic layer.Organic layer is washed with saturated sodium-chloride, organic layer is dense after anhydrous sodium sulfate is dry Contracting, residue obtain white solid 19b using methylene chloride/methanol as eluant, eluent, using column chromatography for separation, yield 50% (two steps), LC-ESI-MS:459[M+H]。
The preparation of 25. target compound 20a~20i of embodiment
Operating procedure: by corresponding compound in compound 14a~14i (0.5mmol), nafoxidine (2.5mmol) and Cyclopropyl carboxaldehyde (1.5mmol) is dissolved in methylene chloride (10mL), stirs 10 minutes at room temperature, TMS- is added after being cooled to zero degree Cl (2.5mmol) then reacts 2 hours at room temperature, and solution is washed with water respectively with saturated common salt water washing, nothing after organic layer merges Aqueous sodium persulfate is dried, filtered and concentrated rear pillar and chromatographs to obtain white solid 20a~20i.
Chemical reagent and data characterization:
Target compound 20a (R1=H), reagent: compound 14a (0.5mmol), nafoxidine (2.5mmol), cyclopropyl Formaldehyde (1.5mmol), TMS-Cl (2.5mmol), product are white solid, yield 70%,1H NMR(400MHz,CDCl3)δ 8.50 (d, J=2.0Hz, 1H), 8.37 (s, 1H), 8.04 (dd, J=2.4Hz, 8.4Hz, 1H), 7.45 (t, J=7.6Hz, 2H), 7.28-7.24 (m, 1H), 7.19 (d, J=8.0Hz, 2H), 7.09 (d, J=8.4Hz, 1H), 6.57 (d, J=8.8Hz, 1H),5.67(s,2H),4.98-4.92(m,1H),4.32-4.14(m,1H),3.62-3.10(m,1H),2.34-2.27(m, 2H),2.06-2.03(m,2H),1.90-1.76(m,3H),1.24-1.22(m,2H),0.88-0.79(m,2H).LC-ESI- MS:507[M+H]。
Target compound 20b (R1=4- fluorine), reagent: compound 14b (0.5mmol), nafoxidine (2.5mmol), ring Propyl formaldehyde (1.5mmol), TMS-Cl (2.5mmol), product are white solid, yield 68%, LC-ESI-MS:525 [M+H].
Target compound 20c (R1=2- fluorine), reagent: compound 14c (0.5mmol), nafoxidine (2.5mmol), ring Propyl formaldehyde (1.5mmol), TMS-Cl (2.5mmol), product are white solid, yield 65%, LC-ESI-MS:525 [M+H].
Target compound 20d (R1=3,4- difluoro), reagent: compound 14d (0.5mmol), nafoxidine (2.5mmol), cyclopropyl carboxaldehyde (1.5mmol), TMS-Cl (2.5mmol), product are white solid, yield 68%, LC-ESI- MS:543[M+H]。
Target compound 20e (R1=3,4- difluoro), reagent: compound 14e (0.5mmol), nafoxidine (2.5mmol), cyclopropyl carboxaldehyde (1.5mmol), TMS-Cl (2.5mmol), product are white solid, yield 65%, LC-ESI- MS:543[M+H]。
Target compound 20f (R1=4- chlorine), reagent: compound 14f (0.5mmol), nafoxidine (2.5mmol), ring Propyl formaldehyde (1.5mmol), TMS-Cl (2.5mmol), product are white solid, yield 64%, LC-ESI-MS:541 [M+H].
Target compound 20g (R1=4- methyl), reagent: compound 14g (0.5mmol), nafoxidine (2.5mmol), Cyclopropyl carboxaldehyde (1.5mmol), TMS-Cl (2.5mmol), product are white solid, yield 60%, LC-ESI-MS:521 [M+ H]。
Target compound 20h (R1=4- methoxyl group), reagent: compound 14h (0.5mmol), nafoxidine (2.5mmol), cyclopropyl carboxaldehyde (1.5mmol), TMS-Cl (2.5mmol), product are white solid, yield 57%, LC-ESI- MS:537[M+H]。
Target compound 20i (R1=4- trifluoromethyl), reagent: compound 14i (0.5mmol), nafoxidine (2.5mmol), cyclopropyl carboxaldehyde (1.5mmol), TMS-Cl (2.5mmol), product are white solid, yield 60%, LC-ESI- MS:575[M+H]。
The preparation of embodiment 26. target compound 21a and 21b
Operating procedure: the aldehyde (1.5mmol) of compound 14a (0.5mmol), nafoxidine (2.5mmol) and substitution is molten Solution stirs 10 minutes at room temperature in methylene chloride (10mL), TMS-Cl (2.5mmol) is added after being cooled to zero degree, then room temperature It is lower reaction 2 hours, solution be washed with water respectively with saturated common salt water washing, organic layer merge after anhydrous sodium sulfate dry, filter simultaneously Concentration rear pillar chromatographs to obtain white solid 21a~21b.
Target compound 21a: compound 14a (0.5mmol), nafoxidine (2.5mmol), 3- methyl oxa- ring butyl- 3- Formaldehyde (1.5mmol), TMS-Cl (2.5mmol), product are white solid, yield 20%, LC-ESI-MS:537 [M+H].
Target compound 21b: compound 14a (0.5mmol), nafoxidine (2.5mmol), 2- methyl -2- (4- methyl piperazine Piperazine -1- base) propionic aldehyde (2.5mmol), TMS-Cl (2.5mmol), product is white solid, yield 15%, LC-ESI-MS:607 [M +H]。
The preparation of 27. target compound 22a~22d of embodiment
Operating procedure: by corresponding compound in compound 15a~15d (0.5mmol), nafoxidine (2.5mmol) and Cyclopropyl carboxaldehyde (1.5mmol) is dissolved in methylene chloride (10mL), stirs 10 minutes at room temperature, TMS- is added after being cooled to zero degree Cl (2.5mmol) then reacts 2 hours at room temperature, and solution is washed with water respectively with saturated common salt water washing, nothing after organic layer merges Aqueous sodium persulfate is dried, filtered and concentrated rear pillar and chromatographs to obtain white solid 22a~22d.
Chemical reagent and data characterization:
Target compound 22a (R2=4- fluorine), reagent: compound 15a (0.5mmol), nafoxidine (2.5mmol), ring Propyl formaldehyde (1.5mmol), TMS-Cl (2.5mmol), product are white solid, yield 45%, LC-ESI-MS:525 [M+H].
Target compound 22b (R2=3- fluorine), reagent: compound 15b (0.5mmol), nafoxidine (2.5mmol), ring Propyl formaldehyde (1.5mmol), TMS-Cl (2.5mmol), product are white solid, yield 48%, LC-ESI-MS:525 [M+H].
Target compound 22c (R2=4- methyl), reagent: compound 15c (0.5mmol), nafoxidine (2.5mmol), Cyclopropyl carboxaldehyde (1.5mmol), TMS-Cl (2.5mmol), product are white solid, yield 47%, LC-ESI-MS:521 [M+ H]。
Target compound 22d (R2=6- methyl), reagent: compound 15d (0.5mmol), nafoxidine (2.5mmol), Cyclopropyl carboxaldehyde (1.5mmol), TMS-Cl (2.5mmol), product are white solid, yield 45%, LC-ESI-MS:521 [M+ H]。
The preparation of 28. target compound 23a~23f of embodiment
Operating procedure: by corresponding compound in compound 16a~16c (0.5mmol), nafoxidine (2.5mmol) and Substituted aldehyde (1.5mmol) is dissolved in methylene chloride (10mL), stirs 10 minutes at room temperature, TMS-Cl is added after being cooled to zero degree (2.5mmol), then at room temperature react 2 hours, solution be washed with water respectively with saturated common salt water washing, organic layer merge after it is anhydrous Sodium sulphate, which is dried, filtered and concentrated rear pillar chromatography or reversed-phase HPLC purifying, can obtain white solid 23a~23f.
Chemical reagent and data characterization:
Target compound 23a (R1=H): reagent: compound 16a (0.5mmol), nafoxidine (2.5mmol), cyclopropyl Formaldehyde (1.5mmol), TMS-Cl (2.5mmol)；White solid 23a can be obtained after column chromatography, yield 45%,1H NMR(400MHz, CDCl3) δ 8.34 (s, 1H), 8.04 (m, 1H), 7.45 (t, J=8.0Hz, 2H), 7.30-7.26 (m, 1H), 7.19 (d, J= 8.0Hz, 2H), 6.93 (d, J=8.4Hz, 1H), 6.66 (brs, 1H), 5.76 (s, 2H), 4.97-4.92 (m, 1H), 4.51- 4.74(m,0.5H),4.26-4.17(m,1H),3.98-3.93(m,0.5H),3.34-3.06(m,1H),2.35-2.24(m, 2H),2.09-2.03(m,3H),1.83-1.74(m,1H),1.28-1.21(m,2H),0.88-0.79(m,2H).LC-ESI- MS:525[M+H].Compound 23a passes through reverse phase preparative HPLC, can obtain target compound (E) -23a: yield 35%, LC- ESI-MS:525[M+H]；(Z) -23a: yield 7%, LC-ESI-MS:525 [M+H].
Target compound 23b (R1=4- fluorine): reagent: compound 16b (0.5mmol), nafoxidine (2.5mmol), ring Propyl formaldehyde (1.5mmol), TMS-Cl (2.5mmol)；Column, which chromatographs, can obtain target compound 23b, yield 54%, LC-ESI-MS: 543[M+H]。
Target compound 23c (R1=2,3- difluoro): reagent: compound 16c (0.5mmol), nafoxidine (2.5mmol), cyclopropyl carboxaldehyde (1.5mmol), TMS-Cl (2.5mmol)；Column chromatography can obtain target compound 23c, yield 49%, LC-ESI-MS:561 [M+H].
Target compound 23d (R1=H): reagent: compound 16a (0.5mmol), nafoxidine (2.5mmol), isobutylaldehyde (1.5mmol), TMS-Cl (2.5mmol)；Column chromatography can obtain target compound 23d: yield 54%,1H NMR(400MHz, CDCl3)δ8.32(s,1H),8.06-8.02(m,1H),7.74-7.71(m,0.5H),7.55-7.52(0.5H),7.45(t,J =7.6Hz, 2H), 7.30-7.26 (m, 1H), 7.19 (d, J=7.6Hz, 2H), 6.93 (d, J=8.0Hz, 1H), 5.82 (brs, 2H),4.98-4.93(m,1H),4.59-4.49(m,0.5H),4.30-4.26(m,0.5H),4.04-3.91(m,0.5H), 3.84-3.74(m,0.5H),3.00-3.13(m,1H),2.95-2.88(m,1H),2.34-2.24(m,3H),2.05-2.01 (m, 1H), 1.83-1.78 (m, 1H), 1.13 (d, J=5.2Hz, 6H) .LC-ESI-MS:527 [M+H].
Target compound 23e (R1=H): reagent: compound 16a (0.5mmol), nafoxidine (2.5mmol), 3- methyl Butyraldehyde (1.5mmol), TMS-Cl (2.5mmol)；Column chromatography can obtain target compound 23e: yield 56%, LC-ESI-MS:541 [M+H]。
Target compound 23f (R1=H): reagent: compound 16a (0.5mmol), nafoxidine (2.5mmol), 3,3- bis- Methylbutyraldehyd (1.5mmol), TMS-Cl (2.5mmol)；Column chromatography can obtain target compound 23f: yield 54%, LC-ESI-MS: 555[M+H]。
The preparation of 29. target compound 24a of embodiment~for 24 hours
Operating procedure: the aldehyde (1.5mmol) of compound 16a (0.5mmol), nafoxidine (2.5mmol) and substitution is molten Solution stirs 10 minutes at room temperature in methylene chloride (10mL), TMS-Cl (2.5mmol) is added after being cooled to zero degree, then room temperature It is lower reaction 2 hours, solution be washed with water respectively with saturated common salt water washing, organic layer merge after anhydrous sodium sulfate dry, filter simultaneously Concentration rear pillar chromatography or reversed-phase HPLC purifying can obtain white solid 24a~for 24 hours.
Target compound 24a: reagent: compound 16a (0.5mmol), nafoxidine (2.5mmol), trimethyl-acetaldehyde (1.5mmol), TMS-Cl (2.5mmol)；White solid 24a, yield 31%, LC-ESI-MS:541 [M+ can be obtained after column chromatography H].Compound 24a passes through reverse phase preparative HPLC, can obtain target compound (E) -24a: yield 25%, LC-ESI-MS:541 [M+H]；(Z) -24a: yield 5%, LC-ESI-MS:541 [M+H].
Target compound 24b: compound 16a (0.5mmol), nafoxidine (2.5mmol), 3- methyl oxa- ring butyl- 3- Formaldehyde (1.5mmol), TMS-Cl (2.5mmol), product are white solid, yield 18%, LC-ESI-MS:555 [M+H].
Target compound 24c: compound 16a (0.5mmol), nafoxidine (2.5mmol), 2- (azetidin -1- base) - 2 methyl propanal (1.5mmol), TMS-Cl (2.5mmol), product are white solid, yield 15%, LC-ESI-MS:582 [M+ H]。
Target compound 24d: compound 16a (0.5mmol), nafoxidine (2.5mmol), 2- ethyoxyl -2- methyl-prop Aldehyde (1.5mmol), product are white solid, yield 12%, LC-ESI-MS:571 [M+H].
Target compound 24e: compound 16a (0.5mmol), piperidines (1.0mmol), 2- methyl -2- morpholine propionic aldehyde (1.0mmol), TMS-Cl (2.5mmol), product are white solid, yield 20%, LC-ESI-MS:612 [M+H].
Target compound 24f: reagent: compound 16a (0.5mmol), nafoxidine (2.5mmol), 2- methyl -2- (first Base (oxa- ring butyl- 3- yl) amino) propionic aldehyde (1.5mmol), TMS-Cl (2.5mmol)；Column chromatography can obtain target compound 24f, Yield 60%, LC-ESI-MS:612 [M+H].
Target compound 24g: reagent: compound 16a (0.5mmol), nafoxidine (2.5mmol), 2- methyl -2- (6- Oxa- -2- azaspiro [3.3] hept- 2- yl) propionic aldehyde (1.5mmol), TMS-Cl (2.5mmol)；Column chromatography can obtain target compound 24g, yield 52%, LC-ESI-MS:624 [M+H].
Target compound is for 24 hours: reagent: compound 16a (0.5mmol), nafoxidine (2.5mmol), 2- methyl -2- (4- (oxa- ring butyl- 3- yl) piperazine -1- base) propionic aldehyde (1.5mmol), TMS-Cl (2.5mmol)；White solid can be obtained after column chromatography For 24 hours, yield 29%, LC-ESI-MS:667 [M+H].Compound passes through reverse phase preparative HPLC for 24 hours, can obtain target compound (E)-and for 24 hours: yield 24%, LC-ESI-MS:667 [M+H]；(Z)-and for 24 hours: yield 4%, LC-ESI-MS:667 [M+H].
The preparation of 30. target compound 25a~25b of embodiment
Operating procedure: by corresponding compound, nafoxidine (2.5mmol) and ring in compound 17 or 18 (0.5mmol) Propyl formaldehyde (1.5mmol) is dissolved in methylene chloride (10mL), stirs 10 minutes at room temperature, TMS-Cl is added after being cooled to zero degree (2.5mmol), then at room temperature react 2 hours, solution be washed with water respectively with saturated common salt water washing, organic layer merge after it is anhydrous Sodium sulphate is dried, filtered and concentrated rear pillar and chromatographs to obtain white solid 25.
Chemical reagent and data characterization:
Target compound 25a (Y1=N, Y2=N, Y3=CH): reagent: compound 17 (0.5mmol), nafoxidine (2.5mmol), cyclopropyl carboxaldehyde (1.5mmol), TMS-Cl (2.5mmol), product are white solid, yield 35%, LC-ESI- MS:508[M+H]。
Target compound 25b (Y1=CH, Y2=CH, Y3=N): reagent: compound 18 (0.5mmol), nafoxidine (2.5mmol), cyclopropyl carboxaldehyde (1.5mmol), TMS-Cl (2.5mmol), product are white solid, yield 38%, LC-ESI- MS:507[M+H]。
The preparation of 31. target compound 26a~26b of embodiment
Operating procedure: the aldehyde (1.5mmol) of compound 19a (0.5mmol), nafoxidine (2.5mmol) and substitution is molten Solution stirs 10 minutes at room temperature in methylene chloride (10mL), TMS-Cl (2.5mmol) is added after being cooled to zero degree, then room temperature It is lower reaction 2 hours, solution be washed with water respectively with saturated common salt water washing, organic layer merge after anhydrous sodium sulfate dry, filter simultaneously Concentration rear pillar chromatography or reversed-phase HPLC obtain white solid 26a~26b.
Target compound 26a: reagent: compound 19a (0.5mmol), nafoxidine (2.5mmol), 2- methyl -2- (4- (oxa- ring butyl- 3- yl) piperazine -1- base) propionic aldehyde (1.5mmol), TMS-Cl (2.5mmol)；White solid can be obtained after column chromatography 26a, yield 25%, LC-ESI-MS:653 [M+H].Compound 26a passes through reverse phase preparative HPLC, can obtain target compound (E) -26a: yield 20%, LC-ESI-MS:653 [M+H]；(Z) -26a: yield 4%, LC-ESI-MS:653 [M+H].
Target compound 26b: compound 19a (0.5mmol), nafoxidine (2.5mmol), trimethyl-acetaldehyde (1.5mmol), TMS-Cl (2.5mmol)；White solid 26b, yield 32%, LC-ESI-MS:527 [M+ can be obtained after column chromatography H]。
The preparation of 32. target compound 26c of embodiment
Operating procedure:
Step 1: compound 19a (0.5mmol) to be dissolved in the mixed solvent of methanol (4mL) and methylene chloride (4mL) In, piperidines (2.0mmol) and N- (1- formyl cyclopropyl)-t-butyl carbamate (0.75mmol) is added, is heated to reflux anti- Cooling concentration after answering 6 hours, residue are dissolved in ethyl acetate successively with water and saturated common salt water washing, organic layer anhydrous slufuric acid Filtering and concentrating after sodium is dry, the product after column purification are directly used in next step.
Step 2: product obtained in the previous step is dissolved in methylene chloride (5mL), it is added TFA (2mL), it is small reacts 5 at room temperature Shi Hou, concentration, residue obtain white solid product 26c, yield 13%, LC-ESI-MS:526 [M+H] after column purification.
The preparation of 33. target compound 27 of embodiment
Operating procedure: by compound 16d (0.5mmol), nafoxidine (2.5mmol) and cyclopropyl carboxaldehyde (1.5mmol) It is dissolved in methylene chloride (10mL), is stirred 10 minutes at room temperature, TMS-Cl (2.5mmol) is added after being cooled to zero degree, then room The lower reaction of temperature 2 hours, solution be washed with water respectively with saturated common salt water washing, anhydrous sodium sulfate dries, filters after organic layer merges And be concentrated rear pillar chromatography can obtain white solid 27, yield 15%, LC-ESI-MS:525 [M+H].
The preparation of 34. target compound 28 of embodiment
Operating procedure: by compound 19b (0.5mmol), nafoxidine (2.5mmol) and trimethyl-acetaldehyde (1.5mmol) It is dissolved in methylene chloride (10mL), is stirred 10 minutes at room temperature, TMS-Cl (2.5mmol) is added after being cooled to zero degree, then room The lower reaction of temperature 2 hours, solution be washed with water respectively with saturated common salt water washing, anhydrous sodium sulfate dries, filters after organic layer merges And be concentrated rear pillar chromatography can obtain white solid 28, yield 33%, LC-ESI-MS:527 [M+H].
The test of the external Btk kinase inhibiting activity of embodiment 35.
The external Btk kinase inhibiting activity measuring method of the compounds of this invention:
Drug is dissolved in the stock solution that 10mM (mmol/L) is made in DMSO, and be diluted to 50 × test concentrations medical fluid it is standby With, test concentrations with 3 times of gradient dilutions, respectively 25nM (nmol/L), 8.33nM, 2.78nM, 0.93nM, 0.31nM, 0.10nM.10 μ L 50 × drug reserve liquids are added in 96 orifice plates, add 90 μ 1 × kinase buffer liquids of L, on the oscillator Concussion 10 minutes.It takes 5 μ L to be transferred to 384 orifice plates from each hole of 96 orifice plates, 2 multiple holes is set in 384 orifice plates.
Kinase reaction: prepare 2.5 × kinase buffer liquid: enzyme is added in 1 × kinases basis buffer；Preparation 2.5 × short Peptide solution: the small peptide of FAM label and ATP are added in 1 × kinases basis buffer.In added with 5 μ L medical fluid, 384 orifice plate, add Enter 10 μ 2.5 × kinase buffer liquids of L, is incubated at room temperature 10 minutes.It is added 10 μ L 2.5 × small peptide solution in 384 orifice plates, 28 DEG C It is incubated for 1 hour.25 μ L terminate liquids are added and stop reaction.Reading calculates compound to the inhibiting rate of enzyme, and the Fitting Calculation goes out BTK and swashs The IC of enzyme50, test result is shown in Table 1.
1 part of compounds of table is to BTK kinase inhibiting activity
Compound BTK(IC50,μM) Compound BTK(IC50,μM)
Yi Bu replaces Buddhist nun +++ 24a +++
20a +++ 24d +++
20b +++ 24e +++
21a +++ 24f +++
21b +++ 24g +++
22a ++ 24h +++
22b ++ 25a ++
22c ++ 25b ++
22d ++ 26a ++
23a +++ 26b ++
23d +++ 26c ++
23e +++ 27 ++
23f +++ 28 +
Note: "+": 1 μM≤IC50≤100μM；" ++ ": 0.01 μM≤IC50≤1μM；" +++ ": IC50≤0.01μM；
The experiment of 36. Kinase Selectivity of embodiment
1 × kinases the basis buffer and reaction for detecting respective kinases in preparing experiment as required stop buffer.
Untested compound configuration:
1) it is stand-by to configure 50 × compound stock solution by DMSO；
2) 5 times of each compounds of the diluted method of concentration gradient are pressed in 96 orifice plates, until 6 to 7 concentration guarantee in every hole Injection volume is 10 μ l, while 100 μ lDMSO is added as blank control group, and the not negative control group of plus enzyme substrate；
3) still further prepare one piece of 96 orifice plate, take 10 μ l above compounds that 90 μ l 1 × kinases basis buffers are added, mix Even 10min.
Board under test prepares:
1) mixed liquor 5 μ l to 384 orifice plates in 96 orifice plates of above-mentioned configuration, two multiple holes of each compound are taken.
Kinase reaction:
1) 2.5 × kinase solution is configured, corresponding 1 × kinases basis buffer is added；
2) 2.5 × polypeptide solution is configured, the polypeptide and ATP of FAM label are added in 1 × kinases basis buffer；
3) 2.5 × kinase solution of 10 μ l is added in 384 orifice plate to be measured, is placed at room temperature for 10min, is then added 10 μ l's 2.5 × polypeptide solution reacts at 28 DEG C and 25 μ l reaction is added after 1h stops buffer.
Caliper program read plate, and the IC that respective compound inhibits kinases is obtained using data50Value, test result are shown in Table 2。
Inhibitory activity of 2 part of compounds of table to a variety of kinases
Kinases Yi Bu replaces Buddhist nun 20a 21b 23a 24f 24h
ITK ++ + + + + +
EGFR +++ + + + + +
BLK +++ ++ ++ ++ ++ ++
CSK ++ + + + + +
FGR + + + + + +
HCK ++ + + + + +
JAK3 ++ + + + + +
FLT3 ++ + + + + +
Note: "+": 1 μM≤IC50≤100μM；" ++ ": 0.01 μM≤IC50≤1μM；" +++ ": IC50≤0.01μM
The test result of table 2 shows that the compound that the present invention designs is obvious to the selective advantage of kinases, to ITK, CSK, The inhibitory activity of the kinases such as FGR, HCK, JAK3, FLT3 is very weak, and the activity of most of kinases is all larger than 1000nM, therefore, right The Kinase Selectivity of BTK is substantially better than her cloth for Buddhist nun, thus, in terms of the side effect caused by bad because of selectivity of such compound There to be apparent advantage.
37. solubility test of embodiment
Weigh the test-compound 10mg for being ground into fine powder, respectively at 25 DEG C ± 2 DEG C a certain amount of water (1mL, 10mL, In 100mL), it is considered as completely every the dissolution situation in strength shaking in 5 minutes 30 seconds, observation 30 minutes such as without visible solute Dissolution.The dissolubility of part of compounds of the present invention is shown in Table 3.
The dissolubility of 3 part of compounds of table
Compound Dissolve situation Phenomenon
Yi Bu replaces Buddhist nun It is almost insoluble It cannot be dissolved in 100mL solvent
20a It is atomic molten It is dissolved in 10~100mL solvent
21b It is atomic molten It is dissolved in 10~100mL solvent
23a It is atomic molten It is dissolved in 10~100mL solvent
24f It is atomic molten It is dissolved in 10~100mL solvent
24h Slightly soluble It is dissolved in 1~10mL solvent
25a It is atomic molten It is dissolved in 10~100mL solvent
26a It is atomic molten It is dissolved in 10~100mL solvent
Embodiment 38. combines invertibity to test
Following methods, which can be distinguished, forms the compound of irreversible covalent bond (for example, the not propylene of cyano-containing with its target spot Amide compound) with formed reversible covalent bonds compound (that is, the compound of the present invention or its stereoisomer or its solid are different Structure body mixture or its pharmaceutically acceptable salt or solvate): when the concentration of protein target is higher than compound concentration, no Reversible covalent compound and reversible covalent compound can all be combined with its protein target, then use disturbance treatment these It reacts to disturb the folding of the target, these disturbances include the guanidine hydrochloride denaturation of 5M and use trypsin digestion.Due to from target Dissociation, reversible covalent compound will return to solution, without reversible covalent compound then still in conjunction with target.Use tandem mass spectrum The high performance liquid chromatography of method coupling, the concentration of compound in the solution of front and back is disturbed by check and evaluation, and testing result is shown in Table 4.
Table 4 combines invertibity to test
The testing result of table 4 proves that under natural and state of disturbance, irreversible covalent compound is all exhausted from solution, and The compound of the present invention exhausts under native state, and then returns in solution under denaturation or Digestive States, shows of the invention What compound or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt or solvate were formed It is reversible covalent bond.

Claims (10)

1. a kind of compound, which is characterized in that the structure with general formula I:
Or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt or solvate；
Wherein:
A is selected from CRaOr N, wherein RaSelected from hydrogen, halogen, substituted or unsubstituted alkyl；
B is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted naphthenic base, substituted or unsubstituted heterocycle, substitution Or unsubstituted aryl, substituted or unsubstituted heteroaryl；
R1Selected from substituted or non-substituted alkyl, substituted or non-substituted alkoxy, substituted or non-substituted naphthenic base, replace or Non-substituted heterocycle；
N is selected from 0,1,2；
X is selected from O, S ,-S (=O) ,-S (=O)2, NH, C (=O), CH2,-NHC (=O) O ,-NHC (=O) or-C (=O) NH；
Y1, Y2, Y3, Y4It is independently selected from C (Rd), N, and at least one be N, RdSelected from hydrogen, halogen, alkyl, halogenated alkyl, hydroxyl alkane Base, halohydroxyalkyl, alkoxy, halogenated alkoxy or cyano；
Z is selected from C (=O) ,-S (=O)2,-S (=O).
2. compound according to claim 1, which is characterized in that the A is selected from CH, CF, CCl or N.
3. compound according to claim 1, which is characterized in that the structure with general formula II:
Each R2It is independently hydrogen, halogen, alkyl, halogenated alkyl, hydroxyalkyl, halohydroxyalkyl, alkoxy, halogenated alkoxy Or cyano.
4. compound according to claim 3, which is characterized in that with general formula III-A, III-B, III-C or III-D Structure:
R3Selected from hydrogen, halogen, alkyl, halogenated alkyl, hydroxyalkyl, halohydroxyalkyl, alkoxy, halogenated alkoxy or cyano.
5. compound according to claim 1, which is characterized in that the C that * is marked in Formulas I is R configuration or S configuration.
One of 6. described in any item compounds according to claim 1~5, which is characterized in that have the following structure:
Or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt or solvate.
7. a kind of pharmaceutical composition, which is characterized in that including one in compound described in any one of claim 1 to 6 Kind is a variety of.
8. one kind compound as described in claim 1 to 6 any one is being prepared independent or is being treated with other drugs use in conjunction From the disease benefited in the active inhibition of bruton's tyrosine kinase, the application in obstruction and illness drug.
9. application as claimed in claim 8, which is characterized in that the disease is selected from lymphoma mantle cell, diffusivity large B cell Lymthoma, follicular lymphoma, chronic lymphocytic leukemia, chronic lymphocytic leukemia, B cell prolymphocyte are white Blood disease, lymphoplasmacytic lymphoma/macroglobulinemia Waldenstron, splenic marginal zone lymthoma, plasma cell myeloma, Plasmacytoma, extranodal marginal zone B cell lymphoma, lymphoma nodal marginal zone B cell, mantle cell lymphoma, the vertical big B of diaphragm Cell lymphoma, intravascular large B cell lymphoma, lymphoma primary effusion, Burkitt lymphoma/leukaemia or lymthoma Sample granulomatosis.
10. application as claimed in claim 8, which is characterized in that the disease is selected from heteroimmune disease or graft is anti- Host disease, multiple sclerosis, ankylosing spondylitis, dysautonomia, myasthenia gravis, inflammatory bowel disease, blood vessel Inflammation, arthritis, lupus, rheumatoid arthritis, psoriasis arthropathica, osteoarthritis, pemphigus, nettle rash, asthma, Si Di That disease, adolescent arthritis, diabetes, Hashimoto thyroiditis, Order thyroiditis, Graves' disease, rheumatoid joint Scorching syndrome, Guillain-Barre syndrome, acute diseminated encephalomyelitis, Addision's disease, opsoclonus-myoclonic syndrome, Antiphospholipid antibody syndrome, alpastic anemia, oneself immunity hepatitis, chylous diarrhea, goodpasture's syndrome, idiopathic Thrombocytopenic purpura, optic neuritis, chorionitis, primary biliary cirrhosis, Reiter syndrome, takayasu's arteritis, Temporal arteritis, warm type autoimmune hemolytic anemia, Wegner's granulomatosis, psoriasis, alopecia universalis, behcet disease, Confirmed fatigue, familial dysautonomia, mullerianosis, interstitial cystitis, chorionitis or Vulvodynia, Xiu Ge Lan Shi xerophthalmia, non-not Gram xerophthalmia.
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