CN101448505A - P13 kinase antagonists - Google Patents

P13 kinase antagonists Download PDF

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CN101448505A
CN101448505A CNA2007800123688A CN200780012368A CN101448505A CN 101448505 A CN101448505 A CN 101448505A CN A2007800123688 A CNA2007800123688 A CN A2007800123688A CN 200780012368 A CN200780012368 A CN 200780012368A CN 101448505 A CN101448505 A CN 101448505A
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unsubstituted
replacement
alkyl
heterocyclylalkyl
aryl
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Z·A·奈特
O·威廉姆斯
K·M·舒卡
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University of California
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University of California
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Abstract

The present invention provides novel PI3-Kinase antagonists and methods of use thereof.

Description

The PI3 kinase antagonists
The cross reference of related application
The application requires the priority of No. the 60/744th, 270, the U.S. Provisional Patent Application of No. the 60/744th, 269, U.S. Provisional Patent Application submitting on April 4th, 2006 and submission on April 4th, 2006, fits into this paper as a reference in these two parts of applications.
The rights statement that the research and development of being subsidized by federal government is done to invent
The present invention is subjected to NIH and authorizes support (AI44009).U.S. government enjoys certain right to the present invention.
Background of invention
Synthetic (Fruman etc., 1998) of phosphoinositide 3-kinase (PI3-Ks) catalysis phosphatidylinositols (PI) second message,second messenger PI (3) P, PI (3,4) P2 and PI (3,4,5) P3 (PIP3).Under suitable cellular environment, these three kinds of lipids are controlled multiple physiological processes, comprise cell growth, survival, differentiation and chemotaxis (Katso etc., 2001).PI3-K family comprises 15 kinds of kinases (Katso etc., 2001) with unique substrate specificity, expression pattern and adjusting pattern.I class PI3-K (p110, p110, p110 and p110) produces PIP3 by tyrosine kinase or the activation of G-G-protein linked receptor, participates in downstream effect device such as Akt/PDK1 approach, Tec family kinases and the GTP of Rho family enzyme.II and III class PI3-K play a crucial role in the transportation in born of the same parents by synthetic PI (3) P and PI (3,4) P2.PIKK is control cell growth (mTORC1) or the protein kinase that detects genomic integrity (ATM, ATR, DNA-PK and hSmg-1).
The importance of these enzymes in many pathophysiological processeses makes PI3-K family become the focus (Ward etc., 2003) of interest as the new class drug targets.This interest is from find the p110 α (Samuels etc. that usually suddenly change recently in primary tumor, 2004) and lipid phosphatase PTEN (a kind of inhibitor of PI3-K signal transduction) be the evidence (Cantley and Neel, 1999) that is the tumor inhibitor of inactivated state usually.Make great efforts exploitation and be used for the treatment of inflammation and autoimmune disease (p110 δ, p110 γ and mTOR), thrombosis (p110 β), the micromolecule PI3-K inhibitor of viral infection (PIKK) and cancer (p110 α, mTOR etc.).Recently, selective depressant (Camps etc., 2005 of first kind of these enzyme have been reported; Condliffe etc., 2005; Jackson etc., 2005; Knight etc., 2004; Lau etc., 2005; Sadhu etc., 2003).
The present invention has satisfied these and other needs by a kind of novel PI3-kinase antagonists is provided.
Summary of the invention
The invention provides and find it is the noval chemical compound of effective PI3-kinase antagonists.
On the one hand, the invention provides the affine pocket of PI3-kinases shown in the following formula (I) in conjunction with antagonist (for example, the affine pocket quinazolone of PI3-kinases antagonist) or PI3-kinase antagonists.
On the other hand, the invention provides the kinase catalytic active method of reduction PI3-.This method comprises makes the PI3-kinases combine antagonist (for example, the affine pocket quinazolone of PI3-kinases antagonist) or the contacted step of PI3-kinase antagonists with the affine pocket of PI3-kinases of the general formula (I) that reduces active consumption.
On the other hand, the invention provides the method for treatment disease, this method comprises the disease to the object treatment PI3-kinase activity mediation of this treatment of needs.This method comprises that the affine pocket of PI3-kinases of the general formula (I) that gives object treatment effective dose is in conjunction with antagonist (for example, the affine pocket quinazolone of PI3-kinases antagonist) or PI3-kinase antagonists.
On the other hand, the invention provides the method for destroying leukocyte function or destroying the osteoclast function.This method comprises that making leukocyte or osteoclast combine antagonist (for example, the affine pocket quinazolone of PI3-kinases antagonist) or PI3-kinase antagonists with the affine pocket of PI3-kinases of the general formula (I) of destruction function consumption contacts.
Brief Description Of Drawings
Fig. 1 has shown the structure from the representative compounds of 11 kinds of chemical types of PI3-K inhibitor.
Fig. 2 has shown the structure of isotype selectivity PI3-K inhibitor.The structure of ATP in the A:p110 gamma activity site has highlighted the zones of different of ATP binding pocket.B: the arrangement of the PI3-K inhibitor cocrystallization structure of all reports.Except that PIK-39, Met804 takes conformation upwards in all structures.C: isotype selectivity PI3-K inhibitor and bonded structure of p110 γ or model.D: many target spots PI3-K inhibitor and bonded structure of p110 γ or model.
Fig. 3 has shown selectivity detection and the affine pocket of PI3-kinases.A:PIK-39 and the bonded structure of p110 γ have been pointed out IC87114 bonded model.PIK-293 and PIK-294 are the Pyrazolopyrimidine analogs of IC87114.Phenol stretches into affine pocket between PIK-294, and this chemical compound is stronger to the effect of I class PI3-K.The left figure of B:() ratio of IC50 value between saltant and wild type p110 δ inhibitor and the p110 α/many target spots inhibitor.(middle figure) two kinds of p110 δ inhibitor and wild type, M752I and the bonded dose-effect curve of M752V p110 δ.M752I and M752V sudden change are to the model of the bonded influence of dissimilar inhibitor among (right figure) prompting p110 δ.
Fig. 4: the structure of other PI3-K inhibitor and non-activity analog.
Fig. 5: the kinase whose IC50 value of selectivity PI3-K inhibitor lipotropism matter (μ M).
Fig. 6: the PI3-K inhibitor is to the inhibition of protein kinase.On behalf of 10 μ M inhibitor, numerical value have remaining % activity down.Numerical value is the meansigma methods of three replications.In the time of suitably, with IC50 value record (μ M) in bracket.
Fig. 7 shows the kinase whose sequence of people p110 δ.
Fig. 8 shows the kinase whose sequence of people p110 γ.
Fig. 9 shows the sequence of people p110 alpha kinase.
Figure 10 shows the sequence of people p110 beta kinase.
Detailed Description Of The Invention
I. definition
Abbreviation used herein has connotation conventional in the chemistry and biology field.
When from left to right writing, when pointing out substituted radical by its conventional chemical general formula, they comprise that equally writing from right to left the chemistry that structure obtains is equal to substituting group, for example, and-CH2O-is equal to-OCH2-。
Except as otherwise noted, term ＂ alkyl ＂ itself or as another substituent a part of expression straight chain (namely unbranched) or side chain or cyclic hydrocarbon group, or its combination, they can be fully saturated, single or how unsaturated, can comprise divalence or multivalence group, the carbon atom number with appointment (is C1-C 10Represent 1-10 carbon atom). The example of saturated hydrocarbyl includes but not limited to: group such as methyl, ethyl, n-pro-pyl, isopropyl, positive fourth Base, the tert-butyl group, isobutyl group, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropyl methyl, for example positive penta Analog or the isomers of base, n-hexyl, n-heptyl, n-octyl etc. Unsaturated alkyl has one or many The individual pair of key or triple bond. The example of unsaturated alkyl includes but not limited to: vinyl, 2-acrylic, butylene Base, 2-isopentene group, 2-(butadienyl), 2,4-pentadienyl, 3-(Isosorbide-5-Nitrae-pentadienyl), acetenyl, 1-With 3-propinyl, 3-butynyl and their analog and isomers.
Term ＂ alkylidene ＂ itself or as another substituent part, the divalent group that the expression alkyl is derived, such as but not limited to :-CH2CH 2CH 2CH 2-、-CH 2CH＝CHCH 2-、-CH 2C≡CCH 2-、- CH 2CH 2CH(CH 2CH 2CH 3)CH 2-. Usually, alkyl (or alkylidene) has 1-24 carbon atom, this Bright preferably have 10 or a group of carbon atom still less. ＂ low alkyl group ＂ or ＂ low-grade alkylidene ＂ are than short chain Alkyl or alkylidene have 8 or carbon atom still less usually. " alkynylene " is the subclass of alkylidene, and be this Alkylidene comprises the triple bond between at least one adjacent carbon atom.
Except as otherwise noted, the assorted alkyl ＂ itself of term ＂ or be selected from the stable straight or branched that the hetero atom of O, N, P, Si and S constitutes by at least one carbon atom and at least one with other terms combination expressions, or cyclic hydrocarbon group, or its combination, wherein nitrogen, the randomly oxidation of p and s atom, nitrogen heteroatom can be randomly quaternized.Hetero atom O, N, P and S can be positioned at any interior location of assorted alkyl or be positioned at the position that alkyl links to each other with the molecule remainder with Si.Example includes but not limited to :-CH 2-CH 2-O-CH 3,-CH 2-CH 2-NH-CH 3,-CH 2-CH 2-N (CH 3)-CH 3,-CH 2-S-CH 2-CH 3,-CH 2-CH 2,-S (O)-CH 3,-CH 2-CH 2-S (O) 2-CH 3,-CH=CH-O-CH 3,-Si (CH 3) 3,-CH 2-CH=N-OCH 3,-CH=CH-N (CH 3)-CH 3, O-CH 3,-O-CH 2-CH 3With-CN.Two or three hetero atoms can appear continuously at the most, for example, and-CH 2-NH-OCH 3With-CH 2-O-Si (CH 3) 3Similarly, the assorted alkylidene ＂ itself of term ＂ or as another substituent part, the expression deutero-divalent group of alkyl of mixing, such as but not limited to :-CH 2-CH 2-S-CH 2-CH 2-and-CH 2-S-CH 2-CH 2-NH-CH 2-.For assorted alkylidene group, hetero atom can occupy any or two chain ends (as, alkylidene oxygen, alkylidene dioxygen, alkylidene amino, alkylidene diaminourea etc.).In addition, for alkylidene and assorted alkylidene linking group, the direction of writing the general formula of linking group does not hint the orientation of linking group.For example, general formula-C (O) OR '-representative-C (O) OR '-and-R ' OC (O)-.As mentioned above, the assorted alkyl of term used herein comprises those groups by hetero atom link molecule remainder, as-C (O) R ' ,-C (O) NR ' ,-NR ' R ＂ ,-OR ' ,-SR ' and/or-SO 2R '.The assorted alkyl ＂ of narration ＂, when the concrete assorted alkyl of narration is as-NR ' R ＂ etc. then, should be understood that the assorted alkyl of term and-NR ' R ＂ is not redundant or mutually exclusive.On the contrary, the concrete assorted alkyl of narration is to know degree in order to increase.Therefore, the assorted alkyl ＂ of term ＂ here should not be construed as and repels concrete assorted alkyl as-NR ' R ＂ etc.
Except as otherwise noted, term ＂ cycloalkyl ＂ and ＂ Heterocyclylalkyl ＂ itself or represent the annular form of ＂ alkyl ＂ and the assorted alkyl ＂ of ＂ respectively with the combination of other terms.In addition, for Heterocyclylalkyl, hetero atom can occupy the position that heterocycle links to each other with the molecule remainder.The example of cycloalkyl includes but not limited to: cyclopenta, cyclohexyl, 1-cyclohexenyl group, 3-cyclohexenyl group, suberyl etc.The example of Heterocyclylalkyl includes but not limited to: 1-(1,2,5,6-tetrahydro pyridyl), piperidino, 2-piperidyl, 3-piperidyl, 4-morpholinyl, morpholinyl, oxolane-2-base, oxolane-3-base, Tetramethylene sulfide-2-base, Tetramethylene sulfide-3-base, 1-piperazinyl, 2-piperazinyl etc.The divalent derivative of term ＂ ring alkylidene ＂ and ＂ heterocycle alkylidene ＂ difference finger ring alkyl and Heterocyclylalkyl.
Except as otherwise noted, term ＂ halo ＂ or ＂ halogen ＂ itself or as another substituent a part of expression fluorine, chlorine, bromine or iodine atom.In addition, term such as ＂ haloalkyl ＂ represent to comprise single haloalkyl and multi-haloalkyl.For example, term ＂ halo (C 1-C 4) alkyl ＂ includes but not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chloro butyl, 3-bromo propyl group etc.
Except as otherwise noted, term ＂ aryl ＂ represents how unsaturated, aromatic hydrocarbon substituent group, and it can be monocycle or condense together or covalently bound together multi-ring (preferred 1-3 ring).Term ＂ heteroaryl ＂ represents to comprise (under polycyclic situation, each comprises in independently encircling) 1-4 heteroatomic aryl (or ring) that is selected from N, O and S, and wherein, nitrogen and sulphur atom are randomly oxidized, and nitrogen-atoms is randomly quaternized.Heteroaryl can be connected in the remainder of molecule by carbon atom or hetero atom.The nonrestrictive example of aryl and heteroaryl comprises phenyl, the 1-naphthyl, the 2-naphthyl, the 4-xenyl, the 1-pyrrole radicals, the 2-pyrrole radicals, the 3-pyrrole radicals, the 3-pyrazolyl, the 2-imidazole radicals, the 4-imidazole radicals, pyrazinyl, the 2-oxazolyl, the 4-oxazolyl, 2-phenyl-4-oxazolyl, the 5-oxazolyl, the 3-isoxazolyl, the 4-isoxazolyl, the 5-isoxazolyl, the 2-thiazolyl, the 4-thiazolyl, the 5-thiazolyl, the 2-furyl, the 3-furyl, the 2-thienyl, the 3-thienyl, the 2-pyridine radicals, the 3-pyridine radicals, the 4-pyridine radicals, the 2-pyrimidine radicals, the 4-pyrimidine radicals, the 5-benzothiazolyl, purine radicals, the 2-benzimidazolyl, the 5-indyl, the 1-isoquinolyl, the 5-isoquinolyl, the 2-quinoxalinyl, the 5-quinoxalinyl, 3-quinolyl and 6-quinolyl.Above-mentioned aryl and heteroaromatic ring system substituent group separately is selected from following acceptable substituent group.Term ＂ arlydene ＂ and ＂ heteroarylidene ＂ represent the divalent group of aryl and heteroaryl respectively.
For concisely, when term ＂ aryl ＂ and other term couplings (as, aryloxy group, arylthio, aryl alkyl), term ＂ aryl ＂ comprises above-mentioned aryl and hetero-aromatic ring.Therefore, term ＂ aryl alkyl ＂ is intended to the group (as benzyl, phenethyl, pyridylmethyl etc.) that comprises that aryl links to each other with alkyl, comprises the alkyl (as phenoxymethyl, 2-pyridyloxy methyl, 3-(1-naphthoxy) propyl group etc.) that carbon atom (as methylene) is replaced by oxygen atom.Yet term ＂ halogenated aryl ＂ used herein only covers the aryl that is replaced by one or more halogens.
If assorted alkyl, Heterocyclylalkyl or heteroaryl comprise the atom (for example, 3-7 unit) of specific quantity, term " unit " expression carbon atom or hetero atom.
Term used herein " oxo " expression connects the oxygen of carbon atom with two keys.
The replacement of above-mentioned term (as ＂ alkyl ＂, ＂ assorted alkyl ＂, ＂ cycloalkyl ＂ and ＂ Heterocyclylalkyl ＂, ＂ aryl ＂, ＂ heteroaryl ＂ and their divalent group derivant) group shown in expression comprises separately and do not replace form.The preferred substituents of every type of group is provided below.
The substituent group of alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl unit price and bivalence deriveding group (comprising the group that usually is called alkylidene, thiazolinyl, assorted alkylidene, assorted thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group and heterocycloalkenyl) can be one or more groups that are selected from down group, includes but not limited to :-OR ' ,=O ,=NR ' ,=N-OR ' ,-NR ' R ＂ ,-SR ' ,-halogen ,-SiR ' R ＂ R " ' ,-OC (O) R ' ,-C (O) R ' ,-CO 2R ' ,-C (O) NR ' R ＂ ,-OC (O) NR ' R ＂ ,-NR ＂ C (O) R ' ,-NR '-C (O) NR ＂ R " ' ,-NR ＂ C (O) OR ' ,-NR-C (NR ' R ＂)=NR " ' ,-S (O) R ' ,-S (O) 2R ' ,-S (O) 2NR ' R ＂ ,-NRSO 2R ' ,-CN and-NO 2, its quantity is 0 to (2m '+1), m ' is the total number of carbon atoms in these groups.R ', R ＂, R " ' hydrogen, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl (as the aryl that is replaced by 1-3 halogen), replacement or unsubstituted alkyl, alkoxyl or thio alkoxy or aryl alkyl preferably represented independently of one another with R ＂ ＂.As used herein, ＂ alkoxyl ＂ is the alkyl that links to each other with the molecule remainder by the bivalence oxygen groups.When The compounds of this invention comprised more than one R group, for example each R group was independently selected, and is same, if having more than one R ', R ＂, R " ' and during R ＂ ＂ group, they are also independently selected separately.When R ' and R ＂ were connected in same nitrogen-atoms, they can be combined to form 4-, 5-, 6-or 7-unit ring with nitrogen-atoms.For example ,-NR ' R ＂ includes but not limited to 1-pyrrolidinyl and 4-morpholinyl.By above-mentioned substituent discussion, it will be understood by those skilled in the art that term ＂ alkyl ＂ comprises the group of carbon atom in conjunction with other groups outside the dehydrogenation, as haloalkyl (as ,-CF 3With-CH 2CF 3) and acyl group (as ,-C (O) CH 3,-C (O) CF 3,-C (O) CH 2OCH 3Deng).
Be similar to the above discussion of alkyl substituent, the exemplary substituent group of aryl and heteroaryl (and divalent derivative) can change, and for example is selected from: halogen ,-OR ' ,-NR ' R ＂ ,-SR ' ,-halo ,-SiR ' R ＂ R " ' ,-OC (O) R ' ,-C (O) R ' ,-CO 2R ' ,-C (O) NR ' R ＂ ,-OC (O) NR ' R ＂ ,-NR ＂ C (O) R ' ,-NR '-C (O) NR ＂ R " ' ,-NR ＂ C (O) OR ' ,-NR-C (NR ' R ＂ R " ')=NR ＂ ＂ ,-NR-C (NR ' R ＂)=NR " ' ,-S (O) R ' ,-S (O) 2R ' ,-S (O) 2NR ' R ＂ ,-NRSO 2R ' ,-CN and-NO 2,-R ' ,-N 3,-CH (Ph) 2, fluoro (C 1-C 4) alkoxyl or fluoro (C 1-C 4) alkyl, its quantity is from 0 sum to the open chemical valence of aromatic ring system; Wherein, R ', R ＂, R " ' preferably be independently selected from hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl and replacement or unsubstituted heteroaryl with R ＂ ＂.When The compounds of this invention comprised an above R group, for example each R group was independently selected, and is same, if having more than one R ', R ＂, R " ' and during R ＂ ＂ group, they are also independently selected separately.
Two substituent groups on aryl or the hetero-aromatic ring adjacent atom can randomly form general formula-T-C (O)-(CRR ') qThe ring of-U-, wherein T and U be independently-NR-,-O-,-CRR '-or singly-bound, q is the integer of 0-3.Perhaps, two substituent groups on aryl or the hetero-aromatic ring adjacent atom can be randomly by general formula-A-(CH 2) rThe group of-B-replaces, wherein A and B be independently-CRR '-,-O-,-NR-,-S-,-S (O)-,-S (O) 2-,-S (O) 2NR '-or singly-bound, r is the integer of 1-4.A singly-bound in the new ring of Xing Chenging can randomly be replaced by two keys like this.Perhaps, two substituent groups on aryl or the hetero-aromatic ring adjacent atom can be randomly by general formula-(CRR ') s-X '-(C ＂ R " ') d-substituent group replace, wherein s and d are the integer of 0-3 independently, X ' is-O-,-NR '-,-S-,-S (O)-,-S (O) 2-or-S (O) 2NR '-.Substituent R, R ', R ＂ and R " ' preferably be independently selected from hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl and replacement or unsubstituted heteroaryl.
As used herein, term ＂ hetero atom ＂ or ＂ ring hetero atom ＂ comprise oxygen (O), nitrogen (N), sulfur (S), phosphorus (P) and silicon (Si).
Term ＂ aminoalkyl ＂ used herein refers to and the covalently bound amino of alkylidene joint group.Amino is-NR ' R ＂, wherein, R ' and R ＂ are selected from hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl usually.
Term ＂ substituent group ＂ used herein represents to be selected from down the group of group:
(A)-OH ,-NH 2,-SH ,-CN ,-CF 3,-NO 2, oxygen, halogen, unsubstituted alkyl, unsubstituted assorted alkyl, unsubstituted cycloalkyl, unsubstituted Heterocyclylalkyl, unsubstituted aryl, unsubstituted heteroaryl and
(B) alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by at least one substituent group that is selected from down group:
(i) oxygen ,-OH ,-NH 2,-SH ,-CN ,-CF 3,-NO 2, halogen, unsubstituted alkyl, unsubstituted assorted alkyl, unsubstituted cycloalkyl, unsubstituted Heterocyclylalkyl, unsubstituted aryl, unsubstituted heteroaryl and
(ii) alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are selected from down substituent group replacement of group by at least one:
(a) oxygen ,-OH ,-NH 2,-SH ,-CN ,-CF 3,-NO 2, halogen, unsubstituted alkyl, unsubstituted assorted alkyl, unsubstituted cycloalkyl, unsubstituted Heterocyclylalkyl, unsubstituted aryl, unsubstituted heteroaryl and
(b) alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are replaced by at least one substituent group that is selected from down group: oxygen ,-OH ,-NH 2,-SH ,-CN ,-CF 3,-NO 2, halogen, unsubstituted alkyl, unsubstituted assorted alkyl, unsubstituted cycloalkyl, unsubstituted Heterocyclylalkyl, unsubstituted aryl and unsubstituted heteroaryl.
The substituent group ＂ of term ＂ size restrictions used herein or the substituted radical ＂ of ＂ size restrictions represent to be selected from all above substituent groups described in " substituent group ", and wherein, each replacement or unsubstituted alkyl are to replace or unsubstituted C 1-C 20Alkyl, each replacement or unsubstituted assorted alkyl are to replace or the assorted alkyl of unsubstituted 2-20 unit, and each replacement or unsubstituted cycloalkyl are to replace or unsubstituted C 4-C 8Cycloalkyl, each replacement or unsubstituted Heterocyclylalkyl are to replace or unsubstituted 4-8 unit Heterocyclylalkyl.
The rudimentary substituted radical ＂ of rudimentary substituent group ＂ of term ＂ used herein or ＂ represents to be selected from all above substituent groups described in " substituent group ", and wherein, each replacement or unsubstituted alkyl are to replace or unsubstituted C 1-C 8Alkyl, each replacement or unsubstituted assorted alkyl are to replace or the assorted alkyl of unsubstituted 2-8 unit, and each replacement or unsubstituted cycloalkyl are to replace or unsubstituted C 5-C 7Cycloalkyl, each replacement or unsubstituted Heterocyclylalkyl are to replace or unsubstituted 5-7 unit Heterocyclylalkyl.
The compounds of this invention can exist by salt form.The present invention includes these salt.The example of applicable salt form comprises: hydrochlorate, hydrobromate, sulfate, mesylate, nitrate, maleate, acetate, citrate, fumarate, tartrate (for example (+)-tartrate, (-)-tartrate or their mixture, comprise racemic mixture), succinate, benzoate and with the salt of aminoacid such as glutamic acid.These salt can be prepared by method known to those skilled in the art.Also comprise base addition salts, as sodium, potassium, calcium, ammonium, organic amino or magnesium salt, or similar salt.When The compounds of this invention comprised relative basic functionality, the required acid in this chemical compound that can make neutral form and the respective pure form of q.s or the suitable atent solvent contacted and obtains acid-addition salts.The example of acceptable acid-addition salts comprises the salt example hydrochloric acid salt that is formed by mineral acid, hydrobromate, nitrate, carbonate, bicarbonate, phosphate, dibasic alkaliine, dihydric phosphate, sulfate, disulfate, hydriodate, or phosphite etc., and the salt of organic acid formation, as acetate, propionate, isobutyrate, maleate, malonate, benzoate, succinate, suberate, fumarate, lactate, mandelate, phthalate, benzene sulfonate, tosilate, citrate, tartrate, mesylate etc.Also comprise the salt of amino acid whose salt such as arginine salt etc. and organic acid such as glucuronic acid or galacturonic acid etc.Some specific The compounds of this invention can comprise alkalescence and acidic functionality simultaneously, makes chemical compound can be converted into alkali or acid-addition salts.
Preferably by salt and alkali or acid being contacted and separating the regenerate chemical compound of neutral form of parent compound in a usual manner.The chemical compound of parent form is being different from various salt forms, for example dissolubility in polar solvent aspect some physical property.
Some The compounds of this invention can non-solvent compound form and solvate form thereof (comprising hydrate forms) existence.Usually, solvate form thereof is equal to non-solvent compound form, and comprises within the scope of the invention.Some The compounds of this invention can many crystallizations shape or amorphous form existence.Usually, all physical form are equal in the application that the present invention considered, comprise within the scope of the invention.
Some The compounds of this invention has asymmetric carbon atom (optics or chiral centre) or two key; Enantiomer, racemate, diastereomer, tautomer, geometric isomer, can be defined as according to the absolute stereo chemistry (R)-or (S)-stereoisomeric forms in any ratio, amino acid whose (D)-or (L)-form and independent isomer all comprise within the scope of the invention.To such an extent as to The compounds of this invention does not comprise that its character known in the art is too unstable and can not synthesize and/or isolating material.The present invention is intended to comprise the chemical compound of raceme and optical voidness form.Can adopt chiral synthon or Chirality Reaction reagent preparation optical activity (R)-and (S)-, or (D)-and (L)-isomer, or adopt routine techniques to resolve.When chemical compound as herein described comprised ethylene linkage or other how much asymmetric centers, except as otherwise noted, this chemical compound comprised E and Z geometric isomer.
Term ＂ tautomer ＂ used herein refers to that balance exists and can be easily be converted into a kind of alternative two or more constitutional isomers from a kind of isomeric forms.
It will be understood by those skilled in the art that some The compounds of this invention can tautomeric forms exist, the chemical compound of all these tautomeric forms all comprises within the scope of the invention.
Except as otherwise noted, structure shown in this paper also is intended to comprise the stereochemical form of all structures; That is, the R of each asymmetric center and S configuration.Therefore, the single three-dimensional chemical isomer of The compounds of this invention and enantiomer and non-enantiomer mixture all comprise within the scope of the invention.
Except as otherwise noted, structure shown in this paper is intended to also comprise that difference only is to exist one or more chemical compounds that are rich in isotopic atom.For example, have structure of the present invention but hydrogen is replaced by deuterium or tritium, perhaps carbon is rich in 13C-or 14The carbon of C-replace chemical compound comprise within the scope of the invention.
The compounds of this invention can also comprise the atom isotope of non-natural proportion at the one or more atoms place that constitutes this chemical compound.For example, available radiosiotope such as tritium ( 3H), iodine-125 ( 125I) or carbon-14 ( 14C) radio-labelled compound.No matter whether all isotopic variations of The compounds of this invention exist radioactivity, all comprises within the scope of the invention.
Term ＂ pharmaceutically acceptable salt ＂ is intended to comprise the specified substituent part according to existing on the chemical compound described herein, uses the salt of the reactive compound of nontoxic relatively acid or alkali preparation.When The compounds of this invention comprises relative acidic functionality, can contact with the respective pure form of q.s or the required alkali in suitable inert solvents by the chemical compound that makes neutral form and obtain base addition salts.The example of pharmaceutically acceptable base addition salts comprises sodium, potassium, calcium, ammonium, organic amino or magnesium salt or similar salt.When The compounds of this invention comprises relative basic functionality, can contact with the respective pure form of q.s or the required acid in suitable inert solvents by this chemical compound that makes neutral form and obtain acid-addition salts.The example of pharmaceutically-acceptable acid addition comprises by mineral acid acquisition salt example hydrochloric acid salt, hydrobromate, nitrate, carbonate, bicarbonate, phosphate, dibasic alkaliine, dihydric phosphate, sulfate, disulfate, hydriodate, or phosphite etc., and the salt of nontoxic relatively organic acid formation, as acetate, propionate, isobutyrate, maleate, malonate, benzoate, succinate, suberate, the fumarate lactate, mandelate, phthalate, benzene sulfonate, tosilate, citrate, tartrate, mesylate etc.Also comprise salt of amino acid whose salt such as arginine salt etc. and organic acid such as glucuronic acid or galacturonic acid etc. (referring to for example, Berge etc., ＂ Pharmaceutical Salts ＂ (pharmaceutical salts), Journal ofPharmaceutical Science, 1977,66,1-19).Some specific The compounds of this invention can comprise alkalescence and acidic functionality simultaneously, makes chemical compound can be converted into alkali or acid-addition salts.
Except salt form, the present invention also provides the prodrug forms of chemical compound.Chemical compound prodrug as herein described is meant and experiences chemical change easily so that those chemical compounds of The compounds of this invention to be provided under physiological conditions.In addition, prodrug can be converted into The compounds of this invention by chemistry or biochemical method in the environment that exsomatizes.For example, when placing the percutaneous plaster bank with suitable enzyme or chemical reagent, prodrug can slowly be converted into The compounds of this invention.
When term ＂ one ＂ or ＂ of ＂ are used to represent the substituent group group of this paper, represent at least one.For example, when chemical compound was replaced by " one " alkyl or aryl, this chemical compound was randomly replaced by at least one alkyl and/or at least one aryl.And when a part was replaced by the R group, this group was called " R-replaces ".Replace if part is R-, then this part is replaced by at least one R substituent group, and each R substituent group optional be different.
The description of The compounds of this invention is subjected to the restriction of chemical bonding principle well known by persons skilled in the art.Therefore, when group is replaced by one or more substituent groups, these substituent selector combination bonding principles, can not form intrinsic instability and/or those skilled in the art known under environmental condition (for example under aqueous, neutrality and some the known physiological conditions) tend to unstable compounds.For example, Heterocyclylalkyl or heteroaryl link to each other with the remainder of molecule by ring hetero atom, meet chemical bonding principle well known by persons skilled in the art, thereby avoid forming intrinsic unstable compounds.
The ＂ of term ＂ treatment ＂ or ＂ treatment is meant and successfully cures or improve damage, pathological changes or disease, and the index that comprises any objective or subjective parameters is as alleviating; Relax; Reduce symptom or make the patient tolerate damage, pathological changes or disease more; The speed of degeneration or deterioration slows down; Make the final situation of degeneration lighter; Improve patient body or mental health conditions.Treatment or relief of symptoms can be based on objective or subjective parameters; The result who comprises physical examination, neural interview and/or psychosis assessment.For example, some methods as herein described are successfully treated cancer by reducing cancer incidence rate or alleviation cancer.
" effective dose " is meant to be enough to treat, prevent or the amount of the symptom that palliates a disease." effective dose " also can be described as " treatment effective dose ".＂ alleviates ＂ symptom (and the grammer of this term expression-form of equal value) expression serious symptom or frequency reduces, or transference cure.The ＂ prevention effective dose ＂ of medicine shows when giving object, and medicine will have specified preventive effect, as prevents or postpone generation (or recurrence) probability that (or recurrence) or reduction disease or its symptom take place disease.Give a dosage and do not certainly lead to preventive effect completely, only after giving a series of dosage, just can produce complete preventive effect.Therefore, but one or many prevents effective dose.Term used herein " active reduction amount " refers to respect to the situation that does not have antagonist, reduces the amount of the required antagonist of enzymatic activity.Term used herein " function destruction amount " refers to respect to the situation that does not have antagonist, destroys the amount of the required antagonist of osteoclast or leukocyte function.
Term used herein " antagonist " or " The compounds of this invention " are meant the chemical compound of general formula (I), or the affine pocket of PI3-kinases is in conjunction with antagonist (for example, the affine pocket quinazolone of PI3-kinases antagonist)." chemical compound of general formula (I) " comprises all embodiments of general formula (I) hereinafter described.
The II.PI3-kinase antagonists
In one aspect, the invention provides novel PI3-kinase antagonists.In some embodiments, described PI3-kinase antagonists is that the affine pocket of PI3-kinases is in conjunction with antagonist (for example, the affine pocket quinazolone of PI3-kinases antagonist).The affine pocket of PI3-kinases of the present invention is the chemical compound that comprises the affine pocket bound fraction of PI3-kinases in conjunction with antagonist.The affine pocket quinazolone of PI3-kinases of the present invention antagonist is the Quinazolinone compounds that comprises the replacement of the affine pocket bound fraction of PI3-kinases.The PI3-kinases is affine, and the pocket bound fraction is a substituent group, in case contact the space of promptly filling in the affine pocket of corresponding PI3-kinases with p110 α, p110 β, p110 γ or p110 δ kinases.In some embodiments, the affine pocket bound fraction of PI3-kinases is subjected to displacement at least one hydrone in the affine pocket of PI3-kinases.The PI3-kinases is affine, and the pocket bound fraction also can interact with one or more aminoacid of a part that forms the affine pocket of PI3-kinases.Provide the affine pocket of relevant PI3-kinases and definite substituent group whether to fill the description of the spatial method in the affine pocket of PI3-kinases below.
In some embodiments, the affine pocket quinazolone of PI3-kinases antagonist also comprises pyrazolopyrimidine substituent group or pyrrolopyrimidine substituent group.In some related embodiment, pyrazolopyrimidine substituent group or pyrrolopyrimidine substituent group are covalently bonded in the quinazolone core, and the affine pocket bound fraction of PI3-kinases is covalently attached to pyrazolopyrimidine substituent group or pyrrolopyrimidine substituent group.
In some embodiments, PI3-kinase antagonists of the present invention has general formula:
Figure A200780012368D00231
In general formula (I), q is the integer (for example 1) of 0-5; Z is the integer (for example 1) of 0-10; X is=CH-or=N-.L 1Be key, replacement or unsubstituted alkylidene, replacement or unsubstituted assorted alkylidene, replacement or unsubstituted ring alkylidene, replacement or unsubstituted heterocycle alkylidene, replacement or unsubstituted arlydene or replacement or unsubstituted heteroarylidene.
R 1And R 2Be independently halogen ,-CN ,-OR 5,-S (O) nR 6,-NR 7R 8,-C (O) R 9, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl, wherein n is the integer of 0-2.R 1It also can be the affine pocket bound fraction of PI3-kinases.R 3And R 4Be independently hydrogen, halogen ,-CN ,-OR 5,-S (O) nR 6,-NR 7R 8,-C (O) R 9, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl, wherein n is the integer of 0-2.
R 5Be independently hydrogen ,-C (O) R 10, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl.R 6Be independently hydrogen ,-NR 11R 12, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl.N is 1 or 2 o'clock, R 6It is the group outside the dehydrogenation.
R 7Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently.R 8Be independently hydrogen ,-S (O) nR 13,-C (O) R 14, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl.
R 9Be independently-NR 15R 16, hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl.R 10Be independently hydrogen ,-NR 17R 18, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl.
R 14Be independently hydrogen ,-NR 19R 20, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl; With
R 11, R 12, R 13, R 15, R 16, R 17, R 18, R 19Or R 20Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently.
In some embodiments, the PI3-kinases is affine, and the pocket bound fraction can form hydrogen bond with the pendant amine of K833, and K833 is the aminoacid in the affine pocket of PI3-kinases.
In some embodiments, R 1Be halogen, replacement or unsubstituted halo (C 1-C 6) alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aryl (C 1-C 6) alkyl or replacement or unsubstituted heteroaryl (C 1-C 6) alkyl.R 1It also can be halogen, replace or unsubstituted phenyl, replace or unsubstituted furyl, replace or unsubstituted pyrrole radicals, replace or unsubstituted thiophenyl or replacement or unsubstituted benzo thiophenyl, replace or unsubstituted indyl, replace or the unsubstituted quinolines base, replace or the unsubstituted pyridine base, replace or unsubstituted 1H-pyrrolo-[2,3-c] pyridine radicals, replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridine radicals, replace or unsubstituted thiazolyl, replace or unsubstituted imidazole radicals, replace or do not replace the De oxazolyl, replace or unsubstituted isoxazolyl, replace or unsubstituted pyrazolyl, replace or unsubstituted isothiazolyl, replace or unsubstituted cyclohexyl, replace or unsubstituted morpholino, replace or unsubstituted piperidyl or replacement or unsubstituted tetrahydro pyridyl.
In other embodiments, R 1Be phenyl, furyl, pyrrole radicals, thiophenyl or benzo thiophenyl, separately randomly by one or more R 21Substituent group replaces.R 21Be this section defined (1) or (2) independently.Therefore, R 21Can be (1) halogen ,-CN ,-OR 22,-C (O) R 23,-NR 24R 25,-S (O) wNR 26R 27Or-S (O) wR 28Symbol w is the integer of 0-2.R 22, R 23, R 24, R 25, R 26, R 27Or R 28Be hydrogen, alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyl-alkyl, Heterocyclylalkyl-alkyl, aryl alkyl or heteroaryl alkyl independently, randomly replaced by unsubstituted alkyl, unsubstituted assorted alkyl, unsubstituted cycloalkyl, unsubstituted Heterocyclylalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl-alkyl, unsubstituted Heterocyclylalkyl-alkyl, unsubstituted aryl alkyl or unsubstituted heteroaryl alkyl.R 21Also can be (2) (C 1-C 10) the assorted alkyl of alkyl, 2-10 unit, C 3-C 8Cycloalkyl, 3-8 unit Heterocyclylalkyl, aryl or heteroaryl, randomly by halogen ,-OH ,-CN ,-NH 2, unsubstituted alkyl, unsubstituted assorted alkyl, unsubstituted cycloalkyl, unsubstituted Heterocyclylalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl-alkyl, unsubstituted Heterocyclylalkyl-alkyl, unsubstituted aryl alkyl or unsubstituted heteroaryl alkyl replace.
In some embodiments, R 1The phenyl of position and para-orientation between being, or the phenyl of a position and a position replacement.That is R, 1Be 4, the phenyl or 3 that 5-replaces, the phenyl that 5-replaces.In some relevant embodiments, 4, the phenyl or 3 that 5-replaces, the phenyl that 5-replaces is independently by R 21(such as defining the last period) replacement.In some embodiments, R 21Be halogen or-OR 22R 21Also can be fluorine, R 22Can be hydrogen or unsubstituted C 1-C 4Alkyl (for example, methyl).In other embodiments, R 1It is the phenyl (being the phenyl that 4-replaces) of para-orientation.
In some embodiments, L 1Be to replace or unsubstituted alkylidene (for example, replacement or unsubstituted alkynylene.In other embodiments, L 1Be to replace or unsubstituted methylene, replacement or unsubstituted ethylidene, replacement or unsubstituted propylidene, replacement or unsubstituted butylidene, replacement or unsubstituted ethynylene or replacement or unsubstituted inferior third-2-alkynes.In some relevant embodiments, R 1Be-CN ,-OR 5, NR 7R 8, R 21-replacement or unsubstituted cycloalkyl, R 21-replacement or unsubstituted aryl, R 21-replacement or unsubstituted heteroaryl, R 21-replace or unsubstituted C 1-C 4Alkyl.R 21Can be halogen ,-OR 22,-NR 24R 25Or unsubstituted C 1-C 4Alkyl.R 5, R 7, R 8, R 22, R 24Or R 25Can be hydrogen or unsubstituted C independently 1-C 4Alkyl (for example, methyl).
In some embodiments, R 2Be halogen ,-OH ,-CN ,-NH 2, unsubstituted alkyl, unsubstituted assorted alkyl, unsubstituted cycloalkyl, unsubstituted Heterocyclylalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl-alkyl, unsubstituted Heterocyclylalkyl-alkyl, unsubstituted aryl alkyl or unsubstituted heteroaryl alkyl.R 2Also can be halogen or unsubstituted alkyl.In some embodiments, R 2Be fluorine or unsubstituted C 1-C 4Alkyl (for example, methyl).
R 3Can be halogen ,-OH ,-CN ,-NH 2, unsubstituted alkyl, unsubstituted assorted alkyl, unsubstituted cycloalkyl, unsubstituted Heterocyclylalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl-alkyl, unsubstituted Heterocyclylalkyl-alkyl, unsubstituted aryl alkyl or unsubstituted heteroaryl alkyl.R 3Also can be unsubstituted C 1-C 4Alkyl (for example, methyl).
In some embodiments, R 4Be halogen ,-OH ,-CN ,-NH 2, unsubstituted alkyl, unsubstituted assorted alkyl, unsubstituted cycloalkyl, unsubstituted Heterocyclylalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl-alkyl, unsubstituted Heterocyclylalkyl-alkyl, unsubstituted aryl alkyl or unsubstituted heteroaryl alkyl.
In some embodiments, R 2And R 3Be unsubstituted C independently 1-C 4Alkyl, R 4Be NH 2, q is 1, z is 1.
In some embodiments, above each substituent group described in the chemical compound of general formula (I) is replaced by at least one substituent group.More specifically say, in some embodiments, above the heteroaryl alkyl of the aryl alkyl of the Heterocyclylalkyl-alkyl of the cycloalkyl-alkyl of the heteroaryl of the aryl of the Heterocyclylalkyl of the cycloalkyl of the assorted alkyl of the alkyl of each replacement described in the chemical compound of general formula (I), replacement, replacement, replacement, replacement, replacement, replacement, replacement, replacement and/or replacement is replaced by at least one substituent group.In other embodiments, at least one or all these group is replaced by the substituent group of at least one size restrictions.Perhaps, at least one or all these group is replaced by at least one rudimentary substituent group.
In other embodiment of the chemical compound of general formula (I), each replacement or unsubstituted alkyl are to replace or unsubstituted C 1-C 20Alkyl comprises that cycloalkyl-alkyl (is cycloalkyl-(C 1-C 20) alkyl), Heterocyclylalkyl-alkyl (is Heterocyclylalkyl-(C 1-C 20) alkyl), aryl alkyl (is aryl-(C 1-C 20) alkyl) or the heteroaryl alkyl that replaces (be heteroaryl-(C 1-C 20) alkyl) and the part of formation alkyl.Each replacement or unsubstituted assorted alkyl are to replace or the assorted alkyl of unsubstituted 2-20 unit.Each replacement or unsubstituted cycloalkyl are to replace or unsubstituted C 4-C 8Cycloalkyl comprises that cycloalkyl-alkyl (is C 4-C 8Cycloalkyl-alkyl or C 4-C 8Cycloalkyl-(C 1-C 20) alkyl) and the part of formation cycloalkyl.Each replacement or unsubstituted Heterocyclylalkyl are to replace or unsubstituted 4-8 unit Heterocyclylalkyl, comprise that Heterocyclylalkyl-alkyl (is 4-8 unit's Heterocyclylalkyl-alkyl or 4-8 unit Heterocyclylalkyl-(C 1-C 20) alkyl) and the part of formation Heterocyclylalkyl.
Perhaps, each replacement or unsubstituted alkyl are to replace or unsubstituted C 1-C 8Alkyl, each replacement or unsubstituted assorted alkyl are to replace or the assorted alkyl of unsubstituted 2-8 unit, and each replacement or unsubstituted cycloalkyl are to replace or unsubstituted C 5-C 7Cycloalkyl, each replacement or unsubstituted Heterocyclylalkyl are to replace or unsubstituted 5-7 unit Heterocyclylalkyl, comprise cycloalkyl-alkyl, Heterocyclylalkyl-alkyl, heteroaryl alkyl and aryl alkyl, as described in the previous paragraph.
In another embodiment, The compounds of this invention comprises any or all chemical compounds shown in the following table 1.
The affine pocket of III.PI3-kinases
Term used herein " the affine pocket of PI3-kinases " is meant corresponding to the hole in p110 α, p110 β, p110 γ and the p110 δ of light shaded areas shown in Fig. 2 A, the 2C of labelling " affine pocket " and the 2D.Fig. 2 A, 2C and 2D have shown the computer model of p110 γ crystal structure.In p110 γ, the surface of the affine pocket of PI3-kinases is at least in part by side chain K833, D964, I879 and D841 be combined into (p110 γ sequence is seen Fig. 8).Corresponding cavity surface among the p110 δ is at least in part by side chain K779, D911, I825 and D787 be combined into (the p110 delta sequences are seen Fig. 7).Corresponding cavity surface in the p110 α is at least in part by side chain K802, D933, I848 and D810 be combined into (p110 α sequence is seen Fig. 9).Corresponding cavity surface in the p110 β is at least in part by side chain K805, D937, I851 and D813 be combined into (p110 β sequence is seen Figure 10).ATP can not enter the affine pocket of PI3-kinases.
The affine pocket of PI3-kinases of p110 δ can be described as the affine pocket of p110 δ in this article.Similarly, the affine pocket of PI3-kinases of p110 γ can be described as the affine pocket of p110 γ in this article.The affine pocket of PI3-kinases comprises lysine 779, and according to computer model, lysine 799 forms hydrogen bond (Fig. 2 D) with the pyridine nitrogen of PIK-90 and the phenol oxygen of PI103, and PIK-90 and PI103 are the inhibitor of p110 δ.Based on these microcomputer modellings result, designed novel antagonist based on PIK-39 and IC87114 chemical constitution, as described below.
Shown in Fig. 2 C, PIK-39 does not contain PI3-kinases binding pocket part.As shown in Figure 3A, IC87114 contacts with E880 and V882 in conjunction with the territory maintenance at the ATP of p110 δ, but also lacks PI3-kinases binding pocket part.By phenol (PI3-kinases binding pocket part) between inserting in the C3 position of the pyrazolopyrimidine of IC87114, can enter the affine pocket of PI3-kinases (Fig. 3 A), causing p110 δ to suppress usefulness increases 60-doubly.
As mentioned above, PI3-kinases binding pocket partly is in case contact the spatial replacement part that will fill in the corresponding PI3-kinases binding pocket with p110 α, p110 β, p110 γ or p110 δ.For example, the affine pocket bound fraction of PI3-kinases is in a single day to contact the spatial replacement part that will fill in the affine pocket of p110 δ with p110 δ.Similarly, the affine pocket bound fraction of p110 α is in a single day to contact the spatial replacement part that will fill in the affine pocket of p110 α with p110 α.In some embodiments, the methionine of equal value that exists among the side chain methionine 804 of antagonist and p110 γ or p110 α .p110 β or the p110 δ interacts or makes it be subjected to displacement (seeing Fig. 7-10).
In some embodiments, PI3-kinases binding pocket part also with the aminoacid of component part PI3-kinases binding pocket interact (as bonding).In some relevant embodiments, interaction is hydrogen bond, Van der Waals interaction, ionic bond, covalent bond (as disulfide bond) or hydrophobic interaction.
VI. determine the packing space in the affine pocket of PI3-kinases
In order to determine that whether the affine pocket bound fraction of PI3-kinases fills the space in the affine pocket of PI3-kinases, has adopted the microcomputer modelling technology.The affine pocket of PI3-kinases of inquiry is fitted in the computer picture of p110 γ in conjunction with antagonist (being test compound).P110 γ computer picture derives from the cocrystallization structure in conjunction with the parsing of the people p110 γ of PIK-39.Can adopt PyMOL molecular imaging system to produce this image.Example wherein is building up to IC87114 and PIK-294 in the p110 γ kinases computer picture that derives from p110 γ-PIK-39 cocrystallization structure as shown in Figure 3A.Referring to Knight etc., Cell 125:733-745 (2006).
Usually, the anacom model avoids any total space to collide, with the requirement of the satisfied affine pocket of inquiring about of PI3-kinases in conjunction with the crucial hydrogen bond of formation between antagonist and the p110 γ albumen (as V882 and M804).In some embodiments, carry out the minimum calculating of the energy energy of optimizing integration.Adopt these technology, those skilled in the art can determine easily whether the affine pocket of PI3-kinases of inquiry comprises the affine pocket bound fraction of spatial PI3-kinases in the affine pocket of filling PI3-kinases in conjunction with antagonist.
In some embodiments, the affine pocket of PI3-kinases of analysis and consult is in conjunction with whether forming at least one key (as hydrogen bond) between the aminoacid of the affine pocket of PI3-kinases in conjunction with antagonist and the affine pocket of component part PI3-kinases of antagonist with definite inquiry.Adopt aforementioned calculation machine modeling technique, the distance on one or more aminoacid of the part of the affine pocket of definite formation PI3-kinases and the affine pocket bound fraction of PI3-kinases between the potential contact point.Based on this distance, can those skilled in the art can determine to form between one or more aminoacid of a part of the affine pocket of PI3-kinases and the affine pocket bound fraction of PI3-kinases and form at least one key.
V. general synthetic
Appropriate combination by known synthetic method is synthesized chemical compound of the present invention.The technology that is applicable to synthetic The compounds of this invention is apparent and obtainable to various equivalent modifications.It is in order to set forth triable the whole bag of tricks in some synthetic The compounds of this invention that following discussion is provided.Yet these are discussed is not in order to limit the scope of employed reaction in the The compounds of this invention preparation process or reaction sequence.
Scheme 1
Figure A200780012368D00291
In scheme 1, R 1, R 2, R 3, X and q as mentioned above.Can adopt for example SOCl 2E1 is converted into acid chloride with ortho-aminobenzoic acid, then with the amido functional group direct reaction of aniline, obtains corresponding amide E2.Then, adopt chloracetyl chloride to finish the cyclisation of E2.In the presence of alkali, the chlorine with iodo-pyrazolopyrimidine or iodo-pyrrolopyrimidine replacement E3 forms E4.At last, by the suitable boric acid of Suzuki-Miyaura coupling, the iodine of E4 is by R 1Replace.
VI. method
On the other hand, the invention provides and reduce the PI3 kinases, as the method for p110 δ kinases or the kinase whose catalytic activity of p110 γ.This method comprises the contacted step of PI3-kinase antagonists (the affine pocket of PI3-kinases that is general formula (I) combines antagonist or PI3-kinase antagonists) that makes PI3 kinases (for example, p110 δ kinases) and active reduction amount.In some embodiments, antagonist is the affine pocket quinazolone of a PI3-kinases antagonist.In some embodiments, with respect to the antagonism of anti-p110 α, p110 β and/or p110 γ, PI3-kinase antagonists specificity is at p110 δ.In some embodiments, with respect to the antagonism of anti-p110 α and/or p110 β, PI3-kinase antagonists specificity is at p110 δ.In some embodiments, with respect to the antagonism of anti-p110 α, PI3-kinase antagonists specificity is at p110 δ.In some embodiments, with respect to the antagonism of anti-p110 α and/or p110 β, PI3-kinase antagonists specificity is at p110 γ.In some embodiments, with respect to the antagonism of anti-p110 α, PI3-kinase antagonists specificity is at p110 γ.
In some embodiments, if with respect to the antagonism of anti-p110 β and/or p110 α, PI3-kinase antagonists specificity is at p110 γ, and then the PI3-kinase antagonists is the PI3-kinase antagonists of general formula (I), in the formula, and R 1Be 4, the phenyl that 5-replaces.In some relevant embodiments, 4, the phenyl that 5-replaces is independently by R 21Replace.R 21Can be halogen or-OR 22R 21Also can be fluorine, R 22Can be hydrogen or unsubstituted C 1-C 4Alkyl (for example, methyl).
In other embodiments, if with respect to the antagonism of anti-p110 α, p110 β and/or p110 γ, PI3-kinase antagonists specificity is at p110 δ, and then the PI3-kinase antagonists is the PI3-kinase antagonists of general formula (I), in the formula, and R 1Be 3, the phenyl that 5-replaces.In some relevant embodiments, 3, the phenyl that 5-replaces is independently by R 21Replace.R 21Can be halogen or-OR 22R 21Also can be fluorine, R 22Can be hydrogen or unsubstituted C 1-C 4Alkyl (for example, methyl).
In some embodiments, the IC50 of anti-p110 δ kinases and/or p110 γ hangs down at least 1.5,2.0,3.0,4.0,5.0,10,20,30,40,50,60,70,80,90,100,200,500 or 100 times than the IC50 of anti-p110 α and/or p110 β.In other embodiments, the IC50 of the antagonist of anti-p110 δ kinases and/or p110 γ is less than 100 μ M, 50 μ M, 40 μ M, 30 μ M, 20 μ M, 10 μ M, 5 μ M, 1 μ M, 0.5 μ M, 0.1 μ M, 50nM, 10nM, 1nM.0.5nM, 0.1nM, 50pM, 10pM or 1pM.
On the other hand, the invention provides the method for the object of this treatment of needs being treated the disease of PI3-kinase activity (for example, p110 δ kinase activity or p110 γ kinase activity) mediation.This method comprises the PI3-kinase antagonists (being the affine pocket antagonist of PI3-kinases or the PI3-kinase antagonists of general formula (I)) that gives object treatment effective dose.In some embodiments, antagonist is the affine pocket quinazolone of a PI3-kinases antagonist.
In some embodiments, disease is hematologic malignancies, inflammation, autoimmune disease or cardiovascular diseases.In some embodiments, disease is hematologic malignancies or autoimmune disease.The example of hematologic malignancies comprises acute myeloid leukemia (AML), chronic granulocytic leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM) and myelodysplastic syndrome (MDS).The example of inflammation disease and autoimmune disease comprises rheumatoid arthritis (RA), systemic lupus erythematosus (sle) (SLE) and asthma.Other diseases comprises bone-absorb again disease and thrombosis.
Disease also can be cancer or cancer metastasis type, comprise for example leukemia, cancer and sarcoma, as the brain cancer, breast carcinoma, cervical cancer, colon cancer, head and neck cancer, hepatocarcinoma, renal carcinoma, pulmonary carcinoma, nonsmall-cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterus and medulloblastoma.Other examples comprise: Hodgkin (Hodgkin ' s Disease), non-Hodgkin lymphoma, multiple myeloma, neuroblastoma, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinaemia, primary brain tumor, cancer, pernicious pancreas insulinoma (malignant pancreatic insulanoma), carcinoid malignant, the urinary system bladder cancer, dermatosis before worsening, carcinoma of testis, lymphoma, thyroid carcinoma, neuroblastoma, esophageal carcinoma, the genitourinary tract cancer, malignant hypercalcemia, carcinoma of endometrium, the adrenal cortex cancer, endocrine tumors and exocrine pancreas cancer and carcinoma of prostate.The disease of p110 δ kinase activity mediation and the detailed description of disease are referring to Sadu etc., and WO 01/81346, will fit into this paper in it as a reference.
On the other hand, the invention provides the method for destroying leukocyte function or destroying the osteoclast function.This method comprises makes leukocyte or osteoclast contact with the PI3-kinase antagonists (being the affine pocket antagonist of PI3-kinases or the PI3-kinase antagonists of general formula (I)) of function destruction amount.In some embodiments, antagonist is the affine pocket quinazolone of a PI3-kinases antagonist.
VII. pharmaceutical preparation
On the other hand, the invention provides and comprise the affine pocket of PI3-kinases in conjunction with antagonist or the chemical compound of general formula (I) and the pharmaceutical composition of pharmaceutically acceptable excipient.It will be understood by those skilled in the art that this pharmaceutical composition comprises the invention described above PI3-kinase antagonists pharmaceutically acceptable salt.
In treatment and/or diagnostic application, can comprise whole body and external or topical preparation The compounds of this invention according to multiple mode of administration.Technology and prescription are usually referring to " Lei Mingdeng: pharmaceutical science with put into practice " (Remington:The Science and Practice of Pharmacy) (the 20th edition) Lippincott, Williams and Wilkins (2000).
Chemical compound of the present invention in dosage range widely effectively.For example, during the treatment adult, adopt daily dose 0.01-1000mg, 0.5-100mg, 1-50mg, for example daily dose 5-40mg.Most preferred daily dose is 10-30mg.Accurately dosage depends on the body weight of the form of route of administration, administered compound, object to be treated, object to be treated and attending doctor's preference and experience.
Pharmaceutically acceptable salt is that those of ordinary skills know, can comprise, such as but not limited to acetate, benzene sulfonate, benzene sulfonate, benzoate, bicarbonate, biatrate, bromide, Ca-EDTA, camsilate, carbonate, citrate, edetate, ethanedisulphonate, propionic ester lauryl sulfate (estolate), esilate, fumarate, gluceptate, gluconate, glutamate, Glu, the glycollyl Arsanilate, hexyl resorcin salt, breathe out amine, hydrobromate, hydrochlorate, Hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, naphthalene sulfonate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, Polygalacturonate, Salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate or teoclate.Other pharmaceutically acceptable salts are referring to for example, " Lei Mingdeng: pharmaceutical science with put into practice " (the 20th edition) Lippincott, Williams and Wilkins (2000).The salt of preferred pharmaceutical compositions for example comprises, acetate, benzoate, bromide, carbonate, citrate, gluconate, hydrobromate, hydrochlorate, maleate, mesylate, naphthalene sulfonate, pamoate (embonate), phosphate, Salicylate, succinate, sulfate or tartrate.
According to the concrete disease for the treatment of, these reagent can be mixed with liquid or solid dosage form, whole body or topical.Reagent can be regularly or lasting low speed releasing pattern send, as is known to the person skilled in the art.The preparation and the technology of administration can be referring to " Lei Mingdeng: pharmaceutical science and put into practice " (the 20th edition) Lippincott, Williams and Wilkins (2000).That suitable route of administration comprises is oral, buccal, suction spray, Sublingual, rectum, transdermal, vagina, through mucous membrane, nasal cavity or enteral administration; Parenteral delivery comprises intramuscular, subcutaneous, intramedullary injection, and in the sheath, directly in the ventricle, in the intravenous, intraarticular, breastbone, in the synovial membrane, in the liver, in the damage, intracranial, intraperitoneal, intranasal or intraocular injection or other delivery modality.
If injection, can be on aqueous solution such as physiology compatible buffers such as Chinese formula solution (preparation and dilution reagent of the present invention in Hank ' ssolution), Ringer's solution (Ringer ' s solution) or the normal saline buffer solution.For mucosal, use the penetrating agent that is fit to wait to see through barrier in the preparation.These penetrating agent are well known in the art.
Using pharmaceutically acceptable inert carrier will be used to put into practice chemical compound as herein described of the present invention is mixed with the dosage form that is fit to the whole body administration and comprises within the scope of the invention.By suitable selection carrier and suitable manufacture method, the present composition specifically is with solution form composition prepared, but parenteral, as the intravenous injection administration.Can adopt pharmaceutically acceptable carrier well known in the art chemical compound to be mixed with the dosage form that is fit to oral administration.These carriers make The compounds of this invention can be mixed with tablet, pill, capsule, liquid, gel, syrup, serosity, suspensoid etc., by object to be treated (for example patient) orally ingestible.
Send for nasal cavity or suction, reagent of the present invention also can be prepared by method known to those skilled in the art, non-limiting solubilizing agent, diluent or dispersant such as the saline of comprising in the preparation, antiseptic such as benzyl alcohol, absorption enhancer and fluorocarbon.
Be applicable to that pharmaceutical composition of the present invention comprises that contained active component is the compositions of effective dose to realize that it specifies purpose.Effective dose fixes in those skilled in the art's the limit of power really, specifically according to detailed description provided herein.
Except that active component, pharmaceutical composition also can comprise suitable pharmaceutically acceptable carrier, includes to be beneficial to excipient and the auxiliary reagent that active component is processed to form pharmaceutical formulation.The preparation that preparation is used for oral administration can be the form of tablet, dragee, capsule or solution.
The pharmaceutical preparation that orally uses can obtain by following process: with reactive compound and solid excipient combination, randomly grind the gained chemical compound and chemical compound is processed into granule, add when needing after the suitable auxiliary reagent, obtain tablet or lozenge core.Suitable excipient specifically is filler such as sugar, comprises lactose, sucrose, mannitol or Sorbitol; Cellulose preparation, for example corn starch, wheaten starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropyl methyl-cellulose, carboxymethyl-sodium cellulosate (CMC) and/or polyvinylpyrrolidone (PVP: polyvidone).When needing, can add disintegrating agent, polyvinylpyrrolidone, agar, alginic acid or its salt such as sodium alginate as crosslinked.
For the lozenge core provides suitable coating.For this reason, use high concentration sugar solution, it randomly comprises arabic gum, Pulvis Talci, polyvinylpyrrolidone, card ripple pool that gel, Polyethylene Glycol (PEG) and/or titanium dioxide, lacquer solution and appropriate organic solvent or solvent liquid.Can add dyestuff-slurry or pigment in tablet or the lozenge coating to differentiate or to characterize the various combination of active compound doses.
What but the pharmaceutical preparation of oral application comprised gelatin preparation pushes the coupling capsule and the soft seal capsule of gelatin and plasticizer such as glycerol or Sorbitol preparation.The capsule that pushes coupling can comprise active component and filler such as lactose, binding agent such as starch, and/or lubricant such as Pulvis Talci or magnesium stearate, and the mixture of stabilizing agent randomly.In soft capsule, reactive compound can be dissolved or suspended in suitable liquid such as fatty oil, liquid Paraffin or the liquid macrogol (PEG).In addition, can add stabilizing agent.
According to disease specific or morbid state to be treated or prevention, can be generally used for treating or preventing the other treatment agent of this disease with inhibitor of the present invention.For example, can chemotherapeutic or other are anti--multiplication agents and inhibitor of the present invention make up and treat hyperplasia and cancer.The example of known chemotherapeutic includes but not limited to: amycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, paclitaxel, interferon and platinum derivatives.
Can include but not limited to anti-inflammatory agent such as corticosteroid, tnf blockers, IL-1RA, azathioprine, cyclophosphamide and sulfasalazine with other examples that inhibitor of the present invention is united the reagent of use; Immunomodulator and immunosuppressant such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroid, cyclophosphamide, azathioprine and sulfasalazine; The stearic enzyme inhibitor of neurotrophic factor such as acetyl group choline, MAO inhibitor, interferon, anticonvulsant, ion channel blocker, riluzole and anti-Parkinson medicine; Treatment cardiovascular diseases's medicine such as beta-Blocking agent, ACE inhibitor, diuretic, Nitrates, calcium channel blocker and statins; The medicine such as corticosteroid, colestyramine, interferon and the anti--virus drugs that are used for the treatment of hepatic disease; The medicine such as corticosteroid, anti-leukemia medicine and the somatomedin that are used for the treatment of hematologic disease; The medicine such as insulin, insulin analog, α glycosidase inhibitor, biguanide and the euglycemic agent that are used for the treatment of diabetes; And the medicine such as the gamma Globulin that are used for the treatment of immune deficiency disorder.
These extra medicaments can be independent of the compositions that contains inhibitor, carry out administration as the part of multiple dose scheme.Perhaps, these medicaments can be with single compositions in the part of inhibitor mixed single dose form together.
The present invention is not subjected to the restriction of the specific embodiment, and these embodiments are intended to set forth various aspects of the present invention.In fact, by above-mentioned explanation, the of the present invention various improved forms except that described herein are that those skilled in the art are conspicuous.These improved forms fall within the scope of the invention.And, any one or more feature of any embodiment of the present invention can with any any one or more characteristics combination of other embodiments of the present invention, and do not deviate from scope of the present invention.For example, PI3-kinases agonist of the present invention mentioned above can be applicable to Therapeutic Method as herein described equally and suppresses kinase whose method.The list of references of quoting among the application is the example in those skilled in the art's level, no matter its content is included into this paper as a reference and aforementioned whether specifically noting comprises.
VIII. embodiment
The following examples are in order to set forth some embodiment of the present invention, rather than limit the scope of the invention.
A. exemplary synthetic schemes
Scheme 2
Figure A200780012368D00351
Scheme 2 has been set forth the synthesis path of some chemical compound shown in the following table 1.Employing scheme 1 and 2 information that provided, and the concrete composite signal of some chemical compound provided below, those skilled in the art will understand the synthesis path of The compounds of this invention at once.
B. some chemical compound is concrete synthetic
1. Synthetic 2-amino-6-methyl-N-o tolyl Benzoylamide
(25g 165mmol) is dissolved in (250mL) in the benzene with 2-amino-6-ar-Toluic acid.(37.5mL 500mmol), spends the night the reactant liquor reflux to add thionyl chloride.Second day vacuum concentration of reaction solution uses the benzene (200mL) of twice to absorb then, and vacuum is removed solvent once more, obtains the oil of black.Oil is dissolved in CHCl 3(400mL), (44mL 412mmol), is heated to backflow with reactant liquor to add ortho-aminotoluene.Afterreaction was complete in 2 hours, by three silica gel chromatographies (15%EtOAc/ hexane) purified product, obtained brown solid (29g, productive rate 73.4%).LR-ESI MS (M+H) +M/z value of calculation 241.1, measured value 240.9.
2. Synthetic 2-(chloromethyl)-5-methyl-3-o-tolyl quinazoline-4 (3H)-ketone
(29mL, (29g in acetic acid 121mmol) (600mL) solution, is heated to backflow with reactant liquor 363mmol) to join 2-amino-6-methyl-N-o tolyl Benzoylamide with chloracetyl chloride.Afterreaction liquid was cooled to room temperature in 2 hours, vacuum concentration.By three silica gel chromatography purified products (behind the twice 15% EtOAc/ hexanes, once using 10% diethyl ether/hexane), produce white solid (8.3g, productive rate 23%).LR-ESIMS (M+H) +M/z value of calculation 299.1, measured value 298.8.
3. Synthetic 2-((4-amino-1H-pyrazolo [3,4-d] pyrimidine-1-yl) methyl)-5-methyl-3-o-tolyl quinazoline-4 (3H)-ketone
(0.15g, 0.5mmol) (0.101g 0.05mmol) joins DMF (10mL) and K with 1H-pyrazolo [3,4-d] pyrimidine-4-amine with 2-(chloromethyl)-5-methyl-3-o-tolyl quinazoline-4 (3H)-ketone 2CO 3(0.138g, 1mmol) in, lucifuge stirred 24 hours under the room temperature.Add water (800mL) and make the product precipitation, and filter and collect.Precipitate is further by RP-HPLC (MeCN:H 2O:0.1% TFA) purification.LR-ESI
MS (M+H) +M/z value of calculation 398.2, measured value 398.1.
4. synthetic compound S2
(3g, 10.0mmol) (3.91g 15.05mmol) joins DMF (50mL) and K with 3-iodo-1H-pyrazolo [3,4-d] pyrimidine-4-amine with 2-(chloromethyl)-5-methyl-3-o-tolyl quinazoline-4 (3H)-ketone 2CO 3(2.77g, 20mmol) in, lucifuge stirred 24 hours under the room temperature.Add water (900mL) and make the product precipitation, and filter and collect.Precipitate is further by silica gel chromatography (2% MeOH/CH 2Cl 2) purification.LR-ESI MS (M+H) +M/z value of calculation 524.1, measured value 523.9.
5. synthetic compound S3
With 2-((4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidine-1-yl) methyl)-5-methyl-3-o-tolyl quinazoline-4 (3H)-ketone (50mg, 0.096mmol), a phenol boric acid (14.5mg, 0.105mmol) and tetrakis triphenylphosphine palladium (22mg 0.019mmol) is dissolved in DME (10mL), EtOH (1.6mL) and Na 2CO 3In the solution of saturated aqueous solution (2.75mL).Under the ar gas environment, reactant liquor is heated to backflow spends the night.This reactant liquor poured in the water in second day, use CH 2Cl 2Aqueous phase extracted three times.With the organic extract vacuum concentration and by RP-HPLC (MeCN:H 2O:0.1% TFA) purification.LR-ESI MS (M+H) +M/z value of calculation 490.2, measured value 490.1.
6. synthetic compound S4
With 2-((4-amino-3-iodo-1H-pyrazolo [3; 4-d] pyrimidine-1-yl) methyl)-5-methyl-3-o-tolyl quinazoline-4 (3H)-ketone (50mg; 0.096mmol), 5-formoxyl benzo [b] thiophene-2-borate (5-formylbenzo[b] thiophene-2-boronic ester) (30.3mg; 0.105mmol) and tetrakis triphenylphosphine palladium (22mg 0.019mmol) is dissolved in DME (10mL), EtOH (1.6mL) and Na 2CO 3In the solution of saturated aqueous solution (2.75mL).Under the ar gas environment, reactant liquor is heated to backflow spends the night.Reactant liquor poured in the water in second day, use CH 2Cl 2Aqueous phase extracted three times.The vacuum concentration organic extract also passes through RP-HPLC (MeCN:H 2O:0.1% TFA) purification.LR-ESI MS (M+H) +M/z value of calculation 558.2, measured value 558.0.
7. synthetic compound S5
With 2-((4-amino-3-iodo-1H-pyrazolo [3; 4-d] pyrimidine-1-yl) methyl)-5-methyl-3-o-tolyl quinazoline-4 (3H)-ketone (50mg; 0.096mmol), 5-formoxyl-3 methyl thiophene-2-boric acid (18.9mg; 0.105mmol) and tetrakis triphenylphosphine palladium (22mg 0.019mmol) is dissolved in DME (10mL), EtOH (1.6mL) and Na 2CO 3In the solution of saturated aqueous solution (2.75mL).Under the ar gas environment, reactant liquor is heated to backflow spends the night.Reactant liquor poured in the water in second day, use CH 2Cl 2Aqueous phase extracted three times.With the organic extract vacuum concentration and by RP-HPLC (MeCN:H 2O:0.1% TFA) purification.LR-ESI
MS (M+H) +M/z value of calculation 522.2, measured value 522.0.
8. synthetic S6
With 2-((4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidine-1-yl) methyl)-5-methyl-3-o-tolyl quinazoline-4 (3H)-ketone (100mg, 0.192mmol), 3,4-Dimethoxyphenyl borate (38.2mg, 0.21mmol) and tetrakis triphenylphosphine palladium (44mg 0.038mmol) is dissolved in DME (20mL), EtOH (3.2mL) and Na 2CO 3In the solution of saturated aqueous solution (5.5mL).Under the ar gas environment, reactant liquor is heated to backflow spends the night.Reactant liquor poured in the water in second day, use CH 2Cl 2Aqueous phase extracted three times.With the organic extract vacuum concentration and by RP-HPLC (MeCN:H 2O:0.1% TFA) purification.LR-ESI MS (M+H) +M/z value of calculation 534.2, measured value 534.0.
9. synthetic S7
With 2-((4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidine-1-yl) methyl)-5-methyl-3-o-tolyl quinazoline-4 (3H)-ketone (100mg, 0.192mmol), 4-Phenoxyphenyl boric acid (44.9mg, 0.21mmol) and tetrakis triphenylphosphine palladium (44mg 0.038mmol) is dissolved in DME (20mL), EtOH (3.2mL) and Na 2CO 3In the solution of saturated aqueous solution (5.5mL).Under the ar gas environment, reactant liquor is heated to backflow spends the night.Reactant liquor poured in the water in second day, use CH 2Cl 2Aqueous phase extracted three times.With the organic extract vacuum concentration and by RP-HPLC (MeCN:H 2O:0.1% TFA) purification.LR-ESI MS (M+H) +M/z value of calculation 566.2, measured value 566.0.
10. synthetic S8
With 2-((4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidine-1-yl) methyl)-5-methyl-3-o-tolyl quinazoline-4 (3H)-ketone (100mg, 0.192mmol), 4-benzyloxy phenylboric acid (47.9mg, 0.21mmol) and tetrakis triphenylphosphine palladium (44mg 0.038mmol) is dissolved in DME (20mL), EtOH (3.2mL) and Na 2CO 3In the solution of saturated aqueous solution (5.5mL).Under the ar gas environment, reactant liquor is heated to backflow spends the night.Reactant liquor poured in the water in second day, use CH 2Cl 2Aqueous phase extracted three times.With the organic extract vacuum concentration and by RP-HPLC (MeCN:H 2O:0.1% TFA) purification.
11. synthetic S33
With 2-((4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidine-1-yl) methyl)-5-methyl-3-o-tolyl quinazoline-4 (3H)-ketone (50mg, 0.096mmol), 3-cyano-phenyl boric acid (15.8mg, 0.105mmol) and tetrakis triphenylphosphine palladium (22mg 0.019mmol) is dissolved in DME (10mL), EtOH (1.6mL) and Na 2CO 3In the solution of saturated aqueous solution (2.75mL).Under the ar gas environment, reactant liquor is heated to backflow spends the night.Reactant liquor poured in the water in second day, use CH 2Cl 2Aqueous phase extracted three times.With the organic extract vacuum concentration and by RP-HPLC (MeCN:H 2O:0.1%TFA) purification.LR-ESI MS (M+H) +M/z value of calculation 499.2, measured value 499.0.
12. Synthetic 2-amino-N-(2-chlorphenyl)-6-methyl benzamide
(2.5g 16.5mmol) is dissolved in the benzene (75mL) with 2-amino-6-ar-Toluic acid.(3.0mL, 41.1mmol), reactant liquor is heated to refluxes then spends the night to add thionyl chloride.Second day vacuum concentration of reaction solution uses the benzene (75mL) of twice to absorb then, and vacuum is removed solvent once more, obtains the oil of black.Oil is dissolved in CHCl 3(75mL), add 2-chloroaniline (3.5mL) and reactant liquor is heated to backflow.Afterreaction was complete in 4 hours, this moment filtering reacting liquid, the vacuum concentration filter liquor, product obtains brown oil (1.94g, productive rate 45%) by silica gel chromatography (25%EtOAc/ hexane) purification.HR-EI MS (M) +M/z value of calculation 260.07, measured value 260.0715.
13. Synthetic 2-(chloromethyl)-3-(2-chlorphenyl)-5-methyl quinazoline-4 (3H)-ketone
(0.72mL, (0.8g is heated to backflow in acetic acid 3.06mmol) (10mL) solution and with reactant liquor 9mmol) to join 2-amino-N-(2-chlorphenyl)-6-methyl benzamide with chloracetyl chloride.2.5 after hour reactant liquor is cooled to room temperature, vacuum concentration.Product obtains white solid (0.353g, productive rate 36%) by silica gel chromatography (10% EtOAc/ hexane) purification.HR-EI MS (M) +M/z value of calculation 318.0327, measured value 318.0321.
14. Synthetic 2-((4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidine-1-yl) methyl)-3-(2-chlorphenyl)-5-methyl quinazoline-4 (3H)-ketone
(0.112g, 0.35mmol) (0.138g 0.053mmol) joins DMF (5mL) and K with 3-iodo-1H-pyrazolo [3,4-d] pyrimidine-4-amine with 2-(chloromethyl)-3-(2-chlorphenyl)-5-methyl quinazoline-4 (3H)-ketone 2CO 3(0.096g, 0.7mmol) in, lucifuge stirred 72 hours under the room temperature.Add water (50mL) and make the product precipitation, filter and collect.Precipitate is further by RP-HPLC (MeCN:H 2O:0.1% TFA) purification.
15. synthetic S1
With 2-((4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidine-1-yl) methyl)-3-(2-chlorphenyl)-5-methyl quinazoline-4 (3H)-ketone (60mg, 0.11mmol), a phenol boric acid (17mg, 0.121mmol) and tetrakis triphenylphosphine palladium (25mg 0.022mmol) is dissolved in DME (10mL), EtOH (1.6mL) and Na 2CO 3In the solution of saturated aqueous solution (2.75mL).Under the ar gas environment, reactant liquor is heated to backflow spends the night.Reactant liquor poured in the water in second day, use CH 2Cl 2Aqueous phase extracted three times.With the organic extract vacuum concentration and by RP-HPLC (MeCN:H 2O:0.1% TFA) purification.LR-ESI MS (M+H) +M/z value of calculation 510.1, measured value 510.0.
16. synthetic S34
With 2-((4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidine-1-yl) methyl)-5-methyl-3-o-tolyl quinazoline-4 (3H)-ketone (50mg, 0.096mmol), 3-sulfonamide phenyl-borate (29.7mg, 0.105mmol) and tetrakis triphenylphosphine palladium (22mg 0.019mmol) is dissolved in DME (10mL), EtOH (1.6mL) and Na 2CO 3In the solution of saturated aqueous solution (2.75mL).Under the ar gas environment, reactant liquor is heated to backflow spends the night.Reactant liquor poured in the water in second day, use CH 2Cl 2Aqueous phase extracted three times.LR-ESI MS (M+H) +M/z value of calculation 553.2, measured value 553.0.
The structural research of C.PI3-kinases
Crystal structure (Walker etc., 2000 of the complex of independent p110 γ and p110 γ and ATP or general-specific inhibitor such as LY294002 and wortmannin have been reported; Walker etc., 1999).In order to study bonded effectiveness of inhibitor and selectivity, at 2.5-2.6
Figure A200780012368D0040140825QIETU
Measure crystal structure under the resolution: quinazoline purine PIK-39, imidazopyridine PIK-90 and phenyl thiazole PIK-93 (Fig. 2) in conjunction with the PI3-K inhibitor of three kinds of chemical types of people p110 γ.
According to these cocrystallization structures and conservative aryl morpholine Pharmacophore Model, produce structural model: pyridine radicals furo pyrimidine PI-103, morpholino chromone PIK-108 and morpholino pyrone KU-55933 (Fig. 2) in conjunction with three kinds of other chemical types of p110 γ.Instruct the modeling of these inhibitor by the observed result that comprises the crucial aryl morpholine pharmacophore that exists among the LY294002 in each chemical compound.
PIK-39 is the isoquinolin purine, suppresses p110 δ with medium nanomolar concentration, suppresses high about 100 times of the concentration of p110 γ and p110 β, to any other PI3-K family member, comprises 110 α non-activities (Fig. 5) under up to the concentration of 100 μ M.By with the cocrystallization structure of p110 γ in the unconventional binding pattern that discloses, realized the biochemistry selectivity (Fig. 2 C) of this chemical compound.Have only the purinethol part of PIK-39 to contact with the ATP binding pocket is inner, this loop systems is rotated about 110 ° with respect to the ATP adenine, about 35 ° of plane torsion.In this orientation, satisfied with the hydrogen bond of Val882 and Glu88 main chain amide and be connected (thereby reappearing the N1 of adenine and hydrogen bond that N6 produces).
Different with other PI3-K inhibitor structures, PIK-39 can not enter active site inside than the pocket of depths (Fig. 2 C is labeled as the light shade of " affine pocket ").On the contrary, aryl-isoquinolin of PIK-39 partly extends to the inlet (Fig. 2 B) of ATP binding pocket.In this zone, kinases is reset by conformation and is held inhibitor, and Met 804 is extruding (packagainst) isoquinolin " downwards " position partly from " making progress " position transition that forms ATP binding pocket top in the rearrangement.This variation is PIK-39 structure distinctive (Fig. 2 B), and the result produces new hydrophobic pocket between the Met 804 of the porch of ATP-binding site and Trp 812.This pocket of coupling of inducing covers 180
Figure A200780012368D0040163010QIETU
Solvent can reach the inhibitor surface area, make PIK-39 realize that nanomole is affine, although the contact in the active site core is limited.
Measure PIK-90 and PIK-93 chemical compound and the bonded cocrystallization structure of p110 γ.The main chain amide nitrogen of PIK-90 and PIK-93 and Val 882 forms hydrogen bond (Fig. 2 D), and this is interaction (Walker etc., 2000) conservative in all known PI3-K inhibitor.Except that this hydrogen bond, the main chain carbonyl of PIK-93 and Val882 forms second hydrogen bond, forms the 3rd hydrogen bond between the side chain of its sulfonamide part and Asp 964.PIK-93 is one of the highest inhibitor of our chemical compound group Semi-polarity (clogP=1.69), and the polar interaction of these expansions can compensate its limited hydrophobic surface zone.
The combination of PIK-90 is similar to PIK-93, has hydrophobic interaction widely but this chemical compound is big, covers 327
Figure A200780012368D0041154110QIETU
Solvent-accessible surface long-pending.For this reason, the pyridine ring of PIK-90 stretches into that PIK-93 can partly arrive and the darker hole (Fig. 2 D, light shade ring) that can not be occupied by ATP.In this zone, the pyridine ring of PIK-90 can stably form hydrogen bond with Lys 833, and we find with carbon replace pyridine nitrogen cause 100 times of affinity losses (PIK-95, Fig. 4).PI-103 is the third many target spot PI3K inhibitor, and according to the aryl morpholine Pharmacophore Model, its phenol moieties stretches into (Fig. 2 D) in the identical pocket.
Two kinds of architectural features make these potent many target spots inhibitor be different from more multi-selection chemical compound in our the chemical compound group.At first, the ATP binding pocket of these chemical compounds is taked the plane conformation, and the high selectivity inhibitor stretches out (Fig. 2) from the occupied plane of ATP.The second, the most potent inhibitor stretch into that ATP can not arrive than depths binding pocket (Fig. 2 A).The most surfaces of this affine pocket is by the side chain contribution of Ile 879.
Purinethol in the PIK-39 structure is replaced by adenine, produces IC87114 model (Fig. 3 A).This replacement provides the IC87114 adenine of correct orientation, forms the hydrogen bond the same with the purinethol of PIK-39, even these two loop systems are rotated 110 ° each other.
Different with other inhibitor chemical types, PIK-39 does not adopt the affine pocket of PI3-kinases (Fig. 2 C).Measure IC87114 Pyrazolopyrimidine analogs (PIK-293) then and contain the inhibitory action of the novel analogs (PIK-294, Fig. 3 A) of a phenol I class PI3-K.The effect of PIK-294 is than 60 times at the most of PIK-293 height (Fig. 3 A).
Disclose the conformation that produces the Met804 that induces pocket with the structure of the bonded PIK-39 of p110 γ and reset, we suppose that it is PIK-39 to p110 δ reason optionally that this conformation is reset.The prediction of this model is that Met 804 sudden changes will be upset the combination of p110 δ-selective depressant (they enter and induce pocket), but can not influence the inhibitor (can not enter this pocket) of other types.The modeling prompting, Met 804 sports β-branched-chain amino acid (as valine or isoleucine) will limit the pocket (Fig. 3 B, right figure) that this residue is reset formation.Therefore, we sport valine or isoleucine with corresponding residue among the p110 δ (Met 752), express and these kinases of purification, measure their sensitivity (Fig. 3 B) to the PI3-K inhibitor.We find that M752I and M752V p110 δ tolerate p110 δ-selective depressant PIK-39 and IC87114, but keep the sensitivity to p110 α/many target spots inhibitor PIK-90, PIK-93 and PI-103.But the unique effect of this chemical type specificity tolerance proof Met 752 in gate induced selective pocket.
Adopt PyMOL molecule drafting system to carry out the antagonist modeling.Use PyMOL comparison function to all p110 γ crystal structures (expression PDB coding in the bracket), comprise that Apo (1E8Y), ATP (1E8X), wortmannin (1E7U), LY294002 (1E7V), Quercetin (1E8W), myricetin (1E90) and staurosporin (1E8Z) and PIK-90, PIK-93 and PIK-39 combining form carries out structure and compare.Use the fragment of PyMOL to set up function is set up inhibitor PIK-108, KU-55933 and PI-103 at LY294002 aryl morpholine support (1E7V) top model.Prop up the model that top of the trellis is set up inhibitor IC87114 at PIK-39 aryl-isoquinolin similarly.
With the PI-103 model construction in protein structure in conjunction with the p110 γ of PIK-90, because the PIK-90 structure comprises the affine pocket (otherwise compare with the bonded p110 γ of LY294002-structure, PIK-90p110 γ structure does not have any conformational difference in aryl morpholine-calmodulin binding domain CaM) of the required expansion of the phenol moieties that holds PIK-103.With the model construction of PIK-108, KU-55933 and IC87114 in protein structure in conjunction with the p110 γ of PIK-39, because these inhibitor have the macoradical that stretches out from the adenine plane, and tend to take unique " Met 804 is downward " induce the coupling pocket.In all inhibitor models, the selection of protein structure and inhibitor binding pattern is based upon on the basis of biochemistry SAR widely and inhibitor geometry.Do not reduce protein structure and inhibitor model as yet as far as possible with the energy of optimizing integration, but must prevent carefully that any total space from colliding and satisfying the requirement of crucial hydrogen bond.
Expression and the analysis of D.p110 α/p85 α, p110 β/p85 α, p110 δ/p85 α and p110 γ
I class PI3-K can buy (p110 α/p85 α, p110 β/p85 α, p110 δ/p85 α derives from upstream company (Upstate), and p110 γ derives from Sigma company (Sigma)) or obtain (Knight etc., 2004) as expression as described in the past.The standard TLC analysis (as described below) of employing lipid kinase determination of activity or high flux membrane are captured to analyze and are measured the IC50 value.Preparation contains kinases, inhibitor (2%DMSO ultimate density), buffer (25mMHEPES, pH7.4,10mM MgCl 2) and the reactant mixture of fresh ultrasonic phosphatidylinositols (100 μ g/ml) carry out kinase reaction.Add the ATP contain 10 μ Ci γ-32P-ATP to final concentration be 10 or 100 μ M to start this reaction, as shown in Figure 5, reaction was carried out 5 minutes under the room temperature.Analyze for TLC, adding 105 μ l 1N HCl is 160 μ l CHCl then 3: MeOH (1:1) cessation reaction.The vortex biphase mixture, simply centrifugal, with applying CHCl in advance 3Gel application of sample pipettor tip organic facies is transferred in the new test tube.Extract is carried out TLC point plate, at the 65:35 normal propyl alcohol: launched 3-4 hour in the solution of 1M acetic acid.With TLC plate drying, be exposed to phosphorometer screen (Storm, peace agate West Asia company (Amersham)) and quantitative then.For each chemical compound, measure the kinase activity under the 10-12 kind inhibitor concentration of maximum concentration (normally 200 μ M) twice dilution.For the chemical compound that shows remarkable activity, IC50 replication 2-4 time, the value of record is this meansigma methods of independently measuring several times.
The result is as shown in table 1.
Table 1
Figure A200780012368D00431
Figure A200780012368D00451
Figure A200780012368D00461
Figure A200780012368D00471
Figure A200780012368D00481
Figure A200780012368D00491
Figure A200780012368D00501
Figure A200780012368D00511
Figure A200780012368D00521
Symbol ++ IC50 is less than 1 μ M in+expression; Symbol ++ expression IC50 value is that 1 μ M is to 100 μ M; And symbol+expression IC50 value is more than 100 μ M.
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Claims (36)

1. chemical compound with following general formula:
Figure A200780012368C00021
In the formula,
Q is the integer of 0-5;
Z is the integer of 0-10;
X is=CH-or=N-;
L 1Be key, replacement or unsubstituted alkylidene, replacement or unsubstituted assorted alkylidene, replacement or unsubstituted ring alkylidene, replacement or unsubstituted heterocycle alkylidene, replacement or unsubstituted arlydene or replacement or unsubstituted heteroarylidene;
R 1And R 2Be independently halogen ,-CN ,-OR 5,-S (O) nR 6,-NR 7R 8,-C (O) R 9, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl, wherein n is the integer of 0-2 independently;
R 3And R 4Be independently hydrogen, halogen ,-CN ,-OR 5,-S (O) nR 6,-NR 7R 8,-C (O) R 9, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 5Be independently hydrogen ,-C (O) R 10, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 6Be independently hydrogen ,-NR 11R 12, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl, if wherein n is 1 or 2, R then 6Not hydrogen;
R 7Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently;
R 8Be independently hydrogen ,-S (O) nR 13,-C (O) R 14, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 9Be independently-NR 15R 16, hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 10Be independently hydrogen ,-NR 17R 18, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 14Be independently hydrogen ,-NR 19R 20, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl; With
R 11, R 12, R 13, R 15, R 16, R 17, R 18, R 19And R 20Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently.
2. chemical compound as claimed in claim 1 is characterized in that R 1Be halogen, replacement or unsubstituted halo (C 1-C 6) alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aryl (C 1-C 6) alkyl or replacement or unsubstituted heteroaryl (C 1-C 6) alkyl.
3. chemical compound as claimed in claim 1 is characterized in that R 1It is halogen, replace or unsubstituted phenyl, replace or unsubstituted furyl, replace or unsubstituted pyrrole radicals, replace or unsubstituted thiophenyl or replacement or unsubstituted benzo thiophenyl, replace or unsubstituted indyl, replace or the unsubstituted quinolines base, replace or the unsubstituted pyridine base, replace or unsubstituted 1H-pyrrolo-[2,3-c] pyridine radicals, replace or unsubstituted 1H-pyrrolo-[2,3-b] pyridine radicals, replace or unsubstituted thiazolyl, replace or unsubstituted imidazole radicals, replace or do not replace the De oxazolyl, replace or unsubstituted isoxazolyl, replace or unsubstituted pyrazolyl, replace or unsubstituted isothiazolyl, replace or unsubstituted cyclohexyl, replace or unsubstituted morpholino, replace or unsubstituted piperidyl or replacement or unsubstituted tetrahydro pyridyl.
4. chemical compound as claimed in claim 3 is characterized in that R 1Be phenyl, furyl, pyrrole radicals, thiophenyl or benzo thiophenyl, separately randomly by one or more R 21Substituent group replaces, wherein R 21Be independently
(1) halogen ,-CN ,-OR 22,-C (O) R 23,-NR 24R 25,-S (O) wNR 26R 27Or-S (O) wR 28, wherein w is the integer of 0-2, R 22, R 23, R 24, R 25, R 26, R 27And R 28Be hydrogen, alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyl-alkyl, Heterocyclylalkyl-alkyl, aryl alkyl or heteroaryl alkyl independently, randomly replaced by unsubstituted alkyl, unsubstituted assorted alkyl, unsubstituted cycloalkyl, unsubstituted Heterocyclylalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl-alkyl, unsubstituted Heterocyclylalkyl-alkyl, unsubstituted aryl alkyl or unsubstituted heteroaryl alkyl; Or
(2) (C 1-C 10) the assorted alkyl of alkyl, 2-10 unit, C 3-C 8Cycloalkyl, 3-8 unit Heterocyclylalkyl, aryl or heteroaryl, randomly by halogen ,-OH ,-CN ,-NH 2, unsubstituted alkyl, unsubstituted assorted alkyl, unsubstituted cycloalkyl, unsubstituted Heterocyclylalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl-alkyl, unsubstituted Heterocyclylalkyl-alkyl, unsubstituted aryl alkyl or unsubstituted heteroaryl alkyl replace.
5. chemical compound as claimed in claim 4 is characterized in that R 1Be phenyl at a position and para-orientation, or the phenyl of a position and a position replacement.
6. chemical compound as claimed in claim 5 is characterized in that R 21Be halogen or-OR 22
7. chemical compound as claimed in claim 6 is characterized in that R 21Be fluorine, R 22Be hydrogen or methyl.
8. chemical compound as claimed in claim 1 is characterized in that q is 1.
9. chemical compound as claimed in claim 1 is characterized in that z is 1.
10. chemical compound as claimed in claim 1 is characterized in that R 2Be halogen ,-OH ,-CN ,-NH 2, unsubstituted alkyl, unsubstituted assorted alkyl, unsubstituted cycloalkyl, unsubstituted Heterocyclylalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl-alkyl, unsubstituted Heterocyclylalkyl-alkyl, unsubstituted aryl alkyl or unsubstituted heteroaryl alkyl.
11. chemical compound as claimed in claim 1 is characterized in that, R 2Be halogen or unsubstituted alkyl.
12. chemical compound as claimed in claim 1 is characterized in that, R 2Be fluorine or unsubstituted C 1-C 4Alkyl.
13. chemical compound as claimed in claim 1 is characterized in that, R 3Be halogen ,-OH ,-CN ,-NH 2, unsubstituted alkyl, unsubstituted assorted alkyl, unsubstituted cycloalkyl, unsubstituted Heterocyclylalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl-alkyl, unsubstituted Heterocyclylalkyl-alkyl, unsubstituted aryl alkyl or unsubstituted heteroaryl alkyl.
14. chemical compound as claimed in claim 1 is characterized in that, R 3It is unsubstituted alkyl.
15. chemical compound as claimed in claim 1 is characterized in that, R 3Be unsubstituted C 1-C 4Alkyl.
16. chemical compound as claimed in claim 1 is characterized in that, R 4Be halogen ,-OH ,-CN ,-NH 2, alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyl-alkyl, Heterocyclylalkyl-alkyl, aryl alkyl or heteroaryl alkyl.
17. chemical compound as claimed in claim 1 is characterized in that, R 2And R 3Be unsubstituted C independently 1-C 4Alkyl; R 4Be NH 2Q is 1; With z be 1.
18. chemical compound as claimed in claim 1 is characterized in that, L 1Be to replace or unsubstituted alkylidene.
19. chemical compound as claimed in claim 1 is characterized in that, L 1Be to replace or unsubstituted alkynylene.
20. chemical compound as claimed in claim 1 is characterized in that, L 1Be to replace or unsubstituted methylene, replacement or unsubstituted ethylidene, replacement or unsubstituted propylidene, replacement or unsubstituted butylidene, replacement or unsubstituted ethynylene or replacement or unsubstituted inferior third-2-alkynes.
21. chemical compound as claimed in claim 20 is characterized in that, R 1Be-CN ,-OR 5,-NR 7R 8, R 21-replacement or unsubstituted cycloalkyl, R 21-replacement or unsubstituted aryl, R 21-replacement or unsubstituted heteroaryl, R 21-replace or unsubstituted C 1-C 4Alkyl, wherein
R 21Be halogen ,-OR 22,-NR 24R 25Or unsubstituted C 1-C 4Alkyl and
R 5, R 7, R 8, R 22, R 24And R 25Be hydrogen or unsubstituted C independently 1-C 4Alkyl.
22. pharmaceutical composition that comprises chemical compound as claimed in claim 1 and pharmaceutically acceptable excipient.
23. one kind is reduced the kinase catalytic active method of PI3-, described method comprises makes described PI3-kinases combine the contacted step of antagonist with the affine pocket of PI3-kinases of active reduction amount.
24. method as claimed in claim 23 is characterized in that, described antagonist is the affine pocket quinazolone of a PI3-kinases antagonist.
25. method as claimed in claim 23 is characterized in that, the PI3-kinases is a p110 δ kinases.
26. one kind is reduced the kinase catalytic active method of PI3-, described method comprises the contacted step of chemical compound of the following general formula that makes described PI3-kinases and active reduction amount:
Figure A200780012368C00061
In the formula,
Q is the integer of 0-5;
Z is the integer of 0-10;
X is=CH-or=N-;
L 1Be key, replacement or unsubstituted alkylidene, replacement or unsubstituted assorted alkylidene, replacement or unsubstituted ring alkylidene, replacement or unsubstituted heterocycle alkylidene, replacement or unsubstituted arlydene or replacement or unsubstituted heteroarylidene;
R 1And R 2Be independently halogen ,-CN ,-OR 5,-S (O) nR 6,-NR 7R 8,-C (O) R 9, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl, wherein n is the integer of 0-2 independently;
R 3And R 4Be independently hydrogen, halogen ,-CN ,-OR 5,-S (O) nR 6,-NR 7R 8,-C (O) R 9, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 5Be independently hydrogen ,-C (O) R 10, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 6Be independently hydrogen ,-NR 11R 12, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl, if wherein n is 1 or 2, R then 6Not hydrogen;
R 7Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently;
R 8Be independently hydrogen ,-S (O) nR 13,-C (O) R 14, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 9Be independently-NR 15R 16, hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 10Be independently hydrogen ,-NR 17R 18, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 14Be independently hydrogen ,-NR 19R 20, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl; With
R 11, R 12, R 13, R 15, R 16, R 17, R 18, R 19And R 20Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently.
27. the method to the disease of the object treatment p110 δ kinase activity mediation of this treatment of needs, described method comprises that the affine pocket of PI3-kinases that gives described object treatment effective dose is in conjunction with antagonist.
28. method as claimed in claim 27 is characterized in that, described antagonist is the affine pocket quinazolone of a PI3-kinases antagonist.
29. method as claimed in claim 27 is characterized in that, described disease is hematologic malignancies, inflammation, autoimmune disease or cardiovascular diseases.
30. method as claimed in claim 27 is characterized in that, described disease is hematologic malignancies or autoimmune disease.
31. method as claimed in claim 27 is characterized in that, described disease is acute myeloid leukemia, chronic granulocytic leukemia, mastocytosis, chronic lymphocytic leukemia, multiple myeloma or myelodysplastic syndrome.
32. method as claimed in claim 27 is characterized in that, described disease is rheumatoid arthritis, systemic lupus erythematosus (sle) or asthma.
33. the method to the disease of the object treatment p110 δ kinase activity mediation of this treatment of needs, described method comprises the chemical compound of the following general formula that gives described object treatment effective dose:
Figure A200780012368C00081
In the formula,
Q is the integer of 0-5;
Z is the integer of 0-10;
X is=CH-or=N-;
L 1Be key, replacement or unsubstituted alkylidene, replacement or unsubstituted assorted alkylidene, replacement or unsubstituted ring alkylidene, replacement or unsubstituted heterocycle alkylidene, replacement or unsubstituted arlydene or replacement or unsubstituted heteroarylidene;
R 1And R 2Be independently halogen ,-CN ,-OR 5,-S (O) nR 6,-NR 7R 8,-C (O) R 9, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl, wherein n is the integer of 0-2 independently;
R 3And R 4Be independently hydrogen, halogen ,-CN ,-OR 5,-S (O) nR 6,-NR 7R 8,-C (O) R 9, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 5Be independently hydrogen ,-C (O) R 10, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 6Be independently hydrogen ,-NR 11R 12, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl, wherein, if n is 1 or 2, R then 6Not hydrogen;
R 7Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently;
R 8Be independently hydrogen ,-S (O) nR 13,-C (O) R 14, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 9Be independently-NR 15R 16, hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 10Be independently hydrogen ,-NR 17R 18, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 14Be independently hydrogen ,-NR 19R 20, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl; With
R 11, R 12, R 13, R 15, R 16, R 17, R 18, R 19And R 20Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently.
34. the method destroying leukocyte function or destroy the osteoclast function, described method comprise described leukocyte or described osteoclast are contacted in conjunction with antagonist with the affine pocket of PI3-kinases of function destruction amount.
35. method as claimed in claim 34 is characterized in that, described antagonist is the affine pocket quinazolone of a PI3-kinases antagonist.
36. the method destroying leukocyte function or destroy the osteoclast function, described method comprise described leukocyte or described osteoclast are contacted with the chemical compound of the following general formula of function destruction amount:
Figure A200780012368C00101
In the formula,
Q is the integer of 0-5;
Z is the integer of 0-10;
X is=CH-or=N-;
L 1Be key, replacement or unsubstituted alkylidene, replacement or unsubstituted assorted alkylidene, replacement or unsubstituted ring alkylidene, replacement or unsubstituted heterocycle alkylidene, replacement or unsubstituted arlydene or replacement or unsubstituted heteroarylidene;
R 1And R 2Be independently halogen ,-CN ,-OR 5,-S (O) nR 6,-NR 7R 8,-C (O) R 9, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl, wherein n is the integer of 0-2 independently;
R 3And R 4Be independently hydrogen, halogen ,-CN ,-OR 5,-S (O) nR 6,-NR 7R 8,-C (O) R 9, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 5Be independently hydrogen ,-C (O) R 10, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 6Be independently hydrogen ,-NR 11R 12, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl, if wherein n is 1 or 2, R then 6Not hydrogen;
R 7Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently;
R 8Be independently hydrogen ,-S (O) nR 13,-C (O) R 14, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 9Be independently-NR 15R 16, hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 10Be independently hydrogen ,-NR 17R 18, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 14Be independently hydrogen ,-NR 19R 20, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl; With
R 11, R 12, R 13, R 15, R 16, R 17, R 18, R 19And R 20Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl independently.
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