CN1902195A - Modulators of cellular adhesion - Google Patents

Modulators of cellular adhesion Download PDF

Info

Publication number
CN1902195A
CN1902195A CNA2004800398028A CN200480039802A CN1902195A CN 1902195 A CN1902195 A CN 1902195A CN A2004800398028 A CNA2004800398028 A CN A2004800398028A CN 200480039802 A CN200480039802 A CN 200480039802A CN 1902195 A CN1902195 A CN 1902195A
Authority
CN
China
Prior art keywords
compound
aryl
alkyl
independently
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CNA2004800398028A
Other languages
Chinese (zh)
Other versions
CN1902195B (en
Inventor
沈旺
肯尼斯·巴尔
约翰·D·欧斯洛博
钟民
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bausch and Lomb Ireland Ltd
Original Assignee
Sunesis Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sunesis Pharmaceuticals Inc filed Critical Sunesis Pharmaceuticals Inc
Priority to CN201610157969.9A priority Critical patent/CN105820160B/en
Priority claimed from PCT/US2004/036942 external-priority patent/WO2005044817A1/en
Publication of CN1902195A publication Critical patent/CN1902195A/en
Application granted granted Critical
Publication of CN1902195B publication Critical patent/CN1902195B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Abstract

The present invention provides compounds having formula (I): and pharmaceutically acceptable derivatives thereof, wherein R1-R4, n, p, A, B, D, E, L and AR<1> are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of disorders mediated by the CD11/CD18 family of cellular adhesion molecules (e.g., LFA-1).

Description

Modulators of cellular adhesion
Right of priority
60/517,535 the right of priority that the application requires the U.S. Provisional Application of submitting on April 8th, 2,004 60/560,517 and submitted on November 5th, 2003, the full content of described application is merged in this paper as a reference.
Background of invention
The research of carrying out has during the decade in the past helped to illustrate the molecular events of participating in the cells in vivo interphase interaction, particularly relates to mobile and those incidents of activatory of cell in the immunity system.Generally referring to Springer, T.Nature, 1990,346,425-434.Cell surface proteins, particularly cell adhesion molecule (" CAM ") and " white corpuscle integrin (leukointegrins) ", comprise that LFA-1, MAC-1 and gp150.95 (being called CD18/CD11a, CD18/CD11b and CD18/CD11c) have correspondingly become the theme of medicament research and development, purpose is to intervene white corpuscle and spills into the process that infringement position and white corpuscle move to different targets.For example, thought at present before the white corpuscle as the pressure component of inflammatory response overflows, the activation of structural expression integrin on white corpuscle, follow by integrin (as, LFA-1) between the cell-cell adhesion molecule (ICAM) different with one or more closely ligand/receptor interact, the cell-cell adhesion molecule is appointed as on the vascular endothelial cell surface and the ICAM-1 that expresses on other white corpuscle, ICAM-2, ICAM-3 or ICAM-4.The interaction of CAM and white corpuscle integrin is the bring into normal play committed step of function of immunity system.Think cytotoxicity that immunologic process such as antigen presentation, T are cell-mediated and white corpuscle overflow all need by with the cell adhesion of the interactional ICAM mediation of white corpuscle integrin.Generally referring to Kishimoto, T.K.; Rothlein; R.R.Adv.Pharmacol.1994,25,117-138 and Diamond, M., Springer, T., CurrentBiology, 1994,4,506-532.
Significantly, because the effect of interaction in immunne response of CAM and white corpuscle integrin, expectation is regulated these specificitys and is interacted, to realize desired therapeutic effect (as, inhibitory phase mutual effect in the situation of overactive immunne response).Importantly, verifiedly can realize by medicine at arbitrary component to interactional antagonistic action between CAM and the white corpuscle integrin.Particularly, CAM such as for example ICAM-1 or white corpuscle integrin are suppressed inflammatory response such as for example LFA-1 effectively at any one or two kinds of blocking-up in these molecules.The inflammation that is suppressed by the antibody of CAM or white corpuscle integrin and the external model of immunne response comprise antigen or mitogen inductive lymphopoiesis, lymphocytic homotypic aggregation, cell-mediated cytolysis and the antigen-specific inductive tolerance of T.The dependency of in vitro tests has obtained the support of use at the in vivo test of the antibody of ICAM-1 or LFA-1.For example, at the antibody of LFA-1 can prevent thyroid transplantation repel and prolong the allograft of mouse cardiac survival (Gorski, A., Immunology Today, 1994,15,251-255).More meaningfully, antibody at ICAM-1 has shown as usefulness (Rothlein in the body of the antiphlogiston in human diseases such as kidney allograft repulsion and the rheumatoid arthritis, R.R., S charschmidt, L., Adhesion Molecules; Wegner, C.D., Ed.; 1994,1-38, Cosimi, people such as C.B., J.Immunol., 1990,144,4604-4612 and Kavanaugh, A. wait the people, Arthritis Rheum.1994,37,992-1004) with at the antibody of LFA-1 in bone marrow transplantation with prevent to show immunosuppressive action (Fischer in the early stage repulsion of kidney allograft, A. wait people, Lancet, 1989,2,1058-1060 and Le Mauff, people such as B., Transplantation, 1991,52,291-295).
As mentioned above, after deliberation anti-LFA-1 or this interactional application of anti-ICAM-1 antibody antagonism.In addition, after deliberation LFA-1 or ICAM-1 peptide, fragment or peptide antagonists (referring to for example United States Patent (USP) 5,149,780,5,288,854,5,340,800,5,424,399,5,470,953, open WO90/03400, WO90/13316 of PCT, WO90/10652, WO91/19511, WO92/03473, WO94/11400, WO95/28170, JP4193895, EP314863, EP362526, EP362531) and the small molecules antagonist.For example, described in the literature and influenced CAM and the interactional several small molecules of white corpuscle integrin.Discovery from Trichilia rubra root isolating natural product cell in vitro in conjunction with the test in have inhibition (Musza, people such as L.L., Tetrahedron, 1994,50,11369-11378).Find a series of molecule (Boschelli, people such as D.H., J.Med.Chem., 1994,37,717 and Boschelli, D.H. wait people, J.Med.Chem., 1995,38,4597-4614) in reverse passive Arthus reaction, have Orally active, reverse passive Arthus reaction is to be the induction type inflammatory model (Chang of feature with the neutrophilic granulocyte gathering, Y.H. wait people, Eur.J.Pharmacol., 1992,69,155-164).Also find another serial molecule in the delayed type hypersensitivity of rat, have Orally active (Sanfilippo, people such as P.J., J.Med.Chem., 1995,38,1057-1059).It is non-specific working that all these molecules appear, perhaps by suppressing ICAM-1 and other proteinic transcribing, perhaps work by the mechanism inhibition white corpuscle integrin activation of the unknown, and none seems the interaction of direct antagonism CAM and white corpuscle integrin at intramolecularly.
Obviously, though after deliberation several compounds be used for the treatment of application, still need to develop the interactional new therapy that can regulate between CAM and the white corpuscle integrin.Particularly, the expectation exploitation interactional therapy that can be used as the therapeutical agent of immunity and/or inflammatory diseases between target (the preferred inhibition) LFA-1 and the ICAM-1 optionally.
Summary of the invention
As mentioned above, still need exploitation can regulate interactional new therapy between CAM and the white corpuscle integrin.The invention provides the new compound of general formula (I),
Figure A20048003980200291
And pharmaceutical compositions, as common description and subclass in this article, this compound can be used as the conditioning agent of the CD11/CD18 family of cell adhesion molecule.Therefore, it is diseases related that these compounds can be used for for example treating multiple LFA-1, comprises immunity and/or inflammatory diseases.
In yet another aspect, the invention provides the method for treatment by any disease of the CD11/CD18 family mediation of cell adhesion molecule, this method comprises the compound of the present invention to the main body drug treatment significant quantity that needs are arranged.
Definition
As used in this article, term " aliphatic " comprises saturated and undersaturated straight chain (that is, non-side chain) or branched chain aliphatic hydrocarbons, and it is optional to be replaced by one or more functional groups.As understood by a person skilled in the art, " aliphatic " is intended to include but not limited to alkyl, thiazolinyl, alkynyl part in this article.Therefore, as used in this article, term " alkyl " comprises the alkyl of straight chain and side chain.Similarly convention is applicable to that other generic term is as " thiazolinyl ", " alkynyl " or the like.In addition, as used in this article, term " alkyl ", " thiazolinyl ", " alkynyl " etc. comprise substituted and unsubstituted group.In certain embodiments, as used in this article, " low alkyl group " is used to represent to have those alkyl (substituted, unsubstituted, side chain or non-side chain) of about 1-6 carbon atom.
In certain embodiments, be used for alkyl of the present invention, thiazolinyl and alkynyl and comprise about 1-20 aliphatic carbon atom.In some other embodiment, be used for alkyl of the present invention, thiazolinyl and alkynyl and comprise about 1-10 aliphatic carbon atom.In other embodiments, be used for alkyl of the present invention, thiazolinyl and alkynyl and comprise about 1-8 aliphatic carbon atom.In other embodiments, be used for alkyl of the present invention, thiazolinyl and alkynyl and comprise about 1-6 aliphatic carbon atom.In other embodiments, be used for alkyl of the present invention, thiazolinyl and alkynyl and comprise about 1-4 aliphatic carbon atom.Therefore, exemplary aliphatic group includes but not limited to for example methyl, ethyl, n-propyl, sec.-propyl, allyl group, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, sec.-amyl sec-pentyl secondary amyl, isopentyl, tert-pentyl, n-hexyl, Sec-Hexyl part or the like, and it can have one or more substituting groups in addition.Thiazolinyl includes but not limited to for example vinyl, propenyl, butenyl, 1-methyl-2-butene-1-base etc.Representational alkynyl includes but not limited to ethynyl, 2-propynyl (propargyl), 1-proyl etc.
As used in this article, term " alicyclic " is meant the compound of the character that has made up aliphatics and ring compound, it includes but not limited to compound cycloalkyl monocyclic or polycyclic aliphatic hydrocarbon and bridge joint, and it is chosen wantonly and is replaced by one or more functional groups.As understood by a person skilled in the art, " alicyclic " is intended to include but not limited to cycloalkyl, cycloalkenyl group and cycloalkynyl radical part in this article, and it is chosen wantonly and is replaced by one or more functional groups.Therefore, exemplary alicyclic radical for example include but not limited to cyclopropyl ,-CH 2-cyclopropyl, cyclobutyl ,-CH 2-cyclobutyl, cyclopentyl ,-CH 2-cyclopentyl, cyclohexyl ,-CH 2-cyclohexyl, cyclohexenyl ethyl, cyclohexyl ethyl, norcamphyl part etc., it can have one or more substituting groups in addition.
As used in this article, term " alkoxyl group " or " alkyl oxy " are meant saturated (that is O-alkyl) or undersaturated (that is, O-thiazolinyl and the O-alkynyl) group that is connected with parent molecular moiety by Sauerstoffatom.In certain embodiments, alkyl comprises about 1-20 aliphatic carbon atom.In some other embodiment, alkyl comprises about 1-10 aliphatic carbon atom.In other embodiments, be used for alkyl of the present invention and comprise about 1-8 aliphatic carbon atom.In other embodiments, alkyl comprises about 1-6 aliphatic carbon atom.In other embodiments, alkyl comprises about 1-4 aliphatic carbon atom.The example of alkoxyl group includes but not limited to methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, neopentyl oxygen, positive hexyloxy etc.
As used in this article, term " sulfenyl alkyl " is meant saturated (that is S-alkyl) or unsaturated (that is, S-thiazolinyl and the S-alkynyl) group that is connected with parent molecular moiety by sulphur atom.In certain embodiments, alkyl comprises about 1-20 aliphatic carbon atom.In some other embodiment, alkyl comprises about 1-10 aliphatic carbon atom.In other embodiments, be used for alkyl of the present invention and comprise about 1-8 aliphatic carbon atom.In other embodiments, alkyl comprises about 1-6 aliphatic carbon atom.In other embodiments, alkyl comprises about 1-4 aliphatic carbon atom.The example of sulfenyl alkyl includes but not limited to methyl sulfenyl, ethyl sulfenyl, propyl group sulfenyl, sec.-propyl sulfenyl, normal-butyl sulfenyl etc.
Term " alkylamino " is meant the group with structure-NHR ', wherein the alkyl that just defining for this paper of R '.Term " aminoalkyl group " is meant to have structure NH 2R '-group, the alkyl that just defining for this paper of R ' wherein.In certain embodiments, alkyl comprises about 1-20 aliphatic carbon atom.In some other embodiment, alkyl comprises about 1-10 aliphatic carbon atom.In other embodiments, be used for alkyl of the present invention and comprise about 1-8 aliphatic carbon atom.In other embodiments, alkyl comprises about 1-6 aliphatic carbon atom.In other embodiments, alkyl comprises about 1-4 aliphatic carbon atom.The example of alkylamino includes but not limited to methylamino, ethylamino, sec.-propyl amino etc.
Substituent some example of above-mentioned aliphatic (and other) part of compound of the present invention include but not limited to aliphatic, alicyclic, assorted aliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, assorted alkylaryl, miscellaneous alkyl aryl, assorted miscellaneous alkyl aryl, alkoxyl group, aryloxy, assorted alkoxyl group, heteroaryloxy, alkyl sulfenyl, artyl sulfo, assorted alkyl sulfenyl, heteroaryl sulfenyl, F, Cl, Br, I ,-OH ,-NO 2,-CN ,-CF 3,-CH 2CF 3,-CHCl 2,-CH 2OH ,-CH 2CH 2OH ,-CH 2NH 2,-CH 2SO 2CH 3,-C (O) R x,-CO 2(R x) ,-CON (R x) 2,-OC (O) R x,-OCO 2R x,-OCON (R x) 2,-N (R x) 2,-S (O) 2R x,-NR x(CO) R x, R wherein xWhen occurring, include but not limited to aliphatic independently at every turn, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl, wherein as mentioned above and aliphatic as described herein, alicyclic, assorted aliphatic, heterocyclic, alkylaryl, or in the miscellaneous alkyl aryl substituting group any can be substituted or unsubstituted, side chain or non-side chain, saturated or undersaturated, and wherein as mentioned above and as described herein any in aryl or the heteroaryl substituting group can be substituted or unsubstituted.Usually applicable substituent other example is by the specific embodiments explanation shown in the described embodiment herein.
Usually, as used in this article, term " aromatic series part " is meant stable monocycle or polycyclic, preferably has a unsaturated part of 3-14 carbon atom, its each can be substituted or unsubstituted.In certain embodiments, term " aromatic series part " is meant at each annular atoms and has perpendicular to the p-track of plane of a loop and satisfy that the πDian Zi number is the planar rings of the Huckel's rule of (4n+2) (wherein n is an integer) in the ring wherein.Do not satisfy in these aromaticity standards one or whole monocycle or many rings, unsaturated part is defined as in this article is " non-aromatic ", and be included in the term " alicyclic ".
Usually, as used in this article, term " heteroaromatic part " is meant monocycle or the unsaturated part of polycyclic that preferably has 3-14 carbon atom, it can be substituted or unsubstituted separately, and in ring, (that is, replace ring carbon atom) and comprise that at least one is selected from the heteroatoms of O, S and N.In certain embodiments, term " heteroaromatic part " is meant such planar rings, and it comprises at least one heteroatoms, has perpendicular to the p-track of plane of a loop and the πDian Zi number of satisfied wherein ring at each annular atoms is the Huckel's rule of (4n+2) (wherein n is an integer).
Should also be appreciated that, as defined herein, the aromatic series part can be connected by alkyl or assorted moieties with the heteroaromatic part, therefore also comprise-(alkyl) aromatic series part ,-(assorted alkyl) aromatic series part ,-(assorted alkyl) heteroaromatic part ,-(assorted alkyl) heteroaromatic part.Therefore, as used in this article, phrase " aromatic series or heteroaromatic part " and " aromatic, heteroaromatic ,-(alkyl) aromatic ,-(assorted alkyl) aromatic ,-(assorted alkyl) heteroaromatic and-(assorted alkyl) heteroaromatic " be interchangeable.Substituting group includes but not limited to cause to form any in the aforementioned substituting group of mentioning of stable compound, that is, be used for the described substituting group of aliphatic portion or be used for the substituting group of other parts disclosed herein.
As used in this article, the not obviously difference of its ordinary meaning of this term is meant the unsaturated cyclic part that comprises at least one aromatic nucleus in term " aryl " and this area.In certain embodiments, " aryl " is meant monocycle or the bicyclic carbocyclic system with one or two aromatic nucleus, and it includes but not limited to phenyl, naphthyl, tetralyl, 2,3-indanyl, indenyl etc.
As used in this article, the not obviously difference of its ordinary meaning of this term is meant the ring-type aromatic group with five to ten annular atomses in term " heteroaryl " and this area, and one of them annular atoms is selected from S, O and N; Zero, one or two annular atoms are the other heteroatoms that is independently selected from S, O and N, and remaining annular atoms is a carbon, this group is connected with the rest part of molecule via any annular atoms, such as for example, pyridyl, pyrazinyl, pyrimidyl, pyrryl, pyrazolyl, imidazolyl, thiazolyl, _ azoles base, different _ the azoles base, thiadiazolyl group, _ di azoly, thienyl, furyl, quinolyl, isoquinolyl, or the like.
Should be appreciated that, aryl and heteroaryl (comprising bicyclic aryl) can be unsubstituted or substituted, wherein replace to comprise with including but not limited to any or a plurality of one or more hydrogen atoms of replacing independently above it in the lower section: aliphatic, alicyclic, assorted aliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, assorted alkylaryl, miscellaneous alkyl aryl, assorted miscellaneous alkyl aryl, alkoxyl group, aryloxy, assorted alkoxyl group, heteroaryloxy, the alkyl sulfenyl, artyl sulfo, assorted alkyl sulfenyl, the heteroaryl sulfenyl, F, Cl, Br, I,-OH,-NO 2,-CN ,-CF 3,-CH 2CF 3,-CHCl 2,-CH 2OH ,-CH 2CH 2OH ,-CH 2NH 2,-CH 2SO 2CH 3,-C (O) R x,-CO 2(R x) ,-CON (R x) 2,-CO (O) R x,-OCO 2R x,-OCON (R x) 2,-N (R x) 2,-S (O) R x,-S (O) 2R x,-NR x(CO) R x, R wherein xWhen occurring, include but not limited to aliphatic independently at every turn, alicyclic, assorted aliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl, or assorted miscellaneous alkyl aryl, wherein as mentioned above and described herein any aliphatic, alicyclic, assorted aliphatic, heterocyclic, alkylaryl, or the substituting group of miscellaneous alkyl aryl can be substituted or unsubstituted, side chain or non-side chain, saturated or undersaturated, and wherein as mentioned above and described herein any aromatic, heteroaromatic, aryl, heteroaryl,-(alkyl) aryl or-(alkyl) heteroaryl substituting group can be substituted or unsubstituted.In addition, should be appreciated that any two adjacent groups can be represented 4,5,6 or 7 yuan substituted or unsubstituted alicyclic part or heterocyclic moiety together.Usually applicable substituent other example is by the specific embodiments explanation shown in the described embodiment herein.
As used in this article, term " cycloalkyl " is meant to have three to seven particularly, the group of preferred three to ten carbon atoms.The cycloalkyl that is fit to includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc., as aliphatic, alicyclic, in the situation of assorted aliphatic portion or heterocyclic moiety, it can randomly be substituted the base replacement, and substituting group includes but not limited to: aliphatic, alicyclic, assorted aliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, assorted alkylaryl, miscellaneous alkyl aryl, assorted miscellaneous alkyl aryl, alkoxyl group, aryloxy, assorted alkoxyl group, heteroaryloxy, the alkyl sulfenyl, artyl sulfo, assorted alkyl sulfenyl, the heteroaryl sulfenyl, F, Cl, Br, I,-OH,-NO 2,-CN ,-CF 3,-CH 2CF 3,-CHCl 2,-CH 2OH ,-CH 2CH 2OH ,-CH 2NH 2,-CH 2SO 2CH 3,-C (O) R x,-CO 2(R x) ,-CON (R x) 2,-CO (O) R x,-OCO 2R x,-OCON (R x) 2,-N (R x) 2,-S (O) 2R x,-NR x(CO) R x, R wherein xWhen occurring, include but not limited to aliphatic independently at every turn, alicyclic, assorted aliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl, wherein as mentioned above and aliphatic as described herein, alicyclic, assorted aliphatic, heterocyclic, alkylaryl, or in the miscellaneous alkyl aryl substituting group any can be substituted or unsubstituted, side chain or non-side chain, saturated or undersaturated, and wherein as mentioned above and as described herein any in aryl or the heteroaryl substituting group can be substituted or unsubstituted.Usually applicable substituent other example is by the specific embodiments explanation shown in the described embodiment herein.
As used in this article, term " assorted aliphatics " is meant that one or more carbon atoms in the main chain wherein are by the displaced aliphatic portion of heteroatoms.Therefore, assorted aliphatic group is meant the aliphatic chain of the oxygen, sulphur, nitrogen, phosphorus or the Siliciumatom that comprise one or more replacement carbon atoms.Assorted aliphatic portion can be straight or branched, saturated or undersaturated.In certain embodiments, assorted aliphatic portion is substituted by the one or more hydrogen atoms on it are replaced with the one or more parts that include but not limited in the following substituting group independently: aliphatic, alicyclic, assorted aliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, alkoxyl group, aryloxy, assorted alkoxyl group, heteroaryloxy, alkyl sulfenyl, artyl sulfo, assorted alkyl sulfenyl, heteroaryl sulfenyl, F, Cl, Br, I ,-OH ,-NO 2,-CN ,-CF 3,-CH 2CF 3,-CHCl 2,-CH 2OH ,-CH 2CH 2OH ,-CH 2NH 2,-CH 2SO 2CH 3,-C (O) R x,-CO 2(R x) ,-CON (R x) 2,-CO (O) R x,-OCO 2R x,-OCON (R x) 2,-N (R x) 2,-S (O) 2R x,-NR x(CO) R x, R wherein xWhen occurring, include but not limited to aliphatic independently at every turn, alicyclic, assorted aliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl, wherein as mentioned above and aliphatic as described herein, alicyclic, assorted aliphatic, heterocyclic, alkylaryl, or in the miscellaneous alkyl aryl substituting group any can be substituted or unsubstituted, side chain or non-side chain, saturated or undersaturated, and wherein as mentioned above and as described herein any in aryl or the heteroaryl substituting group can be substituted or unsubstituted.Usually applicable substituent other example is by the specific embodiments explanation shown in the described embodiment herein.
As used in this article, term " Heterocyclylalkyl ", " heterocycle " or " heterocyclic " are meant the compound of the character that has made up heterolipid fat compounds of group and ring compound, it includes but not limited to have saturated and the unsaturated monocycle or the polycyclic loop systems of 5-16 atom, wherein at least one annular atoms is the heteroatoms (wherein nitrogen and sulfur heteroatom can be chosen wantonly oxidized) that is selected from O, S and N, and wherein loop systems is optional is replaced by one or more functional groups as defined herein.In certain embodiments, term " Heterocyclylalkyl ", " heterocycle " or " heterocyclic " is meant that wherein at least one annular atoms is for being selected from O, 5 of the heteroatomic non-aromatic of S and N (wherein nitrogen and sulfur heteroatom can be chosen wantonly oxidized), 6 or 7 yuan of rings or many cyclic groups, it includes but not limited to two or three cyclic groups, comprise that having one to three is independently selected from oxygen, the heteroatomic fused six-membered rings of sulphur and nitrogen, wherein (i) each 5 yuan of ring have 0 to 2 two key, each 6 yuan of ring has 0 to 2 two key, has 0 to 3 two key with each 7 yuan of ring, (ii) nitrogen and sulfur heteroatom can be chosen wantonly oxidized, (iii) nitrogen heteroatom can be chosen wantonly by quaternized and (iv) any above-mentioned heterocyclic ring and can be fused to aryl or heteroaryl ring.Representational heterocycle includes but not limited to various heterocycles, as furyl, thio-furan base (thiofuranyl), pyranyl, pyrryl, thienyl, pyrrolidyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, piperidyl, piperazinyl, _ azoles base, _ oxazolidinyl, different _ the azoles base, different _ oxazolidinyl, two _ azoles base, thiadiazolyl group, _ di azoly, tetrazyl, triazolyl, the thiatriazole base, _ triazolyl, thiadiazolyl group, _ di azoly, morpholinyl, thiazolyl, thiazolidyl, isothiazolyl, the isothiazole alkyl, the dithiazole base, the dithiazole alkyl, tetrahydrofuran base, with their the thick and analog derivative of benzo.In certain embodiments, used " substituted heterocycle; or Heterocyclylalkyl or heterocycle " base, as used in this article, it is meant heterocycle as defined above, or Heterocyclylalkyl or heterocyclic group, on these groups one, two or three hydrogen atoms are included but not limited to that following substituting group replaces: aliphatic, alicyclic, assorted aliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, assorted alkylaryl, miscellaneous alkyl aryl, assorted miscellaneous alkyl aryl, alkoxyl group, aryloxy, assorted alkoxyl group, heteroaryloxy, the alkyl sulfenyl, artyl sulfo, assorted alkyl sulfenyl, the heteroaryl sulfenyl, F, Cl, Br, I,-OH,-NO 2,-CN ,-CF 3,-CH 2CF 3,-CHCl 2,-CH 2OH ,-CH 2CH 2OH ,-CH 2NH 2,-CH 2SO 2CH 3,-C (O) R x,-CO 2(R x) ,-CON (R x) 2,-CO (O) R x,-OCO 2R x,-OCON (R x) 2,-N (R x) 2,-S (O) 2R x,-NR x(CO) R x, R wherein xWhen occurring, include but not limited to aliphatic independently at every turn, alicyclic, assorted aliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl, wherein as mentioned above and aliphatic as described herein, alicyclic, assorted aliphatic, heterocyclic, alkylaryl, or in the miscellaneous alkyl aryl substituting group any can be substituted or unsubstituted, side chain or non-side chain, saturated or undersaturated, and wherein as mentioned above and aromatic as described herein, heteroaromatic, in the substituting group of aryl or heteroaryl any can be substituted or unsubstituted.Usually applicable substituent other example is by the specific embodiments explanation shown in the described embodiment herein.
In addition, should be appreciated that, as mentioned above and described herein any alicyclic part or heterocyclic moiety can comprise and its condensed aryl or heteroaryl moieties.Usually applicable substituent other example is by the specific embodiments explanation shown in the described embodiment herein.
As used in this article, term " halo " and " halogen " are meant the atom that is selected from fluorine, chlorine, bromine and iodine.
Term " haloalkyl " expression has the alkyl as defined above of one, two or three coupled halogen atom, and it illustrates by group such as chloro methyl, bromoethyl, trifluoromethyl etc.
As used in this article, term " amino " is meant primary amine (NH 2), secondary amine (NHR x), tertiary amine (NR xR y) or quaternary amine (N +R xR yR z), R wherein x, R yAnd R zBe aliphatic as defined herein, alicyclic, assorted aliphatic portion, heterocyclic, aromatic series part or heteroaromatic part independently.Amino example includes but not limited to methylamino, dimethylamino, ethylamino, diethylamino, diethylamino carbonyl, methylethyl amino, sec.-propyl amino, piperidino-(1-position only), trimethylammonium amino and propyl group amino.
As used in this article, term " acyl group " is meant that (=O) the group of R, wherein R is aliphatic, alicyclic, assorted aliphatic portion, heterocyclic, aromatic series part or heteroaromatic part as defined herein to general formula-C.
As used in this article, term " sulfoamido " is meant general formula-SO 2NR xR yGroup, R wherein xAnd R yBe hydrogen or aliphatic, alicyclic, assorted aliphatic portion, heterocyclic, aromatic series part, heteroaromatic part or acyl moiety independently for defining herein.
As used in this article, term " benzoylamino " is meant general formula PhNR x-group, R wherein xFor hydrogen or be aliphatic, alicyclic, assorted aliphatic portion, heterocyclic, aromatic series part, heteroaromatic part or the acyl moiety of definition herein.
As used in this article, term " C 1-6Alkylidene group " be meant and include only carbon and hydrogen atom, have a saturated divalent radical that substituted or unsubstituted, the straight or branched of free valency "-" all arranged to six carbon atom, at the two ends of group.
As used in this article, term " C 2-6Alkenylene " be meant and include only carbon and hydrogen atom, have the two unsaturated divalent radicals that substituted or unsubstituted, the straight or branched of free valency "-" all arranged to six carbon atom, at the group two ends; wherein degree of unsaturation only exists with two key forms, and wherein two key may reside between the rest part of first carbon of chain and molecule.
As used in this article, term " aliphatic ", " assorted aliphatic ", " alkyl ", " thiazolinyl ", " alkynyl ", " assorted alkyl ", " assorted thiazolinyl ", " assorted alkynyl " etc. comprise the group of substituted and unsubstituted, saturated and undersaturated, straight chain and side chain.Similarly, term " alicyclic ", " heterocyclic ", " Heterocyclylalkyl ", " heterocycle " etc. comprise substituted and unsubstituted, saturated and undersaturated group.In addition, term " cycloalkyl ", " cycloalkenyl group ", " cycloalkynyl radical ", " Heterocyclylalkyl ", " heterocycloalkenyl ", " heterocycle alkynyl ", " aromatic ", " heteroaromatic ", " aryl ", " heteroaryl " etc. comprise substituted and unsubstituted group.
Term used herein " protecting group ", be meant concrete functional group as, O, S or N are sealed temporarily, make optionally to react at another reactive site of polyfunctional compound.In preferred embodiments, protecting group is optionally reacted with good yield, and obtaining for calculated reaction is stable protected substrate; Protecting group must optionally be removed with good yield by reagent nontoxic, other functional group of not attack that obtain easily, preferred; Protecting group forms segregative derivative (more preferably not producing new three-dimensional center); Protecting group has minimum other functionality, to avoid other response location.As describing in detail, can use oxygen, sulphur, nitrogen and carbon protecting group herein.For example, as describing in detail, in certain embodiments, use some exemplary oxygen protecting group herein.These oxygen protecting groups include but not limited to methyl ether, substituted methyl ether (as, MOM (methoxymethyl ether), MTM (methyl sulfenyl methyl ether), BOM (benzyl oxygen ylmethyl ether), PMBM or MPM (to methoxy-benzyl oxygen ylmethyl ether) only give some instances); Substituted ethyl ether, substituted benzylic ether, silyl ether (as, TMS (trimethyl silyl ether), TES (triethylsilyl ether), TIPS (triisopropyl silyl ether), TBDMS (t-butyldimethylsilyl ether), tribenzyl silyl ether, TBDPS (t-butyldiphenylsilyl ether) only give some instances); Ester (as, manthanoate, acetic ester, benzoic ether (Bz), trifluoro-acetate, dichloro acetic acid ester only give some instances), carbonic ether, cyclic acetal and ketal.In some other exemplary, use nitrogen-protecting group.These nitrogen-protecting groups include but not limited to carbamate (comprise Urethylane, ethyl ester and substituted urethanum (as, Troc), only give some instances); Acid amides, cyclic imide derivative, N-alkyl and N-arylamines, imine derivative and enamine derivates only give some instances.Some other exemplary protecting group describes in detail in this article, yet, should be appreciated that the present invention does not plan to be subject to these protecting groups; On the contrary, use the standard of using among above-mentioned and the present invention can easily determine the protecting group of multiple other equivalence.In addition, the kinds of protect base is at " the Protective Groups in Organic Synthesis " third edition, Greene, T.W. and Wuts, P.G., Eds., John Wiley ﹠amp; Sons describes among the New York:1999, and its full content is merged in this paper as a reference.
As used in this article, term " natural amino acid " is meant that any that find is common in naturally occurring protein, naturally occurring L-amino acid: glycine (Gly), L-Ala (Ala), Xie Ansuan (Val), leucine (Leu), Isoleucine (Ile), Methionin (Lys), arginine (Arg), Histidine (His), proline(Pro) (Pro), Serine (Ser), Threonine (Thr), phenylalanine (Phe), tyrosine (Tyr), tryptophane (Trp), Aspartic Acid (Asp), L-glutamic acid (Glu), asparagine (Asn), glutamine (Gln), halfcystine (Cys) and methionine(Met) (Met).
As used in this article, term " non-natural amino acid " is meant all amino acid that is not natural amino acid.This for example comprise α-, β-, D-, L-amino-acid residue and general formula Compound, wherein side chain R is different from naturally occurring amino acid whose side chain.
In general, as used in this article, term " amino acid " comprises natural amino acid and non-natural amino acid.
As used in this article, term " bioisostere (bioisostere) " general reference has two or more compounds or the part of similar shape of molecule and/or volume.In certain embodiments, bioisostere has approximately uniform electron distributions.In some other embodiment, bioisostere shows similar biological.In preferred embodiments, bioisostere has similar shape of molecule and volume; Has approximately uniform electron distributions; And show similar biological.
As used in this article, when being applied to compound of the present invention, term " isolating " is meant that this compound is isolating and/or (ii) produce by hand, prepare or make by the people from some component at least relevant in essence with them or when they are produced for (i).
As used in this article, the salt of any pharmacologically acceptable salt, ester or this ester of this compound of term " pharmaceutically useful derivative " expression, or any other adducts or derivative, they can provide (directly or indirectly) the described compound in other places or its metabolite or residue herein to patient's administration the time.Therefore, pharmaceutically acceptable derivative especially comprises prodrug.Prodrug is the derivative of compound, and it has significantly reduced pharmacological activity usually, and it comprises other responsive part and is used for being removed in vivo to obtain the parent molecule as pharmacological active substance.The example of prodrug is an ester, and it is cracking in vivo, obtains compound of interest.The prodrug of multiple compound, to be used for the parent compound derivatize be known with material and the method that produces prodrug, and can be suitable for the present invention.Following this paper discusses some exemplary pharmaceutical compositions and pharmaceutically acceptable derivative in more detail.
As used in this article, term " pharmacologically acceptable salt " is meant that those salt are suitable for the human and zootic tissue of contact and do not have over-drastic toxicity, stimulation, transformation reactions etc. in rational medical judgment scope, and has rational benefit/risk ratio.The pharmacologically acceptable salt of the compound of amine, carboxylic acid and other type is for well known to a person skilled in the art.For example people such as S.M.Berge at J.Pharmaceutical Sciences, describes pharmacologically acceptable salt in detail among the 66:1-19 (1977), and described document is merged in this paper as a reference.Salt can original place preparation in the last separation of The compounds of this invention and purge process, or individually by with free alkali or free acid functional group and the reagent react preparation that is fit to, as following general description.For example, can be with free alkali functional group and the acid-respons that is fit to.In addition, when compound of the present invention had acidic moiety, its pharmacologically acceptable salt that is fit to can comprise metal-salt such as an alkali metal salt, as sodium salt or sylvite; Alkaline earth salt such as calcium salt or magnesium salts.The example of pharmaceutically useful, nontoxic acid salt is the amino salt that forms with mineral acid example hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid and perchloric acid, or the salt that forms with organic acid such as acetate, oxalic acid, toxilic acid, tartrate, citric acid, succsinic acid or propanedioic acid, or the salt by other method used in the art such as ion-exchange formation.Other pharmacologically acceptable salt comprises adipate, alginates, ascorbate salt, aspartate, benzene sulfonate, benzoate, hydrosulfate, borate, butyrates, camphorate, camsilate, Citrate trianion, cyclopentane propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxyethanesulfonic acid salt, lactobiose hydrochlorate (lactobionate), lactic acid salt, lauroleate, dodecyl sulfate, malate, maleate, malonate, methane sulfonates, the 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, embonate, pectate (pectinate), persulphate, 3-phenylpropionic acid salt, phosphoric acid salt, picrate, pivalate, propionic salt, stearate, succinate, vitriol, tartrate, thiocyanate-, tosilate, the undecane hydrochlorate, valerate, or the like.Representational an alkali metal salt or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium, or the like.In addition, when suitable, pharmacologically acceptable salt comprises nontoxic ammonium salt, quaternary ammonium and uses counterion such as the amine positively charged ion of halogen ion, hydroxide radical, carboxylate radical, sulfate radical, phosphate radical, nitrate radical, low price alkyl azochlorosulfonate and the formation of aryl sulfonic acid root.
As used in this article, term " pharmaceutically acceptable ester " is meant the ester of hydrolysis in vivo, and is included in human body content destructible to obtain those of parent compound or its salt.The ester group that is fit to for example comprises derived from those of pharmaceutically acceptable aliphatic carboxylic acid, particularly alkanoic acid, olefin(e) acid, naphthenic acid and docosandioic acid, and wherein each alkyl or alkenyl part advantageously has and is no more than 6 carbon atoms.The example of concrete ester comprises manthanoate, acetic ester, propionic ester, butyric ester, acrylate and ethyl succinate.
As used in this article, term " pharmaceutically useful prodrug " is meant those prodrugs of compound of the present invention, it is suitable for the human and zootic tissue of contact and does not cause over-drastic toxicity, stimulation, transformation reactions etc. in rational medical judgment scope, has rational benefit/danger ratio, with be effectively for their intended purpose, and may the time the zwitterionic form of compound of the present invention.Term " prodrug " is meant the compound that for example is converted into parent compound shown in the following formula in vivo by hydrolysis in blood rapidly.Comprehensively discuss at T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, among the Vol.14 ofthe A.C.S.Symposium Series and at Edward B.Roche, ed., BioreversibleCarriers in Drug Design, American Pharmaceutical Association and Pergamon Press provide in 1987, and the both is merged in this paper as a reference.
As used in this article, term " disease of LFA-1 mediation " generally is meant the pathological state that is interacted and caused by the cell adhesion that involves the LFA-1 acceptor on the lymphocyte.The example of this disease includes but not limited to T cell inflammatory response such as inflammatory dermatosis, comprises psoriatic; Relevant with inflammatory bowel reply (as Crohn disease and ulcerative colitis); The adult respiratory distress syndrome; Dermatitis; Meningitis; Encephalitis; Uveitis; Allergy situation such as eczema and asthma; Other situation of replying with the infiltration that relates to the T cell and chronic inflammatory; Skin hypersensitivity (comprising toxicodendron and poison oak); Atherosclerosis; White corpuscle adhesion defective; Autoimmune disease such as rheumatoid arthritis, systemic lupus erythematous (SLE), diabetes, multiple sclerosis, Reynaud ' s syndromes, autoimmune thyroiditis, experimental autoimmune encephalomyelitis, house Glenn syndromes, type i diabetes, juvenile onset diabetes; Typically in pulmonary tuberculosis, sarcoidosis, polymyositis, granulomatosis and vasculitis, find by the cytokine immunne response relevant with the Delayed Hypersensitivity of T cell mediated; Pernicious anemia; Relate to the disease that white corpuscle oozes out; Disease and all types of transplanting of the multiple organ injury syndromes of CNS inflammatory diseases, septicemia or wound secondary, autoimmune hemolytic anemia, myasthenia gravis (myethamia gravis), antigen-antibody complex mediation comprise and transplant anti-host disease or the anti-transplantation disease of host.
As used in this article, the described herein compound of the present invention of term " LFA-1 antagonist " general reference, it plays the effect as CD11a and/or CD18 and ICAM-1, ICAM-2 or the interactional competitive inhibitor of ICAM-3.
As used in this article, term " treatment " is meant that generally compound of the present invention can be used for the mankind or animal, is used for the tentative diagnosis of disease at least.Compound of the present invention will postpone or slow down the progress of disease, thereby prolong the individual life-span.
As used in this article, term " prevention " is meant that generally compound of the present invention can be used for the administration to the patient, and described patient also is not diagnosed as when administration may suffer from this disease but usually expectation will develop into this disease or be in the danger that increases day by day of this disease.In certain embodiments, compound of the present invention slows down the development of symptom, postpones the outbreak of disease or prevents individual development to become this disease fully.
As used in this article, term " biological sample " includes but not limited to cell culture or its extract; Derive from animal vivisection material or its extract of (as, Mammals); With blood, saliva, urine, ight soil, seminal fluid, tears or other body fluid, or its extract.For example, term " biological sample " be meant derive from any living organism or by the sample of its drainage or any solid or liquid of excretory, living organism comprises that unicellular microorganism (as bacterium and yeast) and multicellular organism are (as plant and animal, as vertebrates or Mammals, particularly healthy or outwardly like healthy human subject or be subjected to be diagnosed or the situation studied or the human patients of sickness influence).Biological sample can be any form, comprises solid material such as tissue, cell, cell granule, cell extract, cell homogenates or cell fraction; Or vivisection or biofluid.Biofluid can derive from any position (as blood, saliva (or comprising mouthful collutory of cheek cell), tears, blood plasma, serum, urine, bile, cerebrospinal fluid, amniotic fluid, peritoneal fluid, and Pleural fluid, or derive from wherein cell, moisture or vitreous humor, or any health juice), transudate, the secretory product fluid of abscess or any other infection or inflammation position (as derive from), or derive from the joint (as natural joint or be subjected to disease such as rheumatoid arthritis, osteoarthritis, the joint of gout or septic arthritis influence) fluid.Biological sample can derive from any organ or tissue (comprising vivisection or necrotomy sample) and maybe can comprise cell (primary cell or culturing cell) or be suitable for any, tissue or the substratum of organ.Biological sample can comprise that also tissue slice is as being used for the obtained freezing microtome section of histology purpose.Biological sample also comprises by the mixture of the biomolecules of the partially or completely classification generation of cell or tissue homogenate, comprises protein, lipid, carbohydrate and nucleic acid.Though preferred sample is taken from the human subject, biological sample can derive from any animal, plant, bacterium, virus, yeast etc.As used in this article, term animals is meant the human and inhuman animal that is in any one etap, comprises for example Mammals, bird, Reptilia, Amphibians, fish, worm and unicellular.Cell culture and biological tissue sample are considered to many animals.In some exemplary, the non-human animal be Mammals (as, rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, ox, primate or pig).Animal can be transgenic animal or human cloned.If expectation, biological sample can pass through roughing, comprises preliminary isolation technique.
Some description of Preferred Embodiments of the present invention
The invention provides the interactional compound between the white corpuscle integrin family that regulates adhesion molecule in the born of the same parents (as, ICAM-1 ,-2 and-3) and acceptor.In certain embodiments, compound of the present invention is an antagonist, and can be used for treating the disease of CD11/CD18 mediation.In interested especially some embodiment, compound of the present invention can be used for treating the disease of Mac-1 and LFA-1 mediation.In other embodiments, compound can be used for treating the disease of LFA-1 mediation, as inflammatory diseases and autoimmune disease, only gives some instances.
1) general remark of The compounds of this invention
Compound of the present invention comprises the compound of the general formula (I) as following further definition:
Figure A20048003980200441
And pharmaceutically acceptable derivative;
R wherein 1And R 2Be hydrogen, amino acid side chain, aliphatic, alicyclic, assorted aliphatic portion, heterocyclic, aromatic series part or heteroaromatic part independently of one another, perhaps R wherein 1And R 2Be alicyclic part or heterocyclic moiety together, perhaps be together
Figure A20048003980200451
R wherein 1ABe hydrogen, aliphatic, alicyclic, assorted aliphatic portion, heterocyclic, aromatic series part or heteroaromatic part;
R 3Be-C (=O) OR 3A,-C (=O) H ,-CH 2OR 3A,-CH 2O-C (=O)-alkyl ,-C (=O) NH (R 3A) or-CH 2X 0, R wherein 3AWhen occurring, be hydrogen, protecting group, aliphatic, alicyclic, assorted aliphatic portion, heterocyclic, aromatic series part or heteroaromatic part, perhaps R independently at every turn 3AWith R 1Or R 2Form heterocyclic moiety together, wherein X 0For being selected from the halogen of F, Cl, Br or I;
R 4When occurring at every turn independently for hydrogen, halogen ,-CN ,-NO 2, aliphatic, alicyclic, assorted aliphatic portion, heterocyclic, aromatic series part or heteroaromatic part, perhaps be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, R G1And R G2Be hydrogen, aliphatic, alicyclic, assorted aliphatic portion, heterocyclic, aromatic series part or heteroaromatic part independently;
N is the integer of 0-3;
A R1Be aromatic series part, heteroaromatic part, alicyclic part or heterocyclic moiety;
A, B, D and E are connected by singly-bound or two key under the situation that valency allows; Wherein A, B, D and E are C=O, CR at every turn independently when occurring iR Ii, NR i, CR i, N, O, S, S (=O) or SO 2R wherein iWhen occurring at every turn independently for hydrogen, halogen ,-CN ,-NO 2Aliphatic, alicyclic, assorted aliphatic portion, heterocyclic, aromatic series part or heteroaromatic part perhaps are-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, R G1And R G2Be hydrogen, aliphatic, alicyclic, assorted aliphatic portion, heterocyclic, aromatic series part or heteroaromatic part, perhaps R independently iAny two adjacent situations represent alicyclic part, heterocyclic, aromatic series part or heteroaromatic part together;
P is the integer of 0-4; With
L is for existing or for V-W-X-Y-Z, wherein V, W, X, Y and Z when occurring at every turn independently for do not exist, C=O, NR L1,-O-,-C (R L1)=,=C (R L1)-,-C (R L1) (R L2), C (=N-O-R L1), C (=N-R L1) ,-N=, S (O) 0-2Substituted or unsubstituted C 1-6Alkylidene group or C 2-6The optional independently quilt-C of alkenylene chain, wherein maximum two non-conterminous MU (methylene unit) (=O)-,-CO 2-,-C (=O) C (=O)-,-C (=O) NR L3-,-OC (=O)-,-OC (=O) NR L3-,-NR L3NR L4-,-NR L3NR L4C (=O)-,-NR L3C (=O)-,-NR L3CO 2-,-NR L3C (=O) NR L4-,-S (=O)-,-SO 2-,-NR L3SO 2-,-SO 2NR L3-,-NR L3SO 2NR L4-,-O-,-S-or-NR L3-replace; R wherein L3And R L4When occurring, be hydrogen, alkyl, assorted alkyl, aromatic series part, heteroaromatic part or acyl group independently at every turn; Perhaps aliphatic, alicyclic, assorted aliphatic portion, heterocyclic, aromatic series part or heteroaromatic part; And R L1And R L2When occurring, be hydrogen, hydroxyl, protected hydroxyl, amino, protected amino, sulfenyl, protected sulfenyl, halogen, cyano group, isocyanic ester, carboxyl, carboxyalkyl, formyl radical, methanoyl, azido-, nitro, urea groups, thioureido, thiocyano, alkoxyl group, aryloxy, sulfydryl, sulfoamido, benzoylamino, tosyl group independently at every turn; or aliphatic, alicyclic, assorted aliphatic portion, heterocyclic, aromatic series part or heteroaromatic part, the perhaps R that occurs of one or many wherein L1And R L2Form alicyclic part or heterocyclic moiety or form aromatic series part or heteroaromatic part together or with one of V, W, X, Y or Z.In yet another aspect, the invention provides the compound of formula (II):
Wherein AR has a following structure:
Or
And pharmaceutically acceptable derivative;
R wherein 1, R 2, R 3, R 4, A, B, D, E, n, p be generally aforesaid and the definition described in classification and the subclass in this article; With
Y 1, Y 2And Y 3Be CR independently of one another 4Or N;
Condition is, when AR is following structure
Figure A20048003980200471
Or
Figure A20048003980200472
Y wherein 1Be CH or N, and p is 0-2,
R then 4Be not carbocyclic ring, aryl, heteroaryl or heterocycle, and A, B, D and E do not comprise isocyclic part, aryl, heteroaryl or heterocyclic moiety.
In certain embodiments, for the compound of formula (II), AR represents to have the part of one of following structure:
Figure A20048003980200473
Wherein each n that occurs is the integer of 0-6; R 4When occurring, be hydrogen, halogen, CN, isocyanic ester, NO independently at every turn 2,-P (=O) (YR P5) 2, alkyl, cycloalkyl, assorted alkyl, heterocyclic moiety, or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, and R G1And R G2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic moiety independently.Y is key or O at every turn independently when occurring; R P5When occurring, be alkyl, assorted alkyl, aryl or heteroaryl independently at every turn, perhaps when Y is O, R P5Also can be hydrogen, and R 4AWhen occurring, be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic moiety or nitrogen-protecting group independently at every turn; R wherein 4And R 4AAny twice adjacent appearance can form cycloalkyl, heterocyclic, aryl or heteroaryl together.In some exemplary embodiment, AR has following structure:
Figure A20048003980200482
In other exemplary, AR has following structure:
Figure A20048003980200483
X wherein 0Be the halogen that is selected from F, Cl, Br and I independently when occurring at every turn.
In certain embodiments, X 0When occurring Cl at every turn.
The many important subclass of each aforementioned classification is worth mentions that separately these subclasses comprise the subclass of aforementioned classification, wherein:
I) R 1And R 2Be independently of one another hydrogen, amino acid side chain ,-(CH 2) mOH ,-(CH 2) mAryl ,-(CH 2) mHeteroaryl (wherein m is 0-6) ,-CH (R 1A) (OR 1B) ,-CH (R 1A) (NHR 1B), U-T-Q or optional alkyl, cycloalkyl, assorted alkyl or the heterocyclic moiety that is replaced by U-T-Q, wherein U for do not exist ,-O-,-S (O) 0-2-,-SO 2N (R 1A) ,-N (R 1A)-,-N (R 1A) C (=O)-,-N (R 1A) C (=O)-O-,-N (R 1A) C (=O)-N (R 1B)-,-N (R 1A)-SO 2-,-C (=O)-,-C (=O)-O-,-O-C (=O)-, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl ,-C (=O)-N (R 1A)-,-O-C (=O)-N (R 1A)-,-C (=N-R 1E)-,-C (=N-R 1E)-O-,-C (=N-R 1E)-N (R 1A)-,-O-C (=N-R 1E)-N (R 1A)-,-N (R 1A) C (=N-R 1E)-,-N (R 1A) C (=N-R 1E)-O-, N (R 1A) C (=N-R 1E)-N (R 1B)-,-P (=O) (OR 1A)-O-or-P (=O) (R 1A)-O-; Wherein T for do not exist, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part and wherein Q be hydrogen, halogen, cyano group, isocyanic ester ,-OR 1B,-SR 1B-N (R 1B) 2,-NHC (=O) OR 1B,-NHC (=O) N (R 1B) 2,-NHC (=O) R 1B,-NHSO 2R 1B,-NHSO 2N (R 1B) 2,-NHSO 2NHC (=O) OR 1B,-NHC (=O) NHSO 2R 1B,-C (=O) NHC (=O) OR 1B,-C (=O) NHC (=O) R 1B,-C (=O) NHC (=O) N (R 1B) 2,-C (=O) NHSO 2R 1B,-C (=O) NHSO 2N (R 1B) 2,-C (=S) N (R 1B) 2,-SO 2R 1B,-SO 2-O-R 1B,-SO 2-N (R 1B) 2,-SO 2-NHC (=O) OR 1B,-SO 2-NHC (=O)-N (R 1B) 2,-SO 2-NHC (=O) R 1B,-O-C (=O) N (R 1B) 2,-O-C (=O) R 1B,-O-C (=O) NHC (=O) R 1B,-O-C (=O) NH-SO 2R 1B,-O-SO 2R 1B, or alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl or heteroaryl moieties, perhaps R wherein 1And R 2Be the cycloalkyl heterocyclic moiety together, perhaps be together
R wherein 1AAnd R 1BWhen occurring at every turn independently for hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl or heteroaryl moieties ,-COR 1C, or-CONR 1CR 1DR wherein 1CAnd R 1DWhen occurring, be hydrogen, hydroxyl or alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl or heteroaryl moieties independently at every turn; And R 1EFor hydrogen, aliphatic, alicyclic, assorted aliphatic portion, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part ,-CN ,-OR 1C,-NR 1CR 1DOr-SO 2R 1C
Ii) R 3Be carboxyl, protected carboxyl or its prodrug, wherein R 3Be C (=O) R 3A, R wherein 3ABe hydroxyl, alkoxyl group, cycloalkyloxy, aralkoxy, the aromatic ring alkoxyl group, aryloxy, alkyl-carbonyl oxygen base alkyl oxy, the alkoxy-carbonyl oxy alkyl oxy, alkoxy carbonyl alkyl oxygen base, naphthene base carbonyl oxygen base alkyl oxy, cyclo alkoxy carbonyl oxygen base alkyl oxy, the cyclo alkoxy carbonyl alkyl oxy, aryl carbonyl oxygen base alkyl oxy, aryl carbonyl oxygen oxygen base alkyl oxy, aryl carbonyl oxygen base alkyl oxy, alkoxyalkyl ketonic oxygen base alkyl oxy, one of or following structure:
Figure A20048003980200501
Iii) R 3Be-C (=O) OR 3A,-C (=O) H ,-CH 2OR 3A,-CH 2O-C (=O)-alkyl ,-C (=O) NH (R 3A) or-CH 2X 0R wherein 3AWhen occurring, be hydrogen, protecting group, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently at every turn, or R 3AWith R 1Or R 2Form heterocyclic moiety together; X wherein 0For being selected from the halogen of F, Cl, Br or I;
Iv) R 3Be-C (=O) OR 3AR wherein 3ABe hydrogen, protecting group, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part, perhaps R 3AWith R 1Or R 2Form heterocyclic moiety together;
V) R 3Be-C (=O) OR 3AR wherein 3ABe C 1-5Alkyl;
Vi) R 3Be-C (=O) OR 3AR wherein 3ABe C 1-3Alkyl;
Vii) R 3Be-C (=O) OR 3AR wherein 3ABe ethyl;
Viii) R 3Be-C (=O) OR 3AR wherein 3ABe benzyl;
Ix) R 3Be CO 2H;
X) R 3Be-C (=O) OR 3A, R wherein 3AAs above-mentioned subclass ii)-ix) in any one definition ,-C (=O) NHC (R 1) (R 2) R 3For having the part of following structure:
Figure A20048003980200511
Ar wherein 2Be cycloalkyl, heterocyclic, aryl or heteroaryl moieties; And R SBe hydrogen, alkyl, assorted alkyl, aryl, heteroaryl, or be-G 0R G1, G wherein 0For-O-,-S-or-NR G2-, R G1And R G2Be hydrogen, aliphatic, alicyclic, assorted aliphatic portion, heterocyclic, aromatic series part or heteroaromatic part independently;
Xi) wherein-C (=O) NHCH (CO 2R 3A) CH (R S) Ar 2Have following stereochemical above-mentioned subclass x) compound:
Xii) R 3Be-C (=O) OR 3A, R wherein 3AFor as above-mentioned subclass ii)-ix) in any one definition and-C (=O) NHC (R 1) (R 2) R 3For having the part of following structure:
Figure A20048003980200513
R wherein 1ABe Ar 2,-OR 1B,-SR 1BOr-NR 1BR 1COr alkyl or assorted moieties; Ar 2Be cycloalkyl, heterocyclic, aryl or heteroaryl moieties; R wherein 1BAnd R 1CBe hydrogen, alkyl, assorted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, perhaps R independently 1BAnd R 1CThe nitrogen-atoms that connects with them forms heterocyclic moiety or heteroaryl moieties;
Xiii) wherein-C (=O) NHCH (CO 2R 3A) CH 2NHC (=O) R 1AHave following stereochemical above-mentioned subclass xii) compound:
Figure A20048003980200514
Xiv) R 3Be-C (=O) OR 3A, R wherein 3AFor as above-mentioned subclass ii)-ix) in any one definition and-C (=O) NHC (R 1) (R 2) R 3For having the part of following structure:
Figure A20048003980200515
Ar wherein 2Be cycloalkyl, heterocyclic, aryl or heteroaryl moieties; R 2ABe hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl ,-C (=O) R 2BOr-SO 2R 2B, R wherein 2BBe alkyl, cycloalkyl, assorted alkyl, heterocyclic radical, aryl or heteroaryl; Or R 2AWith Ar 2On substituting group form substituted or unsubstituted heterocyclic moiety or heteroaryl moieties together;
Xv) wherein-C (=O) NHCH (CO 2R 3A) CH 2N (R 2A) Ar 2Have following stereochemical above-mentioned subclass xiv) compound:
Figure A20048003980200521
Xvi) R 3Be-C (=O) OR 3A, R wherein 3AFor as above-mentioned subclass ii)-ix) in any one definition and-C (=O) NHC (R 1) (R 2) R 3For having the part of following structure:
R wherein 2ABe hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl, aryl, heteroaryl ,-C (=O) R 2BOr-SO 2R 2B, R wherein 2BBe alkyl, cycloalkyl, assorted alkyl, heterocyclic radical, aryl or heteroaryl; Or R 2AWith R 2COr R 2DForm substituted or unsubstituted heterocyclic moiety or heteroaryl moieties together; R 2CFor hydrogen, CN ,-C=NMe ,=NO 2,=NC (=O) NH 2,=NS (O) 2R ,=NS (O) 2NRR ' ,-SO 2R 2G, or aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part; Wherein R and R ' are hydrogen or methyl independently of one another, R 2GBe low alkyl group; R 2DBe Ar 2, hydrogen, halogen, CN, NO 2, aliphatic, assorted aliphatic, alkylaryl or miscellaneous alkyl aryl part, perhaps be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, R G1And R G2Be hydrogen, aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently;
Xvii) wherein-C (=O) NHCH (CO 2R 3A) CH 2N (R 2A) C (=NR 2C) R 2DHave following stereochemical above-mentioned subclass xvi) compound:
Figure A20048003980200531
Xviii) wherein-C (=O) NHCH (CO 2R 3A) CH 2N (R 2A) C (=NR 2C) R 2DAbove-mentioned subclass xvii with following structure) compound:
R wherein 2EAnd R 2FBe hydrogen or aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part, perhaps R independently of one another 2EAnd R 2FForm substituted or unsubstituted heterocyclic moiety or heteroaryl moieties together;
Xix) wherein-C (=O) NHCH (CO 2R 3A) CH 2N (R 2A) C (=NR 2C) R 2DAbove-mentioned subclass xvii with following structure) compound:
R wherein 2CFor hydrogen, CN ,-C=NMe ,=NO 2,=NC (=O) NH 2,=NS (O) 2R or=NS (O) 2NRR '; Wherein R and R ' are hydrogen or methyl independently of one another;
Xx) wherein-C (=O) NHCH (CO 2R 3A) CH 2N (R 2A) C (=NR 2C) R 2DAbove-mentioned subclass xvii with following structure) compound:
Figure A20048003980200534
R wherein 2CFor hydrogen, CN ,-C=NMe ,=NO 2,=NC (=O) NH 2,=NS (O) 2R or=NS (O) 2NRR '; Wherein R and R ' are hydrogen or methyl independently of one another;
Xxi) wherein-C (=O) NHCH (CO 2R 3A) CH 2N (R 2A) C (=NR 2C) R 2DAbove-mentioned subclass xvii with following structure) compound:
Figure A20048003980200541
Xxii) wherein-C (=O) NHCH (CO 2R 3A) CH 2N (R 2A) C (=NR 2C) R 2DAbove-mentioned subclass xvii with following structure) compound:
Figure A20048003980200542
Xxiii) wherein-C (=O) NHCH (CO 2R 3A) CH 2N (R 2A) C (=NR 2C) R 2DAbove-mentioned subclass xvii with following structure) and compound xviii):
Or its bioisostere;
R wherein 2A, R 2D, R 2EAnd R 2FAs at above-mentioned xvi) and xviii) in definition;
Xxiv) the compound subclass xxiii of bioisostere wherein) with one of following structure:
Figure A20048003980200551
R wherein 2CBe low alkyl group;
Xxv) R wherein 2DFor or R 2EAnd R 2FThe nitrogen-atoms that connects with their forms the above-mentioned subclass xxiii of the part with one of following structure) compound:
Figure A20048003980200552
Wherein s is the integer of O to 6; R P1When occurring, be hydrogen, halogen, CN, isocyanic ester, NO independently at every turn 2,-P (=O) (YR P5) 2, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, R G1And R G2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently; Y is key or O at every turn independently when occurring; R P5When occurring, be alkyl, assorted alkyl, aryl or heteroaryl independently at every turn, perhaps when Y is O, R P5Also can be hydrogen; R P2When occurring, be hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part or nitrogen-protecting group independently at every turn; Wherein any two adjacent R P1And R P2Can form cycloalkyl, heterocyclic, aryl or heteroaryl moieties together;
Xxvi) R wherein 2DFor or R 2EAnd R 2FThe nitrogen-atoms that connects with their forms the above-mentioned subclass xxv of the part with one of following structure) compound:
R wherein P1When occurring at every turn independently for hydrogen, halogen, methyl ,-OCH 3,-OH ,-NH 2,-NHCH 3, or-N (CH 3) 2
Xxvii) R wherein 2DFor or R 2EAnd R 2FThe nitrogen-atoms that connects with their forms the above-mentioned subclass xxvi of the part with one of following structure) compound:
Figure A20048003980200561
Xxviii) R 3Be-C (=O) OR 3A, R wherein 3AFor as above-mentioned subclass ii)-ix) in any one definition ,-C (=O) NHC (R 1) (R 2) R 3For having the part of following structure:
Figure A20048003980200562
Ar wherein 2Be cycloalkyl, heterocyclic, aryl or heteroaryl moieties;
Xxix) xiv subclass x)-xii))-xv) and xxviii) compound; R wherein 2DBe Ar 2Ar wherein 2Subclass xvi for one of following structure) compound:
Figure A20048003980200563
Figure A20048003980200571
Figure A20048003980200581
Wherein s is the integer of 0-6 when occurring at every turn; W is the integer of 0-6; X 1Be CHR P1Or NR P2X 2And X 3Be CHR independently P1, NR P2, CHSO 2R P3Or NSO 2R P3R P1When occurring, be hydrogen, halogen, CN, isocyanic ester, NO independently at every turn 2,-P (=O) (YR P5) 2, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl ,-(aliphatics) aryl or-(aliphatics) heteroaryl moieties or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, R G1And R G2Be independently hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl ,-(aliphatics) aryl or-(aliphatics) heteroaryl moieties; Y is key or O at every turn independently when occurring; R P5When occurring, be alkyl, assorted alkyl, aryl or heteroaryl independently at every turn, perhaps when Y is O, R P5Also can be hydrogen; R P2When occurring, be hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part or nitrogen-protecting group independently at every turn; Wherein any two adjacent R P1And R P2Can form cycloalkyl, heterocyclic, aryl or heteroaryl moieties together; R P3When occurring at every turn independently for alkyl, aryl, heteroaryl or-N (R P2) 2
Xxx) Ar wherein 2Above-mentioned subclass xxix for one of following structure) compound:
Wherein s, X 1, X 2And X 3As above-mentioned xx) in definition; X 5Be O, S or NR P2R P1When occurring, be hydrogen, halogen, CN, isocyanic ester, NO independently at every turn 2,-P (=O) (YR P5) 2, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part, or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, R G1And R G2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently; Y is key or O at every turn independently when occurring; R P5When occurring, be alkyl, assorted alkyl, aryl or heteroaryl independently at every turn, or when Y is O R P5Also can be hydrogen; R P2When occurring, be hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part or nitrogen-protecting group independently at every turn; Wherein any two adjacent R P1And R P2Can form cycloalkyl, heterocyclic, aryl or heteroaryl moieties together; R P3When occurring at every turn independently for alkyl, aryl, heteroaryl or-N (R P2) 2
Xxxi) compound above-mentioned subclass xxx), wherein R P1When occurring at every turn independently for hydrogen, halogen ,-P (=O) (YR P5) 2, low alkyl group or assorted moieties or be-GR G1, wherein G be-O-,-S-,-NR G2-or-SO 2-, R G1And R G2Be hydrogen, low alkyl group or aryl independently; Y is key or O at every turn independently when occurring; R P5When occurring at every turn independently for low alkyl group, or when Y is O R P5Also can be hydrogen; R P2When occurring, be hydrogen, low alkyl group or nitrogen-protecting group independently at every turn; Wherein any two adjacent R P1And R P2Can form cycloalkyl, heterocyclic, aryl or heteroaryl moieties together;
Xxxii) Ar wherein 2Above-mentioned subclass xxx with one of following structure) compound:
Figure A20048003980200592
X wherein 1Be N or CR P1S is the integer of 0-6; R P1When occurring, be hydrogen, halogen, CN, NO independently at every turn 2, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, R G1And R G2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently; R P3Be low alkyl group or aryl independently;
Xxxiii) wherein s is 0 subclass xxix), xxx) and compound xxxii);
Xxxiv) wherein s is the xxix of 1 subclass), xxx) and xxxii) compound;
Xxxv) wherein s is 2 subclass xxix), xxx) and compound xxxii);
Xxxvi) Ar wherein 2Above-mentioned subclass x for one of following structure) and compound xi):
Wherein s is the integer of 0-2; R P1When occurring, be hydrogen, halogen, CN, isocyanic ester, NO independently at every turn 2,-OR G1,-SR G1,-NR G1R G2-, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part; Y is key or O at every turn independently when occurring; R P5When occurring at every turn independently for low alkyl group, or when Y is O R P5Also can be hydrogen; R P2When occurring, be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part or nitrogen-protecting group independently at every turn; R P3For low alkyl group or-N (R P2) 2R G1And R G2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently;
Xxxvii) Ar wherein 2Above-mentioned subclass x for one of following structure) and compound xi):
Figure A20048003980200602
Xxxviii) Ar wherein 2Above-mentioned subclass x for one of following structure) and compound xi):
R wherein P3Be low alkyl group; R P2And R G1Be hydrogen or low alkyl group independently;
Xxxix) Ar wherein 2Above-mentioned subclass x for one of following structure) and compound xi):
R wherein P3Be low alkyl group, R G1Be hydrogen or low alkyl group;
X1) R wherein SBe hydrogen, hydroxyl or lower alkoxy and Ar 2Above-mentioned subclass x for one of following structure) and compound xi):
R wherein P3Be low alkyl group; R G1Be hydrogen or low alkyl group;
Xli) R wherein 1AFor alkyl or-NR 1BR 1CSubclass xii) and compound xiii); R wherein 1BAnd R 1CBe hydrogen or low alkyl group independently;
Xlii) R wherein 1AFor-NH 2Or subclass xii) and compound xiii) with part of following structure:
Figure A20048003980200614
R wherein P1Be hydrogen, hydroxyl, low alkyl group or rudimentary assorted alkyl independently; R P2When occurring, be hydrogen or low alkyl group independently at every turn;
Xliii) R wherein 1AFor-NH 2Or subclass xii) and compound xiii) with part of following structure:
R wherein P1Be hydrogen or low alkyl group;
Xliv) R wherein 1ABe cycloalkyl, aryl or subclass xii with part of one of following structure) and compound xiii):
Figure A20048003980200621
Wherein s is 0 to 6 integer; R P1When occurring, be hydrogen, halogen, CN, isocyanic ester, NO independently at every turn 2,-P (=O) (YR P5) 2, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, R G1And R G2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently; Y is key or O at every turn independently when occurring; R P5When occurring, be alkyl, assorted alkyl, aryl or heteroaryl independently at every turn, or when Y is O R P5Also can be hydrogen; R P2When occurring, be hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part or nitrogen-protecting group independently at every turn; Wherein any two adjacent R P1And R P2Can form cycloalkyl, heterocyclic, aryl or heteroaryl moieties together;
Xlv) compound subclass xliv), wherein s is 0 to 2 integer; R P1When occurring at every turn independently for low alkyl group or be-GR G1, wherein G be-O-or-NR G2-, R G1And R G2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently; R P2When occurring, be hydrogen, low alkyl group, aryl or heteroaryl independently at every turn;
Xlvi) R wherein 1ASubclass xxi for part) and compound xxii) with one of following structure:
Wherein s is 0 to 2 integer; X 0Be halogen; R P1When occurring, be hydrogen, hydroxyl, low alkyl group or rudimentary assorted alkyl independently at every turn; G is-O-or-NR G2-, R G1And R G2Be hydrogen or low alkyl group independently; R P2Be hydrogen or low alkyl group independently;
Xlvii) R wherein 1AXlvi for part) compound of subclass with one of following structure:
Figure A20048003980200632
Wherein G be-O-or-NR G2-, R G1And R G2Be hydrogen or low alkyl group independently;
Xlviii) R 3Be-C (=O) OR 3A, R wherein 3AFor as above-mentioned subclass ii)-ix) in any one definition ,-C (=O) NHC (R 1) (R 2) R 3For having the part of following structure:
R wherein P3Be alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl moieties;
Xlix) wherein-NH (R 2A) Ar 2Above-mentioned subclass xiv with one of following structure)-xv) compound:
；
X wherein 1Be N or CR P1S is the integer of 0-5; R P1When occurring, be hydrogen, halogen, CN, NO independently at every turn 2, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part, or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, R G1And R G2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently; And R P3Be alkyl, assorted alkyl, aryl or heteroaryl;
L) wherein s is 0 above-mentioned subclass xlix) compound;
Li) R wherein P1Above-mentioned subclass xlix for hydrogen, halogen or low alkyl group) compound;
Lii) R wherein P1Above-mentioned subclass li for hydrogen, chloro or methyl) compound;
Liii) R wherein P3Above-mentioned subclass xlix for low alkyl group) compound;
Liv) R wherein P3Above-mentioned subclass liii for methyl) compound;
Lv) wherein-NH (R 2A) Ar 2Above-mentioned subclass xlix with following structure) compound:
Figure A20048003980200641
R wherein P1Be hydrogen, halogen or low alkyl group;
Lvi) wherein-NH (R 2A) Ar 2Above-mentioned subclass xlix with following structure) compound:
Figure A20048003980200642
Lvii) have the subclass xvii of following structure) compound:
Figure A20048003980200643
Or its bioisostere;
R wherein P1When occurring at every turn independently for hydrogen, halogen, methyl ,-OCH 3,-OH ,-NH 2,-NHCH 3Or-N (CH 3) 2R 2ABe hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl, aryl, heteroaryl ,-C (=O) R 2BOr-SO 2R 2B, R wherein 2BBe alkyl, cycloalkyl, assorted alkyl, heterocyclic radical, aryl or heteroaryl; With q be 1 or 2;
Lviii) the compound above-mentioned subclass lvii of bioisostere wherein) with one of following structure:
Figure A20048003980200651
Wherein q is 1 or 2; And R 2CBe low alkyl group;
Lix) wherein-C (=O) NHC (=CHAr 2) CO 2R 3ASubclass xxviii with one of following structure) compound:
R wherein P3Be low alkyl group or aryl; X 1And X 2Be N or CR independently P1X 3Be O, S or NR P2R wherein P1Be hydrogen, halogen, CN, NO 2, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, and R G1And R G2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently; And R P2Be hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part;
Lx) wherein-C (=O) NHC (=CHAr 2) CO 2R 3ASubclass xxviii with following structure) compound
Figure A20048003980200661
X wherein 1Be N or CH;
Lxi) R 3Be-C (=O) OR 3A, R wherein 3AFor as above-mentioned subclass ii)-ix) in any one definition and-C (=O) NHC (R 1) (R 2) R 3Be structure-C (=O) NHC (=C (R S) Ar 2) CO 2R 3A, R wherein 3AAnd R SForm substituted or unsubstituted heterocyclic moiety together;
Lxii) wherein-C (=O) NHC (=C (R S) Ar 2) CO 2R 3ASubclass lxi with one of following structure) compound:
Figure A20048003980200662
Ar wherein 2For as defining in classification and the subclass herein; And X 1Be O, S or NH;
Lxiii) wherein-C (=O) NHC (=C (R S) Ar 2) CO 2R 3ASubclass lxi with one of following structure) compound:
Figure A20048003980200663
X wherein 1Be O, S or NH; And X 2Be N or CH;
Lxiv) L for do not exist ,-C (=O) ,-CH 2C (=O) NH-,-CH 2NH-C (=O)-,-O-CH 2-C (=O)-,-CH 2-CH 2-C (=O)-,-CH=CH-C (=O) NH-CH 2-,-CH (OH)-CH 2-O-,-CH (OH)-CH 2-N (CH 3)-,-CH (OH)-CH 2-CH 2-,-CH 2-CH 2-CH (OH)-,-O-CH 2-CH (OH)-,-O-CH 2-CH (OH)-CH 2-,-O-CH 2-CH 2-CH (OH)-, O-CH 2-CH 2-O-,-CH 2-CH 2-CH 2-O-,-CH 2-CH (OH)-CH 2-O ,-CH 2-CH 2-O-,-CH-(CH 3)-NH-C (=O)-,-CH 2-NH-SO 2-,-NH-SO 2-CH 2-,-CH 2-SO 2-NH-,-SO 2NH-CH 2-,-C (=O)-NH-C (=O)-,-NH-C (=O)-NH-,-NH-C (=O)-NH-CH 2-,-CH 2-NH-C (=O)-NH-,-C (=O)-NH-CH 2-C (=O)-NH ,-NH-C (=O)-O-,-O-C (=O)-NH-, or be substituted or unsubstituted C 1-6Alkylidene group or C 2-6The optional independently quilt-C of alkenylene chain, wherein maximum two non-conterminous MU (methylene unit) (=O)-,-CO 2-,-C (=O) C (=O)-,-C (=O) NR L3-,-OC (=O)-,-OC (=O) NR L3-,-NR L3NR L4-,-NR L3NR L4C (=O)-,-NR L3C (=O)-,-NR L3CO 2-,-NR L3C (=O) NR L4-,-S (=O)-,-SO 2-,-NR L3SO 2-,-SO 2NR L3-,-NR L3SO 2NR L4-,-O-,-S-or-NR L3-replace; R wherein L3And R L4When occurring, be hydrogen, alkyl, assorted alkyl, aryl, heteroaryl or acyl group independently at every turn;
Lxv) L for do not exist ,-C (=O) substituted or unsubstituted C 1-6Alkylidene group or C 2-6The optional independently quilt-C of alkenylene chain, wherein maximum two non-conterminous MU (methylene unit) (=O)-,-CO 2-,-C (=O) C (=O)-,-C (=O) NR L3-,-OC (=O)-,-OC (=O) NR L3-,-NR L3NR L4-,-NR L3NR L4C (=O)-,-NR L3C (=O)-,-NR L3CO 2-,-NR L3C (=O) NR L4-,-S (=O)-,-SO 2-,-NR L3SO 2-,-SO 2NR L3-,-NR L3SO 2NR L4-,-O-,-S-or-NR L3-replace; Wherein R appears at every turn L3And R L4Be hydrogen, alkyl, assorted alkyl, aryl, heteroaryl or acyl group independently;
Lxvi) L is not for existing;
Lxvii) L be-C (=O);
Lxviii) L for do not exist ,-C (=O) ,-CH 2C (=O) NH-,-CH 2NH-C (=O)-,-O-CH 2-C (=O)-,-CH 2-CH 2-C (=O)-,-CH=CH-C (=O) NH-CH 2-,-CH (OH)-CH 2-O-,-CH (OH)-CH 2-N (CH 3)-,-CH (OH)-CH 2-CH 2-,-CH 2-CH 2-CH (OH)-,-O-CH 2-CH (OH)-,-O-CH 2-CH (OH)-CH 2-,-O-CH 2-CH 2-CH (OH)-, O-CH 2-CH 2-O-,-CH 2-CH 2-CH 2-O-,-CH 2-CH (OH)-CH 2-O ,-CH 2-CH 2-O-,-CH-(CH 3)-NH-C (=O)-,-CH 2-NH-SO 2-,-NH-SO 2-CH 2-,-CH 2-SO 2-NH-,-SO 2NH-CH 2-,-C (=O)-NH-C (=O)-,-NH-C (=O)-NH-,-NH-C (=O)-NH-CH 2-,-CH 2-NH-C (=O)-NH-,-C (=O)-NH-CH 2-C (=O)-NH ,-NH-C (=O)-O-or-O-C (=O)-NH-;
Lxix) L is-(CH 2) q-, wherein q is 1-5;
Lxx) L is-CH 2-;
Lxxi) L is-(CH 2) 3-;
Lxxii) L is the part with following structure
Lxxii) AR 1Be one of following structure:
Figure A20048003980200682
Figure A20048003980200691
Wherein r is the integer of 0-6 when occurring at every turn; X 1, X 2, X 3And X 4Be N or CR independently of one another Q1AR 3Be heterocyclic, aryl or heteroaryl moieties; R Q1When occurring, be hydrogen, OR independently at every turn Q3, OCF 3, SR Q3, halogen, CN, isocyanic ester, NO 2, CF 3, NR Q3QR Q4,-SO 2R Q3, alkyl-NR Q3R Q4, alkyl-C (=O)-NR Q3R Q4, alkyl-C (=O) R Q3, or aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part, wherein R Q3And R Q4When occurring at every turn independently for hydrogen, protecting group or be aliphatic, assorted aliphatic, aryl or heteroaryl moieties; R Q2Be hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part or nitrogen-protecting group;
Lxxiv) AR 1Be one of following structure:
Figure A20048003980200701
Wherein r is the integer of 0-6 when occurring at every turn; X 1, X 2, X 3And X 4Be N or CR independently Q1X 5Be O, S or NR Q2AR 3Be heterocyclic, aryl or heteroaryl moieties; R Q1When occurring, be hydrogen, OR independently at every turn Q3, OCF 3, SR Q3, halogen, CN, isocyanic ester, NO 2, CF 3, NR Q3QR Q4,-SO 2R Q3, alkyl-NR Q3R Q4, alkyl-C (=O)-NR Q3R Q4, alkyl-C (=O) R Q3, or aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part, wherein R Q3And R Q4When occurring, be hydrogen, protecting group or aliphatic, assorted aliphatic, aryl or heteroaryl moieties independently at every turn; And R Q2Be hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part or nitrogen-protecting group;
Lxxv) AR 1Be one of following structure:
Figure A20048003980200702
Wherein r is for as defined above; X 1, X 2, X 3And X 4Be N or CH independently; X 5Be CHR Q1Or NH; R Q1When occurring, be hydrogen, OR independently at every turn Q3, OCF 3, SR Q3, halogen, CN, isocyanic ester, NO 2, CF 3, NR Q3QR Q4,-SO 2R Q3, alkyl-NR Q3R Q4, alkyl-C (=O)-NR Q3R Q4, alkyl-C (=O) R Q3, or aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part, wherein R Q3And R Q4When occurring, be hydrogen, protecting group or aliphatic, assorted aliphatic, aryl or heteroaryl moieties independently at every turn; And R Q2Be hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part or nitrogen-protecting group;
Lxxvi) AR 1Be one of following structure:
X wherein 0Be F or Cl; X 2Be N or CR Q1X 5Be CH, O, S or NH; R Q1For hydrogen, methyl ,-CF 3,-OCH 3,-COF 3Or halogen;
Lxxvii) AR 1Be one of following structure:
Lxxviii) AR 1Be one of following structure:
Figure A20048003980200713
Lxxix) AR 1-L-is one of following structure:
Figure A20048003980200714
Lxxx) AR 1-L-is one of following structure:
Figure A20048003980200721
Lxxxi) R 4When occurring at every turn independently for hydrogen, halogen ,-CN ,-NO 2, alkyl, alkylidene group, alkynyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part, or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, R G1And R G2Be hydrogen, alkyl, alkylidene group, alkynyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently;
Lxxxii) R 4When occurring, be hydrogen, halogen or low alkyl group independently at every turn;
Lxxxiii) R 4When occurring, be hydrogen or chloro independently at every turn;
Lxxxiv) n is 0;
Lxxxv) n is 2;
Lxxxvi) n is 2 and R 4It when occurring halogen at every turn;
Lxxxvii) n is 2 and R 4When occurring Cl at every turn;
Lxxxviii) p is 1;
Lxxxix) p is 2; And/or
Xc) compound of formula (II) is wherein at-C (=O) NHC (R 1) (R 2) R 3When having following structure:
Figure A20048003980200722
AR 1Not one of following
Figure A20048003980200723
Y wherein 1Be N or CR Q1X 1, X 2, X 3And X 4Be CR independently Q1X5 is NR Q1, O or S; R is 0-3; R Q1When occurring, be CN, NO independently at every turn 2, halogen, CF 3, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part or be GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-C 0-6Alkyl SO 2-,-C 0-6Alkyl SO 2NR G2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-or-NR G2C (=O)-, R G1And R G2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently.
Should be appreciated that, for above-mentioned and described herein each classification and subclass, aliphatic portion or assorted aliphatic portion can be substituted or unsubstituted, cyclic or acyclic, straight or branched independently when any one or many occurs, aryl, heteroaryl, cycloaliphatic part, the assorted aliphatic portion of ring can be substituted or unsubstituted when any one or many occurs.
The reader be also to be understood that above-mentioned i)-to xc) described in variable (as R especially 1, R 2, R 3, R 4, L and AR 1) all possible combination all be considered part of the present invention.Therefore, the present invention includes and pass through variable R 1, R 2, R 3, R 4, L and AR 1Deng and be used at above-mentioned i)-to xc) described in R 1, R 2, R 3, R 4, L, AR 1Deng other variable/substituting group of further definition (as, X 1, X 2, X 3, X 4, R 1A, R 2A, R 2C, R 2DDeng) take any He all formula I that any possible arrangement produces or the compound of II.
For example, above-mentioned i) to xc) described in the example combinations of variable comprise the compound of those formulas I that wherein meets the following conditions:
R 1And R 2Be independently of one another hydrogen, amino acid side chain ,-(CH 2) mOH ,-(CH 2) mAryl ,-(CH 2) mHeteroaryl (wherein m is 0-6) ,-CH (R 1A) (OR 1B) ,-CH (R 1A) (NHR 1B), U-T-Q, or be optional aliphatic, alicyclic, the assorted aliphatic or assorted alicyclic part that is replaced by U-T-Q, wherein U for do not exist ,-O-,-S (O) 0-2-,-SO 2N (R 1A) ,-N (R 1A)-,-N (R 1A) C (=O)-,-N (R 1A) C (=O)-O-,-N (R 1A) C (=O)-N (R 1B)-,-N (R 1A)-SO 2-,-C (=O)-,-C (=O)-O-,-O-C (=O)-, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl ,-C (=O)-N (R 1A)-,-O-C (=O)-N (R 1A)-,-C (=N-R 1E)-,-C (=N-R 1E)-O-,-C (=N-R 1E)-N (R 1A)-,-O-C (=N-R 1E)-N (R 1A)-,-N (R 1A) C (=N-R 1E)-,-N (R 1A) C (=N-R 1E)-O-, N (R 1A) C (=N-R 1E)-N (R 1B)-,-P (=O) (OR 1A)-O-or-P (=O) (R 1A)-O-; T for do not exist, aliphatic, assorted aliphatic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part; Q be hydrogen, halogen, cyano group, isocyanic ester ,-OR 1B,-SR 1B-N (R 1B) 2,-NHC (=O) OR 1B,-NHC (=O) N (R 1B) 2,-NHC (=O) R 1B,-NHSO 2R 1B,-NHSO 2N (R 1B) 2,-NHSO 2NHC (=O) OR 1B,-NHC (=O) NHSO 2R 1B,-C (=O) NHC (=O) OR 1B,-C (=O) NHC (=O) R 1B,-C (=O) NHC (=O) N (R 1B) 2,-C (=O) NHSO 2R 1B,-C (=O) NHSO 2N (R 1B) 2,-C (=S) N (R 1B) 2,-SO 2R 1B,-SO 2-O-R 1B,-SO 2-N (R 1B) 2,-SO 2-NHC (=O) OR 1B,-SO 2-NHC (=O)-N (R 1B) 2,-SO 2-NHC (=O) R 1B,-O-C (=O) N (R 1B) 2,-O-C (=O) R 1B,-O-C (=O) NHC (=O) R 1B,-O-C (=O) NH-SO 2R 1B,-O-SO 2R 1B, or aliphatic, assorted aliphatic, aryl or heteroaryl moieties, perhaps R wherein 1And R 2Be alicyclic part or heterocyclic moiety together, perhaps be together R wherein 1AAnd R 1BWhen occurring at every turn independently for hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part ,-COR 1C, or-CONR 1CR 1DR wherein 1CAnd R 1DWhen occurring, be hydrogen, hydroxyl or aliphatic, assorted aliphatic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently at every turn; And R 1EFor hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part ,-CN ,-OR 1C,-NR 1CR 1DOr-SO 2R 1C
R 3Be-C (=O) OR 3A,-C (=O) H ,-CH 2OR 3A,-CH 2O-C (=O)-alkyl ,-C (=O) NH (R 3A) ,-CH 2X 0R wherein 3AWhen occurring, be hydrogen, protecting group, aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part or R independently at every turn 3AWith R 1Or R 2Form heterocyclic moiety together; X wherein 0For being selected from the halogen of F, Cl, Br or I;
R 4When occurring at every turn independently for hydrogen, halogen ,-CN ,-NO 2, aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part, or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, R G1And R G2Be hydrogen, aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently;
AR 1Be monocycle or polycyclic aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, alicyclic part or heterocyclic moiety;
A, B, D and E are connected by singly-bound or two key under the situation that valency allows; Wherein A, B, D and E are C=O, CR at every turn independently when occurring iR Ii, NR i, CR i, N, O, S, S (=O) or SO 2R wherein iWhen occurring at every turn independently for hydrogen, halogen ,-CN ,-NO 2, aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part, or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, R G1And R G2Be hydrogen, aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently, perhaps any two adjacent R iRepresent alicyclic part, assorted alicyclic part, aryl or heteroaryl moieties together; With
L is for existing or for V-W-X-Y-Z, wherein V, W, X, Y and Z when occurring at every turn independently for do not exist, C=O, NR L1,-O-,-C (R L1)=,=C (R L1)-,-C (R L1) (R L2), C (=N-O-R L1), C (=N-R L1) ,-N=, S (O) 0-2Substituted or unsubstituted C 1-6Alkylidene group or C 2-6The optional independently quilt-C of alkenylene chain, wherein maximum two non-conterminous MU (methylene unit) (=O)-,-CO 2-,-C (=O) C (=O)-,-C (=O) NR L3-,-OC (=O)-,-OC (=O) NR L3-,-NR L3NR L4-,-NR L3NR L4C (=O)-,-NR L3C (=O)-,-NR L3CO 2-,-NR L3C (=O) NR L4-,-S (=O)-,-SO 2-,-NR L3SO 2-,-SO 2NR L3-,-NR L3SO 2NR L4-,-O-,-S-or-NR L3-replace; R wherein L3And R L4When occurring, be hydrogen, alkyl, assorted alkyl, aryl, heteroaryl or acyl group independently at every turn; Or be aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part; R L1And R L2When occurring, be hydrogen, hydroxyl, protected hydroxyl, amino, protected amino, sulfenyl, protected sulfenyl, halogen, cyano group, isocyanic ester, carboxyl, carboxyalkyl, formyl radical, formyl radical oxygen base, azido-, nitro, urea groups, thioureido, thiocyano, alkoxyl group, aryloxy, sulfydryl, sulfoamido, benzoylamino, tosyl group or aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently, perhaps R wherein at every turn L1And R L2When one or many occurs, together, or form alicyclic part or heterocyclic moiety or form aryl or heteroaryl moieties with one of V, W, X, Y or Z.
Other exemplary combined is illustrated to the compound of XIV by following subclass I:
I) have the compound (and pharmaceutically acceptable derivative) of following structure:
Figure A20048003980200761
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; And R B1, R B2And R EBe the substituted or unsubstituted low alkyl group of hydrogen independently.In certain embodiments, R 4AAnd R 4BCl respectively does for oneself.In other embodiments, R B1And R B2One of be hydrogen, another is substituted or unsubstituted low alkyl group.In some exemplary, R B1And R B2The hydrogen of respectively doing for oneself.In some other exemplary, R B1And R B2The low alkyl group of respectively doing for oneself.In some exemplary, R B1And R B2The methyl of respectively doing for oneself.In other embodiments, R EBe hydrogen.In other embodiments, R EBe substituted or unsubstituted low alkyl group.In other embodiments, R EBe substituted or unsubstituted methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, n-pentyl, sec.-amyl sec-pentyl secondary amyl, tert-pentyl or n-hexyl.In certain embodiments, R 4AAnd R 4BCl respectively does for oneself; And R B1And R B2The hydrogen of respectively doing for oneself.
II) have the compound (and pharmaceutically acceptable derivative) of following structure:
Figure A20048003980200762
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; And R EBe the substituted or unsubstituted low alkyl group of hydrogen.In certain embodiments, R 4AAnd R 4BCl respectively does for oneself.In other embodiments, R EBe hydrogen.In other embodiments, R EBe substituted or unsubstituted low alkyl group.In other embodiments, R EBe substituted or unsubstituted methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, n-pentyl, sec.-amyl sec-pentyl secondary amyl, tert-pentyl or n-hexyl.
III) have the compound (and pharmaceutically acceptable derivative) of following structure:
Figure A20048003980200771
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; And R EBe the substituted or unsubstituted low alkyl group of hydrogen.In certain embodiments, R 4AAnd R 4BCl respectively does for oneself.In other embodiments, R EBe hydrogen.In other embodiments, R EBe substituted or unsubstituted low alkyl group.In other embodiments, R EBe substituted or unsubstituted methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, n-pentyl, sec.-amyl sec-pentyl secondary amyl, tert-pentyl or n-hexyl.
IV) have the compound (and pharmaceutically acceptable derivative) of following structure:
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; And R EBe the substituted or unsubstituted low alkyl group of hydrogen.In certain embodiments, R 4AAnd R 4BCl respectively does for oneself.In other embodiments, R EBe hydrogen.In other embodiments, R EBe substituted or unsubstituted low alkyl group.In other embodiments, R EBe substituted or unsubstituted methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, n-pentyl, sec.-amyl sec-pentyl secondary amyl, tert-pentyl or n-hexyl.
V) have the compound (and pharmaceutically acceptable derivative) of following structure:
Figure A20048003980200773
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; R ABe hydrogen, low alkyl group or acyl group; And R EBe the substituted or unsubstituted low alkyl group of hydrogen.In certain embodiments, R 4AAnd R 4BCl respectively does for oneself.In other embodiments, R EBe hydrogen.In other embodiments, R EBe substituted or unsubstituted low alkyl group.In other embodiments, R EBe substituted or unsubstituted methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, n-pentyl, sec.-amyl sec-pentyl secondary amyl, tert-pentyl or n-hexyl.
VI) have the compound (and pharmaceutically acceptable derivative) of following structure:
Figure A20048003980200781
R wherein 4AAnd R 4B0 independently for being selected from the halogen of F, Cl, Br or I; R A1, R A2, R B1And R B2Be the substituted or unsubstituted low alkyl group of hydrogen independently.In certain embodiments, R 4AAnd R 4BCl respectively does for oneself.In certain embodiments, R A1, R A2, R B1And R B2The hydrogen of respectively doing for oneself.
VII) have the compound (and pharmaceutically acceptable derivative) of following structure:
Figure A20048003980200782
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; And R AAnd R BBe the substituted or unsubstituted low alkyl group of hydrogen independently.In certain embodiments, R 4AAnd R 4BCl respectively does for oneself.In certain embodiments, R AAnd R BThe hydrogen of respectively doing for oneself.
VIII) have the compound (and pharmaceutically acceptable derivative) of following structure:
Figure A20048003980200783
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; And R ABe the substituted or unsubstituted low alkyl group of hydrogen.In certain embodiments, R 4AAnd R 4BCl respectively does for oneself.In certain embodiments, R ABe hydrogen.
IX) have the compound (and pharmaceutically acceptable derivative) of following structure:
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; And R BBe the substituted or unsubstituted low alkyl group of hydrogen.In certain embodiments, R 4AAnd R 4BCl respectively does for oneself.In certain embodiments, R BBe hydrogen.
X) have the compound (and pharmaceutically acceptable derivative) of following structure:
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; And R ABe the substituted or unsubstituted low alkyl group of hydrogen.In certain embodiments, R 4AAnd R 4BCl respectively does for oneself.In certain embodiments, R ABe hydrogen.
XI) have the compound (and pharmaceutically acceptable derivative) of following structure:
Figure A20048003980200793
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; R A, R BAnd R EBe the substituted or unsubstituted low alkyl group of hydrogen independently.In certain embodiments, R 4AAnd R 4BCl respectively does for oneself.In certain embodiments, R AAnd R BThe hydrogen of respectively doing for oneself.In some other embodiment, R EBe hydrogen.In other embodiments, R A, R BAnd R EThe hydrogen of respectively doing for oneself.
XII) have the compound (and pharmaceutically acceptable derivative) of following structure:
Figure A20048003980200801
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; R A, R BAnd R EBe the substituted or unsubstituted low alkyl group of hydrogen independently.In certain embodiments, R 4AAnd R 4BCl respectively does for oneself.In certain embodiments, R AAnd R BThe hydrogen of respectively doing for oneself.In some other embodiment, R EBe hydrogen.In other embodiments, R A, R BAnd R EThe hydrogen of respectively doing for oneself.
XIII) have the compound (and pharmaceutically acceptable derivative) of following structure:
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; With A and B be N or CH independently.In certain embodiments, R 4AAnd R 4BCl respectively does for oneself.In certain embodiments, A is N.In certain embodiments, A is CH.In certain embodiments, B is N.In certain embodiments, A is CH.In certain embodiments, A and the B N that respectively does for oneself.In certain embodiments, A is CH.In certain embodiments, A and the B CH that respectively does for oneself.
XIV) have the compound (and pharmaceutically acceptable derivative) of following structure:
Figure A20048003980200803
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; With A and B be N or CH independently.In certain embodiments, R 4AAnd R 4BCl respectively does for oneself.In certain embodiments, A is N.In certain embodiments, A is CH.In certain embodiments, B is N.In certain embodiments, A is CH.In certain embodiments, A and the B N that respectively does for oneself.In certain embodiments, A is CH.In certain embodiments, A and the B CH that respectively does for oneself.
In certain embodiments, for the compound of above-mentioned classification I-XIV, AR 1-L-is the part with one of following structure:
Figure A20048003980200811
With-C (=O) NHC (R 1) (R 2) R 3For having the part of one of following structure:
Figure A20048003980200812
Or its bioisostere;
R wherein 2AAnd R 3AAs defined in herein classification and the subclass; And R 2DFor having the part of one of following structure:
Figure A20048003980200813
Wherein s is 0 to 6 integer; R P1When occurring, be hydrogen, halogen, CN, isocyanic ester, NO independently at every turn 2,-P (=O) (YR P5) 2, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part, or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, R G1And R G2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently; Y is key or O at every turn independently when occurring; R P5When occurring, be alkyl, assorted alkyl, aryl or heteroaryl independently at every turn, or when Y is O R P5Also can be hydrogen; R P2When occurring, be hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part or nitrogen-protecting group independently at every turn; Wherein any two adjacent R P1And R P2Can form cycloalkyl, heterocyclic, aryl or heteroaryl moieties together.
In certain embodiments, R 2AAnd R 3AThe hydrogen of respectively doing for oneself.
In certain embodiments, R 2DFor having the part of one of following structure:
Figure A20048003980200821
R wherein P1When occurring at every turn independently for hydrogen, halogen, methyl ,-OCH 3,-OH ,-NH 2,-NHCH 3, or-N (CH 3) 2
In certain embodiments, R 2DFor having the part of one of following structure:
Figure A20048003980200822
Be also to be understood that for each above-mentioned subclass I-XIV it is interested especially that multiple other subclass is arranged, it includes but not limited to above-mentioned i)-xc) those classifications and above-mentioned and the classification in the embodiment of this paper, subclass and kind.
Some aforesaid compounds can comprise one or more asymmetric centers, therefore can have a plurality of isomeric forms, as, steric isomer and/or diastereomer.Therefore, compound of the present invention and pharmaceutical compositions thereof can be the form of independent enantiomer, diastereomer or geometrical isomer, perhaps can be the form of the mixture of steric isomer.In certain embodiments, compound of the present invention is the compound of enantiomer-pure.In some other embodiment, provide the mixture of steric isomer or diastereomer.
In addition, some compound as described herein, can have one or more pairs of keys, and unless otherwise indicated, it can be used as Z or E isomer exists.The present invention comprise in addition as the compound of the independent isomer that is substantially free of other isomer or, as the compound of the racemic mixture of the mixture of different isomerization body such as steric isomer.Except above-claimed cpd itself, the present invention also comprise these compounds pharmaceutically acceptable derivative, comprise the composition of one or more compounds of the present invention and one or more pharmaceutically acceptable vehicle or additive.
But compound through type of the present invention (I) or compound (II) be the crystallization preparation under different conditions, and can be used as general formula (I) or a kind of polymorphic form of compound (II) or the combination existence of multiple polymorphic form that forms a part of the present invention.For example, can use the different solvents that is used for recrystallization or the different mixtures of solvent; By under differing temps, carrying out crystallization; By in crystallisation process, using from very identifying and/or prepare different polymorphic forms near the different types of cooling of very slow refrigerative.Also can cool off gradually subsequently or cool off fast and obtain polymorphic form by heating or melting compound.The existence of polymorphic form can be surveyed nuclear magnetic resonance spectroscopy, Infrared spectroscopy, dsc, x-ray diffractogram of powder and/or other technical measurement by solid.Therefore, but the present invention includes compound of the present invention, their derivative, their tautomeric forms, their steric isomer, their polymorphic form, their pharmacologically acceptable salt, their acceptable solvent thing and comprise their pharmaceutical compositions.
2) pharmaceutical compositions
As mentioned above, the invention provides new compound, it has the biological characteristics of the disease that can be used for treating Mac-1 and LFA-1 mediation.
Therefore, provide pharmaceutical compositions in another aspect of the present invention, it comprises any described compound (or its prodrug, pharmacologically acceptable salt or other pharmaceutically acceptable derivative) herein, and randomly comprises pharmaceutically acceptable carrier.In certain embodiments, these compositions randomly comprise the therapeutical agent that one or more are other in addition.Perhaps, the administration of compound of the present invention and one or more other therapeutical agents can be made up the patient's administration that needs having.For example, be used for combining administration with the pharmaceutical compositions of The compounds of this invention or being included in the antiphlogiston that wherein other therapeutical agent can be approval, perhaps it can be experience Food and Drug Administration (U.S. food and Drug Administration) approval and finally gets the Green Light and is used for the treatment of by in many medicines of any disease of Mac-1 or LFA-1 mediation any.Be also to be understood that the free state that some compound of the present invention can be used for the treatment of exists, and perhaps exists as its pharmaceutically acceptable derivative when suitable.
As mentioned above, pharmaceutical compositions of the present invention comprises pharmaceutically acceptable carrier in addition, as used in this article, it comprises any He all solvents, thinner or other liquid medium, dispersion or suspension aids, tensio-active agent, isotonic agent, thickening material or emulsifying agent, sanitas, solid binder, lubricant etc., as long as the concrete formulation that is suitable for expecting.Remington ' sPharmaceutical Sciences, Sixteenth Edition, E.W.Martin (MackPublishing Co., Easton, Pa., 1980) discloses variety carrier and the known technology of preparing that is used to prepare pharmaceutical compositions.Unless the mounting medium of any routine is incompatible with compound of the present invention, as produce any undesirable biological action or with any other component interaction of deleterious mode and pharmaceutical compositions, its application is considered within the scope of the invention.Some examples that can be used as the material of pharmaceutically acceptable carrier include but not limited to carbohydrate, as lactose, dextrose plus saccharose; Starch is as W-Gum and yam starch; Mierocrystalline cellulose and derivative thereof are as Xylo-Mucine, ethyl cellulose and rhodia; Powder dress tragacanth; Fructus Hordei Germinatus; Gelatin; Talcum; Vehicle such as theobroma oil and suppository wax; Oils such as peanut oil, oleum gossypii seminis, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soybean oil; Glycols is as propylene glycol; The ester class is as ethyl oleate and Laurate ethyl; Agar; Buffer reagent such as magnesium hydroxide and aluminium hydroxide; Lalgine; Pyrogen-free water; Isotonic saline solution; Ringer ' s solution; Ethanol and phosphate buffered saline buffer, and other nontoxic compatible lubricant such as sodium lauryl sulphate and Magnesium Stearate, and tinting material, release agent, Drug coating, sweeting agent, seasonings and spices, judgement according to the preparation Designers also can exist sanitas and antioxidant in composition.
The liquid dosage form that is used for oral administration includes but not limited to pharmaceutically useful emulsion, microemulsion, solution, suspension, syrup and elixir.Except that active compound, liquid dosage form can comprise the inert diluent that is generally used in this area, such as for example, the fatty acid ester of water or other solvent, solubilizing agent and emulsifying agent such as ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol, polyoxyethylene glycol and anhydro sorbitol, and composition thereof.Except that inert diluent, oral compositions can also comprise auxiliary agent such as wetting agent, emulsifying agent and suspending agent, sweeting agent, seasonings and spices.
Can use suitable dispersion agent or wetting agent and suspending agent according to technology preparation injectable formulation as known in the art such as aseptic injectable water-based or oily suspensions.Aseptic injectable formulation also can be aseptic injectable solution, suspension or the emulsion in acceptable nontoxic thinner of non-enteron aisle or solvent, for example is the solution in 1,3 butylene glycol.Adoptable acceptable medium and solvent are water, Ringer ' s solution, U.S.P. and isotonic sodium chlorrde solution.In addition, adopt aseptic expressed oil as solvent or suspension medium usually.For this reason, the expressed oil of any gentleness be can adopt, synthetic monoglyceride or triglyceride comprised.In addition, lipid acid such as oleic acid can be used for preparing injectable formulation.
Injectable formulation can be by for example by bacterium detention type strainer filtration sterilization or by sterilizing in conjunction with the disinfectant of the sterilization solids composition form in the injectable medium that can dissolve or be dispersed in sterilized water or other sterilization before using.
For the effect of prolong drug, often expectation delays the absorption of medicine from subcutaneous injection or intramuscularly.This can be by using liquid suspension or having poor water miscible crystallinity or the amorphous substance realization.Then, the uptake rate of medicine depends on its dissolution rate, and dissolution rate can depend on crystallographic dimension and crystalline form again.Perhaps, can be by medicine dissolution or the delay that is suspended in the oil medium medicament forms of realizing parenterai administration be absorbed.Produce injectable depot forms by forming the microcapsule matrix of medicine in biodegradable polymkeric substance such as polylactide-polyglycolic acid.The character that depends on the concrete polymkeric substance of the ratio of medicine and polymkeric substance and employing, speed that can control drug release.The example of other biodegradable polymkeric substance comprises (poly-(ortho ester) and poly-(acid anhydrides).Also by medicine being trapped in preparation depot injectable formulation in liposome compatible or the microemulsion with bodily tissue.
The composition that is used for rectum or vagina administration is preferably suppository, it can be by being mixed with compound of the present invention and the non-irritating vehicle or the carrier that are fit to, vehicle or carrier such as theobroma oil, polyoxyethylene glycol or suppository wax, it is solid in envrionment temperature but is liquid under body temperature, so its fusion and release of active compounds in the chamber of rectum or vagina.
The solid dosage that is used for oral administration comprises capsule, tablet, pill, powder and particle.In this solid dosage, active compound and the pharmaceutically acceptable vehicle of at least a inert or carrier such as Trisodium Citrate or Lin Suanergai and/or a) filler or extender such as starch, lactose, sucrose, glucose, N.F,USP MANNITOL, and silicic acid, b) tackiness agent, such as for example, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic, c) wetting agent such as glycerine, d) disintegrating agent such as agar--agar, lime carbonate, yam starch or tapioca (flour), Lalgine, some silicate, and yellow soda ash, e) solution retarding agent such as paraffin, f) absorption enhancer such as quaternary ammonium compound, g) wetting agent is such as for example cetyl alcohol and glyceryl monostearate, h) sorbent material such as kaolin and wilkinite, and i) lubricant such as talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate, and composition thereof mix.In the situation of capsule, tablet and pill, formulation also can comprise buffer reagent.
The solids composition that also can adopt similar type is as the soft gelatin capsule of the filling of using vehicle such as lactose and high molecular weight polyethylene glycol etc. and the filler in the hard gelatin capsule.Can use that known other dressing prepares tablet, drageeing, capsule, pill and particulate solid dosage in dressing and shell such as enteric coating and the field of pharmaceutical preparations.They optionally comprise opalizer and can for only or preferentially discharge composition of active ingredient in certain part of enteron aisle, optionally discharge with delayed mode.The example of spendable embedding composition comprises polymkeric substance and wax.The solids composition that also can adopt similar type is as the soft gelatin capsule of the filling of using vehicle such as lactose and high molecular weight polyethylene glycol etc. and the filler in the hard gelatin capsule.
Active compound also can be and the micro encapsulation seal form of one or more vehicle as mentioned above.Can use dressing and shell such as enteric coating, discharge that known other dressing prepares tablet, drageeing, capsule, pill and particulate solid dosage in control dressing and the field of pharmaceutical preparations.In this solid dosage, active compound can be mixed with at least a inert diluent such as sucrose, lactose and starch.As in ordinary production, this formulation also can comprise the other material that is different from inert diluent, as, tablet lubricants and other sheet agent aid such as Magnesium Stearate and Microcrystalline Cellulose.In the situation of capsule, tablet and pill, formulation also can comprise buffer reagent.They optionally comprise opalizer and can for only or preferentially discharge composition of active ingredient in certain part of enteron aisle, optionally discharge with delayed mode.The example of spendable embedding composition comprises polymkeric substance and wax.
The present invention includes the pharmaceutically acceptable topical formulations of compound of the present invention.As used in this article, term " pharmaceutically useful topical formulations " is meant by preparation being applied to epidermis and is used for the acceptable any preparation of pharmacy of the intradermal administration of The compounds of this invention.In certain embodiments of the invention, topical formulations comprises carrier system.The effective carrier of pharmacy include but not limited to solvent (as, alcohol, polyalcohols, water), creme, lotion, paste, finish, emplastrum, liposome, powder, emulsion, microemulsion and buffering solution (as, hypotonic salt solution or buffer saline) or this area in become known for any other carrier of the topical of medicine.The more detailed tabulation of carrier as known in the art provides by the reference of standard in this area, Remington ' sPharmaceutical Sciences for example, the 16th edition, 1980 and the 17th editions, 1985, the both is by Mack Publishing Company, Easton, Pa. publish, its disclosure is incorporated into this paper as a reference in full.In some other embodiment, topical formulations of the present invention can comprise vehicle.Can use any pharmaceutically acceptable vehicle as known in the art to prepare pharmaceutically acceptable topical formulations of the present invention.The example that can be included in the vehicle in the topical formulations of the present invention includes but not limited to sanitas, antioxidant, benefit humectant, softener, buffer reagent, solubilizing agent, other permeate agent, skin-protecting agent, tensio-active agent and propelling agent and/or is used for other therapeutical agent with compound combination of the present invention.The sanitas that is fit to includes but not limited to alcohols, quaternary amines, organic acid, parabens and phenols.The antioxidant that is fit to includes but not limited to xitix and ester, sodium bisulfite, Yoshinox BHT, butylated hydroxyanisol, vitamin-E and sequestrant such as EDTA and citric acid.The benefit humectant that is fit to includes but not limited to glycerine, sorbyl alcohol, polyoxyethylene glycol, urea and propylene glycol.The buffer reagent that is fit to that is used for the present invention includes but not limited to the damping fluid of citric acid, hydrochloric acid and lactic acid.The solubilizing agent that is fit to includes but not limited to aliquat, cyclodextrin, peruscabin, Yelkin TTS and polysorbate.The skin-protecting agent that is fit to that can be used in the topical formulations of the present invention includes but not limited to vitamin E oil, wallantoin, Simethicone, glycerine, vaseline and zinc oxide.
In certain embodiments, pharmaceutically acceptable topical formulations of the present invention comprises at least a compound of the present invention and penetration enhancers.Several Factors is depended in the selection of topical formulations, comprises physics-chem characteristic, their stability, obtainable processing unit and cost constraints in preparation of the situation that will treat, compound of the present invention and other vehicle.As used in this article, term " penetration enhancers " is meant can transport pharmacologically active chemical compounds by stratum corneum and enter epidermis or the reagent of corium, and preferably, it has seldom or do not have system to absorb.Estimated the validity that multiple compound is used to strengthen the percutaneous speed of drug osmotic.Referring to for example Percutaneous Penetration Enhancers, Maibach H.I. and Smith H.E. (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), it has investigated the application and the check of various skin penetration enhancers; With people such as Buyuktimkin, Chemical Means ofTransdermal Drug Permeation Enhancement in Transdermal and TopicalDrug Delivery Systems, Gosh T.K., Pfister W.R., Yum S.I. (Eds.), Interpharm Press Inc., Buffalo Grove, Ill. (1997).In some exemplary, be used for permeate agent of the present invention include but not limited to triglyceride level (as, soybean oil), aloe composition (as, the aloe-vera gel), ethanol, Virahol, octoly phenyl polyoxyethylene glycol, oleic acid, poly(oxyethylene glycol) 400, propylene glycol, N-dodecyl methyl sulfoxide, fatty acid ester (as, isopropyl myristate, Laurate methyl, XU 61518.10 and single oleic acid propylene glycol ester) and N-Methyl pyrrolidone.
In certain embodiments, composition can be the form of paste, paste, creme, lotion, gelifying agent, powder, solution, sprays, inhalation or paster.In some exemplary, the preparation of composition of the present invention is a creme, and it can comprise saturated or unsaturated fatty acids such as stearic acid, palmitinic acid, oleic acid, Zoomeric acid, hexadecyl alcohol or oleyl alcohol in addition, preferred especially stearic acid.Creme of the present invention also can comprise nonionic surface active agent, for example polyoxyl-40-stearate.In certain embodiments, active ingredient is mixed with the damping fluid that the sanitas of pharmaceutically acceptable carrier and any needs maybe may need under aseptic condition.Ophthalmic preparation, ear drop and eye drops have also been considered within the scope of the invention.In addition, the present invention has considered the application of percutaneous plaster, and it has provides the additional advantage of compound to the controlled delivery of health.By with compound dissolution or be distributed in the suitable medium and produce this formulation.As mentioned above, penetration enhancers can also be used to increase the flux that compound passes skin.Speed can be by providing rate controlling membranes or being controlled by compound is dispersed in polymeric matrix or the gel.
Should also be appreciated that, compound of the present invention and pharmaceutical compositions can be formulated as and be used for combination therapy, that is to say, compound and pharmaceutical compositions can be prepared with the therapy or the medical treatment of one or more other expectations, or carry out simultaneously with the therapy or the medical care precess of one or more other expectations, administration before or after the therapy of one or more other expectations or medical treatment.The concrete combination therapy (therapy or operation) that is used for scheme for combining will be considered therapy and/or the consistency of operation and the result of treatment that expectation will realize expected.The treatment that be also to be understood that employing can realize for the desired effect of same disease (for example, can with compound of the present invention and the administration simultaneously of another kind of antiphlogiston), perhaps they can realize different effects (as, control any side effect).
In certain embodiments, pharmaceutical compositions of the present invention comprise in addition one or more other therapeutic activity components (as, antiphlogiston and/or light-weight additive).For purpose of the present invention, term " light-weight additive " is meant the side effect that concentrates on palliate a disease symptom and/or treatment plan and is not the treatment of being used for the treatment of property.For example, palliative treatment comprises anodyne, antiemetic and anti-nausea pill.
3) research application, pharmaceutical application and methods of treatment
Research is used
According to the present invention, can be known in the art be used for identifying has any available test of compound of the ability of the ability of the relevant CD11/CD18 acceptor of ability, antagonism and the white corpuscle of the adhesion between the white corpuscle integrin family that regulates adhesion molecule and acceptor in the born of the same parents and/or antagonism Mac-1 and/or LFA-1 and tests compound of the present invention.For example, test can be cell or acellular, body in or external, high-throughput or small throughput form, or the like.
Therefore, in one aspect, interested especially compound of the present invention comprises those that wherein meet the following conditions:
Regulate the adhesion between the white corpuscle integrin family of adhesion molecule in the born of the same parents (as, ICAM-1 ,-2 and-3) and acceptor;
Showing can the antagonism CD11/CD18 acceptor relevant with white corpuscle;
Showing can antagonism Mac-1 and/or the ability of LFA-1; With
The treatment of diseases that can be used for the LFA-1 mediation.
As describing in detail in this paper example, measure compound regulate the T cell to the test of the ability of 5dICAM-Ig adhesion (as, cell attachment test) in, some compound of the present invention shows IC 50Value≤50 μ M.In some other embodiment, compound of the present invention shows IC 50Value≤40 μ M.In some other embodiment, compound of the present invention shows IC 50Value≤30 μ M.In some other embodiment, compound of the present invention shows IC 50Value≤20 μ M.In some other embodiment, compound of the present invention shows IC 50Value≤10 μ M.In some other embodiment, compound of the present invention shows IC 50Value≤7.5 μ M.In certain embodiments, compound of the present invention shows IC 50Value≤5 μ M.In some other embodiment, compound of the present invention shows IC 50Value≤2.5 μ M.In certain embodiments, compound of the present invention shows IC 50Value≤1 μ M.In some other embodiment, compound of the present invention shows IC 50Value≤750nM.In some other embodiment, compound of the present invention shows IC 50Value≤500nM.In some other embodiment, compound of the present invention shows IC 50Value≤250nM.In some other embodiment, compound of the present invention shows IC 50Value≤100nM.In other embodiments, exemplary compound shows IC 50Value≤75nM.In other embodiments, exemplary compound shows IC 50Value≤50nM.In other embodiments, exemplary compound shows IC 50Value≤40nM.In other embodiments, exemplary compound shows IC 50Value≤30nM.In other embodiments, exemplary compound shows IC 50Value≤20nM.In other embodiments, exemplary compound shows IC 50Value≤10nM.In other embodiments, exemplary compound shows IC 50Value≤5nM.
Pharmaceutical application and methods of treatment
As mentioned above, described herein some compound shows common activity as the conditioning agent of adhering between the adhesion molecule in the born of the same parents.More specifically, compound exhibits of the present invention goes out the ability of the antagonism CD11/CD18 acceptor relevant with white corpuscle, and shows the interactional ability of antagonism LFA-1 in certain embodiments.Therefore, in certain embodiments, compound of the present invention can be used for treating the disease of LFA-1 mediation.
Therefore, in another aspect of the present invention, be provided for the method for the disease of treatment (or prevention) LFA-1 mediation, it comprises described formula (I) or compound (II) to the main body drug treatment significant quantity that needs are arranged herein.In certain embodiments, be provided for treating the method for the disease of LFA-1 mediation, comprise the compound of the present invention of main body drug treatment significant quantity that needs are arranged or comprise the pharmaceutical compositions of compound of the present invention, realizing the needed amount of desired effects and in the time.
In certain embodiments, this method relates to compound or its pharmaceutically acceptable derivative to main body (including but not limited to the mankind or animal) the drug treatment significant quantity that needs are arranged.
As mentioned above, the invention provides new compound, it has the biological property of the disease that can be used for treating Mac-1 and/or LFA-1 mediation.In certain embodiments, compound of the present invention can be used for treating psoriatic, relevant with inflammatory bowel reply (as Crohn disease and ulcerative colitis), dermatitis, meningitis, encephalitis, uveitis, allergy situation such as eczema and asthma, relate to the situation that T cellular infiltration and chronic inflammatory are replied, skin hypersensitivity (comprising toxicodendron and poison oak), atherosclerosis, autoimmune disease such as rheumatoid arthritis, systemic lupus erythematous (SLE), diabetes, multiple sclerosis, Reynaud ' s syndromes, autoimmune thyroiditis, experimental autoimmune encephalomyelitis, house Glenn syndromes, juvenile onset diabetes, typically in pulmonary tuberculosis, sarcoidosis, polymyositis, find in granulomatosis and the vasculitis by the cytokine immunne response relevant with the Delayed Hypersensitivity of T cell mediated, pernicious anemia, relate to the disease that white corpuscle oozes out, the CNS inflammatory diseases, the multiple organ injury syndromes of septicemia or wound secondary, autoimmune hemolytic anemia, myasthenia gravis, the disease of antigen-antibody complex mediation, all types of transplanting, comprise and transplant anti-host disease or host versus graft disease, HIV and rhinovirus infection, and pulmonary fibrosis, only give some instances.
As more specifically describing herein, usually, compound of the present invention can be used as the interactional antagonist between the white corpuscle integrin family of adhesion molecule in the born of the same parents (as, ICAM-1 ,-2 or-3) and acceptor.Therefore, in certain embodiments, the invention provides the compound that can be used for treating by the disease of the CD11/CD18 family mediation of cell adhesion molecule.In interested especially some embodiment, the invention provides the compound that can be used for treating by the disease of Mac-1 and/or LFA-1 mediation.For example, compound of the present invention can be concrete is used for the treatment of inflammatory diseases, organ-graft refection and autoimmune disease, only gives some instances.
Therefore, as mentioned above,, be provided for treating method, comprise formula (I) or compound (II) the main body drug treatment significant quantity that needs are arranged by the disease of the CD11/CD18 family mediation of cell adhesion molecule in another aspect of the present invention.In interested especially some embodiment, method of the present invention can be used for treating the disease by Mac-1 or LFA-1 mediation.Should be appreciated that the method according to this invention can be with compound and composition with any amount and any route of administration administration of effective treatment by the disease of the CD11/CD18 family mediation of cell adhesion molecule.For example, in some exemplary, compound of the present invention can be used as adhesion molecule in Mac-1 or LFA-1 and the born of the same parents (as, ICAM-1) interactional antagonist between, therefore, this compound can be used for treating the disease of LFA-1 mediation, it includes but not limited to psoriatic, relevant with inflammatory bowel reply (as Crohn disease and ulcerative colitis), dermatitis, meningitis, encephalitis, uveitis, allergy situation such as eczema and asthma, relate to the situation that T cellular infiltration and chronic inflammatory are replied, skin hypersensitivity (comprising toxicodendron and poison oak), atherosclerosis, autoimmune disease such as rheumatoid arthritis, systemic lupus erythematous (SLE), diabetes, multiple sclerosis, Reynaud ' s syndromes, autoimmune thyroiditis, experimental autoimmune encephalomyelitis, house Glenn syndromes, juvenile onset diabetes, that typically in pulmonary tuberculosis, find and the relevant immunne response of delayed hypersensitivity by cytokine and T-cell mediated, sarcoidosis, polymyositis, granulomatosis and vasculitis, pernicious anemia, relate to the disease that white corpuscle oozes out, the CNS inflammatory diseases, the multiple organ injury syndromes of septicemia or wound secondary, autoimmune hemolytic anemia, myasthenia gravis, the disease of antigen-antibody complex mediation, all types of transplanting, comprise and transplant anti-host disease or the anti-transplantation disease of host, HIV and rhinovirus infection, pulmonary fibrosis, or the like, only give some instances.Therefore, as used in this article, express " significant quantity " be meant medicine be used for adhesion molecule in the antagonism born of the same parents (as, ICAM) and the interaction between the white corpuscle integrin family of acceptor and show enough amounts of result of treatment.The exact amount that needs is different with the difference of main body, decides according to the severity of species, age and the general situation of main body, infection, concrete therapeutical agent, administering mode etc.Preferably compound of the present invention is formulated as and is convenient to administration and the conforming dosage unit form of dosage.As used in this article, express the physics discrete unit that " dosage unit form " is meant the therapeutical agent that is suitable for patient to be treated.Yet, should be appreciated that total daily dosage portion of compound of the present invention and composition is determined according to rational medical judgment by the attending doctor.The concrete treatment effective dose level that is used for any concrete patient or organism is decided according to multiple factor, and described factor comprises the disease to be treated and the severity of this disease; The activity of the particular compound that adopts; The concrete composition that adopts; Patient's age, body weight, general health state, sex and diet; Administration time, route of administration and the discharge rate of the particular compound that adopts; The time length of treatment; The particular compound associating that is used for and adopts or the medicine of administration simultaneously; Extensive known each factor is (referring to for example Goodman and Gilman ' s in medical field, " The Pharmacological Basis ofTherapeutics ", the tenth edition, A.Gilman, J.Hardman and L.Limbird, eds., McGraw-Hill Press, 155-173,2001, it is incorporated into this paper as a reference in full).
Another aspect of the present invention relates to and suppresses the interactional method between the LFA-1 and ICAM-1 among biological sample or the patient, and this method comprises patient's administration or makes the compound of described biological sample contact I or II or comprise described compound compositions.
Another aspect of the present invention relates to the interactional method that suppresses CD11a among biological sample or the patient and/or CD18 and ICAM-1, ICAM-2 or ICAM-3, and this method comprises patient's administration or makes the compound of described biological sample contact I or II or comprise described compound compositions.
In addition, after with required dosage and the preparation of suitable pharmaceutically acceptable carrier, severity according to the infection that will treat is decided, can with pharmaceutical compositions of the present invention to (intracisternally), intravaginal in human and other animal per os, rectum, non-enteron aisle, the pond, intraperitoneal, part (as by powder, paste or drops), through cheek (as mouth with or nasal spray) administration.In certain embodiments, can with compound of the present invention with every day about 0.001mg/kg main body body weight to about 50mg/kg main body body weight, every day about 0.01mg/kg main body body weight arrive about 25mg/kg main body body weight or dosage level that every day, about 0.1mg/kg main body body weight arrived about 10mg/kg main body body weight once a day or multiple dosing, to obtain required result of treatment.Be also to be understood that can with less than 0.001mg/kg or greater than the dosage of 50mg/kg (for example 50-100mg/kg) to the main body administration.In certain embodiments, compound per os or parenterai administration.
The treatment cartridge bag
In other embodiments, the present invention relates to be used for implementing easily and effectively the cartridge bag of the inventive method.Usually, cartridge bag comprises one or more containers of the one or more components that are filled with pharmaceutical compositions of the present invention.This cartridge bag is particularly suitable for delivery of solids oral dosage form such as tablet or capsule.Preferred this cartridge bag comprises a plurality of unitary doses, and can comprise card, and this card has the dosage with their predetermined application order orientation.If expectation can provide memory aid, for example numeral, letter or other mark pattern, or use the calendar inset, specify in the treatment progress chart can dosage time.Perhaps, can comprise the placebo dosage or the calcium dietary supplement that are similar to or are different from pharmaceutical compositions dosage, so that the cartridge bag of acceptable dose every day wherein to be provided.The notice of government organs' regulation of the production, use or the sale that can be the management medicine of optional and this container combination, this notice reflection obtain the approval of production, use or sale that government organs are used for human administration.
Equivalent
Following representative embodiment is intended to help explanation the present invention, and does not plan or they should not regarded as to limit the scope of the invention.In fact, except represent herein and describe those, full content by these documents, comprise subsequently embodiment and the science and technology that this paper is quoted and the reference of patent documentation, multiple improvement of the present invention and many other embodiments thereof it will be apparent to those skilled in the art that.Should be appreciated that in addition the content of the reference that those are cited is merged in this paper as a reference, to help the explanation prior art.
Following examples comprise to be used in puts into practice important Additional Information of the present invention, example and guidance in different embodiments and the Equivalent thereof.
Example
Can further understand compound of the present invention and preparation thereof by embodiment, described embodiment has illustrated preparation or has used the certain methods of these compounds.Yet, should be appreciated that these embodiment do not limit the present invention.Variant of the present invention, no matter now known or further exploitation, all be considered in the scope of the present invention of described herein and claim.
1) general remark of synthetic method:
The practitioner has the information combination that well-established document and this paper about the macrolide chemistry of being used to quote comprise, with the guidance on the synthesis strategy, protecting group and other material and the method that act on synthetic The compounds of this invention.
The multiple references that this paper quotes provides the background information of usefulness, and record is about the similar compound of preparation and compound described or of the present invention or relevant intermediate herein and about preparation, application with can be the information of the administration of interested this compound.
In addition, the practitioner is instructed with reference to concrete guide and the embodiment about various exemplary compound and the intermediate thereof that provide in these documents.
Can further understand compound of the present invention and preparation thereof by embodiment, described embodiment has illustrated preparation or has used the certain methods of these compounds.Yet, should be appreciated that these embodiment do not limit the present invention.Variant of the present invention, no matter now known or further exploitation, all be considered in the scope of the present invention of described herein and following claim.
According to the present invention, can use any available technology production or prepare compound of the present invention or comprise their composition.For example, can use multiple liquid-phase synthesis process, as those of following concrete discussion.Perhaps or in addition, compound of the present invention can use multiple combination technique as known in the art, parallel synthetic and/or solid phase synthesis process preparation.
As described below, should be appreciated that, can be according to the synthetic different compound of the present invention of described method herein.Be used to prepare the starting raw material and the reagent of these compounds or derive from commercial supplier such as Aldrich Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Sigma (St.Louis, MO), perhaps by well known to a person skilled in the art as prepare below with reference to the method described in the document: Fieser and Fieser, 1991, " Reagents forOrganic Synthesis ", 1-17 volume, John Wiley and Sons, New York, NY, 1991; Rodd 1989 " Chemistry of Carbon Compounds ", 1-5 rolls up and augments volume, Elsevier Science Publishers, 1989; " Organic Reactions ", 1-40 volume, John Wiley and Sons, New York, NY, 1991; March 2001, " AdvancedOrganic Chemistry ", the 5th edition, John Wiley and Sons, New York, NY; With Larock 1990, " Comprehensive Organic Transformations:A Guide toFunctional Group Preparations ", the 2nd edition, VCH Publishers.These diagrams are the explanation certain methods that can synthesize compound of the present invention just, can carry out multiple improvement and to noticing that those skilled in the art's suggestion of the present disclosure improves these diagrams to these diagrams.
Starting raw material of the present invention, intermediate and compound can use ordinary method to separate and purifying, comprise filtration, distillation, crystallization, chromatography etc.They can characterize by conventional method, comprise physical constant and spectroscopic data.
General reaction method:
Unless mention particularly, reaction mixture uses the stirring rod of magnetic force driving to stir.Inert atmosphere is meant anhydrous argon gas or anhydrous nitrogen.Reaction by the sample to the reaction mixture of suitable processing carry out tlc, by proton magnetic resonance (PMR) (NMR) or by high pressure lipuid chromatography (HPLC) (HPLC) monitoring.
General post-treating method:
Unless mention particularly, with the reaction mixture cool to room temperature or below the room temperature, water or saturated aqueous ammonium chloride cancellation where necessary then.With the product of expectation water and be fit to and the immiscible solvent of water (as ethyl acetate, methylene dichloride, Anaesthetie Ether) between distribute extraction.The extracting solution that will comprise required product suitably washes with water, washs with saturated brine solution subsequently.The extracting solution that comprises product therein is considered to comprise in the situation of residual oxygenant, before above-mentioned washing process, extracting solution is used in the 10% sodium sulfite solution washing of saturated sodium bicarbonate aqueous solution.The extracting solution that comprises product therein is considered to comprise in the situation of residual acid, before carrying out above-mentioned washing process, extracting solution is washed (product itself that is not included in expectation has those situations of acid properties) with saturated sodium bicarbonate aqueous solution.The extracting solution that comprises product therein is considered to comprise in the situation of residual alkali, before carrying out above-mentioned washing process, with extracting solution with the washing of 10% aqueous citric acid solution (product itself that is not included in expectation has those situations of alkalescence).After washing, will comprise the extracting solution anhydrous magnesium sulfate drying of required product, filter then.Then by the temperature (being usually less than 45 ℃) that is fit under reduced pressure rotary evaporation remove the separated from solvent crude product.
General purification process:
Unless mention particularly, chromatogram purification is meant the hurried column chromatography on silicon-dioxide, uses single solvent or mixed solvent as elutriant.To comprise the elutriant merging of suitably purified required product and be evaporated to constant-quality in the temperature (being usually less than 45 ℃) that is fit to.Final compound is dissolved in 50% contain in the water-acetonitrile, filters and transfer in the bottle, lyophilize under high vacuum is then submitted to be used for biological test at last.
1) exemplary compounds is synthetic:
Unless otherwise indicated, starting raw material or for commercially available or can the chamber is synthetic by experiment easily obtains by those skilled in the art.Following describe, in general terms be used for the method and the general guide of synthetic as the compound described usually and describe in subclass and the kind of this paper herein.In addition, synthetic guidance can be found in disclosed PCT application WO 99/49856 and WO 02/059114, and the full content of described application is merged in this paper as a reference.
Embodiment 1
Present embodiment is described the synthetic of following compound
Figure A20048003980200971
It is according to diagram 1A and the preparation of following process.
Diagram 1A
Figure A20048003980200981
A) (20%, 500mL) solution in was 80 ℃ of heating 4 hours at the HCl aqueous solution with 3-p-methoxy-phenyl ethylamine (0.2mol) and formaldehyde (0.22mol).Then reaction is concentrated into drying, and with resistates be dissolved in Hydrogen bromide (40% aqueous solution, 500mL) in, and refluxed 24 hours.To react concentrated, obtain brownish solid, its not purified use.In resistates, add entry (200mL) and tetrahydrofuran (THF) (" THF ") (300mL) and in the mixture that obtains, add yellow soda ash very carefully (solid 0.5mol), adds tert-Butyl dicarbonate (0.3mol) subsequently.After at room temperature 15 hours, reaction is extracted with ethyl acetate (1L), and organic extracting solution is washed with saturated potassium primary phosphate and salt, also filters with anhydrous magnesium sulfate drying.
After filtrate concentrates, with resistates be dissolved in methylene dichloride (" DCM ", 100mL) in, and to wherein adding acetate (500mL) and sulfuryl chloride (0.6mol) at leisure.After reaction mixture is at room temperature stirred 24 hours, reaction is concentrated into drying, and under high vacuum dry 2 hours in addition.Crude product is used for next step without being further purified.With crude product water-soluble/THF (200mL/400mL) in, and under fully stirring to wherein carefully and lentamente adding yellow soda ash (0.5mol), add tert-Butyl dicarbonate (0.3mol) subsequently.After reaction mixture stirred 12 hours, will react and use phosphoric acid (2M) pH about 7 that neutralizes carefully.With the mixture ethyl acetate extraction (500mLx2) that obtains, and, use anhydrous magnesium sulfate drying, filter also concentrated the extracting solution water and the salt washing that merge.Thick solid obtains white solid from ethyl acetate and hexane (about 1: 2 ratio) recrystallization.Mother liquor is concentrated and cross column purification, use 4: 1 the hexane that contains the 0-10% ethyl acetate: the methylene dichloride wash-out.The yield that merges is 14.5g (23%, from commercially available 3-anisole ethamine meter).MS (API-ES +) m/z:262,264,266 (the M+H-tertiary butyls +).
The above product that obtains is dissolved in DCM (100mL) and the pyridine (50mL).The solution that obtains is cooled to-40 ℃, and to wherein adding trifluoromethanesulfanhydride anhydride (51mmol) at leisure.Reaction mixture was little by little risen again room temperature in 4 hours after, reaction mixture is distributed between ethyl acetate (500mL) and water (100mL), and organic layer water (100mL, twice) and salt solution (50mL) are washed, use anhydrous magnesium sulfate drying, filter and concentrate.Resistates is crossed column purification, and use 5: 1 the hexane that contains the 0-5% ethyl acetate: the DCM wash-out obtains corresponding triflate (9.73g, 48% yield).
With 1 of the triflate of 10mmol, 1.0mmol, the diisopropyl ethyl amine (" DIEA ") of 3-diphenylphosphine propane (" dppp ") and 40mmol is at the anhydrous dimethyl formamide (" DMF ") of 100mL and the anhydrous CH of 50mL 3Mixture among the OH purged 15 minutes with CO, added the Pd (OAc) of 1.0mmol then under CO atmosphere 2Subsequently, the mixture that obtains is spent the night 70 ℃ of stirrings under CO atmosphere.Remove desolvate and with resistates by the column chromatography purifying, use the EtOAc/ hexane= 1/ 4(v/v), obtain compound 1.1 with 56% yield as elutriant.ESI-MS(m/z)：(M +)+Na?382.1； 1H?NMR(CD 3OD，400MHz)：δ7.32(s，1H)，4.60(s，2H)，3.95(s，3H)，3.69(m，2H)，2.84(m，2H)，1.50(s，9H)ppm。
B) the mixture backflow of LiI in the 20mL pyridine of 1.1 (5mmol) and 30mmol spent the night.Except that desolvating and resistates being dissolved in EtOAc.Then with the saturated NH of the solution that obtains 4Anhydrous Na is washed and used to the Cl aqueous solution 2SO 4Dry.Except that desolvating and, obtaining the compound 1.3 of quantitative yield with resistates vacuum-drying.Crude product carries out next step without being further purified.ESI-MS(m/z)：(M-tBu+1)，290。
C) solution of Boc-Dap-OH (10mmol) in methyl alcohol (30mL) was kept light yellow 10 seconds up to color with the processing of trimethyl silyl diazomethane.Mixture is concentrated, and resistates is dissolved among the DCM (30mL).In solution, add triethylamine (20mmol), add 3-thienyl formyl chloride (11mmol) subsequently.After at room temperature 0.5 hour, will react, and concentrate by filtered through silica gel.Resistates is crossed column purification, with the hexane wash-out that contains the 10-50% ethyl acetate.The product that so obtains is dissolved among the DCM (10mL) and (4M in dioxane, 10mL) handles with HCl.After 5 hours, will react concentrated, obtain title compound (total recovery of 60-80%).
D) with neighbour's (7-azepine benzo triazol-1-yl)-N of 1.2 (4mmol), 1.3 (4.4mmol), 5.0mmol, N, N ', the Et of N '-tetramethyl-urea fluoro phosphoric acid salt (" HATU ") and 20mmol 3The mixture of N in the DMF of 20mL at room temperature stirs and spends the night.Except that desolvating and resistates being passed through the column chromatography purifying, use CH 2Cl 2/ EtOAc=6/4 (v/v) obtains compound 1.4 as elutriant with 60% yield.ESI-MS(m/z)：(M+1)556.1。
E) with 2mmol 1.4 at the TFA of 9mL and the CH of 3mL 2Cl 2In solution at room temperature stirred 6 hours.Remove and to desolvate and the saturated NaHCO of resistates 3Aqueous solution dilution.Mixture extracts 3 times with EtOAc.Then with the extracting solution anhydrous Na 2SO 4Dry.Except that desolvating and with resistates vacuum-drying, obtaining compound 1.5, it is without being further purified use.ESI-MS(m/z)：(M+1)456.1.
F) midbody compound 1.11 is according to diagram 1B and the preparation of following process.
Diagram 1B
At room temperature in 100mmol commercially available 6-hydroxyl-[2H]-cumarone-3-ketone (compound 1.8) and the solution of 150mmol imidazoles in the 300mL dry DMF, add 110mmol TERT-BUTYL DIMETHYL CHLORO SILANE (" TBDMSC1 "), the mixture that obtains is in stirred overnight at room temperature, remove and desolvate, resistates is used saturated NH with the EtOAc dilution of 100mL 4The Cl aqueous solution is washed, and uses anhydrous Na 2SO 4Drying is removed and is desolvated, and resistates obtains corresponding intermediates, 70% yield through purifying.ESI-MS(m/z)：(M+H +)265.1。
Intermediate is dissolved in the CH of 100mL 3OH is at the NaBH of room temperature adding 20mmol 4, in stirring at room after 12 hours, reaction mixture is with the acetone treatment of 10mL, then, add the 4.0N HCl of 60mL in mixture, mixture is removed organic solvent in stirred overnight at room temperature, resistates extracts several times with EtOAc, and extract is washed with salt then, uses anhydrous Na 2SO 4Drying is removed the Et that desolvates and resistates is dissolved in 100mmol 3The anhydrous CH of N and 180mL 2Cl 2, at 0 ℃ of PhNTf that adds 66mmol 2, the mixture that obtains removes and desolvates in stirred overnight at room temperature, and resistates obtains compound 1.9,90% yields through purifying. 1H?NMR(400MHz，CD 3Cl)：δ7.75(d，J＝1.9Hz，1H)，7.66(d，J＝8.5Hz，1H)，7.50(s，1H)，7.21(d，J＝8.5Hz，1H)，6.85(d，J＝1.9Hz，1H)ppm。
The Pd (OAc) of the compound 1.9 of 50mmol, the dppp of 2.5mmol (diphenylphosphine-1,3-propane) and 2.5mmol 2Mixture in the anhydrous MeOH of the DIEA of 100mmol, 125mL dry DMF, 125mL stirs under CO atmosphere at 65 ℃ and spends the night, and removes and desolvates, and resistates obtains compound 1.10,65% yields by the column chromatography purifying. 1H?NMR(400MHz，CDCl 3)：δ8.23(s，1H)，7.99(d，J＝8.3Hz，1H)，7.78(s，1H)，7.65(d，J＝8.3Hz，1H)，6.85(s，1H)，3.97(s，3H)ppm；ESI-MS(m/z)：(M+1)177.10。
With the compound 1.10 of 20mmol and the LiOHH of 80mmol 2O is at the THF of 60mL and the H of 15mL 2Mixture among the O adds the 1.0N HCl aqueous solution of 80mL then stirring at room 1 hour, removes organic solvent, and resistates is with the salt solution dilution of 50mL, and mixture extracts with EtOAc then, the extract anhydrous Na 2SO 4Drying is removed and to be desolvated, and resistates vacuum-drying obtains the compound 1.11 of quantitative yield. 1H?NMR(400MHz，CD 3OD)：δ8.14(s，1H)，7.92(m，2H)，7.67(d，J＝8.5Hz，1H)，6.92(s，1H)ppm；ESI-MS(m/z)：(M+H +)163.1。
G) mixture of the HATU of the compound 1.11 of 0.25mmol and 0.26mmol in the DMF of the DIEA of 1mmol and 2mL was stirring at room 30 minutes, the solution of compound 1.5 in the DMF of 1mL that adds 0.22mmol then, the mixture that obtains stirred 12 hours at 45 ℃, remove and desolvate, resistates is through purifying, obtain compound 1.6, the 50-65% yield.Then, compound 1.6 usefulness LiOH (the 1.0M aqueous solution, 0.5mL) hydrolysis 2 hours in THF (3mL), reaction mixture extracts anhydrous magnesium sulfate drying with HCl (aqueous solution) acidifying with ethyl acetate (50mL) then, and concentrate, obtain compound 1, quantitative yield. 1H NMR (400MHz, CD 3OD): δ 7.91 (s, 1H), 7.75 (d, J=8.0Hz, 1H), 7.67 (s, 3H), 7.36 (d, J=8.0HZ, 1H), 7.13 (s, 1H), 6.96 (s, 1H), 5.01 (t, J=6.8Hz, 1H), 4.68 and 4.89 (m, 2H), 3.85 (d, J=6.8Hz, 2H), 3.70 and 4.02 (m, 2H), 2.93 (m, 2H) ppm; ESI-MS (m/z): (M+1) 586.10.
Embodiment 2
Present embodiment is described the synthetic of following compound,
Figure A20048003980201021
It is according to the process preparation of embodiment 1g, and difference is to use the 4-chloro-benzoic acid to replace compound 1.11. 1H NMR (400MHz, CD 3OD): δ 7.64 (m, 2H), 7.35-7.49 (m, 5H), 7.11 (s, 1H), 4.98 (t, J=8.0Hz, 1H), 4.63 and .88 (m, 2H), 3.83 (d, J=8.0Hz, 2H), 3.68 and 3.98 (m, 2H), 2.89 (m, 2H) ppm; ESI-MS (m/z): (M+1) 579.90.
Embodiment 3
Present embodiment is described the synthetic of following compound,
It is according to diagram 2 and the preparation of following process.
Diagram 2
Figure A20048003980201031
A) 0 ℃ to 10mmol commercially available 3.1 at the MeOH of 20mL and the CH of 20mL 2Cl 2In solution in slowly be added in the 2.0M TMSCHN of the 20mmol in the hexane 2, the mixture that obtains was stirring at room 30 minutes.Remove and desolvate, resistates vacuum-drying obtains crude product 3.2.
B) then, the sec.-propyl trinitride of compound 3.2 and 15mmol is at the CuI of 0.2mmol, the Et of 0.2mmolf 3Under the existence of N at the CH of 50mL 3Among the CN in stirred overnight at room temperature.Remove and desolvate, resistates obtains compound 3.3,55% yields by the column chromatography purifying.ESI-MS(m/z)：(M+1)313.20。
C) mixture of compound 3.3 in the dioxane of the 4.0N of 10mL HCl of 2mmol was stirring at room 12 hours.Remove and desolvate, resistates vacuum-drying obtains compound 3.4, quantitative yield.ESI-MS(m/z)：(M+1)213.10。
D) at room temperature 1.1 (3.60g, DCM 10mmol) (20mL) solution is used in 1, and (4.0M 10mL) handles the HCl in the 4-dioxane.After 2 hours, reaction concentrates, and obtains compound 3.5, quantitative yield.
E) compound 3.5 (10mmol) and EDC (2.11g, 11mmol), N, N-dimethyl aminopyridine (" DMAP ", 0.1g), (1.62g 10mmol) mixes in dry DMF (50mL), after at room temperature 15 hours for triethylamine (2.02g) and compound 1.11, reaction mixture dilutes with ethyl acetate (200mL), wash (30mL, 3 times) with water, with anhydrous magnesium sulfate drying and filtration.Resistates after filtrate concentrates is crossed column purification, and the hexane wash-out with containing the 10-30% ethyl acetate obtains title compound (3.7g, 92%): ESI-MS (m/z): (M+1) 213.1.
F) prepare compound 3.7 according to embodiment 1b, difference is to use compound 3.6 to replace compound 1.1.
G) mixture of the HATU of the compound 3.7 of 0.25mmol and 0.26mmol in the DMF of the DIEA of 1mmol and 2mL adds the solution of compound 3.4 in the DMF of 1mL of 0.22mmol then stirring at room 30 minutes.The mixture that obtains stirred 4 hours at 45 ℃.Remove and desolvate, resistates obtains intermediate ester through purifying, and it is handled in THF and water with LiOH then, obtains required compound 3, quantitative yield. 1H NMR (400MHz, CD 3OD) δ 7.90 (s, 2H), 7.74 (m, 1H), 7.64 (s, 1H), 7.34 (m, 1H), 6.93 (s, 1H), 5.03 (m, 1H), 4.82 (m, 1H), 4.65 and 4.88 (m, 2H), 3.72 and 3.97 (m, 2H), 3.40 (m, 1H), 3.18 (m, 1H), 2.90 (m, 2H), 1.55 (m, 6H) ppm; ESI-MS (m/z): (M+1) 570.1.
Embodiment 4
Present embodiment is described the synthetic of following compound,
Figure A20048003980201041
It is according to diagram 3 and the preparation of following process.
Diagram 3
Figure A20048003980201051
A) Boc-DAP-OH (0.2g, 1.0mmol), 2, the 4-dichloro pyrimidine (0.29g, 2.0mmol), (0.51mL 2.9mmol) is heated to 75 ℃ to diisopropylethylamine in ethanol (5mL), kept 14 hours.The reaction mixture cool to room temperature, solvent evaporated under reduced pressure.The crude product 4.1 that obtains is enough pure, can be used for the chemical conversion of back.
B) with crude product resistates 4.1 (0.31g, 1.0mmol) be dissolved in 9: 1 benzene: in the methyl alcohol (5mL), in the reaction mixture that stirs, slowly add trimethyl silyl two azomethane (1.0mL, 2.0M, in hexane) and stirred 1 hour in addition, solvent evaporated under reduced pressure obtains oily crude product resistates.By the silica gel column chromatography purifying, use the hexane wash-out that contains 50% ethyl acetate, obtain pure product 4.2 (0.21g, 65%).
C) (0.21g 0.6mmol) is dissolved in methylene dichloride (5mL) to compound 4.2.Add trifluoroacetic acid (2.5mL), reaction was stirred 1 hour, and the concentrated reaction mixture that obtains obtains amine 4.3, quantitative yield to remove excessive trifluoroacetic acid.
D) prepare compound 4.4 according to embodiment 3d-f, difference is to use the 4-chloro-benzoic acid to replace compound 1.11.
E) prepare compound 4 according to embodiment 3g, difference is to use compound 4.4 to replace compound 3.7, and uses compound 4.3 to replace compound 3.4.
Embodiment 5
Present embodiment is described the synthetic of following compound,
It is according to diagram 4 and the preparation of following process.
Diagram 4
Figure A20048003980201062
A) (1.01g, (0.68mL 13.6mmol), obtains white depositions 10.7mmol) to add the 20M NaOH aqueous solution in the solution in 15mL DMF to Toluidrin.Solution is cooled to 0 ℃, and (0.4mL 6.63mmol), stirred 15 minutes at 0 ℃ slowly to add dithiocarbonic anhydride.Add in addition the 20M NaOH aqueous solution (0.32mL, 6.4mmol) and dithiocarbonic anhydride (0.2mL, 3.31mmol), be reflected at 0 ℃ and stirred 20 minutes, be warmed up to room temperature then, in the time of 30 minutes, all throw outs have become solution, reaction mixture is cooled to 0 ℃, and the adding methyl iodide (1.33mL, 21.364mmol), being reflected at 0 ℃ stirred 20 minutes, stirring at room 1.5 hours, in reaction, add the water of 20mL, with ethyl acetate extraction 5 times.The organic extraction MgSO that merges 4Drying, and be concentrated into driedly, from hot ethyl acetate and hexane recrystallization, obtain 1.44g compound 5.1.ESI-MS(m/z)：(M+H +)200.0。
B) to Boc-Dap-OH (109mg, 0.53mmol) and compound 5.1 (125.7mg, 0.632mmol) in 5mL alcoholic acid solution, add the 1.0M NaOH aqueous solution (0.8mL, 0.8mmol).Reaction is stirred up to transforming fully, be concentrated into then dried, resistates is water-soluble, give a baby a bath on the third day after its birth time with ether, water layer is acidified to pH1 with 2.0M phosphoric acid, uses ethyl acetate extraction 4 times.The ethyl acetate extract MgSO that merges 4Dry and be concentrated into driedly, obtain the compound 5.2 of 160.4mg.ESI-MS(m/z)：(M+Na +)378.0。
C) (160.4mg, 0.452mmol) at 1: 1 methylene dichloride: (it is the ethereal solution of 2.0M, (0.4mL, 0.8mmol)) to add trimethyl silyl two azomethanes in the solution in the methyl alcohol to compound 5.2.Be reflected at stirring at room up to changing into methyl ester fully, be concentrated into dried then.Product obtains the compound 5.3 of 146.6mg by dodging chromatography purification.ESI-MS (m/z): (M+Na +) 270.0; 1H NMR (400MHz, the .1.46 of chloroform-d) (s, 9H), 2.42 (s, 3H), 3.02 (s, 3H), 3.63 (m, 1H), 3.75 (m, 1H), 3.82 (s, 3H), 4.51 (m, 1H).
D) to compound 5.3 (146.6mg 0.40mmol) adds ammonia in the solution in 2mL methyl alcohol, 7N methyl alcohol (0.6mL, 4.2mmol).Mixture is cooled to 0 ℃, (the reaction stirring also reaches room temperature for 75.5mg, the 0.444mmol) solution in the 0.4mL acetonitrile to drip Silver Nitrate, remove after 3 hours and desolvate, resistates is suspended in the ethyl acetate, and by diatomite filtration, concentrated filtrate is to doing, and be dissolved in it in methylene dichloride once more, to wherein adding HCl, 4.0M in dioxane (0.5mL, 2.0mmol).This solution is stirring at room 8 hours, and is concentrated into driedly, obtains compound 5.4, is HCl salt.ESI-MS(m/z)：(M+H +)239。
E) prepare compound 5 according to embodiment 3g, difference is to use compound 4.1 to replace 3.7, and uses compound 5.4 to replace compound 3.4.ESI-MS(m/z)：(M+H +)590.0。
Embodiment 6
Present embodiment is described the synthetic of following compound,
Figure A20048003980201071
It is according to diagram 5 and the preparation of following process.
Diagram 5
A) (L)-Boc-Dap-OH (10mmol), the ethanolic soln of dimethyl N-cyano group dithioimniocarbonate (10mmol) and DIEA (30mmol) was stirring at room 1 hour, add tetramethyleneimine (20mmol) then, to be reflected at 65 ℃ of heating 10 hours, reaction mixture is used saturated NaH with ethyl acetate dilution (150mL) 2PO 4(50mL, water layer pH are 4-6), water (50ml) and saline water extraction.The organic layer anhydrous magnesium sulfate drying filters and concentrates, and crude product is dissolved in 4: 1 DCM: among the MeOH, be cooled to 0 ℃, to wherein adding trimethyl silyl two azomethanes, kept yellow 30 seconds up to it.Solution concentration, resistates is crossed column purification, and the hexane wash-out with containing the 30-100% ethyl acetate obtains title compound, the 20-30% yield.MS(m/z)：240(M-99)。
B) (72mg 0.20mmol) handled 2 hours with HCl (4M is in dioxane) in DCM (1mL) compound 6.1.Reaction mixture concentrates, and obtains compound 6.2.
C) prepare compound 6 according to embodiment 3g, difference is to use compound 6.2 to replace compound 3.4. 1H?NMR(400MHz，CDCl 3)δ7.77(s，1H)，7.63(m，3H)，7.37(d，1H)，6.85(s，1H)，6.32(d，1H)，4.68(s，2H)，4.31(m，1H)，3.85(m，2H)，3.60(m，4H)，2.88(m，2H)，1.89(m，4H)ppm；ESI-MS(m/z)：(M+1)597.1。
Embodiment 7
Present embodiment is described the synthetic of following compound
Figure A20048003980201082
It is according to diagram 6 and the preparation of following process.
Diagram 6
A) (598.8mg 3.2mmol) adds 0.26mL sulfuric acid in the solution in 5mL methyl alcohol to H-2-sulfydryl-His-OH.Mixture was stirring at room 8 hours, add sulfuric acid (0.1mL in addition, 0.6mmol), be reflected at 50 ℃ and stirred 4.5 hours, slowly add yellow soda ash (850.3mg, 8.02mmol), reaction is by the rotary evaporation drying, removing a large amount of methyl alcohol, add 6mL THF and 3mL water and yellow soda ash (0.851g, 8.03mmol) and Boc 2O (696.5mg, 3.19mmol).Be reflected at stirring at room 1 hour, with the ethyl acetate dilution, water and salt washing, organic layer MgSO 4Drying also is concentrated into dried.By dodging chromatography purification, obtain the compound 7.1 of 283.5mg.ESI-MS(m/z)：(M+H +)316.1。
B) compound 7.1 (283.5mg, 0.90mmol) and 3-chlorine peroxybenzoic acid (568.4mg 2.53mmol) is dissolved in the 6mL methylene dichloride and stirring at room 1.5 hours, and reaction is with the methylene dichloride dilution, and is poured in the 1.0M salt of wormwood.Water layer is adjusted to neutral pH with 2.0M phosphoric acid, uses dichloromethane extraction then 3 times, the organic extraction MgSO of merging 4Drying also is concentrated into dried.By dodging chromatography purification, obtain the compound 7.2 of 240.8mg.ESI-MS(m/z)：370.1(M+Na +)，248.1(M-Boc+H +)；1H?NMR(400MHz，CDCl 3)δ1.43(s，9H)，3.14(m，2H)，3.26(s，3H)，3.74(s，3H)，4.61(m，1H)，7.02(s，1H)。
C) to compound 7.2 (240.8mg adds HCl in dichloromethane solution 0.6931mmol), 4.0M in dioxane (1.0mL, 4.0mmol).Be reflected at stirring at room 1.5 hours, and be concentrated into driedly then, obtain compound 7.3, be hydrochloride.ESI-MS(m/z)：(M+H +)248。
D) prepare compound 7 according to embodiment 3g, difference is to use compound 4.1 to replace compound 3.7, and uses compound 7.3 to replace compound 3.4.ESI-MS(m/z)：(M+H +)599.0； 1H?NMR(400MHz，CDCl 3)δ2.88(s，2H)，3.10(m，1H)，3.21(s，3H)，3.34(m，1H)，3.67(1H)，3.97(1H)，4.63(1H)，4.85(1H)，5.04(dd，1H)，7.19(s，1H)，7.49(m，5H)。
Embodiment 8
Present embodiment is described the synthetic of following compound
Figure A20048003980201101
It is according to diagram 7A and the preparation of following process.
Diagram 7A
A) three-necked flask that contains the LiCl of 32mmol carries out flame with gaslight under vacuum, uses N then 2Purge.This process repeats 3 times, so that the LiCl desiccation.In room temperature at N 2(the R that in flask, adds 10mmol under the atmosphere, R)-(-)-pseudoephedrine G-NH2 hydrate (pseudo ephedrine glycinamide hydrate, people such as A.G.Myers, J.Org.Chem., 64:3322-3327 (1999)) and the anhydrous THF of 30mL.Suspension was under agitation handled 1 hour at 0 ℃ with the LiHMDS (1.0M in THF) of 31mmol then, the 3-methylthio group benzyl chloride (people such as S.Laufer who adds 10mmol then, J.Med.Chem., the solution in the anhydrous THF of 5mL 45:2733-2740 (2002)).The mixture that obtains spends the night 0 ℃ of stirring, the shrend that the adds 10mL reaction of going out.Remove and desolvate, resistates dilutes with the water of 50mL.Mixture CH 2Cl 2Extract 3 times, merge organic extraction, use anhydrous Na 2SO 4Dry.Remove then and desolvate, resistates obtains required alkylation intermediate, 70% yield through purifying.ESI-MS(m/z)：(M+H +)359.2。
The mixture of the alkylation intermediate of 5mmol in the 1.0N of 12mL NaOH refluxes, and exhausts up to starting raw material, and mixture is used CH with the water dilution of 20mL 2Cl 2Extract 3 times, then (Boc) of water and 6mmol 2The NaHCO of O and 12mmol 3At 1 of 30mL, stirred 15 hours in the 4-dioxane, remove organic solvent, resistates is used CH with the water dilution of 30mL 2Cl 2Extract.Water is handled to regulate pH value to 4.0 with solid citric acid then, extracts 3 times the organic extraction anhydrous Na then with EtOAc 2SO 4Dry.Remove and desolvate, resistates vacuum-drying obtains compound 8.2, quantitative yield.ESI-MS(m/z)：(M+H +)334.10。
B) at 0 ℃ to the compound 8.2 of 5mmol CH at 10mL 3The CH of OH and 10mL 2Cl 2Mixture in add (trimethyl silyl) two azomethanes (2.0M is in hexane) of 10mmol, the mixture that obtains was stirring at room 30 minutes.Remove and desolvate, resistates vacuum-drying obtains required ester, quantitative yield.ESI-MS(m/z)：(M+H +)348.10。
In room temperature to the CH of ester at 20mL 3The Oxone that adds 12mmol in the solution in the water of OH and 2mL _, the suspension that obtains is stirring at room 15 hours, and reaction mixture concentrates and dilutes with the EtOAc of 50mL, washes with water, uses anhydrous Na 2SO 4Dry.Remove and desolvate, resistates vacuum-drying obtains compound 8.3, quantitative yield. 1H?NMR(400MHz，CD 3Cl)：δ7.82(m，1H)，7.69(s，1H)，7.50(m，1H)，7.43(m，1H)，5.03(m，1H)，4.62(m，1H)，3.74(s，3H)，3.26(m，1H)，3.09(m，1H)，3.03(s，3H)，1.39(s，9H)ppm；ESI-MS(m/z)：(M-tBoc+H +)258.1。
C) mixture of compound 8.3 in the dioxane of the 4.0N of 10mL HCl of 2mmol was stirring at room 15 hours.Remove and desolvate, resistates vacuum-drying obtains compound 8.4, and quantitative yield is hydrochloride. 1H?NMR(400MHz，CD 3OD)：δ7.95(m，1H)，7.87(s，1H)，7.64(m，2H)，4.44(t，J＝6.85Hz，1H)，3.82(s，3H)，3.41(m，1H)，3.29(m，1H)，3.13(s，3H)ppm；ESI-MS(m/z)：(M+H +)258.10。
D) prepare compound 8 according to embodiment 3g, difference is to use compound 4.1 to replace compound 3.7, and uses compound 8.4 to replace compound 3.4. 1H NMR (400MHz, CD 3OD): δ 7.92 (s, 1H), 7.81 (d, J=7.92Hz, 1H), 7.68 (d, J=7.83Hz), 7.56 (t, J=7.83Hz, 1H), 7.30-7.49 (m, 5H), 5.06 (m, 1H), 4.60 and 4.83 (m, 2H), 3.95 and 3.66 (m, 2H), 3.44 (d, J=13.44Hz, 1H), 3.14 (m, 1H), 3.08 (s, 3H), 2.85 (m, 2H) ppm; ESI-MS (m/z): (M+H +) 609.05.
E) compound 8.4 also can be according to diagram 7B and the preparation of following process.
Diagram 7B
Figure A20048003980201121
8.5 (1.0mmoL), methyl iodide (1.2mmoL) and the mixture of salt of wormwood (2mmoL) in the acetone of 20mL were 50 ℃ of heating 3 hours.The solvent of reaction mixture is removed in decompression, and resistates distributes between EtOAc and water.The aqueous solution extracts with EtOAc, and the organic solution of merging is washed with salt, Na 2SO 4Drying is filtered and is concentrated.Crude product is white solid (yield 98%), and it need not the process that purifying is directly used in the back.
(1mmoL) slowly adds LiAlH in the solution of the THF of 4mL at 0 ℃ of compound to above-mentioned preparation 4(1.1mmoL).The reaction mixture room temperature of rising again, and stirred 1 hour, in reaction, sequentially add entry, the 15%NaOH aqueous solution and water and vigorous stirring.Filter and evaporated filtrate, obtain crude product 8.6 (yield 92%).Need not purifying. 1H?NMR(400MHz，CDCl 3)δ.3.05(s，3H)，4.75(s，2H)，7.53(t，J＝7.58Hz，1H)，7.62(d，J＝7.34Hz，1H)，7.81(d，J＝7.83Hz，1H)，7.93(s，1H)。
In room temperature at N 2Down with solid Tetrapropyl ammonium perruthenate (" TPAP ", 0.05mmol) disposable compound 8.6 (1mmoL), the 4-methylmorpholine N-oxide compound (" NMO " that joins stirring; 1.5mmoL) and the mixture of powdery 4A molecular sieve (with being equal in weight of NMO) in the DCM of 5mL in.Reaction mixture filters by short silicagel pad then stirring at room 1 hour, with DCM and AcOEt (1: 1) wash-out.Concentrated filtrate, resistates chromatography purification (SiO 2, AcOEt/ hexane 2: 1), obtain compound 8.7 (yield 72%). 1H?NMR(400MHz，CDCl 3)δ3.14(s，3H)，7.81(t，J＝7.58Hz，1H)，8.21(t，J＝9.05Hz，2H)，8.46(s，1H)，10.12(s，1H)ppm。
In room temperature with N, N, N ', N ' ,-tetramethyl guanidine (" TMG "; 1.05mmole) slowly join (d; l)-the Cbz-α-solution of phosphono glycine trimethyl (1.1mmole) in the DCM of 4mL in; after 15 minutes; mixture is cooled to-30 ℃; drip compound 8.7 (1mmole), mixture kept 20 minutes at-30 ℃, and slowly rose again 0 ℃; solution dilutes with AcOEt, and sequentially uses 1N NaHSO 4Wash with salt.Solution drying (Na 2SO 4), evaporating solvent obtains crude product.Crude product obtains product 8.8 (yield 72%) by chromatography purification (SiO2, AcOEt/ hexane/DCM 3: 3: 1). 1H?NMR(400MHz，CDCl 3)δ2.97(s，3H)，3.86(s，3H)，5.08(s，2H)，6.78(s，1H)，7.34(d，J＝6.36Hz，5H)，7.50(t，J＝7.83Hz，1H)，7.72(d，J＝7.34Hz，1H)，7.85(d，J＝7.34Hz，1H)，8.04(s，1H)。The olefinic proton of a small amount of trans-isomer(ide) 7.19ppm (s, 1H).ESI-MS(m/z)：(M+H +)346。
MeOH (20mL to 8.8 (1mmole) in the glass pressure container, be filled with nitrogen in advance) add chiral catalyst (+)-two ((2S in the solution, 5S)-2, benzene (cyclooctadiene) rhodium (I) a tetrafluoro borate (0.01mmole) 5-dimethyl phospholano).Reactor H then 2Be pressurized to 40psi and at room temperature continue jolting 17 hours, evaporating solvent, resistates are dissolved among the AcOEt and pass through SiO 2Pad filters with AcOEt.Evaporated filtrate obtains crude product 8.9.(yield, 72%). 1HNMR(400MHz，CDCl 3)δ2.98(s，3H)，3.13(dd，J＝13.69，6.36Hz，1H)，3.29(m，1H)，3.76(s，3H)，4.69(m，1H)，5.06(m，2H)，5.44(d，J＝6.85Hz，1H)，7.31(m，5H)，7.41(d，J＝7.34Hz，1H，7.47(t，J＝7.83Hz，1H)，7.72(s，1H)，7.82(d，J＝7.34Hz，1H)。ESI-MS(m/z)：(M+H +)348。
Compound 8.9 uses hydrogen balloons to carry out hydrogenation (Pd/C, MeOH), obtains compound 8.4 (yield 98%).ESI-MS(m/z)：(M+H +)258。
Embodiment 9
Present embodiment is described the synthetic of following compound
Figure A20048003980201141
It is according to diagram 8 and the preparation of following process.
Diagram 8
A) prepare compound 9.1 according to embodiment 1d-e, difference is to use compound 8.4 to replace compound 1.3.
B) prepare compound 9 according to embodiment 3g, difference is to use compound 9.1 to replace compound 3.7, and uses 2 hydroxy cinnamic acid 98 to replace compound 3.4. 1H NMR (400MHz, CD 3OD) δ 7.92 (m, 2H), 7.81 (m, 1H), 7.68 (s, 1H), 7.58 (m, 2H), 7.28 (m, 2H), 7.18 (m, 1H), 6.84 (m, 2H), 5.07 (m, 1H), 4.80 and 4.88 (m, 2H), 3.96 (m, 2H), 3.42 (m, 1H), 3.15 (m, 1H), 3.08 (s, 3H), 2.71-2.91 (m, 2H) ppm; ESI-MS (m/z): (M+H +) 617.10.
Embodiment 10
Present embodiment is described the synthetic of following compound
It is according to embodiment 3g preparation, and difference is to use compound 9.1 to replace compound 3.7, and uses the 2-fluoro cinnamic acid to replace compound 3.4. 1H NMR (400MHz, CD 3OD) δ 7.92 (s, 1H), 7.81 (m, 3H), 7.68 (m, 1H), 7.57 (m, 1H), 7.42 (m, 1H), 7.29 (m, 2H), 7.23 (m, 1H), 7.16 (m, 1H), 5.06 (m, 1H), 4.81 and 4.88 (m, 2H), 3.82 and 3.97 (m, 2H), 3.44 (m, 1H), 3.16 (m, 1H), 3.08 (s, 3H), 2.86 and 2.93 (m, 2H) ppm; ESI-MS (m/z): (M+H +) 619.10.
Embodiment 11
Present embodiment is described the synthetic of following compound,
Figure A20048003980201152
It is according to embodiment 3g preparation, and difference is to use compound 9.1 to replace compound 3.7, and uses 6-indazole carboxylic acid to replace compound 3.4. 1H NMR (400MHz, CD 3OD) δ 8.13 (s, 1H), 7.93 (m, 3H), 7.83 (m, 1H), 7.70 (m, 1H), 7.60 (m, 1H), 7.20 and 7.34 (m, 1H), 5.06 (m, 1H), 4.64 and 4.88 (m, 2H), 3.69 and 3.98 (m, 2H), 3.40 (m, 1H), 3.15 (m, 1H), 3.08 (s, 3H), 2.88 (m, 2H) ppm; ESI-MS (m/z): (M+H +) 615.15.
Embodiment 12
Present embodiment is described the synthetic of following compound,
It is according to embodiment 3g preparation, and difference is to use compound 9.1 to replace compound 3.7, and the 2-indole-carboxylic acid replaces compound 3.4. 1H?NMR(400MHz，CD 3OD)δ7.93(s，1H)，7.83(m，2H)，7.72(m，1H)，7.83(m，1H)，7.57(m，1H)，7.45(m，1H)，7.27(s，1H)，7.20(m，1H)，7.07(m，1H)，6.93(s，1H)，5.08(m，1H)，4.88(m，2H)，4.07(m，2H)，3.46(m，1H)，3.15(m，1H)，3.08(s，3H)，2.96(m，2H)ppm；ESI-MS(m/z)：(M+H +)614.10。
Embodiment 13
Present embodiment is described the synthetic of following compound,
Figure A20048003980201161
It is according to embodiment 3g preparation, and difference is to use compound 9.1 to replace compound 3.7, and uses quinaldinic acid to replace compound 3.4. 1H NMR (400MHz, CD 3OD) δ 8.51 (m, 1H), 8.08 (m, 1H), 8.01 (m, 1H), 7.94 (m, 1H), 7.84 (m, 2H), 7.70 (m, 3H), 7.58 (m, 1H), 7.36 and 7.04 (m, 1H), 5.07 (m, 1H), 4.78 and 4.95 (m, 2H), 3.79 and 4.08 (m, 2H), 3.45 (m, 1H), 3.17 (m, 1H), 3.09 (s, 3H), 2.97 (m, 2H) ppm; ESI-MS (m/z): (M+H +) 626.10.
Embodiment 14
Present embodiment is described the synthetic of following compound,
It is according to diagram 9 and the preparation of following process.
Diagram 9
A) (3.54g adds strong aqua (2.5mL) in ethyl acetate 16mmol) (50mL) solution to 3-carboxyl benzene sulfonyl chloride at 0 ℃.Reaction is used in the HCl neutralization in the dioxane (20mL), with ethyl acetate (100mL) dilution, also filters with anhydrous sodium sulfate drying.Filtrate concentrates, and obtains title compound, and it need not purifying and is used for reaction.
B) crude product compound 14.1 is dissolved among the THF (50mL), (1.0M is in THF to wherein adding borine in 20 minutes, 50mL), be reflected at stirring at room after 15 minutes, reaction is with salt solution (20mL) and water (10mL) dilution, with ethyl acetate (100mL) dilution.Organic extraction also filters with anhydrous sodium sulfate drying.Filtrate concentrates, and obtains title compound, and it need not purifying and is used for reaction.
C) in the solution of crude product compound 14.2 in DCM (100mL), add activatory 4A molecular sieve powder (8g), two chromic acid pyridines (7.55g, 20mmol).Be reflected at stirring at room after 2 hours, reaction mixture filters by silica gel (50g), uses the ethyl acetate rinsing.Resistates after filtrate concentrates with the hexane wash-out that contains the 30-50% ethyl acetate, obtains compound 14.3 (477mg, 16%, 3 step) by the silicagel column purifying.ESI-MS(m/z)：(M+H +)186。
D) prepare compound 14.4 according to embodiment 8e, difference is to use compound 14.3 to replace compound 8.7.MS(ESI +)m/z：260(M+H +)。
E) prepare compound 14 according to embodiment 3g, difference is to use compound 14.4 to replace compound 3.4. 1H?NMR(400MHz，CD 3OD)δ7.89(s，1H)，7.80(s，1H)，7.75(m，2H)，7.64(s，1H)，7.57(d，1H)，7.34(d，2H)，6.939s，1H)，5.00(m，1H)，3.99(m，1H)，3.73(m，1H)，3.40(dd，1H)，3.12(dd，1H)，2.89(m，2H)ppm；ESI-MS(m/z)：616(M+H +)。
Embodiment 15
Present embodiment is described the synthetic of following compound
Figure A20048003980201181
It is according to diagram 10 and the preparation of following process.
Diagram 10
Figure A20048003980201182
A) at-78 ℃ of n-BuLi (1.6M that in the solution of furans in the anhydrous THF of 200mL of 0.2mol, add 0.2mol, in hexane), the solution that obtains was stirring at room 4 hours, then, mixture is cooled to-78 ℃ of dimethyl sulphides of also using 0.21mol, mixture adds the saturated NH of 10mL then in stirred overnight at room temperature 4The Cl aqueous solution.Mixture concentrates in room temperature, the resistates saturated NH of 200mL 4The Cl aqueous solution dilutes and extracts with ether, and anhydrous Na is washed and used to extract with salt then 2SO 4Dry.Remove and to desolvate, distillation residue are collected in the fraction of 135-140 ℃/760mmHg, obtain compound 15.1,55% yields. 1H?NMR(400MHz，CD 3Cl)：δ7.50(s，1H)，6.45(m，1H)，6.39(s，1H)，2.42(s，3H)ppm。
B) at-78 ℃ of n-BuLi (1.6M that in the solution of compound 15.1 in the anhydrous THF of 100mL of 0.1mol, add 0.1mol, in hexane), the solution that obtains was stirring at room 4 hours, then, mixture is cooled to-78 ℃ and also handles with the 0.12mol dry DMF, mixture is in stirred overnight at room temperature.Reaction is by adding the saturated NH of 10mL 4The cancellation of the Cl aqueous solution, enriched mixture.Resistates extracts with the salt solution dilution of 100mL and with EtOAC.Extract is with the salt washing and use anhydrous Na 2SO 4Dry.Remove and desolvate, resistates obtains title compound, 65% yield through purifying. 1H?NMR(400MHz，CD 3Cl)：δ9.52(s，1H)，7.24(d，J＝3.4Hz，1H)，6.42(d，J＝3.4Hz，1H)，2.60(s，3H)ppm；ESI-MS(m/z)：(M+H +)143.1。
C) m-CPBA of the compound 15.2 of 50mmol and 120mmol is at the CH of 100mL 2Cl 2In mixture in stirred overnight at room temperature.The mixture CH of 150mL 2Cl 2Dilution, the saturated NaHCO of mixture 3The solution washing several times.Solution anhydrous Na then 2SO 4Dry and concentrated, resistates obtains compound 15.3,70% yields through purifying. 1H?NMR(400MHz，CD 3Cl)：δ9.83(s，1H)，7.33(m，2H)，3.27(s，3H)ppm；ESI-MS(m/z)：(M+H +)175.0。
D) prepare compound 15.4 according to embodiment 8e, difference is to use compound 15.3 to replace 8.7.ESI-MS(m/z)：(M+H +)248.1。
E) prepare compound 15 according to embodiment, difference is to use compound 15.4 to replace 3.4. 1H NMR (400MHz, CD 3OD): δ 7.92 (s, 1H), 7.76 (m, 1H), 7.67 (s, 1H), 7.34 (m, 1H), 7.13 (s, 1H), 6.69 (s, 1H), 6.49 (s, 1H), 5.11 (m, 1H), 4.73 and 4.88 (m, 2H), 3.76 and 4.02 (m, 2H), 3.46 (m, 1H), 3.30 (m, 1H), 3.17 (s, 3H), 2.94 (m, 2H) ppm; ESI-MS (m/z): (M+H +) 605.05.
Embodiment 16
Present embodiment is described the synthetic of following compound
Figure A20048003980201201
It prepares according to following process.
At the Et of 0 ℃ of compound 8.4 (embodiment 8c or 8e) at 1mmol to 0.2mmol 3The anhydrous CH of N and 5mL 2Cl 2Solution in add 2 of 0.22mmol, the 6-dichlorobenzoyl chloride, the mixture that obtains removes and desolvates resistates vacuum-drying stirring at room 12 hours.Then, the resistates LiOHH of 0.8mmol 2O is at the THF of 2mL and the H of 0.5mL 2Handle among the O.After 30 minutes, in reaction mixture, add the 1.0N HCl aqueous solution of 1.0mL in stirring at room.Remove organic solvent, resistates dilutes with the salt solution of 10mL.Mixture extracts with EtOAc, the extract anhydrous Na 2SO 4Dry.Remove and desolvate, resistates vacuum-drying obtains required compound, 65% yield. 1H?NMR(400MHz，CD 3OD)δ7.92(s，1H)，7.82(d，J＝6.85Hz，1H)，7.71(d，J＝6.85Hz，1H)，7.56(t，J＝7.83Hz，1H)，7.34(m，3H)，5.08(dd，J＝9.78，4.89Hz，1H)，3.45(dd，J＝14.67，4.89Hz，1H)，3.14(dd，J＝14.67，9.78Hz，1H)，3.08(s，3H)ppm；ESI-MS(m/z)：(M+H +)416.00。
Embodiment 17
Present embodiment is described the synthetic of following compound
It prepares according to following process.
(embodiment 6a, (4.0M 1mL) handles compound 6.1 in DCM (1mL) 0.2mmol) to be used in HCl in the dioxane.After 1 hour, evaporating solvent is at 0 ℃ of Et to resistates and 1mmol 3The anhydrous CH of N and 5mL 2Cl 2In add 2 of 0.22mmol, the 6-dichlorobenzoyl chloride, the mixture that obtains removes and desolvates resistates vacuum-drying stirring at room 15 hours.Then, resistates is used in the THF of 2mL and the H of 0.5mL 2The LiOHH of 0.8mmol among the O 2O handles., reaction mixture is joined in the 1.0N HCl aqueous solution of 1.0mL after 30 minutes in stirring at room.Remove organic solvent, resistates dilutes with the salt solution of 10mL.Mixture extracts with EtOAc, the extract anhydrous Na 2SO 4Drying is removed and is desolvated, and resistates vacuum-drying obtains required compound.
Embodiment 18
Present embodiment is described the synthetic of following compound
Figure A20048003980201211
It is according to diagram 11 and the preparation of following process.
Diagram 11
A) at-78 ℃ with 1 normal LiAlH 4(1.0M is in THF) joins in 0 ℃ 1 normal compound 6-indazole carboxylic acid, ethyl ester (Batt, D.G., J.Med.Chem., 43:41-58 (the 2000)) solution.Be reflected at other 30 minutes of-78 ℃ of restir, rise again 0 ℃ then.Slowly add the 1 normal 1M NaOH aqueous solution.The slurry that obtains is filtered by diatomaceous short column and washs with a large amount of ethyl acetate.With the organism MgSO that merges 4Dry also vacuum concentration obtains alcohol 18.1, and its purity is enough high, without being further purified use.
B) 1.1 normal Dess-Martin are crossed iodine alkane (periodinane) join in methylene dichloride 1 normal 18.1 in.At room temperature after the stirring reaction 3 hours, remove by filter the throw out that obtains by the diatomite short column.The diatomite short column is washed with methylene dichloride.The organism that merges is concentrated, obtain aldehyde 18.2, its purity is enough high, without being further purified use.
C) 2.1 normal ethylmagnesium bromide (0.5M is in THF) being joined 0 ℃ refrigerative in advance comprises in 18.2 the THF solution.After 30 minutes, make reaction rise again other 2 hours of room temperature and restir.With the reaction mixture that obtains with the ethyl acetate dilution and wash with water.Then with organic layer MgSO 4Drying is filtered vacuum concentration.Then resistates is passed through silica gel column chromatography purifying (using ethyl acetate and hexane gradient wash-out), obtain pure compound 18.3.
D) to 4-amino-2,6-chlorophenesic acid (1 equivalent) was at 3: 2 THF/H 2Add NaHCO in the mixture among the O 3(1.1 equivalent) and Boc 2O (1.1 equivalent) after stirring is spent the night, will react and use ether extraction, use MgSO 4Drying is filtered vacuum concentration.The not purified use of resistates 18.4.
E) under-78 ℃ to phenol 18.4 (1 equivalent) and 2, add trifluoromethanesulfanhydride anhydride (1.2 equivalent) in the DCM solution of 6-lutidine (2.2 equivalent).After ambient temperature overnight that reaction mixture is risen again gradually, reaction mixture dilutes with ether, washes with water, uses MgSO 4Drying is filtered vacuum concentration.With resistates purifying (using ethyl acetate and hexane gradient wash-out) on silicagel column, obtain pure compound 18.5 then.
F) triflate 18.5 of 10mmol, the dppp of 1.0mmol and the DIEA of 40mmol are at 100mL dry DMF and the anhydrous CH of 50mL 3Mixture among the OH purged 15 minutes with CO, added the Pd (OAc) of 1.0mmol then under CO atmosphere 2Subsequently, the mixture that obtains is spent the night 70 ℃ of stirrings under CO atmosphere.Remove and desolvate, resistates is by the column chromatography purifying, and the hexane wash-out with containing 10-30%EtOAc obtains compound 18.6.
G) 1 normal Boc-aniline 18.6 is dissolved in the H of 6M carefully 2SO 4In the aqueous solution, mixture is cooled to 0 ℃ then.Under vigorous stirring,, in 1.5 hours, add sodium iodide (5 equivalent) subsequently to wherein slowly adding Sodium Nitrite (1.1 equivalents are in water).Be reflected at after the stirred overnight at room temperature, reaction washes with water with the ether dilution, uses MgSO 4Drying is filtered vacuum concentration.With resistates purifying (using ethyl acetate and hexane gradient wash-out) on silicagel column, obtain pure compound 18.7 then.
H) with 1 normal iodide 18.7,1 normal alkynes 18.3,0.05 normal CuI, 5 normal triethylamines are dissolved in the benzene and by syringe needle bubbling N in solution 2Solution outgased in totally 15 minutes.Add 0.05 normal PdCl 2(dPPf) DCM.After 4 hours, also water, salt are washed with the ethyl acetate dilution in reaction.Then with organic layer MgSO 4Drying is filtered vacuum concentration.Resistates obtains pure compound 18.8 by silica gel column chromatography purifying (using ethyl acetate and hexane gradient wash-out) then.
I) be dissolved among the MeOH with 1 normal 18.8 and add 5%Rh/Al 2O 3(20 weight %).Under reduced pressure remove oxygen from flask.Fill the hydrogen recovery internal pressure that the balloon of hydrogen is sent by adding use.Be reflected under the hydrogen atmosphere and stirred 14 hours.To react and filter by Celite pad and vacuum concentration.Resistates obtains pure compound 18.9 by silica gel column chromatography purifying (using ethyl acetate and hexane gradient wash-out) then.
J) 4 normal LiI are joined in the 1 normal compound 18.9 in pyridine.To react and reflux 14 hours, make its cool to room temperature then.To react concentrated and the resistates that obtains be distributed between ethyl acetate and water.The water layer ethyl acetate extraction.The organic layer MgSO that merges 4Drying is filtered, and concentrates.Resistates obtains pure compound 18.10 by silica gel column chromatography purifying (using ethyl acetate and methyl alcohol gradient elution) then.
K) 1 normal compound 18.10,1 normal compound 8.4 (embodiment 8c or 8e), 3 normal DIEA are dissolved among the DMF.Add 1.1 normal HATU.Be reflected at stirring at room 14 hours.Also wash by water, salt with the ethyl acetate dilution for reaction mixture.With the organism MgSO that merges 4Drying is filtered, and concentrates.Resistates obtains pure intermediate ester by silica gel column chromatography purifying (using ethyl acetate and hexane gradient wash-out) then.Ester is dissolved in the methyl alcohol, adds 2 normal 1M LiOH (aqueous solution) subsequently.When finishing, under reduced pressure remove excessive solvent, the acid that will obtain obtains pure compound 18 by the reversed-phase HPLC purifying then.
Embodiment 19
Present embodiment is described the synthetic of following compound
It is by handling compound 18 (embodiment 18) preparation in DCM/TFA (1: 1 ratio) with triethyl silicane (10 equivalent).After LC-MS represents that starting raw material exhausts fully, will react concentrated, resistates obtains title compound by the reversed-phase HPLC purifying.
Embodiment 19
Present embodiment is described the synthetic of following compound
Figure A20048003980201252
It is according to diagram 12 and the preparation of following process.
Diagram 12
A) under-40 ℃, the solution of 1 normal compound 18.7 (embodiment 18g) in THF is handled with 1.0 normal sec.-propyl bromination magnesium.After 0.5 hour, add DMF (5 equivalent), react the ambient temperature overnight of rising again.Also wash by water, salt with the ethyl acetate dilution for reaction mixture.Then with organic layer MgSO 4Drying is filtered vacuum concentration.Resistates obtains pure compound 20.1 by silica gel column chromatography purifying (using ethyl acetate and hexane gradient wash-out) then.
B) 20.1 (1 equivalents) in THF add 2.1 normal ethynyl magnesium bromides (0.5M is in THF) under-78 ℃.Reaction rise again room temperature and stir other 2 hours after, with the reaction mixture that obtains with the ethyl acetate dilution and wash with water.Then with organic layer MgSO 4Drying is filtered vacuum concentration.Resistates obtains pure compound 20.2 by silica gel column chromatography purifying (using ethyl acetate and hexane gradient wash-out) then.
C) with 1 normal compound 20.2,1 normal 1-chloro-4-phenyl-iodide, 0.05 normal CuI, 5 normal triethylamines are dissolved in the benzene and by syringe needle bubbling N in solution 2Solution outgased in totally 15 minutes.Add 0.05 normal PdCl 2(dppf) DCM.After 4 hours, also water, salt are washed with the ethyl acetate dilution in reaction.Then with organic layer MgSO 4Drying is filtered vacuum concentration.Resistates obtains pure compound 20.3 by silica gel column chromatography purifying (using ethyl acetate and hexane gradient wash-out) then.
D) 1 normal compound 20.3 is dissolved among the MeOH.Add 5%Rh/Al 2O 3Under reduced pressure remove oxygen from flask.Fill the hydrogen recovery internal pressure that the balloon of hydrogen is sent by adding use.To be reflected under the hydrogen atmosphere and stir 14 hours.To react by Celite pad and filter and vacuum concentration.Resistates obtains pure compound 20.4 by silica gel column chromatography purifying (using ethyl acetate and hexane gradient wash-out) then.
E) 4 normal LiI are joined in the 1 normal compound 20.4 in pyridine.Reaction refluxed 14 hours, made its cool to room temperature then.To react concentrated and the resistates that obtains be distributed between ethyl acetate and water.The water layer ethyl acetate extraction.The organic layer MgSO that merges 4Drying is filtered, and concentrates.Resistates obtains pure compound 20.5 by silica gel column chromatography purifying (using ethyl acetate and methyl alcohol gradient elution) then.
F) 1 normal compound 20.5,1 normal compound 8.4 (embodiment 8c or 8e), 3 normal DIEA are dissolved in DMF.Add 1.1 normal HATU.Be reflected at stirring at room 14 hours.Also wash by water, salt with the ethyl acetate dilution for reaction mixture.With the organism MgSO that merges 4Drying is filtered, and concentrates.Resistates obtains pure compound 20.6 by silica gel column chromatography purifying (using ethyl acetate and hexane gradient wash-out) then.
G) 1 normal compound 20.6 is dissolved in methyl alcohol, adds 2 normal 1MLiOH (aq) subsequently.When finishing, excessive solvent is removed in decompression, and the acid that will obtain obtains pure powder compounds 20 by reversed-phase HPLC purifying and freeze-drying then.
Embodiment 21
Present embodiment is described the synthetic of following compound
Figure A20048003980201271
It is according to diagram 13 and the preparation of following process.
Diagram 13
Figure A20048003980201272
A) prepare bromine (461 μ L, 9.00mmol) solution in methyl alcohol (6.0mL) down at-78 ℃.Under nitrogen, cold drips of solution is added to-78 ℃ KCN (1.85g, 19.0mmol) mixture in methyl alcohol (6.0mL).After 20 minutes, add pyrroles (0.624mL, methyl alcohol 9.00mmol) (20mL) solution.Make mixture reach-40 ℃ and stirred 0.5 hour.Then it is poured over ice-waterborne and with ether extraction (3x).Wash with the organic layer merging and with saturated sodium thiosulfate and salt.Then with organic phase drying (Na 2SO 4) and concentrate.Thick resistates obtains the compound 21.1 of 734mg (66%) by hurried chromatography purification (the 0-50% ethyl acetate is in hexane), is colourless oily matter, R f(0.24 10% ethyl acetate is in hexane). 1H?NMR(CDCl 3)δ8.68(br?s，1H)，7.03(s，1H)，6.69(s，1H)，6.32(s，1H)。ES(+)MS?m/e＝125(M+H) +。
B) under nitrogen under-10 ℃ to 21.1 (614mg, 4.95mmol) and methyl iodide (0.340mL, the dropping sodium aqueous solution in methyl alcohol 5.45mmol) (40mL) solution (9.90mL, 1M, 9.90mmol).Make rise again envrionment temperature and stirring 0.5 hour of mixture.Then by adding the excessive sodium hydroxide of dry ice cancellation.Mixture is with salt solution dilution and with dichloromethane extraction (3x).With the organic layer drying (Na that merges 2SO 4) and concentrate, obtain the compound 21.2 of 504mg (90%), be dark oily matter, R f(0.35 10% ethyl acetate is in hexane). 1HNMR(CDCl 3)δ8.31(br?s，1H)，6.84(s，1H)，6.38(s，1H)，6.24(s，1H)，2.36(s，3H)。
C) to 0 ℃ compound 21.2 (100mg, drip in methyl alcohol 0.884mmol) (4.0mL) solution sodium periodate in water (4.0mL) (208mg, 0.972mmol).Make the mixture room temperature of rising again, after 15 minutes, LC/MS and TLC show compound 21.2 completely dissolves.Then mixture is filtered, concentrate, resistates is distributed between ethyl acetate and water.Water layer is with ethyl acetate extraction twice, and the organic phase that merges is washed dry (Na with salt 2SO 4) and concentrate, obtain the compound 21.3 of 63mg (55%), be dark oily matter, R f(0.25 ethyl acetate). 1H?NMR(CDCl 3)δ11.74(br?s，1H)，7.00(s，1H)，6.65(s，1H)，6.20(s，1H)，3.03(s，3H)。ES(+)MS?m/e＝130(M+H) +。
D) (60mg adds trifluoroacetic acid (1.0mL) in methylene dichloride 0.464mmol) (2.0mL) solution to compound 21.3.After 15 minutes, LC/MS and TLC show compound 21.3 completely dissolves.Remove in a vacuum and desolvate, resistates in high vacuum dry, is obtained the compound 21.4 of 60mg (100%), be oily matter, R f(0.11 ethyl acetate). 1HNMR(CDCl 3)δ9.16(br?s，1H)，7.28(s，1H)，6.94(s，1H)，6.66(s，1H)，3.02(s，3H)。ES(+)MS?m/e＝130(M+H) +。
E) to compound 21.4 (60mg, 0.464mmol) and Cs 2CO 3(378mg, 1.16mmol) mixture add compound 21.5 (people such as Ferreira, Tetrahedron Letters, 39:9575 (1998); 140mg, acetonitrile solution 0.464mmol).The mixture that obtains is shown starting raw material completely consumed (～1 hour) 60 ℃ of stirrings up to LC/MS and TLC.With the mixture cool to room temperature and with ethyl acetate dilution and water and salt washing.With organic layer drying (Na 2SO 4) and concentrate.Thick resistates obtains the compound 21.6 of 114mg (57%) by hurried chromatography purification (the 0-100% ethyl acetate is in hexane), is heavy-gravity oily matter, R f(0.31 ethyl acetate). 1H?NMR(CDCl 3)δ7.05(s，1H)，6.75(s，1H)，6.50(s，1H)，5.25(m，1H)，4.65(m，1H)，4.40(m，1H)，3.79(s，3H)，2.79(s，3H)，1.47(s，18H)。ES(+)MS?m/e＝275(M-Boc-t-Bu+2H) +。
F) to compound 21.6 (114mg, drip in methylene dichloride 0.265mmol) (1.00mL) solution mCPBA (89.0mg, 0.397mmol).After at room temperature reacting 5 minutes, LC/MS and TLC show compound 21.6 completely dissolves.Mixture is filtered and concentrates.Thick resistates by hurried chromatography purification (the 0-50% ethyl acetate is in hexane), is obtained the compound 21.7 of 89.0mg (75%), be colourless oily matter, R f(0.45 50% ethyl acetate is in hexane). 1H?NMR(CDCl 3)δ7.22(s，1H)，6.69(s，1H)，6.50(s，1H)，5.27(m，1H)，4.65(m，1H)，4.45(m，1H)，3.79(s，3H)，305(s，3H)，1.48(s，18H)。ES(+)MS?m/e＝247(M-2Boc+3H) +。
G) (89.0mg adds HCl (4.00mL, 4.0M is in dioxane) in methylene dichloride 0.0.199mmol) (0.50mL) solution to compound 21.7.The mixture that obtains stirred at ambient temperature up to LC/MS show complete deprotection (～1 hour).Mixture is concentrated, and resistates is dry under high vacuum, obtains the compound 21.8 of 53mg (100%), is white powder.ES(+)MS?m/e＝247(M+H) +。
H) with compound 21.8 (53.0mg, 0.199mmol), compound 4.1 (embodiment 4a, 77.0mg, 0.199mmol), HATU (79.0mg, 0.209mmol), (0.111mL, 0.796mmol) mixture in DMF (1.00mL) is in stirred overnight at room temperature for triethylamine.Then with mixture with ethyl acetate dilution and with the 1.0MHCl aqueous solution, saturated NaHCO 3, salt washing.With organic layer drying (Na 2SO 4) and concentrate.Thick resistates obtains the compound 21.9 of 70.3mg (58%) by hurried chromatography purification (the 0-100% ethyl acetate is in hexane), is white solid, R f(0.16 75% ethyl acetate is in hexane). 1H?NMR(CDCl 3)δ7.46-7.39(m，5H)，7.28(s，1H)，6.73(s，1H)，6.69(br?s，1H)，6.48(s，1H)，5.13(m，1H)，4.83(br?s，1H)，4.56(m，1H)，3.85(s，3H)，3.70(m，1H)，3.04(s，3H)，2.91(br?s，2H)，2.81(s，2H)。ES(+)MS?m/e＝614(M+H) +。
I) to 21.9 (70.3mg, add in THF 0.115mmol) (1.00mL) solution LiOH (the 1.0M aqueous solution, 0.360mL, 0.360mmol).The mixture that obtains is shown complete hydrolysis (～0.5 hour) in stirring at room up to TLC and LC/MS.To react cancellation and be concentrated into dried by adding the 1.0MHCl aqueous solution (0.400mL) then.Resistates is dissolved in dimethyl sulfoxide (DMSO) (" DMSO "; 4.0mL) in and by preparation property RP-HPLC purifying.The fraction that will comprise pure compound merges and concentrates.With resistates freeze-drying 48 hours under high vacuum, obtain the compound 21 of 33.8mg (49%), be white powder. 1H?NMR(CDCl 3)δ7.46-7.39(m，4H)，7.28(m，2H)，7.15(br?s，1H)，6.77(s，1H)，6.38(s，1H)，5.74(br?s，2H)，5.04(m，1H)，4.83(br?s，1H)，4.53(m，3H)，3.69(m，1H)，3.00(s，3H)，2.85(br?s，2H)。ES(+)MS?m/e＝600(M+H) +。
Embodiment 22
Present embodiment is described the synthetic of following compound
It is according to diagram 14 and the preparation of following process.
Diagram 14
Figure A20048003980201311
A) with compound 22.1 (people such as Plobeck, the J.Med.Chem of 5.0g (28.2mmol).43:3878-3894 (2000)) and acetate (50mL) solution of sulfuryl chloride (each 100mmol adds when the reaction beginning and after 15 hours) refluxed 36 hours.Pale solid ether rinsing with concentrated reaction mixture obtains adds DCM (50mL) in the crude product that obtains, add BBr subsequently 3(1.0 M, in DCM, 100mL).After 6 hours, reaction mixture is concentrated, add entry (50mL) carefully.Collect the throw out obtain and be dried by filtration under diminished pressure, obtain thick compound 22.2, quantitative yield.
B) thick compound 22.2 is dissolved in the DCM/ pyridine (50mL/50mL) and is cooled to 0 ℃.To wherein adding trifluoromethanesulfanhydride anhydride (42.3mmol) lentamente, will react then and at room temperature stir 6 hours.Reaction mixture is distributed between ethyl acetate (200mL) and water (50mL), and organic layer water (30mL, twice) and salt washing are with anhydrous sodium sulfate drying and filtration.The resistates that concentrated filtrate is obtained obtains compound 22.3 (3.16g, 32%) by the silica gel column chromatography purifying.ESI-MS(m/z)：(M+H +)364/366。
C) the carbon monoxide bubbling is passed through compound 22.3 (581mg, 1.6mmol), the mixture of BiNAP (0.2mmol), acid chloride (0.2mmol), triethylamine (1mL), anhydrous methanol (3mL) and dry DMF (3mL) 10 minutes, will be reflected at then under the carbon monoxide balloon 65 ℃ of heating 15 hours.Reaction mixture is distributed between ethyl acetate (100mL) and water (25mL), with organic layer water (25mL, twice) and salt washing, with anhydrous magnesium sulfate drying and filtration.The resistates that concentrated filtrate obtains obtains compound 22.4 (213mg, 49%) by the silicagel column purifying.ESI-MS(m/z)：(M+H +)274/276。
D) to sodium hydride (24mg, 1.0mmol) add in the suspension in THF (2mL) compound 22.4 (63mg, 0.23mmol), the 4-chlorobenzyl chloride (55mg, 0.34mmol) and tetrabutylammonium iodide (10mg).After 6 hours, reaction is used the ether rinsing with the ether dilution and by filtered through silica gel.The resistates that concentrated filtrate is obtained passes through the silicagel column purifying, obtains compound 22.5 (50mg, 55%).ESI-MS(m/z)：(M+H +)398/400。
E) the mixture backflow of LiI in the pyridine of 2mL of compound 22.5 (50mg) and 1mmol spent the night.To react vacuum concentration, resistates passed through high vacuum dry 2 hours.The crude compound 22.6 that obtains is without being further purified use.ESI-MS(m/z)：(M+1)，384。
F) prepare compound 22 according to embodiment 3g, difference is to replace compound 3.7 (yield: 82%) with compound 22.6. 1H?NMR(400MHz，dmso-d 6)：9.12(d，1H)，8.54(t，1H)，7.90(s，1H)，7.77(dd，1H)，7.72(dd，1H)，7.42(d，2H)，7.35(d，2H)，7.16(dd，1H)，4.77(m，1H)，4.70(s，2H)，3.64(m，2H)，3.53(t，2H)，3.01(t，2H)ppm。ESI-MS(m/z)：(M+H +)580。
Embodiment 23
Present embodiment is described the synthetic of following compound
It is according to diagram 15 and the preparation of following process.
Diagram 15
Figure A20048003980201331
A) (compound 23.1 10mmol) and in DCM (40mL) solution of triethylamine adds methylsulfonyl chloride (11mml) lentamente, and after 12 hours, reaction is extracted (100mL) with ether, washes with water, with anhydrous magnesium sulfate drying and filtration to Trit-Ser-Ome.Filtrate concentrating obtained compound 23.2, and it is without being further purified use.
B) with crude compound 23.2, the solution stirring of sodiumazide (20mmol) in DMF 15 hours.Reaction is extracted (100mL) with ether, washes with water, with anhydrous magnesium sulfate and filtration.The resistates that concentrated filtrate obtains is crossed column purification, and the hexane wash-out with containing the 0-20% ethyl acetate obtains compound 23.3.
C) with compound 23.3, the cyclopropyl acethlene of 1.5mmol, the CuI of 0.02mmol, the Et of 0.02mmol of 1mmol 3N is at the CH of 6mL 3Mixture among the CN is in stirred overnight at room temperature.Remove and desolvate, resistates obtains compound 23.4,65% yields through purifying. 1HNMR(400MHz，CD 3OD)：δ7.80(s，1H)，7.29-7.31(m，6H)，7.15-7.23(m，9H)，4.49(m，2H)，3.73(m，1H)，3.16(s，3H)，1.99(m，1H)，0.99(m，2H)，0.80(m，2H)ppm；ESI-MS(m/z)：(M+H +)453.15。
D) mixture of the compound 23.4 of 0.5mmol in the dioxane that contains 4.0N HCl of 2mL was stirring at room 1 hour.Remove and desolvate, resistates dilutes with the water of 10mL.Mixture extracts 3 times with ether, and water freeze drier drying obtains compound 23.5, quantitative yield.ESI-MS(m/z)：(M+H +)212.15。
E) prepare compound 23 according to embodiment 3g, difference is to replace compound 3.7 with compound 4.4, replaces compound 3.4 with compound 23.5. 1H NMR (400MHz, CD 3OD): δ .7.74 (s, 1H), 7.33 and 7.49 (m, 5H), 5.25 (m, 1H), 4.63-4.92 (m, 4H), 3.99 and 3.68 (m, 2H), 2.89 (m, 2H), 1.91 (m, 1H), 0.95 (m, 2H), 0.75 (m, 2H) ppm; ESI-MS (m/z): (M+H +) 562.10.
Embodiment 24
Present embodiment is described the synthetic of following compound
It is according to diagram 16 and the preparation of following process.
Diagram 16
A) under 0 ℃ to the 1-of 50mmol bromo-3, add the NaSCH3 of 50mmol in the 100mL anhydrous DMF solution of 5-two fluorobenzene, with the mixture that obtains in stirred overnight at room temperature and with the saturated NH of 10mL 4The Cl aqueous solution is handled.Mixture is used the hexane extraction several times with the water dilution of 1L.Extract washes and uses anhydrous Na with water 2SO 4Dry.Remove and desolvate, resistates obtains compound 24.2,90% yields through purifying. 1H?NMR(400MHz，CD 3Cl)：δ7.15(s，1H)，7.02(d，J＝8.3Hz，1H)，6.89(d，J＝9.2Hz，1H)，2.50(s，3H)ppm。
B) compound 24.2 of 40mmol and the mixture of CuCN in the 100mL dry DMF of 42mmol are spent the night 150 ℃ of stirrings.Mixture extracts several times with the water dilution of 500mL with ether.Then mixture is used rare NH 4The OH aqueous solution and washing are also used anhydrous Na 2SO 4Dry.Remove and desolvate, resistates obtains compound 24.3,50% yields through purifying. 1H?NMR(400MHz，CD 3Cl)：δ7.28(s，1H)，7.17(d，J＝9.2Hz，1H)，7.11(d，J＝6.8Hz，1H)，2.53(s，3H)ppm；ESI-MS(m/z)：(M+H +)168.0。
C) with the KOH of the compound 24.3 of 20mmol and 22mmol at the EtOH of 25mL and the H of 35mL 2Mixture among the O stirred 30 minutes at 60 ℃.With mixture, concentrate, resistates extracts several times with the water dilution of 100mL with EtOAc.The extract anhydrous Na 2SO 4Dry.Remove and to desolvate, resistates vacuum-drying obtains the crude product of compound 24.4.Crude product is used for next step without being further purified.ESI-MS(m/z)：(M+H +)187.0。
D) at the LiAlH that in the 60mL anhydrous THF solution of the compound 24.4 of 20mmol, adds 24mmol under 0 ℃ 4(1.0M is in THF).After stirred overnight at room temperature, in reaction mixture, add saturated NH carefully 4The Cl aqueous solution.Then the suspension that obtains is concentrated.Resistates is dissolved among the 1.0N HCl of 200mL and and extracts several times with EtOAc.With the extract anhydrous Na 2SO 4Dry and concentrated.Subsequently, resistates obtains 5-fluoro-3-methyl mercapto-1-benzylalcohol, 81% yield through purifying. 1H?NMR(400MHz，CD 3Cl)：δ7.03(s，1H)，6.86(m，2H)，4.69(s，2H)，2.51(s，3H)ppm；ESI-MS(m/z)：(M+H +)173.1。
With the 5-fluoro-3-methyl mercapto-1-benzylalcohol of 15mmol and the SOCl of 20mmol 2At the anhydrous CH of 30mL 2Cl 2In mixture refluxed several hours.Then with the CH of mixture with 100mL 2Cl 2Saturated NaHCO is used in dilution 3The aqueous solution, saturated NH 4The Cl aqueous solution, salt washing, and use anhydrous Na 2SO 4Dry.Remove and desolvate, resistates obtains compound 24.5,85% yields through purifying.
E) prepare compound 24.6 according to embodiment 3a-c, difference is to replace 3-methyl sulfenyl benzyl chloride with compound 24.5.
F) prepare compound 24 according to embodiment 3g, difference is to replace compound 3.7 with compound 24.6. 1H NMR (400MHz, CD 3OD): δ 7.92 (s, 1H), 7.80 (s, 1H), 7.75 (d, J=7.83Hz, 1H), 7.74 (s, 1H), 7.59 (d, J=7.34Hz, 1H), 7.49 (d, J=9.29Hz, 1H), 7.07 and 7.35 (m, 2H), 6.96 (s, 1H), 5.10 (dd, J=9.78,4.40Hz, 1H), 4.72 and 4.91 (m, 2H), 3.77 and 4.00 (m, 2H), 3.50 (dd, J=14.18,4.40Hz, 1H), 3.20 (m, 1H), 2.91 (m, 2H) ppm; ESI-MS (m/z): (M+H +) 633.10.
Embodiment 25
Present embodiment is described the synthetic of following compound
Figure A20048003980201361
It is according to diagram 17 and the preparation of following process.
Diagram 17
Figure A20048003980201362
A) under 0 ℃ to the compound 3.2 (embodiment 3a) of 5.0mmol, the Pd (PPh of 0.25mmol 2) 2Cl 2, 0.25mmol CuI at the degassing Et of 15mmol 3Solution in the degassed toluene of N and 40mL adds the isobutyryl chloride of 5.5mmol.The mixture that obtains is also used the saturated NaHCO of 20mL in stirred overnight at room temperature 3The aqueous solution is handled.Organic layer separated and use anhydrous Na 2SO 4Dry.Remove and desolvate, resistates obtains compound 25.1,80% yields by the column chromatography purifying. 1H?NMR(400MHz，CD 3OD)：δ4.38(m，1H)，3.74(s，3H)，2.91(m，2H)，2.61(m，1H)，1.44(s，9H)，1.14(d，J＝6.85Hz，6H)ppm；ESI-MS(m/z)：(M+H +)320.01。
B) under 0 ℃ to the compound 25.1 of 1.0mmol CH at 3mL 3The NH that adds 1.0mmol in the solution among the OH 2NH 2, the mixture that obtains was stirred other 30 minutes.Remove and desolvate,, obtain compound 25.2,65% yields residue purified.
1H NMR (400MHz, CD 3OD): 6.28 and 5.95 (s, s, 1H), 4.39 and 4.19 (m, 1H), 3.72 (s, 3H), 2.91 (m, 2H), 2.70 and 2.98 (m, 1H), 1.43 and 1.45 (s, s, 9H), 1.12 and 1.27 (m, 6H) ppm; ESI-MS (m/z): (M+H +) 312.20.
C) with the mixture of compound 25.2 in the dioxane that contains 4.0N HCl of 4mL of 0.5mmol stirring at room 12 hours.Remove and desolvate,, obtain compound 25.3 resistates vacuum-drying.ESI-MS(m/z)：(M+H +)212.10。
D) prepare compound 25 according to embodiment 3g, difference is to replace compound 3.7 with compound 4.4, replaces compound 3.4 with compound 25.3.
1H NMR (400MHz, CD 3OD): 7.15-7.54 (m, 5H), 6.38 (s, 1H), 5.06 (dd, J=9.78,4.89Hz, 1H), 4.66 and 4.88 (m, 2H), 4.01 and 3.71 (m, 2H), 3.41 (dd, J=15.41,4.65Hz, 1H), 3.18 (dd, J=15.16,4.65Hz, 1H), 3.07 (m, 1H), 2.92 (m, 2H), 1.32 (d, J=7.34Hz, 6H) ppm; ESI-MS (m/z): (M+H +) 563.10.
Embodiment 26
Present embodiment is described the synthetic of following compound
Figure A20048003980201371
It is synthetic according to diagram 18 and following process.
Diagram 18
A) with compound 26.1 (12.4g, 75mmol) and NH 4BF 4(10.5g, water 100mmol) (85mL) solution is handled with dense HCl (15mL), is cooled to 3 ℃, by dripped NaNO in 25 minutes 2(5.18g, water 75mmol) (12mL) solution-treated.The stiff slurry that obtains was stirred 35 minutes, and by solid collected by filtration, water, methyl alcohol and ether rinsing are at N 2Middle dry.With the disposable KOAc that joins stirring of solid (8.1g, 82.5mmol) and 18-hat-6 (0.5g is 1.9mmol) in the mixture in chloroform (170mL).After 70 minutes, add entry (170mL), separatory.The water chloroform extraction, the organic layer water rinse of merging, drying concentrates.Resistates and hexane are ground and, obtain the compound 26.2 of 8.85g (67% yield), be the dark yellow powder by the solid that filtering separation obtains. 1H?NMR(CDCl 3)δ3.96(s，3H)，7.80-7.85(m，2H)，8.14(s，1H)，8.27(s，1H)；ES(+)MS?m/e＝177(M+1)。
B) with compound 26.2 (5.0g, THF 28.4mmol) (56mL) solution with LiOH (the 2M aqueous solution of 21mL 42mmol) is handled, with reaction mixture 50 ℃ of stirrings.After 4 hours, reaction mixture cool to room temperature and dilute with water.The ether rinsing of alkalescence water layer is adjusted to pH3-4 by adding 1M HCl, uses ethyl acetate extraction.Water layer is used ethyl acetate extraction again, and the organic layer of merging salt water rinse is used MgSO 4Drying concentrates, and obtains the compound 26.3 of 4.0g (87% yield). 1H?NMR(CD 3OD)δ7.79-7.87(m，2H)，8.14(s，1H)，8.29(s，1H)；ES(+)MS?m/e＝163(M+1)。
C) (7.5g, DCM 20.8mmol) (30mL) solution is handled with TFA (10mL) with compound 1.1.After 1 hour, reaction mixture is concentrated, obtain the compound 26.4 of 7.8g (100% yield).ES(+)MS?m/e＝261(M+1)。
D) with compound 26.3 (7.8g, 20.8mmol), compound 26.4 (3.4g, 20.8mmol), I-hydroxybenzotriazole hydrate (" HOBt ", 3.5g, 22.3mmol), diisopropyl ethyl amine (" DIEA ", 14mL, (4.4g 22.3mmol) handles DMF 83.3mmol) (100mL) solution with EDCI.After 2 hours, ethyl acetate extraction is handled and used to reaction mixture with 1M HCl.With the organic extraction NaHCO that merges 3The salt water rinse is used in (saturated) rinsing, uses water rinse, MgSO 4Drying concentrates, and obtains the title compound of 8.4g (99% yield).ES(+)MS?m/e＝404(M+1)。
E) (8.4g, (11.1g 83.1mmol) handles pyridine 20.8mmol) (70mL) solution, and reaction mixture is heated to 100 ℃ with lithium iodide with compound 26.5.After 16 hours, dilute with the reaction mixture cool to room temperature and with 1M NaOH (aq).Alkalescence water layer with the ether rinsing to remove most pyridine.Then aqueous portion is acidified to pH3-4 with dense HCl carefully.The slurry that obtains is filtered.The collecting precipitation thing also is dissolved in it among THF, and filtrate is used ethyl acetate extraction.THF and ethyl acetate solution are merged, use the salt water rinse, MgSO 4Drying concentrates, and obtains the compound 26.6 of 7.1g (88% yield).ES(+)MS?m/e＝390(M+1)。
F) with compound 26.6 (3.06g, 7.83mmol) and DIEA (4.6mL, (3.06g 8.06mmol) handles dimethyl formamide 25.4mmol) (" DMF ") solution, and the mixture that obtains is in stirring at room with HATU.After 20 minutes, reaction mixture is sequentially used HClH-DAP (Boc)-OMe, and (2.18g, 8.59mmol) and N, (" DMAP ", 0.568g 4.65mmol) handle the N-dimethyl aminopyridine.After 2.5 hours, reaction is diluted with ethyl acetate, and water is given a baby a bath on the third day after its birth inferior, with the salt washing once, and MgSO 4Drying concentrates.Hurried column chromatography obtains the compound 26.7 of 3.91g (84% yield). 1H NMR (400MHz, the δ 1.42 of chloroform-d) (s, 9H), 2.81 (s, 2H), 3.70 (m, 2H), 3.75 (2H), 3.81 (s, 3H), 4.82 (m, 21H), 4.99 (m, 1H), 7.21 (d, 2H), 7.59 (s, 1H), 7.81 (d, 1H), 8.10 (s, 1H).MS (API-ES +) m/z:590.2 (M+H +), 534.1 (M-t butyl+H +), 490.1 (M-Boc+H +).
G) with compound 26.7 (3.91g, 6.62mmol) DCM solution with HCl (the 4M dioxane solution of 8.3mL 33.2mmol) is handled, with the mixture that obtains in stirring at room.After 2 hours, reaction mixture is concentrated, obtain HCl salt, it is without being further purified use.With the HCl salt in the methyl alcohol (3.94g, 6.99mmol) and triethylamine (" TEA ", 3.0mL, 21.5mmol) with N-cyano group acylimino-S, S-dimethyl-disulfide group carbonic ether (1.37g 8.43mmol) handles, with reaction mixture 50 ℃ of stirrings.After 3.5 hours, reaction mixture is concentrated to remove most methyl alcohol, with the ethyl acetate dilution, wash twice with water, with the salt washing once, MgSO 4Drying concentrates.Hurried column chromatography obtains the compound 26.8 (MS (API-ES of 3.27g (80% yield) +) m/z:588.2 (M+H +).Preparation compound 26.8 (0.10mmol) is at 4: 1 methanol/dichloroethane (" DCE ", 2.5mL) solution in and it is sequentially used methyl alcohol-ammoniacal liquor (0.25mmol) and Silver Nitrate (0.10mmol) processing of 2M.Reaction mixture is finished up to transforming by the LCMS monitoring 50 ℃ of stirrings.Then reaction mixture is passed through diatomite filtration, and adding KOH (the 2M methanol solution of 0.1mL, 0.2mmol).With reaction mixture once more 50 ℃ of stirrings.After 2-4 hour, make reaction mixture directly through preparation property HPLC purifying, obtain compound 26.
Embodiment 27
Present embodiment is described the synthetic of following compound
Figure A20048003980201401
R wherein AAnd R BIndependently of one another for hydrogen, aliphatic portion, aromatic series part, heteroaromatic part or form circular part together.These compounds are according to the method preparation of embodiment 26, and difference is to use formula HNR in step g AR BReplacement amine replace ammonia.The illustrative example of the compound that replaces amine and obtain is as shown in table 1.
Table 1
Figure A20048003980201411
Figure A20048003980201421
Embodiment 28
Present embodiment is described the synthetic of following compound
Figure A20048003980201422
It makes according to diagram 19 and following process.
Diagram 19
A) as implied above, according to Okada, people such as T., Chem.Phar.Bull., 1993,41 (1), 126-131; Frigola, people such as J., J.Med.Chem., 1993,36 (7), the 801-810 disclosed method prepares 28.4 with three chemical steps from compound 28.1.DCM solution with commercially available 28.1 is handled with trifluoromethanesulfonyl chloride in the presence of alkali and is obtained 36.2.Then this product is dissolved in the glycol dimethyl ether (" DME "), replaces the methanesulfonates part by dimethylamine.At last, in MeOH at 45PSI H 2(g) carry out the Pd/C-catalytic hydrogenation under, obtain compound 28.4.
B) according to the method synthetic compound 28 of embodiment 26, difference is to use in step g 3-(dimethylamino) cyclobutanol (35.1) to replace ammonia.
Embodiment 29
Present embodiment is described the synthetic of following compound
Figure A20048003980201432
It makes according to diagram 20 and following process.
Diagram 21
Figure A20048003980201433
A) (compound 29.1 adds N-methylmorpholine (22mmol) and O in THF 10mmol) (15mL) solution to 3-pyrroline-1-benzyl formate SO 4(2mL, 2.5 weight % are in t-BuOH), with the mixture that obtains in stirred overnight at room temperature.Remove and desolvate, resistates is dissolved among the EtOAc (100mL), with rare Na 2SO 3The aqueous solution, saturated NH 4Anhydrous Na is used in the Cl aqueous solution, salt washing 2SO 4Dry.Remove and desolvate, resistates obtains compound 29.2,55% yields by the column chromatography purifying.EIMS (m/z): C 12H 15NO 4(M +)+Na calculated value 260.1, measured value 260.1; 1H NMR (CD 3OD, 400MHz): δ 7.31-7.38 (m, 5H), 5.13 (s, 2H), 4.17 (m, 2H), 3.58 (m, 2H), 3.34 (m, 2H) ppm.
B) with compound 29.2 (1.0mmol) and 10%Pd/C (0.1mmol) mixture in methyl alcohol (5mL) at room temperature at H 2Stirred several hours under the atmosphere.Reaction mixture is filtered, and filtrate concentrates, and resistates vacuum-drying obtains compound 29.3.
C) according to the method synthetic compound 29 of embodiment 26, difference is to use (3R, 4S)-(dihydroxyl) tetramethyleneimine (29.3) replacement ammonia in step g.
Embodiment 30
Present embodiment is described the synthetic of following compound
It is according to diagram 21 and the preparation of following process.
Diagram 21
Figure A20048003980201442
A) will (3R, 4R)-benzyl-3,4-tetramethyleneimine glycol (compound 30.1,1mmol) and 20%Pd (OH) 2The mixture of/C (0.1mmol) in methyl alcohol (10mL) is at room temperature at the H of 45psi 2(g) shook under several hours.Reaction mixture is filtered, filtrate is concentrated, resistates vacuum-drying obtains compound 30.2.
B) according to the method synthetic compound 30 of embodiment 26, difference is to replace ammonia with compound 30.2 in step g.
Embodiment 31
Present embodiment is described the synthetic of following compound
Figure A20048003980201451
It is according to diagram 22 and the preparation of following process.
Diagram 22
Figure A20048003980201452
A) with commercially available 3-pyrroline-1-benzyl formate (compound 28.1,10mmol) and the mixture of m-CPBA (12mmol) in DCM (50mL) in stirred overnight at room temperature.Reaction mixture is with DCM (100mL) dilution and use saturated Na continuously 2SO 3The aqueous solution, salt washing.The organic layer anhydrous Na 2SO 4Drying concentrates then.Resistates obtains compound 31.1,80% yields by chromatography purification.EIMS (m/z): C 12H 13NO 3(M +)+Na calculated value 242.1, measured value 242.1; 1H NMR (CDCl 3, 400MHz): δ 7.36-7.37 (m, 5H), 5.13 (s, 2H), 3.89 (m, 2H), 3.70 (m, 2H), 3.41 (m, 2H) ppm.
B) with compound 31.1 (5mmol) at dense NH 3Mixture in the solution (20mL) spends the night 65 ℃ of stirrings.Reaction mixture is concentrated and vacuum-drying, obtain compound 31.2.This material is without being further purified use.
C) at-20 ℃ with compound 31.2 (10mmol) and Et 3Anhydrous THF (100mL) solution of N (20mmol) was handled by dripping TFAA (10mmol) in 1 hour.After 1 hour, the saturated NH of reaction mixture 4Cl (1mL) aqueous solution is handled.Remove and desolvate, resistates is dissolved in DCM (100mL).Subsequently mixture is sequentially used saturated NH 4The Cl aqueous solution, saturated NaHCO 3The aqueous solution, salt washing.The organic layer anhydrous Na 2SO 4Drying is removed and is desolvated, and resistates obtains compound 31.3 by chromatography purification.
D) at 0 ℃ with compound 31.3 (5mmol) and Et 3The solution of N (10mmol) in anhydrous DCM (20mL) is handled by dripping MsCl (5.5mmol), makes the compound room temperature of rising again gradually.After at room temperature 1 hour, the reaction mixture that will comprise original place generation 31.4 is handled with DBU (30mmol), and the mixture that obtains was stirred several hours.Remove and desolvate, resistates obtains compound 31.5 by chromatography purification.
E) with compound 31.5 (3mmol) and K 2CO 3(6mmol) at the MeOH/H of 2/1 (v/v) 2Mixture among the O (15mL) is in stirring at room.After 24 hours, remove and desolvate the saturated NaHCO of resistates 3The aqueous solution (20mL) is handled, and mixture extracts several times with DCM.Extracting solution Na 2CO 3Drying is removed and is desolvated, and resistates obtains compound 31.6 by chromatography purification.
F) with compound 31.6 (2mmol), NaHCO 3(3mmol), Boc 2O (2.2mmol) 1: 11, the mixture in 4-dioxane/water (20mL) at room temperature stirred several hours.Mixture extracts several times with salt solution (50mL) dilution and with EtOAc.The extracting solution that merges is washed with salt, uses anhydrous Na 2SO 4Drying concentrates.Resistates obtains the intermediate of N-Boc protection by chromatography purification.Mixture in MeOH (5mL) is at room temperature at H with this intermediate (1mmol) and 10%Pd/C (0.1mmol) 2(g) stirred several hours under the atmosphere.Reaction mixture is filtered and filtrate is concentrated, resistates vacuum-drying obtains compound 31.7.
G) prepare compound 31 according to embodiment 26g, difference is to replace ammonia with compound 31.7.
Embodiment 32
Present embodiment is described the synthetic of following compound
Figure A20048003980201471
It is according to diagram 23 and the preparation of following process.
Diagram 23
A) with compound 31.2 (2mmol), NaHCO 3(3mmol), Boc 2O (2.2mmol) 1: 11, the mixture in 4-dioxane/water (20mL) at room temperature stirred several hours.Mixture extracts several times with salt solution (50mL) dilution and with EtOAc.The extracting solution that merges is washed with salt, uses anhydrous Na 2SO 4Drying concentrates.Resistates obtains compound 32.3 by chromatography purification.
B) with compound 32.3 (1mmol) and 10%Pd/C (0.1mmol) mixture in MeOH (5mL) at room temperature at H 2(g) stirred several hours under the atmosphere.Reaction mixture is filtered, filtrate is concentrated, resistates vacuum-drying obtains compound 32.4.
C) prepare compound 32 according to embodiment 26g, difference is to replace ammonia with compound 32.4.
Embodiment 33
Present embodiment is described the synthetic of following compound
It is according to diagram 24 and the preparation of following process.
Diagram 24
A) 0 ℃ with compound 33.1 (10mmol) and DIEA (25mmol) solution in DCM (20mL) handle by dripping chloroformic acid benzyl ester (10mmol), make the reaction mixture room temperature of rising again.After room temperature 2 hours, reaction mixture with ethyl acetate (100mL) dilution, with 1M HCl (50mL) rinsing, is used the salt water rinse, MgSO 4Drying concentrates, and obtains compound 33.2.
B) the solution O in THF (15mL) with compound 33.2 (10mmol) and N-methylmorpholine (22mmol) SO 4(2mL, 2.5 weight % are in t-BuOH) handles, and the mixture that obtains at room temperature stirs and spends the night.Remove and desolvate.Resistates is dissolved among the EtOAc (100mL), uses rare Na 2SO 3The aqueous solution, saturated NH 4Anhydrous Na is used in the Cl aqueous solution, salt washing then 2SO 4Dry.Remove and desolvate, resistates obtains title compound by the column chromatography purifying.
C) with compound 33.3 (1.0mmol) and 10%Pd/C (0.1mmol) mixture in methyl alcohol (5mL) at room temperature at H 2Stirred several hours under the atmosphere.Reaction mixture filters, and filtrate is concentrated, and resistates vacuum-drying obtains compound 33.4.
D) prepare compound 33 according to embodiment 26g, difference is to replace ammonia with compound 33.4.
Embodiment 34
Present embodiment is described the synthetic of following compound
It is according to diagram 25 and the preparation of following process.
Diagram 25
(17.6g, 54.5mmol) mixture in anhydrous acetic acid (40mL) refluxes and stirs 1 hour cool to room temperature then with Tl (OAc).(8.46g 33.3mmol), is heated to backflow with the suspension that obtains to add compound 32.2 (34.6mmol) and iodine.After 9 hours, with the reaction mixture cool to room temperature.By removing by filter the TlI precipitation and using the ether rinsing.Filtrate is concentrated, and resistates is dissolved in ethyl acetate, use MgSO 4Drying, reconcentration obtains compound 34.1.
B) with 34.1 (1.0mmol) and 10%Pd/C (0.1mmol) mixture in methyl alcohol (5mL) at room temperature at H 2Stirred several hours under the atmosphere.Reaction mixture is filtered, filtrate is concentrated, resistates vacuum-drying obtains compound 34.2.
C) prepare compound 34 according to embodiment 26g, difference is to replace ammonia with compound 34.2.
Embodiment 35
Present embodiment is described the synthetic of following compound
Figure A20048003980201493
It is according to diagram 26 and the preparation of following process.
Diagram 26
A) mixture of compound 35.1 (10mmol) in ethanol (20mL) is saturated and in stirred overnight at room temperature with HCl (g).Remove and desolvate, resistates is dissolved among the DCM (100mL), sequentially use TEA (30mmol) and BnBr (11mmol) to handle the solution that obtains, reaction mixture is heated to backflow.After 12 hours, with reaction mixture cool to room temperature and concentrated.Resistates is dissolved in EtOAc (150mL), with salt washing, anhydrous Na 2SO 4Dry.Remove and desolvate, resistates obtains compound 35.2 by chromatography purification.
B) with LiBH 4Anhydrous THF (20mL) solution (20mmol) is at room temperature used THF (5mL) solution-treated of compound 35.2 (5mmol) in the mode that drips.After stirring is spent the night, by adding several dripping with the reaction mixture cancellation.Mixture is concentrated, with salt solution (50mL) dilution, several times with the EtOAc/i-PrOH extraction of 9/1 (v/v).With the extracting solution anhydrous Na that merges 2SO 4Drying is removed and is desolvated, and resistates obtains compound 35.3 by chromatography purification.
C) under-78 ℃ with compound 35.3 (2mmol) and TEA (2.2mmol) solution in anhydrous THF (10mL) (" TFAA " 2.2mmol) handles by dripping trifluoroacetic anhydride.After several hours, mixture is handled with TEA (6mmol), reaction mixture is heated to backflow.Then mixture is concentrated, be dissolved in resistates among the THF (10mL) and water (2.5mL) processing.At room temperature under vigorous stirring, mixture was handled several hours with NaOH (10mmol).Remove and desolvate the saturated NaHCO of resistates 3(20mL) aqueous solution is handled and with the EtOAc/i-PrOH extraction of 9/1 (v/v) several times.With the extracting solution anhydrous Na that merges 2SO 4Drying is removed and is desolvated, and resistates obtains compound 35.4 by chromatography purification.
D) with compound 35.4 (1mmol) and 20%Pd (OH) 2The mixture of/C (0.1mmol) in methyl alcohol (10mL) is at room temperature at the H of 45psi 2(g) shake several hours.Reaction mixture is filtered, filtrate is concentrated, resistates vacuum-drying obtains compound 35.5.
E) prepare compound 35 according to embodiment 26g, difference is to replace ammonia with compound 35.5.
Embodiment 36
Present embodiment is described the synthetic of following compound
Figure A20048003980201511
It is according to embodiment 35 preparation, difference be with (2R, 4S)-the 4-oxyproline is (trans-as D-Hyp-OH) to replace compound 35.1.
Embodiment 37
Present embodiment is described the synthetic of following compound
It is according to embodiment 35 preparation, difference be with (2S, 4R)-(trans-L-1,2-Hyp-OH) replaces compound 35.1 to the 4-oxyproline.
Embodiment 38
Present embodiment is described the synthetic of following compound
It is according to diagram 27 and the preparation of following process.
Diagram 27
Figure A20048003980201522
A) 0 ℃ with HClH-DAP (Boc)-OMe (10mmol) and DIEA (11mmol) solution in DCM (50mL) handle by dripping Benzoyl chloride (11mmol).Make the reaction mixture room temperature of in 3 hours, rising again.Reaction mixture is concentrated, and resistates passes through chromatography purification.This intermediate is handled with the dioxane that contains 4M HCl, the mixture that obtains is at room temperature stirred.After 1 hour, remove and desolvate, obtain compound 38.1, it is without being further purified use.
B) under 0 ℃, DCM (50mL) solution of compound 38.1 (10mmol) and DIEA (12mmol) is handled by dripping p-nitrophenyl chloroformate ester (11mmol), made the reaction mixture room temperature of rising again.After 2 hours, reaction mixture is concentrated, resistates obtains compound 38.2 by chromatography purification.
C) compound 38.2 (10mmol) and TEA (25mmol) solution in 1: 1 DCE/DMF (10mL) is handled with methyl alcohol-ammoniacal liquor (18mmol) of 2M, mixture heating up to 40 ℃.After 15 hours, reaction mixture is concentrated, resistates obtains compound 38.3 by chromatography purification.
D) with compound 38.3 (1.0mmol) and 10%Pd/C (0.1mmol) mixture in methyl alcohol (10mL) at room temperature at the H of 45psi 2(g) shook under several hours.Reaction mixture is filtered, filtrate is concentrated, resistates vacuum-drying obtains compound 38.4.
E) the DMF solution of compound 26.6 (8.0mmol) and DIEA (25mmol) is handled with HATU (8.0mmol), with the mixture that obtains in stirring at room.After 20 minutes, sequentially use compound 38.4 (8.6mmol) and DMAP (0.5mmol) to handle reaction mixture, then with mixture heating up to 60 ℃.After 2.5 hours, will react with the ethyl acetate dilution, water is given a baby a bath on the third day after its birth inferior, with the salt washing once, MgSO 4Drying concentrates.Hurried column chromatography obtains compound 38.5.
F) methyl alcohol (1mL) solution of compound 38.5 (0.15mmol) is handled with 2M methyl alcohol-KOH (0.45mmol), reaction mixture is heated to 50 ℃.After 3 hours, reaction mixture is concentrated into drying, resistates obtains compound 38 through preparation property HPLC purifying.
Embodiment 39
Present embodiment is described the synthetic of following compound
Figure A20048003980201531
R wherein AAnd R BIndependently of one another for hydrogen, aliphatic portion, aromatic series part, heteroaromatic part or form circular part together.These compounds are according to the method preparation of embodiment 38, and difference is to use formula HNR in step c AR BReplacement amine replace ammonia.The illustrative example of the compound that replaces amine and obtain is as shown in table 2.
Table 2
Figure A20048003980201541
Figure A20048003980201551
Embodiment 40
Present embodiment is described the synthetic of following compound
It is according to diagram 28 and the preparation of following process.
Diagram 28
A) sodium bisulfite (50mmol) that will be used in the commercial compound 40.1 (10mmol) among the THF (50mL) in the water (20mL) is handled.After at room temperature reacting 8 hours, reaction is extracted with ethyl acetate (100mL), and organic extracting solution water and salt are washed, and also filters with anhydrous magnesium sulfate drying and obtains thick compound 40.2.
B) in compound 40.2 (10mmol), the slurry of ammonium tetrafluoroborate (12.5mmol) in water (12mL), add dense HCl (2mL).Reaction is cooled to 0 ℃ ℃, to wherein adding Sodium Nitrite (10mmol).Will be reflected at 0 ℃ stir 1 hour after, by solid collected by filtration, with it with methyl alcohol, ether rinsing and dry under vacuum.The HOAc (3mL), the 18-that the solid that obtains are joined stirring are preced with in chloroform (20mL) solution of-6 (0.3mmol).After 1 hour, add entry (10mL) and DCM (20mL).Separate organic layer, with dried over mgso and filtration.With concentrated filtrate, resistates that obtains and hexane grind, and obtain product 40.3.
C) prepare compound 40.4 according to the method that is used to prepare compound 6.1, difference is that R-3-(+)-pyrrolidinol replaces tetramethyleneimine.
D) compound 40.4 is dissolved among the DCM, handles with triethylamine (1.5eq) and diacetyl oxide (1.2eq).The solution that obtains is passed through filtered through silica gel, concentrate.Then resistates is passed through the silica gel column chromatography purifying, obtain compound 40.5.
E) the anhydrous dioxane (2.0eq) that contains 4N HCl of compound 40.5 usefulness in DCM is handled.After starting raw material disappears, will react concentrated, obtain compound 40.6.
F) make compound 40.7 according to the method that is used to prepare compound 1.5, difference is to replace 1.3 with compound 40.6.
G) make compound 40.8 according to the method that is used to prepare compound 1.6, difference is to replace compounds 1.5 and 1.11 with compound 40.7 and 40.3.
H) make compound 40 according to the method that is used to prepare compound 1, difference is to replace 1.6 with compound 40.8.
Embodiment 41
Present embodiment is described the synthetic of following compound
It is according to diagram 29 and the preparation of following process.
Diagram 29
Figure A20048003980201582
Make compound 41 according to the method that is used to prepare compound 3, difference is to replace 3.4 and 3.7 with compound 18.10 and 40.6.Use the chiral column chromatography to separate the pure compound of mapping.
Embodiment 42
Present embodiment is described the synthetic of following compound
Figure A20048003980201583
It is according to diagram 30 and the preparation of following process.
Diagram 30
A) with compound 18.7 (10mmol), 1-oxyethyl group-1-vinyl tributyl tin (10.5mmol), Pd (PPh) 4(0.5mmol) (DME, 50mL) solution in is heated to 80 ℃ up to compound 18.7 disappearances at glycol dimethyl ether.To react cool to room temperature, to wherein adding the 4N HCl aqueous solution (5mL).To react and stir 3 hours and extracted with ether (80mL).Organic extracting solution is washed with salt, uses anhydrous magnesium sulfate drying, filters and concentrates.Resistates obtains compound 42.1 by the column chromatography purifying.
B) the THF solution of inciting somebody to action-78 ℃ compound 42.1 is handled with LDA (2.0eq).After 1 hour, the THF solution of compound 18.2 (1.0eq) is joined in the reaction of dry ice refrigerative.After 3 hours, in reaction, add saturated NH 4The Cl aqueous solution also makes the mixture room temperature of rising again.Reaction mixture is distributed between ethyl acetate and water, and organic layer water and salt washing are with anhydrous magnesium sulfate drying and filtration.The resistates that concentrated filtrate is obtained passes through the silicagel column purifying, obtains compound 42.2.
C) the compound 42.2 usefulness sodium borohydrides (2.0eq) in ethanol are handled.After 1 hour, reaction mixture is distributed between ethyl acetate and water, organic layer is washed with salt, with anhydrous magnesium sulfate drying and filtration.With concentrated filtrate, the resistates that obtains obtains compound 42.3 by the silicagel column purifying.
D) 42.3, the mixture of LiI (3eq) in pyridine refluxes and spends the night.Remove and desolvate, resistates is dissolved in EtOAc.Then with the saturated NH of the solution that obtains 4The Cl aqueous solution is washed, and uses anhydrous Na 2SO 4Dry.Remove and to desolvate, resistates vacuum-drying obtains the compound 42.4 of quantitative yield.Crude product carries out next step without being further purified.
E) make compound 42 according to the method that is used to prepare compound 3, difference is to use compound 42.4 and 40.6 to replace 3.4 and 3.7.Use the chiral column chromatography to separate the pure compound of mapping.
Embodiment 43
Present embodiment is described the synthetic of following compound
It is according to diagram 31 and the preparation of following process.
Diagram 31
Figure A20048003980201602
A) the compound 18.2 usefulness azanols (1.05eq) in ethanol are handled.After 10 hours, will react concentrated, resistates is dry under vacuum, obtain compound 43.1.
B) under the hydrogen of 45psi with 43.1 usefulness catalyzer 20%Pd (OH) 2/ C hydrogenation obtains compound 43.2.
C) (NCS 3eq) handles 43.3 commercially available usefulness N-chlorosuccinimides that will be in tetracol phenixin.Then reaction mixture is diluted with ethyl acetate,, use anhydrous MgSO with 1N NaOH, water and salt washing 4Dry also filtration.Crude product obtains compound 43.4 from the ethyl alcohol recrystallization of heat.
D) the 43.4 usefulness LiOH (2eq, the 2.0N aqueous solution) in THF are handled.After most of starting raw material consumption, mixture is diluted with ethyl acetate, with saturated aqueous ammonium chloride, water and salt washing, use anhydrous MgSO 4Dry also filtration.Crude product obtains compound 43.5 from the ethyl alcohol recrystallization of heat.
E) solution in DMF at room temperature stirred 10 hours with 43.5,43.2 (1.1eq) and EDC (1.0eq).Then mixture is diluted with ethyl acetate,, use anhydrous MgSO with saturated ammonium chloride, water and salt washing 4Dry also filtration.Then crude product and formic acid backflow are finished up to LC-MS demonstration reaction.Evaporating solvent, crude product obtains compound 43.6 by the silicagel column purifying.
F) with 43.6, the mixture of LiI (3eq) in pyridine reflux and spend the night.Remove and desolvate, resistates is dissolved in EtOAc.Then with the saturated NH of the solution that obtains 4Anhydrous Na is washed and used to the Cl aqueous solution 2SO 4Dry.Remove and desolvate, resistates vacuum-drying obtains the compound 43.7 of quantitative yield.Crude product carries out next step without being further purified.
G) make compound 43 according to the method that is used to prepare compound 3, difference is that compound 43.7 and 40.6 replaces 3.4 and 3.7.
Change
Be also to be understood that the every kind of component that is used for synthetic The compounds of this invention can or change before synthesizing after the core texture of structure formula (I).As used in this article, term " makes variation " or " variation " is meant compound of the present invention (I) or any precursor fragment (or its any classification or subclass) are reacted at one or more reactive sites place, to modify functional group or to add functional group's (as, the nucleophilic addition(Adn) of substrate).This paper has described multiple diagram generally, is used for variation by intermediate component or the variation by described core texture, its classification and subclass herein and helps the reader aspect multiple compound synthetic.Should be appreciated that, can adopt the reaction of various variations to be different from those compounds described in this paper example with generation.Only as several examples, when in compound structure, having two key, can carry out epoxidation and aziridineization to produce the epoxide and the aziridine derivative of described compound herein.For guidance other in this area, the practitioner is with reference to " Advanced Organic Chemistry ", March, J., John Wiley ﹠amp; Sons, 2001, the five editions, its full content is merged in this paper as a reference.
2) biological data:
As mentioned above, LFA-ICAM interacts can directly involve multiple inflammatory diseases situation, includes but not limited to transplant rejection, dermatitis, psoriatic, asthma and rheumatoid arthritis.Therefore, the interactional compound that can regulate between the white corpuscle integrin family of adhesion molecule in the born of the same parents (as, ICAM-1 ,-2 and-3) and acceptor can be used for developing new therapeutical agent.The following stated some test that is used to measure ICAM-1:LFA receptors bind, human T-cell's adhesion, T cell proliferation for describing in disclosed PCT application WO 99/49856 and WO 02/05114, its full content is merged in this paper as a reference.WO 99/49856 has also described the generation of total length LFA-1 from 293 clones of the preparation and the purifying of 293 cells, the preparation that is used for the plasmid of expressing human ICAM-1 immune adherence (immunoadhesion), expression ICAM-1 immune adherence.
ICAM-1:LFA receptor binding assays (albumen/albumen test):
Measure the interactional competitive inhibition of CD11a/CD18-ICAM-1 by the inhibitor that adds known quantity to two albumen as described below/albumen pilot system.
Forward Format LFA-1:ICAM-1 tests (PPFF):
With the total length recombinant human LFA-1 albumen of purifying at 0.02M Hepes, 0.15M NaCl, 1mM MnCl 2In be diluted to 2.5 μ g/ml, and with 96 orifice plates (50 μ l/ hole) 4 ℃ down coating spend the night.Plate also at room temperature is used in 0.02M Hepes, 0.15M NaCl, 1mM MnCl with lavation buffer solution (0.05%Tween among the PBS) washing 2In 1%BSA sealing.Plate is washed.Be added in the test damping fluid (at 0.02M Hepes, 0.15M NaCl, 1mM MnCl 2In 0.5%BSA) in suitably the inhibitor to 2 times in 50 μ l/ holes of dilution ultimate density and at room temperature cultivated 1 hour.Add 50 μ l/ holes test be diluted in the damping fluid 50ng/ml purifying recombinant human 5 structural domain ICAM-Ig and incubated at room temperature 2 hours.Plate washing and the use anti-HuIgG of goat (Fc)-HRP are at room temperature carried out detecting in 1 hour bonded ICAM-Ig.100 μ l/ hole tmb substrate developments 10-30 minute also at room temperature used in the plate washing.1MH with 100 μ l/ holes 2PO 4Stop the colorimetric development and reading to read plate at 450nM on the plate device.
Following alternate albumen/albumen pilot system also quantitative assay to the interactional competitive inhibition of CD11a/CD18-ICAM-1.
PLM2 antibody capture LFA-1:ICAM-1 tests (PLM2)
With the monoclonal antibody PLM-2 of the antagonism people CD18 of NOT-function sealing (as people such as Hildreth, Molecular Immunology, Vol.26, No.9, pp.883-895,1989) being diluted to 5 μ g/ml and will flat 96 orifice plates being coated with 100 μ l/ holes down at 4 ℃ in PBS spends the night.At room temperature plate is used in test damping fluid (0.02M Hepes, 0.15M NaCl, 1mM MnCl 2) in 0.5%BSA sealing 1 hour.With plate 50mM Tris pH7.5,0.1M NaCl, 0.05%Tween 20 and 1mM MnCl 2Washing.The total length recombinant human LFA-1 albumen of purifying is diluted to 2 μ g/ml and adds the 100ml/ hole to plate in the test damping fluid, cultivated 1 hour down at 37 ℃.With plate washing 3 times.Be added in the inhibitor in the 50 μ l/ holes of suitably diluting in the test damping fluid, cultivated 30 minutes to 2 times of ultimate densities and at 37 ℃.Be added in the recombinant human 5 structural domain ICAM-Ig (ultimate density 80ng/ml) of the purifying in the 50ml/ hole that is diluted to 161ng/ml in the test damping fluid, and cultivated 2 hours at 37 ℃.Plate washing and the use anti-HuIgG of goat (Fc)-HRP are at room temperature carried out detecting in 1 hour bonded ICAM-Ig.With plate washing and at room temperature use tmb substrate development 5-10 minute in 100 μ l/ holes.1MH with 100 μ l/ holes 3PO 4Stop the colorimetric development and reading to read plate at 450nM on the plate device.
Human T-cell's adherence test (cell attachment test)
End user T-lymphoid cell line HuT 78 carries out T cell adhesion test.With goat anti--HuIgG (Fc) is diluted to 2 μ g/ml and was coated with 96 orifice plates 1 hour with the 50ml/ hole down at 37 ℃ in PBS.Plate was sealed 1 hour with the 1%BSA that the PBS washing also at room temperature is used among the PBS.5 structural domain ICAM-Ig are diluted to 100ng/ml in PBS, and under 4 ℃, 50 μ l/ holes are joined among the plate O/N.With HuT 78 cells with 100g centrifugal and with the cell granule at 5%CO 2Incubator in handled about 5 minutes down at 37 ℃ with 5mM EDTA.With cell at 0.14M NaCl, 0.02M Hepes, 0.2% glucose and 0.1mM MnCl 2Washing and centrifugal in (test damping fluid).Cell is resuspended in the test damping fluid to 3.0 * 10 6C/ml.Inhibitor is diluted to 2 times of ultimate densities in the test damping fluid also at room temperature cultivated 30 minutes with the HuT78 cell is pre-.The cell and the inhibitor that add 100 μ l/ holes in plate were also at room temperature cultivated 1 hour.Add the PBS in 100 μ l/ holes and with plate sealing, the centrifugal counter-rotating of 100g 5 minutes.To dish out in the cell slave plate that not adhere to and on paper handkerchief, blot excessive PBS.In plate, add the p-nitrophenyl n-ethanoyl-β-D-glucosaminide (0.257g is in the 100ml citrate buffer) in 60 μ l/ holes and cultivated 1.5 hours at 37 ℃.50mM glycine/5mMEDTA with 90 μ l/ holes stops enzyme reaction and is reading to read plate at 405nM on the plate device.Use Landegren, U. (1984), J.Immunol.Methods, 57, the p-nitrophenyl n-ethanoyl-β among the 379-388-D-glucosaminide method is measured the adhesion of HUT 78 cells to 5dICAM-Ig.
The T cell proliferation test:
This test activation of serving as reasons produces lymphopoietic external model, is by (Springer, Nature, the 346:425 (1990)) of the cross induction of TXi Baoshouti and LFA-1 when interacting with antigen presenting cell.
Microtiter plate (Nunc 96 holes guarantee with ELISA) is spent the night in CD3 monoclonal antibody (Immunotech 0178) precoating of the 0.07 μ g/ml in aseptic PBS of 4 ℃ of anti-people Fc of the goat with the 2 μ g/mL of 50 μ l (Caltag H10700) and 50 μ l.Second day sucking-off coating solution.With plate usefulness PBS washed twice and at 37 ℃ of 5d-ICAM-1-IgG that add the 17ng/ml of 100 μ l, kept 4 hours then.With plate PBS washed twice, add the CD4+T cell then.Derive from the lymphocyte of peripheral blood from the separation of whole blood that derives from healthy donors of heparinization.Another method obtains whole blood for adopting art (leukophoresis) by the white corpuscle list from healthy donors.Blood is diluted to 1: 1 with salt solution, layering and on LSM centrifugal 30 minutes (every 100ml contains 6.2g Ficoll and 9.4g diztrizoate sodium) of 2500xg (Organon Technica, NJ).Use medullary cell to exhaust reagent method (Myeloclear, Cedarlane Labs, Hornby, Ontario, Canada) exhaustion monocyte.PBL is resuspended among 90% heat-killed foetal calf serum and the 10%DMSO, is divided into the five equilibrium aliquot and is stored in the liquid nitrogen.After thawing, cell is resuspended in is supplemented with 10% heat-killed foetal calf serum (Intergen, Purchase, NY), the RPMI 1640 substratum (Gibco of 1mM Sodium.alpha.-ketopropionate, 3mM L-glutaminate, 1mM non-essential amino acid, 500 μ g/ml penicillin, 50 μ g/ml Streptomycin sulphates, 50 μ g/ml gentamicins (Gibco), Grand Island, NY) in.
Realize the purifying (Human CD4 Cell Recovery Column Kit#CL110-5Accurate) of CD4+T cell by negative system of selection (negative selection method).Under 37 ℃ at 5%CO 2Be 100 with each micro titer plate well down, the CD4+T cell of 000 purifying (90% purity) was cultivated 72 hours in the substratum (RPMI 1640 (Gibco) is supplemented with 10% heat-killed FBS (Intergen), 0.1mM non-essential amino acid, 1nM Sodium.alpha.-ketopropionate, 100 units/ml penicillin, 100 μ g/ml Streptomycin sulphates, 50 μ g/ml gentamicins, 10mM Hepes and 2mM glutamine) of 100mL.When cultivating beginning, in plate, add inhibitor.Reply by the propagation that the titrating thymidine that adds 1 μ Ci/ hole in the process last 6 hours before harvested cell is measured in these cultures.Measure radiolabeled combination by liquid scintillation counting(LSC) (Packard 96 hole gathering device sum counters).The result is expressed as count per minute (cpm).
External mixed lymphocytes culture model:
External model (the A.J.Cunningham of mixed lymphocytes culture model for transplanting, the propagation that " Understanding Immunology; Transplantation Immunology " 157-159 page or leaf (1978), its examination Different L FA-1 antagonist are replied people's mixed lymphocytes and the effect of effector arm.
The separation of cell: the monocyte (PBMC) that derives from peripheral blood from the separation of whole blood that derives from healthy donors of heparinization.Blood is diluted to 1: 1 with salt solution, layering and on LSM centrifugal 30 minutes (every 100ml contains 6.2g Ficoll and 9.4g diztrizoate sodium) of 2500xg (OrganonTechnica, NJ).Another method obtains whole blood for adopting art by the white corpuscle list from healthy donors.Separate PBMC as mentioned above, it is resuspended among 90% heat-killed foetal calf serum and the 10%DMSO, be divided into the five equilibrium aliquot and be stored in the liquid nitrogen.After thawing, cell is resuspended in is supplemented with 10% heat-killed foetal calf serum (Intergen, Purchase, NY), the RPMI 1640 substratum (Gibco of 1mM Sodium.alpha.-ketopropionate, 3mM L-glutaminate, 1mM non-essential amino acid, 500 μ g/ml penicillin, 50 μ g/ml Streptomycin sulphates, 50 μ g/ml gentamicins (Gibco), Grand Island, NY) in.
Mixed lymphocytes is replied (MLR): set up unidirectional people's mixed lymphocytes and cultivate in flat 96 hole microtiter plates.With 1.5 * 10 5The stimulator PBMSc co-cultivation of the allos radiation in 200 μ l perfect mediums of effector PBMC and equivalent (3000rads, 3 minutes 52 seconds).When cultivating beginning, add the LFA-1 antagonist.With culture under 37 ℃ at 5%CO 2In cultivated 6 days, use then 1 μ Ci/ hole the 3H-thymidine (6.7Ci/mmol, NEN, Boston, MA) pulse was cultivated 6 hours.(Packard, Canberra Canada) go up the results culture at the Packard cell harvestor.By liquid scintillation counting(LSC) measure [ 3H] the TdR combination.The result is expressed as count per minute (cpm).

Claims (75)

1. by the isolated compound of structure (I) expression:
And pharmaceutically acceptable derivative;
R wherein 1And R 2Be independently of one another hydrogen, amino acid side chain ,-(CH 2) mOH ,-(CH 2) mAryl ,-(CH 2) mHeteroaryl, wherein m be 0-6 ,-CH (R 1A) (OR 1B) ,-CH (R 1A) (NHR 1B), U-T-Q or optional aliphatic, alicyclic, the assorted aliphatic or assorted alicyclic part that is replaced by U-T-Q, wherein U for do not exist ,-O-,-S (O) 0-2-,-SO 2N (R 1A) ,-N (R 1A)-,-N (R 1A) C (=O)-,-N (R 1A) C (=O)-O-,-N (R 1A) C (=O)-N (R 1B)-,-N (R 1A)-SO 2-,-C (=O)-,-C (=O)-O-,-O-C (=O)-, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl ,-C (=O)-N (R 1A)-,-O-C (=O)-N (R 1A)-,-C (=N-R 1E)-,-C (=N-R 1E)-O-,-C (=N-R 1E)-N (R 1A)-,-O-C (=N-R 1E)-N (R 1A)-,-N (R 1A) C (=N-R 1E)-,-N (R 1A) C (=N-R 1E)-O-, N (R 1A) C (=N-R 1E)-N (R 1B)-,-P (=O) (OR 1A)-O-or-P (=O) (R 1A)-O-; T for do not exist, aliphatic, assorted aliphatic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part; With Q be hydrogen, halogen, cyano group, isocyanic ester ,-OR 1B,-SR 1B-N (R 1B) 2,-NHC (=O) OR 1B,-NHC (=O) N (R 1B) 2,-NHC (=O) R 1B,-NHSO 2R 1B,-NHSO 2N (R 1B) 2,-NHSO 2NHC (=O) OR 1B,-NHC (=O) NHSO 2R 1B,-C (=O) NHC (=O) OR 1B,-C (=O) NHC (=O) R 1B,-C (=O) NHC (=O) N (R 1B) 2,-C (=O) NHSO 2R 1B,-C (=O) NHSO 2N (R 1B) 2,-C (=S) N (R 1B) 2,-SO 2R 1B,-SO 2-O-R 1B,-SO 2-N (R 1B) 2,-SO 2-NHC (=O) OR 1B,-SO 2-NHC (=O)-N (R 1B) 2,-SO 2-NHC (=O) R 1B,-O-C (=O) N (R 1B) 2,-O-C (=O) R 1B,-O-C (=O) NHC (=O) R 1B,-O-C (=O) NH-SO 2R 1B,-O-SO 2R 1B, or aliphatic, assorted aliphatic, aryl or heteroaryl moieties, perhaps R wherein 1And R 2Be alicyclic part or heterocyclic moiety together, perhaps be together R wherein 1AAnd R 1BWhen occurring at every turn independently for hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part ,-COR 1C, or-CONR 1CR 1DR wherein 1CAnd R 1DWhen occurring, be hydrogen, hydroxyl or aliphatic, assorted aliphatic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently at every turn; And R 1EFor hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part ,-CN ,-OR 1C,-NR 1CR 1DOr-SO 2R 1C
R 3Be-C (=O) OR 3A,-C (=O) H ,-CH 2OR 3A,-CH 2O-C (=O)-alkyl ,-C (=O) NH (R 3A) ,-CH 2X 0R wherein 3AWhen occurring, be hydrogen, protecting group, aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part, perhaps R independently at every turn 3AWith R 1Or R 2Form heterocyclic moiety together; X wherein 0For being selected from the halogen of F, Cl, Br or I;
R 4When occurring at every turn independently for hydrogen, halogen ,-CN ,-NO 2, aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part, perhaps be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NRG 2C(=O)-or-SO 2NR G2-, and R G1And R G2Be hydrogen, aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently;
N is the integer of 0-4;
AR 1Be monocycle or polycyclic aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, alicyclic or heterocyclic part;
A, B, D and E are connected by singly-bound or two key under the situation that valency allows; Wherein A, B, D and E are C=O, CR at every turn independently when occurring iR Ii, NR i, CR i, N, O, S, S (=O) or SO 2R wherein 1When occurring at every turn independently for hydrogen, halogen ,-CN ,-NO 2, aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, and R G1And R G2Be hydrogen, aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently, perhaps any two adjacent R 1Represent alicyclic, assorted alicyclic, aryl or heteroaryl moieties together;
P is the integer of 0-4; With
L is for existing or for V-W-X-Y-Z, wherein V, W, X, Y and Z when occurring at every turn independently for do not exist, C=O, NR L1,-O-,-C (R L1)=,=C (R L1)-,-C (R L1) (R L2), C (=N-O-R L1), C (=N-R L1) ,-N=, S (O) 0-2Substituted or unsubstituted C 1-6Alkylidene group or C 2-6The optional independently quilt-C of alkenylene chain, wherein maximum two non-conterminous MU (methylene unit) (=O)-,-CO 2-,-C (=O) C (=O)-,-C (=O) NR L3-,-OC (=O)-,-OC (=O) NR L3-,-NR L3NR L4-,-NR L3NR L4C (=O)-,-NR L3C (=O)-,-NR L3CO 2-,-NR L3C (=O) NR L4-,-S (=O)-,-SO 2-,-NR L3SO 2-,-SO 2NR L3-,-NR L3SO 2NR L4-,-O-,-S-or-NR L3-replace; R wherein L3And R L4When occurring, be hydrogen, alkyl, assorted alkyl, aryl, heteroaryl or acyl group independently at every turn; Or aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part; And R L1And R L2When occurring, be hydrogen, hydroxyl, protected hydroxyl, amino, protected amino, sulfenyl, protected sulfenyl, halogen, cyano group, isocyanic ester, carboxyl, carboxyalkyl, formyl radical, formyl radical oxygen base, azido-, nitro, urea groups, thioureido, thiocyano, alkoxyl group, aryloxy, sulfydryl, sulfoamido, benzoylamino, tosyl group or aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently, perhaps R wherein at every turn L1And R L2One or many occur together, or form alicyclic or heterocyclic moiety or form aryl or heteroaryl moieties with one of V, W, X, Y or Z.
2. the compound of claim 1, wherein R 3Be carboxyl, protected carboxyl, or its prodrug, wherein R 3Be C (=O) R 3A, R wherein 3ABe hydroxyl, alkoxyl group, cycloalkyloxy, aralkoxy, the aromatic ring alkoxyl group, aryloxy, alkyl-carbonyl oxygen base alkyl oxy, the alkoxy-carbonyl oxy alkyl oxy, alkoxy carbonyl alkyl oxygen base, naphthene base carbonyl oxygen base alkyl oxy, cyclo alkoxy carbonyl oxygen base alkyl oxy, the cyclo alkoxy carbonyl alkyl oxy, aryl carbonyl oxygen base alkyl oxy, aryloxy ketonic oxygen base alkyl oxy, aryl carbonyl oxygen base alkyl oxy, alkoxyalkyl ketonic oxygen base alkyl oxy, one of or following structure:
Figure A2004800398020005C1
3. the compound of claim 1, wherein compound has following structure:
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; And R B1, R B2And R EBe the substituted or unsubstituted low alkyl group of hydrogen independently.
4. the compound of claim 1, wherein compound has following structure:
Figure A2004800398020005C3
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; And R EBe the substituted or unsubstituted low alkyl group of hydrogen.
5. the compound of claim 1, wherein compound has following structure:
Figure A2004800398020005C4
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; And R EBe the substituted or unsubstituted low alkyl group of hydrogen.
6. the compound of claim 1, wherein compound has following structure:
Figure A2004800398020006C1
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; And R EBe the substituted or unsubstituted low alkyl group of hydrogen.
7. the compound of claim 1, wherein compound has following structure:
Figure A2004800398020006C2
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; R ABe hydrogen, low alkyl group or acyl group; And R EBe the substituted or unsubstituted low alkyl group of hydrogen.
8. the compound of claim 1, wherein compound has following structure:
Figure A2004800398020006C3
R wherein 4AAnd R 4BIndependently for being selected from F, Cl, Br or I halogen; R A1, R A2, R B1And R B2Be the substituted or unsubstituted low alkyl group of hydrogen independently.
9. the compound of claim 1, wherein compound has following structure:
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; And R AAnd R BBe the substituted or unsubstituted low alkyl group of hydrogen independently.
10. the compound of claim 1, wherein compound has following structure:
Figure A2004800398020007C1
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; And R ABe the substituted or unsubstituted low alkyl group of hydrogen.
11. the compound of claim 1, wherein compound has following structure:
Figure A2004800398020007C2
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; And R BBe the substituted or unsubstituted low alkyl group of hydrogen.
12. the compound of claim 1, wherein compound has following structure:
Figure A2004800398020007C3
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; And R ABe the substituted or unsubstituted low alkyl group of hydrogen.
13. the compound of claim 1, wherein compound has following structure:
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; R A, R BAnd R EBe the substituted or unsubstituted low alkyl group of hydrogen independently.
14. the compound of claim 1, wherein compound has following structure:
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; R A, R BAnd R EBe the substituted or unsubstituted low alkyl group of hydrogen independently.
15. the compound of claim 1, wherein compound has following structure:
Figure A2004800398020008C2
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; And A and B are N or CH independently.
16. the compound of claim 1, wherein compound has following structure:
Figure A2004800398020008C3
R wherein 4AAnd R 4BIndependently for being selected from the halogen of F, Cl, Br or I; And A and B are N or CH independently.
17. the compound of claim 1, wherein-C (=O) NHC (R 1) (R 2) R 3For having the part of following structure:
Ar wherein 2Be cycloalkyl, heterocyclic, aryl or heteroaryl moieties; And R SFor hydrogen, alkyl, assorted alkyl, aryl, heteroaryl or be-G 0R G1, G wherein 0For-O-,-S-or-NR G2-, and R G1And R G2Be the part of hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aromatic or heteroaromatic independently.
18. the compound of claim 1, wherein-C (=O) NHC (R 1) (R 2) R 3For having the part of following structure:
R wherein 1ABe Ar 2,-OR 1B,-SR 1BOr-NR 1BR 1COr alkyl or assorted moieties; And Ar 2Be cycloalkyl, heterocyclic, aryl or heteroaryl moieties; R wherein 1BAnd R 1CBe hydrogen, alkyl, assorted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, perhaps R independently 1BAnd R 1CThe nitrogen-atoms that connects with them forms heterocyclic moiety or heteroaryl moieties.
19. the compound of claim 1, wherein-C (=O) NHC (R 1) (R 2) R 3For having the part of following structure:
Figure A2004800398020009C2
Ar wherein 2Be cycloalkyl, heterocyclic, aryl or heteroaryl moieties; And R 2ABe hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl ,-C (=O) R 2BOr-SO 2R 2B, R wherein 2BBe alkyl, cycloalkyl, assorted alkyl, heterocyclic radical, aryl or heteroaryl; Or R 2AWith Ar 2On substituting group form substituted or unsubstituted heterocyclic moiety or heteroaryl moieties together.
20. the compound of claim 1, wherein-C (=O) NHC (R 1) (R 2) R 3For having the part of following structure:
Figure A2004800398020009C3
Wherein t is 1-3; And R P3Be alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl moieties.
21. the compound of claim 20, wherein t is 2, and R P3Be alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl moieties.
22. the compound of claim 1, wherein-C (=O) NHC (R 1) (R 2) R 3For having the part of following structure:
Figure A2004800398020010C1
Ar wherein 2Be cycloalkyl, heterocyclic, aryl or heteroaryl moieties.
23. the compound of claim 1, wherein-C (=O) NHC (R 1) (R 2) R 3For having the part of following structure:
Figure A2004800398020010C2
R wherein 2ABe hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl, aryl, heteroaryl ,-C (=O) R 2BOr-SO 2R 2B, R wherein 2BBe alkyl, cycloalkyl, assorted alkyl, heterocyclic radical, aryl or heteroaryl; Or R 2AWith R 2COr R 2DForm substituted or unsubstituted heterocyclic moiety or heteroaryl moieties together; R 2CFor hydrogen, CN ,-C=NMe ,=NO 2,=NC (=O) NH 2,=NS (O) 2R ,=NS (O) 2NRR ' ,-SO 2R 2G, or aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part; Wherein R and R ' are hydrogen or methyl independently of one another, and R 2GBe low alkyl group; And R 2DBe Ar 2, hydrogen, halogen, CN, NO 2, aliphatic, assorted aliphatic, alkylaryl or miscellaneous alkyl aryl part or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, and R G1And R G2Be hydrogen, aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently.
24. the compound of claim 20, wherein-C (=O) NHCH (CO 2R 3A) CH 2N (R 2A) C (=NR 2C) R 2DFor having the part of following structure:
Figure A2004800398020011C1
R wherein 2EAnd R 2FBe hydrogen or aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part, perhaps R independently of one another 2EAnd R 2FForm substituted or unsubstituted heterocyclic moiety or heteroaryl moieties together.
25. the compound of claim 20, wherein-C (=O) NHCH (CO 2R 3A) CH 2N (R 2A) C (=NR 2C) R 2DFor having the part of one of following structure:
R wherein 2CFor hydrogen, CN ,-C=NMe ,=NO 2,=NC (=O) NH 2,=NS (O) 2R or=NS (O) 2NRR '; Wherein R and R ' are hydrogen or methyl independently of one another.
26. the compound of claim 20, wherein-C (=O) NHCH (CO 2R 3A) CH 2N (R 2A) C (=NR 2C) R 2DFor having the part of one of following structure:
Or its bioisostere;
R wherein 2EAnd R 2FBe hydrogen or aliphatic, alicyclic, assorted aliphatic, assorted alicyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part, perhaps R independently of one another 2EAnd R 2FForm substituted or unsubstituted heterocyclic moiety or heteroaryl moieties together.
27. the compound of claim 23, wherein bioisostere has one of following structure:
Figure A2004800398020012C1
R wherein 2CBe low alkyl group.
28. the compound of claim 23, wherein R 2DBe part or R with one of following structure 2EAnd R 2FThe nitrogen-atoms that connects with them forms the part with one of following structure:
Figure A2004800398020013C1
Wherein s is 0 to 6 integer; R P1When occurring, be hydrogen, halogen, CN, isocyanic ester, NO independently at every turn 2,-P (=O) (YR P5) 2, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part, or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, and R G1And R G2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently; Y is key or O at every turn independently when occurring; R P5When occurring, be alkyl, assorted alkyl, aryl or heteroaryl independently at every turn, or when Y is O R P5Also can be hydrogen; And R P2When occurring, be hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part or nitrogen-protecting group independently at every turn; Wherein any two adjacent R P1And R P2Can form cycloalkyl, heterocyclic, aryl or heteroaryl moieties together.
29. the compound of claim 25, wherein R 2DBe part or R with one of following structure 2EAnd R 2FThe nitrogen-atoms that connects with them forms the part with one of following structure:
Figure A2004800398020013C2
R wherein P1When occurring at every turn independently for hydrogen, halogen, methyl ,-OCH 3,-OH ,-NH 2,-NHCH 3, or-N (CH 3) 2
30. the compound of claim 26, wherein R 2DBe part or R with one of following structure 2EAnd R 2FThe nitrogen-atoms that connects with them forms the part with one of following structure:
Figure A2004800398020013C3
31. the compound of claim 26, wherein-C (=O) NHCH (CO 2R 3A) CH 2N (R 2A) C (=NR 2C) R 2DHave following structure:
Or its bioisostere;
R wherein P1When occurring at every turn independently for hydrogen, halogen, methyl ,-OCH 3,-OH ,-NH 2,-NHCH 3Or-N (CH 3) 2R 2ABe hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl, aryl, heteroaryl ,-C (=O) R 2BOr-SO 2R 2B, R wherein 2BBe alkyl, cycloalkyl, assorted alkyl, heterocyclic radical, aryl or heteroaryl; With q be 1 or 2.
32. the compound of claim 31, wherein bioisostere has one of following structure:
Figure A2004800398020014C3
Wherein q is 1 or 2; And R 2CBe low alkyl group.
33. the compound of claim 17, wherein R 3ABe hydrogen, low alkyl group, phenyl or benzyl independently.
34. the compound of claim 17, wherein Ar 2Be one of following structure:
Wherein s is the integer of 0-2; R P1When occurring, be hydrogen, halogen, CN, isocyanic ester, NO independently at every turn 2,-OR G1,-SR G1,-NR G1R G2-, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part; Y is key or O at every turn independently when occurring; R P5When occurring at every turn independently for low alkyl group, or when Y is O R P5Also can be hydrogen; R P2When occurring, be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part or nitrogen-protecting group independently at every turn; R P3For low alkyl group or-N (R P2) 2And R G1And R G2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently.
35. the compound of claim 30, wherein Ar 2Be one of following structure:
36. the compound of claim 17, wherein Ar 2Be one of following structure:
Figure A2004800398020015C3
R wherein P3Be low alkyl group and R G1Be hydrogen or low alkyl group.
37. the compound of claim 18, wherein R 1AFor-NH 2Or have a part of following structure:
R wherein P1Be hydrogen, hydroxyl, low alkyl group or rudimentary assorted alkyl independently; And R P2When occurring, be hydrogen or low alkyl group independently at every turn.
38. the compound of claim 37, wherein R 1AFor-NH 2Or have a part of following structure:
Figure A2004800398020016C2
R wherein P1Be hydrogen or low alkyl group.
39. the compound of claim 18, wherein R 1AFor having the part of one of following structure:
Wherein s is 0 to 2 integer; R P1When occurring at every turn independently for low alkyl group or be-GR G1, wherein G be-O-or-NR G2-, and R G1And R G2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently; And R P2When occurring, be hydrogen, low alkyl group, aryl or heteroaryl independently at every turn.
40. the compound of claim 39, wherein R 1AFor having the part of one of following structure:
Figure A2004800398020017C1
Wherein G be-O-or-NR G2-, and R G1And R G2Be hydrogen or low alkyl group independently.
41. the compound of claim 19, wherein-NH (R 2A) Ar 2Be one of following structure:
Figure A2004800398020017C2
X wherein 1Be N or CR P1S is the integer of 0-5; And R P1When occurring, be hydrogen, halogen, CN, NO independently at every turn 2, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, and R G1And R G2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently; And R P3Be alkyl, assorted alkyl, aryl or heteroaryl.
42. the compound of claim 41, wherein-NH (R 2A) Ar 2Have following structure:
R wherein P1Be hydrogen, halogen or low alkyl group.
43. the compound of claim 22, wherein-C (=O) NHC (R 1) (R 2) R 3Be one of following structure:
R wherein P3Be low alkyl group or aryl; X 1And X 2Be N or CR independently P1X 3Be O, S or NR P2R wherein P1Be hydrogen, halogen, CN, NO 2, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, and R G1And R G2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently; And R P2Be hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part.
44. the compound of claim 43, wherein R P3Be low alkyl group; And R P2Be hydrogen or low alkyl group.
45. each compound, wherein R in the claim 17,18,19 and 22 or 23 2DBe Ar 2, Ar wherein 2Be one of following structure:
Wherein s, X 1, X 2And X 3As above-mentioned xx) in definition; X 5Be O, S or NR P2R P1When occurring, be hydrogen, halogen, CN, isocyanic ester, NO independently at every turn 2,-P (=O) (YR P5) 2, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, and R G1And R G2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently; Y is key or O at every turn independently when occurring; R P5When occurring, be alkyl, assorted alkyl, aryl or heteroaryl independently at every turn, or when Y is O R P5Also can be hydrogen; R P2When occurring, be hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part or nitrogen-protecting group independently at every turn; Wherein any two adjacent R P1And R P2Can form cycloalkyl, heterocyclic, aryl or heteroaryl moieties together; And R P3When occurring at every turn independently for alkyl, aryl, heteroaryl or-N (R P2) 2
46. the compound of claim 45, wherein Ar 2Be one of following structure:
X wherein 1Be N or CR P1S is the integer of 0-6; R P1When occurring, be hydrogen, halogen, CN, NO independently at every turn 2, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-, -C (=O) NR-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, and R G1And R G2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently; And R P3Be low alkyl group or aryl independently.
47. the compound of claim 1, wherein-C (=O) NHC (R 1) (R 2) R 3Has structure-C (=O) NHC (=C (R S) Ar 2) CO 2R 3A, R wherein 3AWith R SForm substituted or unsubstituted heterocyclic moiety together.
48. the compound of claim 47, wherein-C (=O) NHC (=C (R S) Ar 2) CO 2R 3ABe one of following structure:
Figure A2004800398020020C1
Ar wherein 2Be heterocycle, aryl or heteroaryl; And X 1Be O, S or NH.
49. the compound of claim 47, wherein-C (=O) NHC (=C (R S) Ar 2) CO 2R 3ABe one of following structure:
X wherein 1Be O, S or NH; And X 2Be N or CH.
50. the compound of claim 1, wherein L for do not exist ,-C (=O) ,-CH 2C (=O) NH-,-CH 2NH-C (=O)-,-O-CH 2-C (=O)-,-CH 2-CH 2-C (=O)-,-CH=CH-C (=O) NH-CH 2-,-CH (OH)-CH 2-O-,-CH (OH)-CH 2-N (CH 3)-,-CH (OH)-CH 2-CH 2-,-CH 2-CH 2-CH (OH)-,-O-CH 2-CH (OH)-,-O-CH 2-CH (OH)-CH 2-,-O-CH 2-CH 2-CH (OH)-, O-CH 2-CH 2-O-,-CH 2-CH 2-CH 2-O-,-CH 2-CH (OH)-CH 2-O ,-CH 2-CH 2-O-,-CH-(CH 3)-NH-C (=O)-,-CH 2-NH-SO 2-,-NH-SO 2-CH 2-,-CH 2-SO 2-NH-,-SO 2NH-CH 2-,-C (=O)-NH-C (=O)-,-NH-C (=O)-NH-,-NH-C (=O)-NH-CH 2-,-CH 2-NH-C (=O)-NH-,-C (=O)-NH-CH 2-C (=O)-NH ,-NH-C (=O)-O-or-O-C (=O)-NH-; Substituted or unsubstituted C 1-6Alkylidene group or C 2-6The optional independently quilt-C of alkenylene chain, wherein maximum two non-conterminous MU (methylene unit) (=O)-,-CO 2-,-C (=O) C (=O)-,-C (=O) NR L3-,-OC (=O)-,-OC (=O) NR L3-,-NR L3NR L4-,-NR L3NR L4C (=O)-,-NR L3C (=O)-,-NR L3CO 2-,-NR L3C (=O) NR L4-,-S (=O)-,-SO 2-,-NR L3SO 2-,-SO 2NR L3-,-NR L3SO 2NR L4-,-O-,-S-or-NR L3-replace; R wherein L3And R L4When occurring, be hydrogen, alkyl, assorted alkyl, aryl, heteroaryl or acyl group independently at every turn.
51. the compound of claim 1, wherein L for do not exist ,-C (=O) ,-CH 2C (=O) NH-,-CH 2NH-C (=O)-,-O-CH 2-C (=O)-,-CH 2-CH 2-C (=O)-,-CH=CH-C (=O) NH-CH 2-,-CH (OH)-CH 2-O-,-CH (OH)-CH 2-N (CH 3)-,-CH (OH)-CH 2-CH 2-,-CH 2-CH 2-CH (OH)-,-O-CH 2-CH (OH)-,-O-CH 2-CH (OH)-CH 2-,-O-CH 2-CH 2-CH (OH)-, O-CH 2-CH 2-O-,-CH 2-CH 2-CH 2-O-,-CH 2-CH (OH)-CH 2-O ,-CH 2-CH 2-O-,-CH-(CH 3)-NH-C (=O)-,-CH 2-NH-SO 2-,-NH-SO 2-CH 2-,-CH 2-SO 2-NH-,-SO 2NH-CH 2-,-C (=O)-NH-C (=O)-,-NH-C (=O)-NH-,-NH-C (=O)-NH-CH 2-,-CH 2-NH-C (=O)-NH-,-C (=O)-NH-CH 2-C (=O)-NH ,-NH-C (=O)-O-or-O-C (=O)-NH.
52. the compound of claim 1, wherein L for do not exist ,-C (=O) substituted or unsubstituted C 1-6Alkylidene group or C 2-6The optional independently quilt-C of alkenylene chain, wherein maximum two non-conterminous MU (methylene unit) (=O)-,-CO 2-,-C (=O) C (=O)-,-C (=O) NR L3-,-OC (=O)-,-OC (=O) NR L3-,-NR L3NR L4-,-NR L3NR L4C (=O)-,-NR L3C (=O)-,-NR L3CO 2-,-NR L3C (=O) NR L4-,-S (=O)-,-SO 2-,-NR L3SO 2-,-SO 2NR L3-,-NR L3SO 2NR L4-,-O-,-S-or-NR L3-replace; R wherein L3And R L4When occurring, be hydrogen or methyl independently at every turn.
53. the compound of claim 1, wherein L is not for existing.
54. the compound of claim 1, wherein L be-C (=O).
55. the compound of claim 1, wherein L is substituted or unsubstituted C 1-6Alkylidene group or C 2-6The optional independently quilt-C of alkenylene chain, wherein maximum two non-conterminous MU (methylene unit) (=O)-,-C (=O) NR L3-,-OC (=O)-,-NR L3C (=O)-,-S (=O)-,-SO 2-,-NR L3SO 2-,-SO 2NR L3-,-O-or-NR L3-replace; R wherein L3And R L4When occurring, be hydrogen or methyl independently at every turn.
56. the compound of claim 1, wherein L is-(CH 2) q-, wherein q is 1-5.
57. the compound of claim 1, wherein L is the part with following structure
Figure A2004800398020022C1
58. the compound of claim 1, wherein AR 1Be one of following structure:
Figure A2004800398020022C2
Wherein r is the integer of 0-6 when occurring at every turn; X 1, X 2, X 3And X 4Be N or CR independently Q1X 5Be O, S or NR Q2AR 3Be heterocyclic, aryl or heteroaryl moieties; R Q1When occurring, be hydrogen, OR independently at every turn Q3, OCF 3, SR Q3, halogen, CN, isocyanic ester, NO 2, CF 3, NR Q3QR Q4,-SO 2R Q3, alkyl-NR Q3R Q4, alkyl-C (=O)-NR Q3R Q4, alkyl-C (=O) R Q3, or aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part, wherein R Q3And R Q4When occurring, be hydrogen, protecting group or aliphatic, assorted aliphatic, aryl or heteroaryl moieties independently at every turn; And R Q2Be hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part or nitrogen-protecting group.
59. the compound of claim 58, wherein AR 1Be one of following structure:
Figure A2004800398020023C1
X wherein 0Be F or Cl; X 2Be N or CR Q1X 5Be CH, O, S or NH; R Q1For hydrogen, methyl ,-CF 3,-OCH 3,-OCF 3Or halogen.
60. the compound of claim 59, wherein AR 1Be one of following structure:
Figure A2004800398020023C2
61. the compound of claim 60, wherein AR 1Be one of following structure:
Figure A2004800398020023C3
62. the compound of claim 1, wherein AR 1-L-is one of following structure:
63. the compound of claim 62, wherein AR 1-L-is one of following structure:
64. each compound, wherein AR among the claim 3-16 1-L-is the part with one of following structure:
Figure A2004800398020024C1
With-C (=O) NHC (R 1) (R 2) R 3For having the part of one of following structure:
Figure A2004800398020024C2
Or its bioisostere;
R wherein 2AAnd R 3AAs the classification of this paper and the definition in the subclass; And R 2DFor having the part of one of following structure:
Figure A2004800398020024C3
Wherein s is 0 to 6 integer; R P1When occurring, be hydrogen, halogen, CN, isocyanic ester, NO independently at every turn 2,-P (=O) (YR P5) 2, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part or be-GR G1, wherein G be-O-,-S-,-NR G2-,-CO-,-SO-,-SO 2-,-C (=O) O-,-C (=O) NR G2-,-OC (=O)-,-NR G2C (=O)-or-SO 2NR G2-, and R G1And R G2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, heterocyclic, aryl, heteroaryl, alkylaryl or miscellaneous alkyl aryl part independently; Y is key or O at every turn independently when occurring; R P5When occurring, be alkyl, assorted alkyl, aryl or heteroaryl independently at every turn, or when Y is O R P5Also can be hydrogen; And R P2When occurring, be hydrogen, aliphatic, alicyclic, assorted aliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, miscellaneous alkyl aryl, assorted alkylaryl or assorted miscellaneous alkyl aryl part or nitrogen-protecting group independently at every turn; Wherein any two adjacent R P1And R P2Can form cycloalkyl, heterocyclic, aryl or heteroaryl moieties together.
65. the compound of claim 64, wherein R 2AAnd R 3AThe hydrogen of respectively doing for oneself.
66. the compound of claim 64, wherein R 2DFor having the part of one of following structure:
Figure A2004800398020025C1
R wherein P1When occurring at every turn independently for hydrogen, halogen, methyl ,-OCH 3,-OH ,-NH 2,-NHCH 3, or-N (CH 3) 2
67. the compound of claim 66, wherein R 2DFor having the part of one of following structure:
Figure A2004800398020025C2
68. pharmaceutical compositions, it comprises:
Each compound among the claim 1-67, and pharmaceutically acceptable derivative; With
Pharmaceutically acceptable carrier or thinner, and optional further comprise other therapeutical agent.
69. the pharmaceutical compositions of claim 68, wherein compound exists with the amount of the adhesion between cell integrin family of adhesion molecule in effective adjusting born of the same parents (as, ICAM-1 ,-2 and-3) and acceptor.
70. the pharmaceutical compositions of claim 68, wherein compound exists with the amount of effective antagonism CD11/CD18 acceptor relevant with white corpuscle.
71. the pharmaceutical compositions of claim 68, wherein compound exists with the amount of effective antagonism Mac-1 and/or LFA-1.
72. treatment, prevention or alleviate in the main body by the immunity of the CD11/CD18 family mediation of cell adhesion molecule or the method for inflammatory response or illness comprise each compound among the claim 1-67 of main body drug treatment significant quantity.
73. the method for claim 72, wherein the CD11/CD18 family of cell adhesion molecule is LFA-1.
74. treatment, prevention or alleviate immunity in the main body or the method for inflammatory response or illness comprise each compound among the main body administration claim 1-67 that needs are arranged.
75. the method for claim 74, wherein illness is selected from T cell inflammatory response such as inflammatory dermatosis, comprises psoriatic; Relevant with inflammatory bowel reply (as Crohn disease and ulcerative colitis); The adult respiratory distress syndrome; Dermatitis; Meningitis; Encephalitis; Uveitis; Allergy situation such as eczema and asthma and relate to the infiltration of T cell and other situation that chronic inflammatory is replied; Skin hypersensitivity (comprising toxicodendron and poison oak); Atherosclerosis; White corpuscle adhesion defective; Autoimmune disease such as rheumatoid arthritis, systemic lupus erythematous (SLE), diabetes, multiple sclerosis, Reynaud ' s syndromes, autoimmune thyroiditis, experimental autoimmune encephalomyelitis, house Glenn syndromes, type i diabetes, juvenile onset diabetes; Typically in pulmonary tuberculosis, sarcoidosis, polymyositis, granulomatosis and vasculitis, find by the cytokine immunne response relevant with the Delayed Hypersensitivity of T cell mediated; Pernicious anemia; Relate to the disease that white corpuscle oozes out; Disease and all types of transplanting of the multiple organ injury syndromes of CNS inflammatory diseases, septicemia or wound secondary, autoimmune hemolytic anemia, myasthenia gravis, antigen-antibody complex mediation comprise and transplant anti-host disease or the anti-transplantation disease of host.
CN200480039802.8A 2003-11-05 2004-11-05 Modulators of cellular adhesion Active CN1902195B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610157969.9A CN105820160B (en) 2003-11-05 2004-11-05 Modulators of cellular adhesion

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US51753503P 2003-11-05 2003-11-05
US60/517,535 2003-11-05
US56051704P 2004-04-08 2004-04-08
US60/560,517 2004-04-08
PCT/US2004/036942 WO2005044817A1 (en) 2003-11-05 2004-11-05 Modulators of cellular adhesion

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN201610157969.9A Division CN105820160B (en) 2003-11-05 2004-11-05 Modulators of cellular adhesion

Publications (2)

Publication Number Publication Date
CN1902195A true CN1902195A (en) 2007-01-24
CN1902195B CN1902195B (en) 2016-03-23

Family

ID=37657540

Family Applications (1)

Application Number Title Priority Date Filing Date
CN200480039802.8A Active CN1902195B (en) 2003-11-05 2004-11-05 Modulators of cellular adhesion

Country Status (2)

Country Link
CN (1) CN1902195B (en)
SI (1) SI1682537T1 (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101817770A (en) * 2010-03-02 2010-09-01 江苏工业学院 Method for preparing methylthio-benzoic acid
CN102056485A (en) * 2008-04-15 2011-05-11 萨可德公司 Topical LFA-1 antagonists for use in localized treatment of immune related disorders
CN105943534A (en) * 2008-04-15 2016-09-21 萨可德生物科学公司 Topical LFA-1 antagonists for use in localized treatment of immune related disorders
CN107857728A (en) * 2017-11-20 2018-03-30 成都惟邦药业有限公司 A kind of synthetic method of Li Feisite intermediates
TWI681958B (en) * 2017-06-30 2020-01-11 台灣神隆股份有限公司 Process for preparing lifitegrast and intermediates thereof
WO2020114202A1 (en) * 2018-12-07 2020-06-11 苏州旺山旺水生物医药有限公司 Method for preparing compound lifitegrast
CN111747941A (en) * 2019-03-29 2020-10-09 成都惟邦药业有限公司 Synthesis method of lifustat
CN113072471A (en) * 2021-03-02 2021-07-06 四川美大康华康药业有限公司 Lifeiste intermediate and preparation method thereof
CN114656379A (en) * 2022-04-27 2022-06-24 成都道合尔医药技术有限公司 Synthetic method of sitagliptin intermediate

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102056485A (en) * 2008-04-15 2011-05-11 萨可德公司 Topical LFA-1 antagonists for use in localized treatment of immune related disorders
CN105943534A (en) * 2008-04-15 2016-09-21 萨可德生物科学公司 Topical LFA-1 antagonists for use in localized treatment of immune related disorders
CN101817770A (en) * 2010-03-02 2010-09-01 江苏工业学院 Method for preparing methylthio-benzoic acid
CN101817770B (en) * 2010-03-02 2013-06-19 江苏工业学院 Method for preparing methylthio-benzoic acid
CN110831938A (en) * 2017-06-30 2020-02-21 台湾神隆股份有限公司 Process for the preparation of sitagliptin and intermediates thereof
TWI681958B (en) * 2017-06-30 2020-01-11 台灣神隆股份有限公司 Process for preparing lifitegrast and intermediates thereof
CN110831938B (en) * 2017-06-30 2023-08-01 台湾神隆股份有限公司 Process for the preparation of rituximab and intermediates thereof
CN107857728A (en) * 2017-11-20 2018-03-30 成都惟邦药业有限公司 A kind of synthetic method of Li Feisite intermediates
WO2020114202A1 (en) * 2018-12-07 2020-06-11 苏州旺山旺水生物医药有限公司 Method for preparing compound lifitegrast
CN111285855A (en) * 2018-12-07 2020-06-16 苏州旺山旺水生物医药有限公司 Method for preparing compound Lifitegrast
CN111747941A (en) * 2019-03-29 2020-10-09 成都惟邦药业有限公司 Synthesis method of lifustat
CN111747941B (en) * 2019-03-29 2023-10-10 成都惟邦药业有限公司 Synthesis method of leflunomide
CN113072471A (en) * 2021-03-02 2021-07-06 四川美大康华康药业有限公司 Lifeiste intermediate and preparation method thereof
CN114656379A (en) * 2022-04-27 2022-06-24 成都道合尔医药技术有限公司 Synthetic method of sitagliptin intermediate

Also Published As

Publication number Publication date
CN1902195B (en) 2016-03-23
SI1682537T1 (en) 2012-08-31

Similar Documents

Publication Publication Date Title
CN1166667C (en) Imidazoimidazoles and triazoles as anti-inflammatory agents
CN1085666C (en) 6-aryl pyrido (2,3-d) pyrimidines and naphthyridines for inhibiting protein tyrosine kinase medicated cellular proliferation
CN1230431C (en) Arylmethy lamine derivatives for use as tryptase inhibitors
CN1219780C (en) Heterocyclic compounds binding chemotactic factor receptor
CN101031559A (en) Novel cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors
CN1046725C (en) Condensed imidazole compounds, their production and use
CN1596253A (en) Spiro-hydantoin compounds useful as anti-inflammatory agents
CN1503673A (en) antiinflammation agents
CN1934091A (en) Imidazole compounds for the treatment of neurodegenerative disorders
CN1976916A (en) Selected CGRP - antagonists, process for preparing them and their use as pharmaceutical compositions
CN1070646A (en) Imidazo-fused iso and heterocycle, their preparation method contains their composition and their application
CN1142817A (en) 1N-alkyl-N-arylpyrimidinamines and derivatives thereof
CN1484633A (en) N (phenylsulphonyl) glycine derivatives and their therapentic use
CN1503793A (en) N-substituted nonabyl-heterocyclic nmda/nrzb antagonists
CN1867560A (en) 4-pyrimidone derivatives and their use as peptidyl peptidase inhibitors
CN1913886A (en) Heterocyclic aspartyl protease inhibitors
CN1184425A (en) 5 -substituted -3 -(1, 2, 3, 6 -tetrahydro -pyridin -4 -yl) - and 3 -(piperidin -4 -yl) -1h -indoles: new 5 -HT1f agonists
CN1479739A (en) Heterocyclic ether substituted imidazoquinolie compounds
CN1599729A (en) HIV protease inhibitors, compositions containing the same, their pharmaceutical uses and materials for their synthesis
CN1930146A (en) Piperidinylcarbonyl-pyrrolidines and their use as melanocortin agonists
CN1597667A (en) Quinazoline derivatives as angiogenesis inhibitors
CN1753670A (en) Novel derivatives of benzimidazole and imidazo-pyridine and their use as medicaments
CN1377347A (en) Pharmaceutically active sulfonamide derivatives
CN1438991A (en) Cyclopentyl-substituted glutaramide derivatives as inhibitors of neutral endopeptidase
CN101031296A (en) Modulators of muscarinic receptors

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1095815

Country of ref document: HK

ASS Succession or assignment of patent right

Owner name: SACDE CO.,LTD.

Free format text: FORMER OWNER: SUNECIS PHARMACY CO.,LTD.

Effective date: 20091218

C41 Transfer of patent application or patent right or utility model
TA01 Transfer of patent application right

Effective date of registration: 20091218

Address after: California, USA

Applicant after: SARCODE Corp.

Address before: California, USA

Applicant before: SUNESIS PHARMACEUTICALS, Inc.

C53 Correction of patent of invention or patent application
CB02 Change of applicant information

Address after: California, USA

Applicant after: SARCODE BIOSCIENCE Inc.

Address before: California, USA

Applicant before: Sarcode Corp.

COR Change of bibliographic data

Free format text: CORRECT: APPLICANT; FROM: SARCODE CORP. TO: SARCODE BIOSCIENCE, INC.

C14 Grant of patent or utility model
GR01 Patent grant
TR01 Transfer of patent right

Effective date of registration: 20200424

Address after: Basel, Switzerland

Patentee after: NOVARTIS AG

Address before: California, USA

Patentee before: SARCODE BIOSCIENCE Inc.

TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20240315

Address after: Ai Erlandubailin

Patentee after: Bausch & Lomb Ireland Ltd.

Country or region after: Ireland

Address before: Basel, SUI

Patentee before: NOVARTIS AG

Country or region before: Switzerland

TR01 Transfer of patent right