CN101702908A - hiv-1 protease inhibitors - Google Patents

hiv-1 protease inhibitors Download PDF

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CN101702908A
CN101702908A CN200880016701A CN200880016701A CN101702908A CN 101702908 A CN101702908 A CN 101702908A CN 200880016701 A CN200880016701 A CN 200880016701A CN 200880016701 A CN200880016701 A CN 200880016701A CN 101702908 A CN101702908 A CN 101702908A
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alkyl
compound
heterocyclic radical
amino
amido
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A·阿利
M·D·阿尔特曼
S·G·安朱姆
H·曹
S·谢拉潘
M·X·费尔南德斯
M·吉尔森
V·凯里斯
N·金
E·纳利韦卡
M·普拉布
T·M·拉纳
K·K·R·加鲁达马加里塞
C·A·希菲尔
B·蒂多尔
M·N·L·纳拉姆
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University of Massachusetts UMass
University of Maryland at Baltimore
Massachusetts Institute of Technology
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University of Massachusetts UMass
University of Maryland Biotechnology Institute UMBI
Massachusetts Institute of Technology
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    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07K14/81—Protease inhibitors

Abstract

Described are novel protease inhibitors and methods for using said protease inhibitors in the treatment of human immunodeficiency virus (HIV) infection.

Description

The HIV-1 proteinase inhibitor
Related application
The application requires the U.S. Provisional Application series number 60/919 of submission on March 23rd, 2007,896, the U.S. Provisional Application series number of submitting on March 23rd, 2,007 60/919,819, the U.S. Provisional Application series number of submitting on June 4th, 2,007 60/941, the U.S. Provisional Application series number 60/941 that on June 4th, 786 and 2007 submitted to, 829 right of priority, they all are incorporated into this paper by quoting in full.
Government supports
The support that obtains the fund P01 GM 066524 that government authorizes by national health research institute (National Institutes ofHealth)/national allergy and transmissible disease research institute (National Institutes of Allergy andInfectious Diseases) of the present invention.Government has some right to the present invention.
Background of invention
Human immunodeficiency virus type 1 (HIV-1) proteolytic enzyme enters the necessary 26S Proteasome Structure and Function albumen of virus maturation and plays a key role in viral life cycle by viral Gag and Gag-Pol polyprotein are handled.Suppress the generation that HIV-1 proteolytic enzyme causes non-infectious virion, and thereby become the therapeutic goal likely of the antiviral therapy among the AIDS patient.
Proteinase inhibitor (PIs) is the effective antiretroviral agent that the patient that human immunodeficiency virus (HIV) is arranged is infected in treatment.In the guidance of international AIDS association-USA (IAS-USA) and U.S. sanitary and Department of Public Enterprises (DHHS), the recommended part of several known PIs as patient's " preferred version ".Yet because virus mutation, the application of these medicines has related to the chemical sproof development of irreversible HIV sometimes.
In fact, the most effective anti-AIDS medicine that the HIV-1 proteinase inhibitor is being represented up to now to be reported, and be the main component of high reactivity antiretroviral therapy (HAART).During the decade nearest, the medicine that 8 kinds of FDA check and approve and the discovery of several other medicines in the clinical trial phase of back have been caused based on the medicinal design of structure.The HIV-1 proteinase inhibitor of present listing, Saquinavir, Indinavir, ritonavir, viracept see nelfinaivr, amprenavir, rltonavir, Reyataz R and tipranavir are the competitive inhibitor that is combined in the active sites of enzyme entirely.Except the medicine tipranavir of approval recently, all inhibitor through approval are developed according to transition state simulation notion, and contain can not cracked dipeptides isostere as the multiple of core support of simulation HIV-1 protease substrate transition state.Exploitation and the anti-AIDS HIV-1 of clinical importing proteinase inhibitor are considered to the very ten-strike based on the medicinal design of structure.
Aspect the mortality ratio that reduces the HIV-1 infected patient, obtained remarkable success based on the anti-AIDS chemotherapy of HIV-1 proteolytic enzyme and reverse transcriptase inhibitors.Yet it is the key factor of the clinical failure of antiviral therapy that present pharmaceutical admixtures is had the appearance of chemical sproof HIV-1 mutant.In general, in the presence of medicine, when the sudden change in the target protein makes the albumen reservation function, resistance just appears.Under the situation of HIV-1 proteolytic enzyme, when (even under situation that proteinase inhibitor exists) enzyme can be at least 9 different positionss cracking Gal and Pol polypeptide, make virus mutation, resistance just typically appears.The resistance of virus is considered to the key factor of the clinical failure of antiviral therapy.The high speed duplicating that occurs being attributable to virus relatively fast of drug-resistant virus mutant adds because the inherent mutating speed of the height that the distortion of hiv reverse transcriptase causes among the HIV patient who receives treatment.And present HIV-1 proteinase inhibitor is designed to suppress the single variant of HIV-1 proteolytic enzyme.
For the proteinase inhibitor that major part is ratified at present, the appearance of multidrug resistance (MDR) mutant forms great challenge (Condra .Nature1995 such as J.H., 374,569-571 to the effectiveness of these medicines; And Clavel, F. etc. N.Engl.J.Med.2004,350,1023-1035.).In recent years, focus (Koh .Antimicrob.Agents Chemother.2003 such as Y., 47, the 3123-3129 of the effort of further investigation the exploitation that suppresses the activated HIV-1 proteinase inhibitor of future generation of MDR virus have been become; Surleraux .J.Med.Chem.2005 such as D.L.N.G., 48,1813-1822; And Surleraux ..J.Med.Chem.2005 such as D.L.N.G., 48,1965-1973).
Be easy to generate the virus strain of anti-other medicines mainly due to same basic mechanism, so, develop different types of therapeutical agent and can not solve a chemical sproof difficult problem fully proteinase inhibitor.Therefore, resistance is the HIV medicine of other main kind, the main clinical difficult problem of reverse transcriptase inhibitors, and be easy to clinical preceding medicine, for example resistance of fusion inhibitor of generation in substratum to upgrading.
Therefore, be that exploitation is more insensitive and/or to the present more activated medicine of proteolytic enzyme resistance HIV-1 strain to resistance to the challenge of research institution, for example, the HIV-1 proteinase inhibitor.The present invention reaches high throughput chemical and screening compound by integrating clinical data, external virusology, albumen crystallography, computation model and chemical design, tackles this challenge.Owing to suppress its activity is clinical effective, and hiv protease is attracting especially target; Yet it can develop and allow produce chemical sproof mass mutation when keeping the enzyme function.Because the design of initial proteinase inhibitor is based on structure, there is huge knowledge storage in this albumen.
Summary of the invention
The present invention is to the discovery of small part based on new small molecular protein enzyme inhibitors (PIs).This paper describes these inhibitor and preparation and using method.Because these inhibitor do not exceed substrate on the proteolytic enzyme in conjunction with the scope of coating, expect that these inhibitor will reduce the possibility that the mediation persister produces.
On the one hand, the invention is characterized in PIs as herein described, or its enantiomorph, diastereomer or its pharmacy acceptable salt and comprise pharmaceutical carrier and the medicinal compositions that is used to suppress hiv protease of PI as herein described of treatment significant quantity.
On the other hand, the invention is characterized in compound as herein described by treating significant quantity or medicinal compositions treatment HIV patient's method.In certain embodiments, described method also comprises and gives second kind of therapeutical agent, for example, and non-nucleoside reverse transcriptase inhibitor (NNRTI), for example efavirenz (Sustiva TM), nevirapine (Viramune TM) and Delavirdine (Rescriptor TM); Nucleoside reverse transcriptase inhibitor (NRTI), for example AZT (zidovudine, Retrovir TM)/3TC (lamivudine, Epivir TM) and d4T (stavudine, Zerit TM)/3TC and d-medicine (ddI[didanosine, Videx TM/ VidexEC TM], ddC[zalcitabine, Hivid TM], d4T); Nucleotide reverse transcriptase inhibitors, for example tynofovir (Viread TM); And fusion inhibitor, for example En Fuwei peptide (Fuzeon TM).In certain embodiments, the part as high reactivity antiretroviral therapy (HAART) scheme gives compound or medicinal compositions.
Except as otherwise noted, the meaning of all technology used herein and scientific terminology all with the present invention under the same meaning of general understanding of a those of ordinary skill in field.At purposes of the present invention, this paper describes certain methods and raw material; Also can adopt method and raw material that other is suitable for known in the art.Raw material, method and embodiment do not plan to limit only with explaining.All publications that this paper mentions, patent application, patent and other reference all are incorporated into this paper by quoting in full.If any conflict,, comprise that definition is as the criterion with the application.
According to following detailed description and accompanying drawing and according to claims, other features and advantages of the present invention will be conspicuous.
The summary of figure
Fig. 1 a-b describes the possible route of synthesis of selected The compounds of this invention.
Fig. 2 a-k classified description inverase.
Fig. 3 describes the synthetic of the proteinase inhibitor contain [A] oxyethylamine (HEA) nuclear or [B] hydroxyalkyl vinyl (HE) nuclear.Crucial: (a) EtOH, 70 ℃; (b) aq.Na 2CO 3, CH 2Cl 2, r.t.; (c) TFA, CH 2Cl 2(d) Et 3N, THF; (e) R 4X 2CO 2H, EDCI, HOBt, DIPEA, 0 ℃-r.t.; (f) H 2, Pd/C, MeOH, r.t; (g) aq.NaHCO 3, EtOAc, 0 ℃-r.t..
Fig. 4 describes and to contain the azepine-oxyethylamine (proteinase inhibitor of the nuclear of azepine-HEA) synthetic.Crucial: (a) (CH 3) 2CHOH, 80 ℃ of (b) H 2, Pd/C, MeOH, r.t.; (c) R 4X 2CO 2H, EDCI, HOBt, DIPEA, 0 ℃ to r.t.; (d) TFA, CH 2Cl 2(e) R 3X 1CO 2H, EDCI, HOBt, DIPEA, 0 ℃ to r.t.; Aq.NaHCO 3, EtOAc.
Fig. 5 describes as the isobutyl-of P1 ' part and (S)-comparison of 2-methyl butyl part: and to the wild-type of HIV-1 proteolytic enzyme and the inhibition activity of MDR mutant.
Fig. 6 describes selected formula I compound and corresponding K iValue.
Fig. 7 describes selected formula I compound.
Fig. 8 describes the chemical structure of amprenavir (APV) 1, TMC114 2 and selected The compounds of this invention 3.
Fig. 9 describes the synthetic flow process of expression intermediate N benzene base oxazolidine-5-carboxylic acid 9 and 10.Crucial: (a) n-BuLi, THF ,-78 ℃ are spent the night to r.t.; (b) RuCl 3.H 2O, CH 3CN-CCl 4-H 2O (2: 2: 3), 0 ℃ to r.t.4-10h.
Figure 10 describes the synthetic flow process of expression The compounds of this invention 20-29.Crucial: (a) EtOH, 80 ℃, 3-4h; (b) aq.Na 2CO 3, CH 2Cl 2, 0 ℃ to r.t., 4-8h; (c) TFA, CH 2Cl 2, 1h; (d) (OCOCl) 2, r.t. spends the night; (e) Et 3N, THF, 0 ℃ to r.t., 4-8h; (f) SnCl 2.2H 2O, EtOAc, 70 ℃, 2h.
Figure 11 describes expression compound 36-39 synthetic flow process.Crucial: (a) iPrOH or EtOH, 80 ℃, 3-4h; (b) aq.Na 2CO 3, CH 2Cl 2, 0 ℃ to r.t., 4-8h; (c) TFA, CH 2Cl 2, 1h; (d) (OCOCl) 2, r.t. spends the night; (e) Et 3N, THF, 0 ℃ to r.t., 4-8h.
Figure 12 describes selected formula XVA/XVB compound and corresponding K iValue.
Figure 13 describes selected formula XIIIA/XIIIB compound and corresponding K iValue.
Figure 14 describes selected formula XVIIA/XVIIB compound and corresponding K iValue.
Figure 15 a-b describes the possible route of synthesis of selected The compounds of this invention.
Figure 16 describes selected compounds to the wild-type of HIV-1 proteolytic enzyme and the inhibition activity of MDR mutant.
Figure 17 a-j describes selected compound and corresponding K in some cases iValue.
Describe in detail
It is still less responsive and/or have more the challenge of active HIV-1 protease inhibitors to suppressing present protease-drug resistance HIV-1 strain that an aspect of of the present present invention, reply exploitation and other HIV medicine compare drug resistance. By integrating clinical data, external virology and high throughput chemical and screening compound, the present invention tackles this challenge. Because its activity of inhibition is clinical effective, hiv protease is especially attracting target; Yet it can develop and allow to produce when keeping the enzyme function and give drug resistance a large amount of sudden changes.
As if significantly, some compound of the present invention is competitive inhibitor, and they are combined in the center avtive spot of protease (that is) of " substrate coating ". Importantly, the design The compounds of this invention is not so that when combined, they significantly exceed the scope of substrate coating; Therefore, they still less may mediate and escape sudden change. Protease inhibitors of the present invention is used for treating easy infected mammal, for example, and the HIV of people and some other primate. In addition, described compound has shown the activity of multidrug resistance (MDR) mutant that suppresses one group of HIV-1 protease. And, as described above, can be used as single therapy or be combined with other therapeutic agent agent, for example, the part as high activity ART (HAART) scheme gives inhibitor of the present invention.
Selected protease inhibitors of the present invention. One aspect of the present invention relates to formula I compound or its pharmaceutically acceptable salt:
Figure G2008800167017D00061
Wherein, when occurring at every turn independently,
X 1For do not exist ,-O-,-S-,-NR-or
Figure G2008800167017D00062
X 2For do not exist ,-O-,-S-,-NR-or
Figure G2008800167017D00063
R 1Be-OH ,-SH or-NHR;
R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl group;
R 2Be hydrogen, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 3Be hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 4Be alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 5Be hydrogen, alkyl, (cycloalkyl) alkyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
The three-dimensional chemical configuration at any three-dimensional center is R, S, or the mixture of these configurations;
Prerequisite is to work as X 1When not existing; R 3Be not
Figure G2008800167017D00071
R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
Prerequisite is X 1Be Or X 2Be
Figure G2008800167017D00073
Or R 3Be amino,
Figure G2008800167017D00075
Figure G2008800167017D00076
Or R 6Be
Figure G2008800167017D00077
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 1Do not exist.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 1Be
Figure G2008800167017D00078
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 2Do not exist.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 1Do not exist; And X 2Do not exist.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 1Be OH.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 2Be aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 2It is aralkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 3Be alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 3Be aryl or heteroaryl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 4Be alkyl, aryl or heteroaryl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 5Be alkyl, (cycloalkyl) alkyl, amino, (amino) alkyl, amido, (amido) alkyl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 5Be alkyl, (cycloalkyl) alkyl or (heterocyclic radical) alkyl.
Another aspect of the present invention relates to formula II compound, or its pharmacy acceptable salt:
Figure G2008800167017D00081
Wherein, when occurring at every turn independently,
X 1For do not exist ,-O-or
Figure G2008800167017D00082
R 3Be alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 4Be aryl, heteroaryl, aralkyl or heteroaralkyl; With
R 6Be alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl or heteroaralkyl;
Prerequisite is to work as X 1When not existing; R 3Be not
Figure G2008800167017D00091
R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
Prerequisite is X 1Be Or R 3Be amino,
Figure G2008800167017D00093
Figure G2008800167017D00094
Figure G2008800167017D00095
Or R 6Be
Figure G2008800167017D00096
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 1Do not exist.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 1Be
Figure G2008800167017D00097
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 3Be alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 3Be aryl or heteroaryl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 4Be alkyl, aryl or heteroaryl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 6Be alkyl, (cycloalkyl) alkyl, amino, (amino) alkyl, amido, (amido) alkyl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 6Be alkyl, (cycloalkyl) alkyl or (heterocyclic radical) alkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 3Be
Figure G2008800167017D00101
Figure G2008800167017D00102
Figure G2008800167017D00111
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 3Be
Figure G2008800167017D00112
Figure G2008800167017D00113
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 4Be
Figure G2008800167017D00114
Figure G2008800167017D00121
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 6Be
Figure G2008800167017D00122
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 6Be
Figure G2008800167017D00124
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 1Do not exist; And R 3Be
Figure G2008800167017D00125
Figure G2008800167017D00131
Another aspect of the present invention relates to and is selected from following compound or its pharmacy acceptable salt:
Figure G2008800167017D00141
Figure G2008800167017D00142
Another aspect of the present invention relates to and is selected from following compound or its pharmacy acceptable salt:
Figure G2008800167017D00143
Figure G2008800167017D00151
Figure G2008800167017D00161
Figure G2008800167017D00171
Figure G2008800167017D00181
Figure G2008800167017D00201
Figure G2008800167017D00211
Figure G2008800167017D00221
Figure G2008800167017D00231
Figure G2008800167017D00241
Figure G2008800167017D00251
Another aspect of the present invention relates to and is selected from following compound or its pharmacy acceptable salt:
Figure G2008800167017D00261
Figure G2008800167017D00262
Another aspect of the present invention relates to the formula III compound, or its pharmacy acceptable salt:
Figure G2008800167017D00272
Wherein, when occurring at every turn independently,
X 1For do not exist ,-O-,-S-,-NR-or
Figure G2008800167017D00273
X 2For do not exist ,-O-,-S-,-NR-or
Figure G2008800167017D00274
R 1Be-OH ,-SH or-NHR;
R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl group;
R 2Be hydrogen, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 3Be hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 4Be alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 5Be hydrogen, alkyl, aralkyl, heteroaralkyl or acyl group;
R 7Be hydrogen, alkyl, (cycloalkyl) alkyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
The three-dimensional chemical configuration at any three-dimensional center is R, S, or the mixture of these configurations;
Prerequisite is to work as X 1When not existing; R 3Be not
Figure G2008800167017D00281
R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
Prerequisite is to work as X 2When not existing; R 4Be not
Figure G2008800167017D00282
R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
Prerequisite is X 1Be Or X 2Be
Figure G2008800167017D00284
R 3Be amino,
Figure G2008800167017D00285
Figure G2008800167017D00286
Figure G2008800167017D00287
Or R 4Be
Figure G2008800167017D00288
Figure G2008800167017D00289
Figure G2008800167017D00291
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 1Do not exist.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 2Do not exist.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 1Do not exist; And X 2Do not exist.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 1Be OH.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 2Be aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 2It is aralkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 3Be alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 3Be aryl or heteroaryl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 3Be
Figure G2008800167017D00292
Figure G2008800167017D00293
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 4Be alkyl, aryl or heteroaryl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 4Be
Figure G2008800167017D00301
Figure G2008800167017D00302
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 5Be hydrogen.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 7Be alkyl, (cycloalkyl) alkyl, amino, (amino) alkyl, amido, (amido) alkyl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 7Be alkyl, (cycloalkyl) alkyl or aralkyl.
Another aspect of the present invention relates to formula IV compound or its pharmacy acceptable salt:
Figure G2008800167017D00303
Wherein, when occurring at every turn independently,
X 1Do not exist or be-O-;
R 3Be alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 4Be aryl, amino, (amino) alkyl, amido, (amido) alkyl, heterocyclic radical, (heterocyclic radical) alkyl, heteroaryl, aralkyl or heteroaralkyl; With
R 7Be alkyl, cycloalkyl, (cycloalkyl) alkyl or aralkyl;
Prerequisite is to work as X 1When not existing; R 3Be not R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
Prerequisite is to work as X 2When not existing; R 4Be not R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
Prerequisite is X 1Be
Figure G2008800167017D00313
Or X 2Be
Figure G2008800167017D00314
R 3Be amino,
Figure G2008800167017D00315
Figure G2008800167017D00316
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 1Do not exist.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 3Be amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 3Be
Figure G2008800167017D00321
Figure G2008800167017D00322
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 4Be aryl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl (heterocyclic radical) alkyl or heterocyclic radical.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 4Be
Figure G2008800167017D00323
Figure G2008800167017D00324
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 7Be alkyl, cycloalkyl or (cycloalkyl) alkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 1Do not exist; And R 3Be amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 1When not existing; R 3Be amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; R 4Be aryl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl (heterocyclic radical) alkyl or heterocyclic radical; And R 7Be alkyl, cycloalkyl or (cycloalkyl) alkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 3Be
Figure G2008800167017D00331
Figure G2008800167017D00332
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 4Be
Figure G2008800167017D00333
Figure G2008800167017D00334
Figure G2008800167017D00341
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 7Be
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 7Be
Another aspect of the present invention relates to and is selected from following compound or its pharmacy acceptable salt:
Figure G2008800167017D00344
Figure G2008800167017D00351
Figure G2008800167017D00361
Figure G2008800167017D00371
Another aspect of the present invention relates to formula V compound, or its pharmacy acceptable salt:
Figure G2008800167017D00372
Wherein, when occurring at every turn independently,
X 1For do not exist ,-O-,-S-,-NR-or
Figure G2008800167017D00373
X 2For do not exist ,-O-,-S-,-NR-or
Figure G2008800167017D00374
R 1Be-OH ,-SH or-NHR;
R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl group;
R 2Be hydrogen, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 3Be hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 4Be alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 5Be hydrogen, alkyl, (cycloalkyl) alkyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
The three-dimensional chemical configuration at any three-dimensional center is R, S, or the mixture of these configurations;
Prerequisite is to work as X 1When not existing; R 3Be not
Figure G2008800167017D00381
R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
Prerequisite is to work as X 2When not existing; R 4Be not
Figure G2008800167017D00382
R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
Prerequisite is X 1Be
Figure G2008800167017D00383
Or X 2Be Or R 3Be amino.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 1Do not exist.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 1Be-O-.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 2Do not exist.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 1Do not exist or be-O-; And X 2Do not exist.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 1Be OH.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 2Be aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 2It is aralkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 3Be alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 3It is heterocyclic radical.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 4It is (heterocyclic radical) alkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 5It is alkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 1Do not exist or be-O-; X 2Do not exist; R 1Be OH; R 2It is aralkyl; R 3It is heterocyclic radical; R 4Be alkyl, aryl or heteroaryl; And R 5It is alkyl.
Another aspect of the present invention relates to formula VII compound, or its pharmacy acceptable salt:
Figure G2008800167017D00391
Wherein, when occurring at every turn independently,
X 1For do not exist ,-O-,-S-,-NR-or
Figure G2008800167017D00392
X 2For do not exist ,-O-,-S-,-NR-or
Figure G2008800167017D00393
R 1Be-OH ,-SH or-NHR;
R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl group;
R 2Be hydrogen, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 3Be hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 4Be alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 5Be hydrogen, alkyl, (cycloalkyl) alkyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
The three-dimensional chemical configuration at any three-dimensional center is R, S, or the mixture of these configurations;
Prerequisite is to work as X 1When not existing; R 3Be not
Figure G2008800167017D00401
R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
Prerequisite is to work as X 2When not existing; R 4Be not
Figure G2008800167017D00402
R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
Prerequisite is X 1Be
Figure G2008800167017D00403
Or X 2Be
Figure G2008800167017D00404
Or R 3Be amino.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 1Do not exist.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 2Do not exist.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein X 1Do not exist; And X 2Do not exist.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 1Be-OH or-NH 2
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 2Be aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 2It is aralkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 3Be alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 3Be (amido) alkyl or heterocyclic radical.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 4Be (amido) alkyl or heterocyclic radical.
In certain embodiments, the present invention relates to the definition of aforesaid compound and any accessory, wherein R 5It is alkyl or aryl.
An aspect of of the present present invention relates to formula XII compound, or its pharmacy acceptable salt:
Figure G2008800167017D00411
Wherein, when occurring at every turn independently,
R 3Be
Figure G2008800167017D00412
Figure G2008800167017D00421
Figure G2008800167017D00422
Wherein, independently, W is selected from-NHR at every turn when occurring 7Or-NHR (CH 2) pN (R 7) 2R 7Be selected from hydrogen, alkyl, aralkyl, heteroaralkyl and acyl group; With p be 1-10; With
R 6Be
Figure G2008800167017D00423
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 3Be
Figure G2008800167017D00431
Figure G2008800167017D00432
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 4Be
Figure G2008800167017D00433
Figure G2008800167017D00434
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 6Be
Figure G2008800167017D00441
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 6Be
Another aspect of the present invention relates to and is selected from following compound or its pharmacy acceptable salt:
Figure G2008800167017D00443
Figure G2008800167017D00444
Figure G2008800167017D00451
Figure G2008800167017D00471
Figure G2008800167017D00481
Figure G2008800167017D00491
Figure G2008800167017D00501
Figure G2008800167017D00511
Figure G2008800167017D00521
Figure G2008800167017D00531
Figure G2008800167017D00551
Another aspect of the present invention relates to and is selected from following compound or its pharmacy acceptable salt:
Figure G2008800167017D00552
Figure G2008800167017D00553
Figure G2008800167017D00561
Another aspect of the present invention relates to and is selected from following compound or its pharmacy acceptable salt
Figure G2008800167017D00571
Figure G2008800167017D00572
Figure G2008800167017D00581
Figure G2008800167017D00591
Figure G2008800167017D00601
Another aspect of the present invention relates to formula XII compound, or its pharmacy acceptable salt:
Figure G2008800167017D00602
Wherein, when occurring at every turn independently,
Figure G2008800167017D00603
Figure G2008800167017D00611
R 4Be
Figure G2008800167017D00613
Wherein, independently, W is selected from-NHR at every turn when occurring 7Or-NHR (CH 2) pN (R 7) 2R 7Be selected from hydrogen, alkyl, aralkyl, heteroaralkyl and acyl group; With p be 1-10; With
R 6Be
Figure G2008800167017D00614
Figure G2008800167017D00615
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 3Be
Figure G2008800167017D00616
Figure G2008800167017D00617
Figure G2008800167017D00621
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 3Be
Figure G2008800167017D00622
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 3Be
Figure G2008800167017D00623
Figure G2008800167017D00624
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 4Be
Figure G2008800167017D00625
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 6Be
Figure G2008800167017D00627
Another aspect of the present invention relates to and is selected from following compound or its pharmacy acceptable salt:
Figure G2008800167017D00631
Figure G2008800167017D00632
Figure G2008800167017D00641
Figure G2008800167017D00651
Figure G2008800167017D00661
Figure G2008800167017D00671
Another aspect of the present invention relates to and is selected from following compound or its pharmacy acceptable salt:
Figure G2008800167017D00672
Figure G2008800167017D00673
Figure G2008800167017D00681
Figure G2008800167017D00691
Another aspect of the present invention relates to formula different-XII compound, or its pharmacy acceptable salt:
Figure G2008800167017D00692
Wherein, when occurring at every turn independently,
R 3Be alkyl, (amino) alkyl, (amido) alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 4Be aryl, heteroaryl, aralkyl or heteroaralkyl; With
R 6Be alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 3Be aryl or heteroaryl.
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 3It is aryl.
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 3Be
Figure G2008800167017D00701
Figure G2008800167017D00702
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 4Be aryl or heteroaryl.
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 4It is aryl.
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 4Be
Figure G2008800167017D00711
Figure G2008800167017D00712
Wherein, independently, W is selected from-NHR at every turn when occurring 7Or-NHR (CH 2) pN (R 7) 2R 7Be selected from hydrogen, alkyl, aralkyl, heteroaralkyl and acyl group; With p be 1-10.
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 6Be alkyl, heterocyclic radical, aryl or heteroaryl.
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 6It is alkyl.
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 6Be
Figure G2008800167017D00713
Figure G2008800167017D00714
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 6Be
Figure G2008800167017D00715
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 6Be
In certain embodiments, the present invention relates to the definition of any aforesaid compound and any accessory, wherein R 3Be aryl or heteroaryl; And R 4Be aryl or heteroaryl.
Synthesizing of selected The compounds of this invention.Can adopt the synthesis flow synthesis of protease inhibitor I, II, III, IV, V and the VII that summarize among Fig. 1 a-b.The definition of each variable with on show shown in the structural formula identical.
Can adopt the synthesis flow shown in Fig. 1 a (going up most) to prepare proteinase inhibitor I, II and V.Such as shown therein, epoxide for example, can react with three-dimensional selection mode with amine, generates amine 2.Amine 2 generates 3 with SULPHURYL CHLORIDE or acyl chloride reaction.Remove protection back and acyl chloride reaction, for example, formation inhibitor I, II or V.
Can adopt the synthesis flow shown in Fig. 1 a (bottom) to prepare proteinase inhibitor III and IV.Can adopt the standard synthesis program to make amino acid 5 be converted into amine 6.Generate acid amides 7 with acid-respons.After going protection, with acyl chloride reaction, formation inhibitor III or IV.
Can adopt the synthesis flow of Fig. 1 b, preparation proteinase inhibitor IV.As shown in flow process, after going protection, epoxide for example, can generate hydrazine 9 with three-dimensional selection mode with protected hydrazine.Hydrazine 9 and acid-respons generate acid amides 10.Under certain conditions, further go protection to generate amine 11, subsequently with acyl chloride reaction, formation inhibitor VII.
As from seeing Fig. 1 a and the 1b, the R group of determining inhibitor by the reagent selecting to be suitable for and starting raw material.Similarly, by selecting suitable starting raw material and reagent, determine the stereochemistry of inhibitor.
Can adopt the synthesis flow shown in Figure 15 a (topmost), preparation proteinase inhibitor XII.Such as shown therein, epoxide for example, can react with three-dimensional selection mode with amine, generates amine 2.Amine 2 and SULPHURYL CHLORIDE or acyl chloride reaction generate 3.After going protection, with acyl chloride reaction, for example, formation inhibitor XI, XII, XV or XVI.
As from seeing Figure 15 a and the 15b,, determine the R group of inhibitor by reagent and the starting raw material of selecting to be suitable for.Similarly, by selecting suitable starting raw material and reagent, determine the stereochemistry of inhibitor.
For example, according to the document program (Brickner .J.Med.Chem.1996 such as S.J., 39, the 673-679 that summarize among Fig. 9; Hester, J.B.WO 2003/006440, is incorporated into this paper by reference; And Thomas .WO such as R.C. 2003/072553 are incorporated into this paper by reference), preparation is used for designed inhibitor synthetic chirality N-Ben Ji oxazolidine-5-carboxylic acid 9 and 10.Obtain the intermediate chiral alcohol with two steps from substituted aniline, 5-(methylol)-3-aryl-oxazolidines-2-ketone 7-8.By the reaction of the aniline 4a-g of the promoted CBZ of n-BuLi protection and (R) of Glycidyl butyrate-or (S)-enantiomorph, generation chiral alcohol 7a and 8a-g.Three step cascade reactions of this one still process comprise with N-lithium class makes the open loop of chiral epoxy thing earlier, with after intramolecular cyclization and last original position ester hydrolysis (Brickner .J.Med.Chem.1996 such as S.J., 39,673-679).The chiral alcohol that the ruthenium chloride oxidation of employing catalytic amount is generated generates required N-Ben Ji oxazolidine-5-carboxylic acid 9a and 10a-g (flow process 1).Under the situation of unsubstituted Ben Ji oxazolidine, (R)-and (S)-enantiomorph, 9a and 10a are respectively from corresponding chiral epoxy thing preparation.All other compounds of the phenyl ring that band replaces, 10b-g only is prepared to (S)-enantiomorph.
Figure 10 explanation is used for preparing the route of synthesis of designed proteinase inhibitor.Intermediate (R)-(hydroxyethylamino) sulphonamide 14-19 (Koh .Antimicrob.Agents Chemother.2003 such as Y., 47, the 3123-3129 for preparing the Boc protection according to the document program; And Surleraux .J.Med.Chem.2005 such as D.L.N.G., 48,1813-1822).In brief, make the chiral epoxy thing that can commercially availablely obtain with isobutylamine, (1S, 2S)-(1-Oxyranyle-2-styroyl) t-butyl carbamate 11 open loops obtain amino alcohol 12.Phenyl SULPHURYL CHLORIDE that replaces and 12 reactions obtain the sulphonamide 14-19 with the coupling of Ben Ji oxazolidine segment.At first, adopt in succession (R) at P2-unsubstituted (R) of (propyloic amino)-sulphonamide isostere-or (S)-3-Ben Ji oxazolidine-5-carboxylic acid 9a or 10a, synthetic 4 kinds of compounds.Before through the phenyl-sulfamide of optimization, 4-p-methoxy-phenyl sulphonamide and 4-aminophenylsulfonamicompounds were used as P2 ' part.Therefore, remove the Boc protection of sulphonamide 14-15, make subsequently the amino alcohol that generated and activating carboxy acid 9a or 10a (R)-or (S)-the enantiomorph reaction, generation target compound 20a-23a (Figure 10).Under the situation of compound 22a and 23a, adopt tin chloride reduction nitro, obtain corresponding aminoderivative 24a and 25a.Must be noted that adopt standard amide coupling condition, the attempt of EDCI/HOBt/DIEA is not very successful and causes yield low, though main because with DMF as solvent, react also extremely slow.In all follow-up reactions, adopt oxalyl chloride, make carboxylic acid 9 and 10 be converted into corresponding acyl chlorides.
Be research structure activity relationship (SAR), (S) the-Ben Ji oxazolidines of the replacement of employing P2 position and the different phenyl sulfamoyl group of P2 ' position, synthesizing series inhibitor.After sulphonamide intermediate 14-19 went protection, (S)-N-Ben Ji oxazolidine that amine that is generated and corresponding carboxylic acid 10b-g activation obtain-5-carbonyl chloride reaction generated target compound 21 and 25-29 (Figure 10).By the reduction nitro, make the compound 23b-f that contains 4-nitrophenyl sulfonamido group in P2 ' position be converted into corresponding 4-aminophenylsulfonamicompounds derivative 25b-f.
Except that above-claimed cpd, also prepare a series of compounds with the variable on 3 different positionss.Isobutyl-on P1 ' position is substituted by three ring primary amine.In addition, from the chiral epoxy thing 11 that can commercially availablely obtain, adopt similar route of synthesis synthesising target compound (Figure 11).In brief, make epoxide 11 open loops, generate amino alcohol 31a-c with primary amine 30a-c.The phenyl SULPHURYL CHLORIDE of various replacements and 31a-c reaction generate sulphonamide 32-35.After midbody compound 32-35 went protection, the amine that is generated and (the S)-N-Ben Ji oxazolidine for preparing from corresponding carboxylic acid 10-5-carbonyl chloride reaction generated target compound 36-39 (Figure 11).
Medicinal compositions.Method as herein described comprises the preparation and the use of medicinal compositions, and medicinal compositions comprises the proteinase inhibitor as herein described as activeconstituents.Also comprise medicinal compositions itself.Can adopt to be similar to route of administration and the dosage used, give these compositions known hiv protease inhibitor.
Should be further appreciated that for treatment some The compounds of this invention can be used as free form,, exist as its pharmaceutically acceptable derivates if perhaps suitable.According to the present invention, pharmaceutically acceptable derivates comprises, but be not limited to, the salt of the pharmacy acceptable salt of The compounds of this invention, ester, this class ester or prodrug or other adducts or derivative, in a single day they be given the patient who needs, compound or its metabolite or the residue (residue) that just can provide this paper to describe in addition directly or indirectly.
Term " pharmacy acceptable salt " refers to those salt as used herein, they are in correct medical judgment scope, the tissue that is suitable for being used for people and rudimentary animal contacts, and does not have over-drastic toxicity, stimulation, transformation reactions etc., and meets rational interests/risk ratio.The pharmacy acceptable salt of the compound of amine/carboxylic acid and other type is known in the art.For example, S.M.Berge etc. are at J.Pharmaceutical Sciences 1977, and detailed pharmacy acceptable salt is incorporated into this paper by reference among the 66:1-19.As described in following cardinal principle, can be during final separation and purifying The compounds of this invention, perhaps respectively by making free alkali or free acid functional group and the reagent react that is suitable for, in-situ preparing salt.For example, free alkali functional group can with the acid-respons that is suitable for.And when The compounds of this invention had acidic moiety, its suitable pharmacy acceptable salt can comprise metal-salt, an alkali metal salt for example, for example, sodium or sylvite; And alkaline earth salt, for example calcium or magnesium salts.The example of pharmaceutically acceptable non-toxic acid additive salt is, with mineral acid, for example, hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid and perchloric acid, perhaps, with organic acid, for example, acetate, oxalic acid, toxilic acid, tartrate, citric acid, succsinic acid or propanedioic acid are perhaps by adopting other method of this area, for example ion-exchange, the amide of formation.Other pharmacy acceptable salt comprises adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, hydrosulfate, borate, butyrates, camphorate, camsilate, Citrate trianion, cyclopentane propionate, digluconate (digluconate), dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxyl-esilate, Lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, maleate, malonate, mesylate, the 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, phosphoric acid salt, picrate, Pivalate, propionic salt, stearate, succinate, vitriol, tartrate, thiocyanate-, tosilate, undecylate, valerate etc.Representational alkaline or alkaline-earth salts comprises sodium, lithium, potassium, calcium, magnesium etc.Other pharmacy acceptable salt comprises, when suitable, adopts counter ion, for example nontoxic ammonium of halogenide, oxyhydroxide, carboxylate salt, vitriol, phosphoric acid salt, nitrate, low-grade alkane sulfonate and aryl sulfonic acid salt formation, quaternary ammonium and amine positively charged ion.
In addition, term " pharmaceutically acceptable ester " refers to the ester of hydrolysis in the body as used herein, comprises being easy to those esters that in human body cracking stays parent compound or its salt.The ester group that is suitable for comprises, for example, derived from pharmaceutically acceptable aliphatic carboxylic acid, those esters of paraffinic acid, alkenoic acid, naphthenic acid and alkanedioic acid (alkanedioic acids) especially, wherein each alkyl or alkenyl part advantageously has and is no more than 6 carbon atoms.The example of specific ester comprises manthanoate, acetic ester, propionic ester, butyric ester, acrylate and ethyl succinate.
In addition, term " pharmaceutically acceptable prodrug " refers to those prodrugs of The compounds of this invention as used herein, it is applicable in correct medical judgment scope with the tissue of people and rudimentary animal and contacts, and there are not undue toxicity, stimulation, transformation reactions etc., match with rational interests/risk ratio, and effective, and when possibility, refer to the zwitterionic form of The compounds of this invention to their desired application.Term " prodrug " refers to that in vivo for example, by the hydrolysis in blood, fast transition generates the compound of the parent compound of following formula.At T.Higuchi and V.Stella, prodrug as new delivery system, A.C.S. specialist paper compilation 14 is rolled up and is edited at Edward B.Roche, bioreversible carrier in the medicinal design, united states drug association and Pergamon press, detailed discussion is provided in 1987, and their boths are incorporated into this paper by reference.
The method of preparation medicinal compositions is known in the art; Referring to, for example, Remington: pharmacy science and practice, 20 editions (Baltimore, MD:Lippincott Williams﹠amp; Wilkins, 2000).Medicinal compositions typically comprises pharmaceutically acceptable carrier.Phrase " pharmaceutically acceptable carrier " comprises the salt solution suitable with administration, solvent, dispersion medium, dressing, antiseptic-germicide and anti-mycotic agent, isotonic agent and absorption delayer etc. as used herein.The active compound that replenishes also can mix in the composition.
Usually the route of administration that medicinal compositions preparation and they are planned is suitable.The example of route of administration comprises parenteral, for example, and by vein, intracutaneous or subcutaneous injection; Or mucous membrane (for example, by per os absorption, suction or rectum or vagina administration) administration.The composition that is intended for use parenteral admin can comprise following component: sterile diluent, for example, water for injection, salt brine solution, fixed oil, polyoxyethylene glycol, glycerine, propylene glycol or other synthetic solvent; Antiseptic-germicide, for example, benzylalcohol or methyl hydroxybenzoate; Antioxidant, for example, xitix or sodium bisulfite; Sequestrant, for example, ethylenediamine tetraacetic acid (EDTA); Buffer reagent, for example, acetate, Citrate trianion or phosphoric acid salt and osmotic pressure regulator, for example sodium-chlor or glucose.Usable acid or alkali, for example, hydrochloric acid or sodium hydroxide in the time of are suitably regulated pH.Parenteral formulation can be encapsulated in ampoule, disposable injection tube or the multiple dose vials that glass or plastics make.
The medicinal compositions that is suitable for injecting purposes can comprise aseptic aqueous solution (wherein activeconstituents is water miscible) or the dispersion liquid and the sterilized powder of preparation sterile injectable solution agent or disperse phase.For intravenously administrable, suitable carrier comprises physiological saline, bacteriostatic water, Cremophor EL TM(BASF, Parsippany, NJ) or phosphate buffered saline (PBS) (PBS).In all cases, composition must be aseptic and should flow to the necessary degree of permission through the syringe administration.Under the condition of preparation and storage, it should be stable, and must be by preservation in order to avoid microorganism, for example contamination of bacterium and fungi.Carrier can be and for example contains, solvent or the dispersion medium and the suitable mixture thereof of water, ethanol, polyvalent alcohol (for example, glycerine, propylene glycol and liquid macrogol etc.).Can for example,, under the situation of disperse phase, adopt tensio-active agent, keep suitable flowability by keeping required particulate size and passing through as lecithin by adopting dressing.Can pass through various antiseptic-germicides and anti-mycotic agent, for example, parabens, butylene-chlorohydrin, phenol, xitix, Thiomersalate etc. reach and prevent action of microorganisms.In many cases, preferably in composition, comprise isotonic agent, for example, sugar, polyvalent alcohol, for example N.F,USP MANNITOL, sorbyl alcohol and/or sodium-chlor.Can be by in composition, comprising the material of delayed absorption, for example, aluminum monostearate and gelatin delay the absorption of injectable composition.
If desired, can mix by the active compound with requirement in the appropriate solvent that contains a kind of or combination in the above-named various composition, Entkeimung prepares the aseptic injectable solution agent subsequently.In general, by being mixed, active compound contains basic dispersion medium and, the preparation dispersion agent from above-mentioned those the aseptic solvent of other required composition.Under the situation at the aseptic powder for preparing the aseptic injectable solution agent, preferred manufacturing procedure is vacuum-drying and freeze-drying, and this generates activeconstituents and adds from the powder of other required composition of its previous Entkeimung solution.
Oral composition generally comprises inert diluent or edible carrier.For per os treatment administration, active compound is combined with vehicle, and adopt tablet, dragee or capsule, for example, the form of gelatine capsule agent.For as mouth wash shua, also can adopt liquid vehicle to prepare composition for oral cavity.Can comprise pharmaceutically compatible tackiness agent and/or auxiliary substance as a composition part.The compound that tablet, pill, capsule, dragee etc. can comprise any following composition or have similarity: tackiness agent, for example Microcrystalline Cellulose, tragacanth gum or gelatin; Vehicle, for example starch or lactose; Disintegrating agent, for example alginic acid, Primogel (sodium starch glycollate) or W-Gum; Lubricant, for example Magnesium Stearate or Sterotes; Glidant, for example colloidal silica; Sweeting agent, for example sucrose or asccharin; Or correctives, for example peppermint, wintergreen oil or orange correctives (orange flavoring).
For inhalation, can or contain suitable propellent from pressurized vessel, for example, and gas, for example the aerosol spray Sprayable of carbonic acid gas or atomizer transmits compound.These class methods are included in U.S. Patent number 6,468, those methods of describing in 798; The document is incorporated into this paper by reference.
Also can give treatment compound as described herein through saturating mucous membrane or transdermal means whole body.Be saturating mucous membrane or transdermal administration, in preparation, adopt the permeate agent that is suitable for permeability barrier.This class permeate agent is generally known in the art, and comprises, for example, for transmucosal administration, washing agent, biliary salts and fusidic acid derivatives.Can carry out transmucosal administration by adopting nose spraying or suppository.For transdermal administration, active compound is mixed with ointment, ointment agent, gelifying agent or creme as generally known in the art.Pass medicine for rectum, also medicinal compositions can be prepared into the form of suppository (for example, using conventional suppository bases, for example theobroma oil and other glyceryl ester) or retention enema.
In one embodiment, avoid fast the preparing carriers treatment compound got rid of with preventing to treat compound in body, for example controlled release preparation comprises graft and micro encapsulation delivery system.Can adopt biodegradable, biocompatible polymkeric substance, for example ethane-acetic acid ethyenyl ester, polyanhydride, polyglycolic acid, collagen, poe and poly(lactic acid).Can adopt standard technique, prepare this class preparation.Also can obtain raw material from Alza company and Nova Pharmaceuticals company limited by commercial sources.Liposome suspension (comprising that target carries the liposome to the cells infected of the monoclonal antibody of virus antigen) also can be used as pharmaceutically acceptable carrier.Can be according to method known to those skilled in the art, for example, as U.S. Patent number 4,522, those methods described in 811 are prepared; The document is incorporated into this paper by reference.
Medicinal compositions can be contained in container, kit, packing or the skimmer, the optional administration specification sheets that has.Kit can comprise one or more compounds as herein described and/or one or more other treatment compound and/or doser, for example, and syringe.
The biological assessment of selected The compounds of this invention.By FRET (fluorescence resonance energy transfer) (FRET) method determine the hiv protease inhibitor activity (Matayoshi .Science1990 such as E.D, 247,954-958).(Arg-Glu (EDANS)-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-Lys (DABCYL)-Arg) carries out mark with energy transfer donator (EDANS) and acceptor (DABCYL) dyestuff at its two ends to protease substrate, to carry out FRET.According to the Morrison equation, by with as the initial velocity of the inhibitor concentration function mapping non-linear regression of match mutually, be inhibited agent in conjunction with dissociation constant (Ki value) (Greco .J.Biol.Chem.1979 such as W.R., 254,12104-12109).The triplicate activity of measuring all synthetic inhibitor antagonism wild-type HIV-1 proteolytic enzyme (Q7K).Present in diagrammatic form inhibitor chemical structure and suppress active (Ki value).
In addition, at one group of multidrug resistance (MDR) mutant of the chemical sproof HIV-1 proteolytic enzyme of representing different patterns separately, research has effective inhibition active one little cover proteinase inhibitor to wild-type protease.The Stanford HIV-1 resistance database (http://HIVdb.stanford.edu) of the HIV-1 infected patient sequence by investigating isolated viral strain (viral isolates) is selected mutant.The pattern of the medicament-resistant mutation that takes place under the selective pressure of three kinds of selected ease variants representatives proteinase inhibitor in three kinds or more kinds of present prescription (Wu .J.Virol.2003 such as T.D., 77,4836-4847).These MDR mutant are L10I, G48V, I54V, L63P, V82A (M1), D30N, L63P, N88D (M2) and L10I, L63P, A71V, G73S, I84V, L90M (M3).Check the inhibition activity of selected proteinase inhibitor antagonism M1-M3 mutant HIV-1 proteolytic enzyme.Be more present two kinds of marketed drugs, also amprenavir (APV) and the selected one group of protease mutant of rltonavir (LPV) inhibition studied.
Methods of treatment.Method as herein described comprises treatment or prophylaxis of viral infections, and for example, HIV infects the method with acquired immune deficiency syndrome (AIDS) (AIDS) or the relevant complex of AIDS (ARC).In general, described method comprises patient's (for example, people or other primate) that needs are arranged or need to have determined the patient of this class treatment, for example, and the patient of (or being identified) infected by HIV, the proteinase inhibitor of treatment significant quantity.Patient that also can treatment PI HIV as described herein, for example, the people among the high risk population.The patient also comprises the women (pregnant woman) who is just nourishing child, and wherein, treatment can reduce HIV and propagate possibility to child.
Except that HIV-1 infects, expect that also method as herein described infects useful to treatment or prevention HIV-2.In HIV-1 virus, expect that described method will effectively suppress any HIV-1 virus strain, for example those strains and hypotype A, B, C, D, E, F, G, H, I, J and K and " circulation recombinant forms " or the CRFs in M, O and the N group.Compound as herein described also can be used for treating any other virus infection, and wherein viral agent has the proteinase inhibitor that can be suppressed by compound as herein described.
As above hereinafter used, " treatment " means and improves at least a clinical symptom or the parameter that HIV infects, perhaps prevent to worsen or prevention HIV propagation, for example, from mother to child.For example, treatment can make virus load (viral load) reduce, and/or increases the amount (" CD4 counting ") of CD4+T cell.When the patient had reduced virus load and/or increased CD4 quantity, treatment also may comprise the increase of the minimizing of keeping virus load and/or CD4 counting so, for example, prevents the recovery of virus load and/or the decline of CD4 quantity.Can adopt methods known in the art to measure these and other clinical correlation parameter.For example, can adopt PCR known in the art or branched DNA (bDNA) test, measure virus load.For example, can adopt hematology, DYNAbeads TM(Dynal Biotech/Invitrogen Corp., Brown Deer, WI), flow cytometry (for example, FACSCount TM, BD Biosciences, Franklin Lakes, NJ) or enzyme linked immunosorbent assay (ELISA) method (referring to, for example, Lyamuya etc., J.Immunol.Methods 195 (1-2): 103-12 (1996); Paxton etc., Clin.Diagn.Lab.Immunol.2 (1): 104-114 (1995); .Arch.Pathol.Lab.Med.121 such as Saah (9): 960-2 (1997); Mwaba etc., Lancet 362 1459-60 (2003)), measure the CD4 number.Health adult and teenager generally have the CD4 number of at least 800 cells of every cubic millimeter of blood; The CD4 number is lower than 200 and relates to serious disease risks (for example, the disease that AIDS-is relevant, for example Kaposi sarcoma or Pneumocystis pneumonia).Present guideline recommendation, treatment HIV should CD4 counting be lower than about 350 and/or virus load began greater than about 50,000 o'clock.
" treatment significant quantity " is to be enough to realize desirable result of treatment, for example, reduces the amount of virus load and/or increase CD4+T cell quantity.Can be in single or divided doses, medication or prescribe medicine, give significant quantity.The treatment significant quantity of composition can be decided with selected composition.Can be once a day or repeatedly and/or once in a week or repeatedly, comprise every other day once giving composition.In certain embodiments, give composition twice or three times every day.Those skilled in the art will appreciate that, some factor includes but not limited to, the seriousness of disease of patient or obstacle, previous treatment, general health situation and/or age, with the indication of any other existence, may influence effective needed dosage of treatment patient and opportunity.Protease inhibitors for treating patient as herein described with the treatment significant quantity can comprise single therapy or serial therapy.
For example, can determine dosage, toxicity and the result of treatment of compound, for example, determine LD50 (lethal dose of 50% colony) and ED50 (the treatment effective dose in 50% colony) by the standard drug program in cell cultures or the laboratory animal.Dosage ratio between toxic action and the therapeutic action is a therapeutic index, and it can be represented as the ratio of LD50/ED50.Preferably show the compound of high therapeutic index.Although can adopt the compound that shows toxic side effect, should carefully select to make the severe side effect minimum and the dosage and the administration progress of result of treatment maximum.
The data that obtain from cell culture test and zooscopy can be used to formulate the dosage range of human.The dosage of this compounds is preferably in the scope of the cyclical level that comprises the ED50 with minimum or totally nontoxic.According to used dosage form and used route of administration, dosage can change in this scope.For any compound that is used for method as herein described, the treatment effective dosage ranges can be estimated from cell culture test at first.Available animal model is further worked out dosage to realize the circulating plasma horizontal extent, as confirming that in cell cultures this scope comprises IC50 (that is, realizing the concentration of the maximum test compounds that suppresses of half of symptom).This category information can be used to confirm more accurately the dosage useful to the people.For example, can measure blood plasma level by high performance liquid chromatography.In certain embodiments, the treatment significant quantity of new proteinase inhibitor as herein described is in about 0.1-10mg/ day or about 0.3-5mg/ daily range.
In certain embodiments, for example, can be as comprising the part of high reactivity antiretroviral therapy (HAART) scheme of one or more other antiretroviral agents, one or more proteinase inhibitor as herein described can with one or more other therapeutical agent Combined Preparation.For example, described method may comprise and give one or more non-nucleoside reverse transcriptase inhibitors (NNRTI), for example, and efavirenz (Sustiva TM), nevirapine (Viramune TM) and Delavirdine (Rescriptor TM), 8 and 9-Cl TIBO (Tivirapine), loviride, TMC-125, reach a Wei Lin, MKC-442, UC 781, UC 782, capravirine, DPC 961, DPC963, DPC082, DPC083, calophylloide plant milk extract A, SJ-1366, TSAO, 4 " deaminizating TSAO, MV150 and MV026048; Nucleoside reverse transcriptase inhibitor (NRTI), for example AZT (zidovudine, Retrovir TM)/3TC (lamivudine, EpiVir TM), emtricitabine (Emtriva TM) and d4T (stavudine, Zerit TM)/3TC and d-medicine (ddI[didanosine, Videx TM/ VidexEC TM], ddC[zalcitabine, HiVid TM], d4T), Abacavir, FTC, DAPD, dOTC and DPC 817; Nucleotide reverse transcriptase inhibitors, for example, tynofovir (Viread TM) and PMEA; Fusion inhibitor, for example, En Fuwei peptide (Fuzeon TM), T20, T1249,5-spiral and D-peptide ADS-J1; Entry inhibitor; The coreceptor binding inhibitors, for example, AMD 3100, AMD-3465, AMD7049, AMD3451 (Bicyclams (disulfonic acid is received)), TAK 779; SHC-C (SCH351125), SHC-D, PRO-140RT inhibitor, for example phosphine formic acid and prodrug; Ribonuclease H inhibitor, for example SP1093V and PD126338; The TAT inhibitor, for example, RO-5-3335, K12 and K37; Integrase inhibitor, for example L 708906, L 731988 and S-1360; Another kind of proteinase inhibitor, for example amprenavir and prodrug GW908, viracept see nelfinaivr, Saquinavir, Indinavir, rltonavir, Palinavir, BMS 186316, Reyataz R, DPC 681, DPC 684, tipranavir, AG1776, mozenavir, GS3333, KNI-413, KNI-272, L754394, L756425, LG-71350, PD161374, PD173606, PD177298, PD178390, PD178392, PNU 140135, TMC114 Crategolic acid and U-140690; Glycosylation inhibitor, for example castanospermine, deoxynojirimycin; Or binding inhibitors, for example dextran sulfate, Suramine, polyanion, solubility CD4, PRO-542 and BMS-806.Other medicines comprise those that propose among the http://aidsinfo.nih.gov/, are incorporated into this paper by reference.
Can be the medicine that suppresses metabolic enzyme with other therapeutical agent agent of one or more medicine administrations as herein described, for example, the inhibitor of Cytochrome P450 (CYP450) enzyme.For example, compound as herein described can with the CYP3A4 inhibitor, for example, ritonavir or CYP2C19, CYP1A2, CYP2D6 or CYP2C9 inhibitor are simultaneously or not administration simultaneously.For example, in U.S.'s publication No. 2006.0069042, describe exemplary 2C9 inhibitor, be incorporated into this paper by reference.
For improving, resist or eliminating HIV and infect and symptom, also can with immunomodulator (for example, Bropirimine, antihuman alpha interferon antibody, IL-2, met-enkephalin, interferon-alpha, HE-2000 and TREXUPONT), antibiotic (for example, pentamidine isethionate (pentamidineisothiorate)), cytokine (for example, Th2), cytokine modulators, chemokine or its acceptor (for example, CCR5) or hormone (for example, tethelin) combination gives The compounds of this invention.
In certain embodiments, described method also comprises and gives second kind of therapeutical agent, second kind of therapeutical agent wherein be selected from amprenavir (
Figure G2008800167017D00831
APV), tipranavir (
Figure G2008800167017D00832
TPV), Indinavir (
Figure G2008800167017D00833
IDV), Saquinavir (
Figure G2008800167017D00834
SQV), rltonavir and ritonavir ( LPV), fosamprenavir (
Figure G2008800167017D00836
FPV), ritonavir (
Figure G2008800167017D00837
RTV), Reyataz R (
Figure G2008800167017D00838
ATZ), viracept see nelfinaivr ( NFV), Bu Ruinawei and Da Lunawei.
In certain embodiments, described method also comprises and gives second kind of therapeutical agent, second kind of therapeutical agent wherein be ritonavir (
Figure G2008800167017D008310
LPV).
In certain embodiments, described method comprises also and gives second kind of therapeutical agent that second kind of therapeutical agent wherein is selected from zidovudine (AZT; Zidovodine;
Figure G2008800167017D008311
), didanosine (didanosine; DdI;
Figure G2008800167017D008312
), zalcitabine (zalcitabine; DdC;
Figure G2008800167017D008313
), lamivudine (3TC;
Figure G2008800167017D008314
), stavudine (2 ', 3 '-two dehydrogenations-3 '-deoxythymidine; D4T;
Figure G2008800167017D008315
), abacavir succinate (1592U89 succinate;
Figure G2008800167017D008316
ABC),
Figure G2008800167017D008317
(La Mifuding ﹠amp; Zidovudine; (-)-3TC﹠amp; AZT) and
Figure G2008800167017D008318
(A Bakawei ﹠amp; La Mifuding ﹠amp; Zidovudine; ABC﹠amp; (-)-3TC﹠amp; AZT).
In certain embodiments, described method comprises also and gives second kind of therapeutical agent that second kind of therapeutical agent wherein is selected from nevirapine (BI-RG-587;
Figure G2008800167017D008319
), Delavirdine (BHAP; U-90152;
Figure G2008800167017D008320
) and (efavirenz; DMP-266;
Figure G2008800167017D008321
).
In certain embodiments, described method also comprises and gives second kind of therapeutical agent, second kind of therapeutical agent wherein be T-20 (
Figure G2008800167017D008322
The En Fuwei peptide; DP-178; Pentafuside; GP41127-162 AA).
In certain embodiments, described method also comprises and gives second kind of therapeutical agent, and second kind of therapeutical agent wherein is TMCC114 or the TMCC114 with the reverse transcriptase inhibitors combination.In certain embodiments, described method also comprises and gives second kind of therapeutical agent, and second kind of therapeutical agent wherein is Lipinavir or the Lupanivir with the reverse transcriptase inhibitors combination.
Can be simultaneously, carry out combination therapy with different preparations respectively or in succession.As selection, can be used as unitary agent and give such combination, activeconstituents discharges from preparation at the same time or separately thus.This paper also provides the composition that comprises at least two kinds of inhibitor as herein described and/or one or more other proteinase inhibitor and/or other therapeutical agent.In certain embodiments, The compounds of this invention can with one or more any anti-HIV-1 compounds (for example, list among Fig. 6 a-k those compounds) combination.Can be at Yeni .JAMA such as P.G. 2004,292 (2), 251-265; Pozniak .Business Briefing:Clinical Virology﹠amp such as A.; Infectious Disease2004,1-7; And Chittick .Antimicrobial Agents and Chemotherapy2006 such as G.E., find among the 1304-1310 can with other compound of one or more The compounds of this invention combinations and the further discussion of combination therapy; They all are incorporated into this paper by reference.
Definition.As defined herein with adopted like that, all definition are interpreted as with the definition of dictionary, the definition in the bonded document and/or the common meaning of described term contrast by reference.
Indefinite article in specification sheets and claims " one " and " one " unless opposite offering some clarification on arranged in addition, are interpreted as meaning " at least one " as used herein.
Term " HIV " is known to those skilled in the art, and refers to human immunodeficiency virus.HIV has two types: HIV-1 and HIV-2.HIV-1 has many different virus strains.The virus strain of HIV-1 is divided into three groups: " mainly " group M, " unusual (outlier) " group O and " newly " group N.On behalf of the ape immune deficiency disorder, these three groups can enter three kinds of human different importing into.In the M-group, have 10 kinds of hypotypes at least or evolve (clades): for example, A, a B, C, D, E, F, G, H, I, J and K evolve." evolve " is one group of organism, species for example, the total similar characteristics derived from common prototype (common ancestor) of its member.Any relating to HIV among the application all comprises all these types and virus strain.
As is known to the person skilled in the art, " retrovirus " is the diploid positive chain RNA virus, and it duplicates by complete DNA intermediate (proviral DNA).Especially, once picornavirus infection, the lentiviral gene group is just entered DNA by the reversed transcriptive enzyme reverse transcription of the encoding viral that carries as albumen in each retrovirus.Viral DNA is incorporated the host cell gene group with cells infected by pseudorandom ground then, forms " provirus " of being inherited by daughter cell.The reverse transcription virus gene group contains at least three kinds of genes: the nuclear of virus and the gag of structural protein coding; The pol coding of reversed transcriptive enzyme, proteolytic enzyme and intergrase; Env coding with virus surface proteins.In retrovirus family, HIV is classified as slow virus, have and the animal slow virus, those slow viruss that for example infect cat (cat family immunodeficiency virus), sheep (visna virus), goat (caprine arthritis-encephalitis virus) and non-human primates (simian immunodeficiency virus) are in genetics and morphologic similarity.
Term " heteroatoms " is generally acknowledged by this area, refers to not to be any atoms of elements of carbon or hydrogen.Exemplary heteroatoms comprises boron, nitrogen, oxygen, phosphorus, sulphur and selenium.
Term " alkyl " is generally acknowledged by this area, comprises the radical of saturated aliphatic group, comprises straight chained alkyl, branched-chain alkyl, cycloalkyl (alicyclic) group, the cycloalkyl of alkyl replacement and the alkyl of cycloalkyl substituted.In certain embodiments, the straight or branched alkyl has about 30 or carbon atom still less (for example, for straight chain C on its main chain 1-C 30, for side chain C 3-C 30), as selection, about 20 or still less.Similarly, cycloalkyl has about 10 carbon atoms from about 3-on its ring structure, as selection, have about 5,6 or 7 carbon on ring structure.
Unless the carbon number amount indicates separately, as mentioned above, " low alkyl group " refers to only have on its backbone structure about 10 carbon of 1-, the perhaps alkyl of about 6 carbon atoms of 1-.Similarly, " low-grade alkenyl " and " low-grade alkynyl " has similar chain length.
Term " aralkyl " is generally acknowledged by this area, refers to the alkyl that is replaced by aryl (for example, aromatics or heteroaromatic group).
Term " alkenyl " and " alkynyl " are generally acknowledged by this area, refer to be similar to abovementioned alkyl and also may replace its unsaturated aliphatic group on length, except containing at least one two key or triple bond respectively.
Term " aryl " is generally acknowledged by this area, finger may comprise 0-4 heteroatomic 5-, 6-and 7-unit mono-cyclic aromatic group, for example, benzene, naphthalene, anthracene, pyrene, pyrroles, furans, thiophene, imidazoles, oxazole, thiazole, triazole, pyrazoles, pyridine, pyrazine, pyridazine and pyrimidine etc.On ring structure, have heteroatomic these aryl and also can be called as " aryl-heterocyclic " or " assorted aromatic hydrocarbons ".Aromatic ring can be by these substituting groups as described herein on one or more ring positions; for example, halogen, trinitride, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl group, amino, nitro, sulfhedryl, imino-, amido, phosphonate group, phosphonous acid base, carbonyl, carboxyl, silyl, ether, alkylthio, alkylsulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic radical, aromatics or heteroaromatic moiety ,-CF 3,-replacements such as CN.Term " aryl " also comprises the multi-loop system with two or more rings, wherein have two or more carbon (ring is " fused rings ") in abutting connection with ring for two, at least one ring wherein is an aromatics, for example, other ring can be cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl and/or heterocyclic radical.
The term neighbour, and to being generally acknowledged by this area, refer to 1 respectively, 2-, 1,3-and 1,4-disubstituted benzene.For example, title 1,2-dimethylbenzene and ortho-xylene are synonyms.
Term " heterocyclic radical ", " heteroaryl " or " heterocyclic group " are generally acknowledged by this area, refer to 3-to about 10-ring structure, and perhaps 3-is to the first ring of about 7-, and its ring structure comprises 1-4 heteroatoms.Heterocycle also can be many rings.Heterocyclic radical comprises, for example, thiophene, thianthrene, furans, pyrans, isobenzofuran, chromene, xanthene, phenol xanthene (phenoxanthene), the pyrroles, imidazoles, pyrazoles, isothiazole isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indoles, indazole, purine, quinolizine, isoquinoline 99.9, quinoline, phthalazines, naphthyridines, quinoxaline, quinazoline, cinnolines, pteridine, carbazole, carboline, phenanthridines, acridine, pyrimidine, phenanthroline, azophenlyene, phenarsazine, thiodiphenylamine, furazan phenoxazine, tetramethyleneimine, oxa-penta ring (oxolane), thia penta ring (thiolane) oxazole, piperidines, piperazine, morpholine, lactone, lactan is azetidinone and pyrrolidone for example, sultam, sultones etc.Heterocycle can be at one or more positions quilt as this type of above-mentioned substituting group; for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhedryl, imino-, amido, phosphonate group, phosphonous acid base, carbonyl, carboxyl, silyl, ether, alkylthio, alkylsulfonyl, ketone, aldehyde, ester, heterocyclic radical, aromatics or heteroaromatic moiety ,-CF 3,-replacements such as CN.
Term " many rings " or " many cyclic groups " are generally acknowledged by this area, refer to two or more rings (for example, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl and/or heterocyclic radical), and wherein two or more carbon are that two adjacency rings are common, and for example, ring is " fused rings ".The ring that connects by non-adjacent atom is being claimed " bridge " ring.Each ring of polycyclic can by as this type of above-mentioned substituting group; for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhedryl, imino-, amido, phosphonate group, phosphonous acid base, carbonyl, carboxyl, silyl, ether, alkylthio, alkylsulfonyl, ketone, aldehyde, ester, heterocyclic radical, aromatics or heteroaromatic moiety ,-CF 3,-replacements such as CN.
Term " carbocyclic ring " is generally acknowledged by this area, refers to that each atom that wherein encircles is the aromatics or the non-aromatic ring of carbon.
Term " nitro " is generally acknowledged by this area, refers to-NO 2Term " halogen " generally acknowledged by this area, refer to-F ,-Cl ,-Br or-I; Term " sulfhedryl " is generally acknowledged by this area, refers to-SH; Term " hydroxyl " refers to-OH; And term " alkylsulfonyl " generally acknowledged by this area, refers to-SO 2 -" halogenide " refers to that the corresponding negatively charged ion of halogen and " false halogenide (pseudohalide) " have Cotton and the Wilkinson definition in 560 pages of propositions of " senior inorganic chemistry ".
Term " amine " and " amino " generally acknowledged by this area, refers to the amine that do not replace and replace, and for example, the part that available general formula is represented :-N (R51) (R50) or [N (R50) is (R53) (R52)] +, wherein R50, R51, R52 and R53 independently represent separately hydrogen, alkyl, alkenyl ,-(CH 2) m-R61, perhaps the N atom that connected of R50 and R51 or R52 and they combines, and is formed on the heterocycle that has 4-8 atom on the ring structure; R61 represents aryl, cycloalkyl, cycloalkenyl group, heterocycle or many rings; And m is the integer between zero or 1-8.In other embodiments, R50 and R51 (and optional R52) each independently represent hydrogen, alkyl, alkenyl or-(CH 2) m-R61.Therefore, as mentioned above, term " alkylamine " comprises having the replacement that connects thereon or the amido of substituted alkyl not, that is, one of R50 and R51 are alkyl at least.
Term " acyl amino " generally acknowledged by this area, refer to the part that available general formula is represented :-N (R50)-C (=O) R54, wherein R50 as mentioned above, R54 represent hydrogen, alkyl, alkenyl or-(CH 2) m-R61, m wherein and R61 are as mentioned above.
Term " amido " is art-recognized to be amino-substituted carbonyl, and comprise the part that can represent by general formula :-C (=O) N (R50) (R51), wherein R50 and R51 are as described above.Some embodiment of acid amides does not comprise the imide of potentially unstable among the present invention.
Term " alkyl thio-base " refers to have the aforesaid alkyl that connects sulfenyl thereon.In certain embodiments, " alkylthio " part by-S-alkyl ,-the S-alkenyl ,-the S-alkynyl and-S-(CH 2) mOne of-R61 expression, m wherein and R61 are as mentioned above.Representational alkylthio comprises methylthio group, ethylmercapto group etc.
Term " carboxyl " generally acknowledged by this area, comprise the part that can represent by general formula :-C (=O)-X50-R55 or-X50-C (=O)-R56, wherein X50 is key or expression oxygen or sulphur, and R55 and R56 represent hydrogen, alkyl, alkenyl ,-(CH 2) m-R61 or pharmacy acceptable salt, R56 represent hydrogen, alkyl, alkenyl or-(CH 2) m-R61, m wherein and R61 are as mentioned above.When X50 is an oxygen and 55 or R56 when being not hydrogen, then this formula is represented " ester ".When X50 is an oxygen, and R55 as mentioned above, and then this part is referred to herein as carboxyl, and especially when R55 was hydrogen, this formula was represented " carboxylic acid ".When X50 is an oxygen, and R56 is when being hydrogen, and then this formula is represented " formyloxy ".In general, when the Sauerstoffatom of following formula was substituted by sulphur, then this formula was represented " thiocarbonyl " group.When X50 is a sulphur, and R55 or R56 be not when being not hydrogen, and then this formula is represented " thioester ".When X50 is a sulphur, and R55 is when being hydrogen, and then this formula is represented " thiocarboxylic acid ".When X50 is a sulphur, and R56 is when being hydrogen, and then this formula is represented " thiocarboxylic ".On the other hand, when X50 is a key, and 55 when being not hydrogen, and then following formula is represented " ketone " group.When X50 is a key, and R55 is when being hydrogen, and then following formula is represented " aldehyde " group.
Term " formamyl " refers to-O (C=O) NRR ' that wherein R and R ' independence are H, aliphatic group, aryl or heteroaryl.
Term " oxo " refer to ketonic oxygen (=O).
Term " oxime " and " oxime ether " generally acknowledged by this area, refer to the part that can represent by general formula :-C (R75) (=NOR), wherein R75 be hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or-(CH 2) m-R61.When R was H, this part was " oxime "; And when R is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or-(CH 2) mDuring-R61, it is " an oxime ether ".
Term " alkoxy grp " or " alkoxyl group " are generally acknowledged by this area, refer to have the aforesaid alkyl that connects oxygen base thereon.Representational alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-, tert.-butoxy etc." ether " is by two covalently bound hydrocarbon of oxygen.Therefore, the substituting group that gives the alkyl of alkyl oxide is or is similar to alkoxyl group, for example can by-O-alkyl ,-the O-alkenyl ,-the O-alkynyl ,-O-(CH 2) mOne of-R61 expression, m wherein and R61 are as mentioned above.
Term " sulfonic group " generally acknowledged by this area, refer to the part that can represent by general formula :-S (=O) 2OR57, wherein R57 is electron pair, hydrogen, alkyl, cycloalkyl or aryl.
Term " sulfate " generally acknowledged by this area, comprise the part that can represent by general formula :-OS (=O) 2OR57, wherein R57 as defined above.
Term " sulfonamido " generally acknowledged by this area, comprises the part that can be represented by general formula :-N (R50)-S (=O) 2OR56, wherein R50 and R56 are as defined above.
Term " sulphonamide " generally acknowledged by this area, refer to the part that can represent by general formula :-S (=O) 2N (R50) (R51), wherein R50 and R51 are as defined above.
Term " alkylsulfonyl " generally acknowledged by this area, refer to the part that can represent by general formula :-S (=O) 2R58, wherein R58 is one of following group: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl.
Term " sulfoxide group " generally acknowledged by this area, and (=O) R58, wherein R58 as defined above to refer to the part that can be represented by general formula :-S.
Can similarly replace alkenyl and alkynyl, to generate, for example, the alkenyl or the alkynyl of amino alkenyl, amino alkynyl, amido alkenyl, amido alkynyl, imino-alkenyl, imino-alkynyl, sulfo-alkenyl, sulfo-alkynyl, carbonyl-replacement.
The definition of each expression, for example, alkyl, m, n etc. when it occurs more than once, are intended to not to be subjected to the restriction of the definition in its other places in same structure in any structure.
Abbreviation Me, Et, Ph, Tf, Nf, Ts and Ms represent methyl, ethyl, phenyl, trifluoromethane sulfonyl group, nine fluorine butane alkylsulfonyls, p-toluenesulfonyl and methylsulfonyl respectively.This area has the more fully abbreviation catalogue that the organic chemistry teacher of ordinary skill is adopted, and is published in first phase of each volume of organic chemistry magazine; This catalogue typically presents with the form of the standard directories that is entitled as abbreviation.
Should understand " replacement " or " quilt ... replace " comprises prerequisite in secret: this class replaces according to the atom that replaces and the valency of substituent permission, and replace and generate stable compound, for example, it can spontaneously for example not change by rearrangement, cyclisation, cancellation or other reaction.
The substituting group that all permissions of including organic compounds also expected in term " replacement ".Aspect widely, the substituting group of permission includes acyclic and ring-type, side chain and unbranched, carbocyclic ring and heterocycle, aromatics and the non-aromatic substituent of organic compounds.Exemplary substituting group comprises, for example, and those that this paper is above-mentioned.For suitable organic compound, the substituting group of permission can be one or more and can be identical or different.At purpose of the present invention, heteroatoms for example nitrogen can have the hydrogen substituting group and/or satisfy the substituting group of any permission of the valent organic compound as herein described of heteroatoms.The present invention does not plan to be subjected to by any way the substituent restriction of the permission of organic compound.
At purpose of the present invention, according to the periodic table of elements, the CAS version, " chemistry and physics handbook ", 67 editions, 1986-87 in the strip of paper used for sealing, identifies chemical element.
Embodiment
Now describe the present invention just prevailingly, by reference following examples, will be easier to understand it, these embodiment are not intended to limit the present invention just to explanation some aspect of the present invention and embodiment.
General experimental arrangement.Right 1H is with 400 MHz and right 13C moves with 100MHz, with the record of Varian 400MHz NMR spectrometer 1H and 13C NMR spectrum.To be worth with respect to the ppm report chemical shift of solvents signals with Hertz (Hz) report coupling constant (J).Carry out thin-layer chromatography (TLC) with E.Merck silica gel 60-F-254 plate, show each spot with UV light.Adopt 230-400 order silica gel (E-Merck) to carry out rapid column chromatography.By adopting formpiston electrospray ionization (ESI), directly inject each compound solution, with Waters Q-TOF Premier mass spectrograph record high resolution mass spectrum (HRMS).Adopt Waters Alliance HT/Micromass ZQ system (ESI), obtain Low Resolution Mass Spectra.From sodium/benzophenone distilled tetrahydrofuran.Buy anhydrous methylene chloride, N from Aldrich, dinethylformamide, benzene and toluene, and former state adopts.All reagent and chemical all use available from commercial supplier and the former state when checking and accepting.
Analyze RPHPLC (reversed-phase high-performance liquid chromatography) (HPLC) with WatersSeparation Module 2695 systems that automatic sampler and Waters 996 photodiode array detectors are housed.Adopt two kinds of different chromatographic systems to determine the purity of final compound.First system: post, WatersNova-Pak RP-C18 (4 μ m, 3.9mmx150mm); Mobile phase A, the aqueous solution of 10mM ammonium acetate; Mobile phase B, acetonitrile.Adopt the flow velocity of 0.8mL/min, carry out gradient elution from 50%B to 100%B through 10min.Second system: post, Agilent Zorbax300SB-C8 (5 m, 4.6mmx250mm); Mobile phase A, the aqueous solution of 0.1% trifluoroacetic acid; Mobile phase B, 0.1% trifluoroacetic acid in acetonitrile.Through 10min,, carry out gradient elution from 50%B to 100%B with the flow velocity of 1mL/min.Containing the retention time of selected compound and the table of purity is shown among Figure 20.
Embodiment 1
The universal method of the CBZ protection of the aniline that replaces
With solid NaHCO 3(32.65g, the 388.5mmols) acetone-water mixture (2: 1) that adds to ice-cooled anils (185mmols) (300mL) in the solution, slowly add subsequently the carbonochloridic acid benzyl ester (27mL, 190mmols).The mashed prod that heating is generated to room temperature and stirring spent the night.Reaction mixture is poured on ice, filters the precipitation that is generated, through water washing and dry.Come purified product by recrystallization from the mixture of hexane and ethyl acetate, obtain the pure products of crystalline solid.Prepare compound 4a-g according to this universal method.
Embodiment 2
The universal method of synthesizing 5-(methylol)- oxazolidones 7 and 8
At dry N 2Under the atmosphere, anils 4 (34.7mmols) solution that cools off the CBZ protection among the anhydrous THF (150mL) is to-78 ℃.(1.6M is in hexane slowly to add n-BuLi; 25mL, 40mmols) solution keeps temperature to be lower than-70 ℃.Under-78 ℃, stirred reaction mixture slowly added chirality butyric acid Racemic glycidol one ester (5g, 34.7mmols) solution among the anhydrous THF after 45 minutes.The mixture that stirring is generated under-78 ℃ 2 hours slowly is heated to room temperature again and stirring is spent the night.Add saturated NH 4Cl aqueous solution quencher reaction.Add ethyl acetate and water, separate each layer.Further use ethyl acetate extraction waterbearing stratum (3 times).With the organic extract of saturated NaCl solution washing through merging, dry (Na 2SO 4), filter and evaporation, generate light yellow solid.Grind this solid with chloroform and hexanes mixtures, and filter, obtain being the purified alcohol of shallow white solid.Prepare compound 8a-g according to this universal method.
Embodiment 3
The universal method of synthesizing phenyl oxazolidinones-5- carboxylic acid 9 and 10
To ice-cooled NaIO 4(35mmols) water (75mL) solution adds mixture C H 3CN and CCl 4(1: 1) alcohol 7 or 8 (10mmols) solution in (100mL).Add solid RuCl 3.H 2O (0.5mmol) in 0 ℃ of following stirred reaction mixture 30 minutes, is heated to room temperature, and stirs 4-6 hour.Add CH 2Cl 2The quencher reaction separates each layer.Further use CH 2Cl 2Extraction waterbearing stratum, the organic extract (Na that is dried through merging 2SO 4) and evaporation, obtain viscous solid.Employing is at CH 2Cl 2+ 1%HCO 225%CH among the H 3The CN mixture is as elutriant, with the column chromatography purification crude product of silica gel.This method provides with good yield and is the required Ben Ji oxazolidine of solid-5-carboxylic acid.Prepare following compound according to this universal method:
Embodiment 4
Open the universal method of the ring of epoxide with amine
With chiral epoxy thing 11 (1-Oxyranyle-2-styroyl) carboxylamine tertiary butyl ester) (10mmol) EtOH (75mL) solution adds to isobutylamine (10mL; Excessive greatly) in, 80 ℃ of following heated mixt 3 hours.After being cooled to room temperature, under reduced pressure removing and desolvate.Recrystallization comes purified product in ethyl acetate-hexane, with the good yield solid product that obtains being white in color.
Embodiment 5
The universal method of synthetic (hydroxyethyl amino)-sulphonamide
CH to ice-cooled secondary amine 12 (5mmol) 2Cl 2(20mL) solution adds Na 2CO 3(8mmol is at 5mL H 2Among the O) aqueous solution, slowly add the CH of SULPHURYL CHLORIDE (5mmol) subsequently 2Cl 2(5mL) solution.After 15 minutes, the reacting by heating mixture is to envrionment temperature, and stirring is detected by tlc up to no starting raw material.Reaction mixture is through CH 2Cl 2Dilution separates each layer.With saturated NaCl solution washing organic extract, dry (Na 2SO 4), filter and evaporation.The mixture that adopts ethyl acetate and hexane through the flash chromatography on silica gel purified product, obtains pure products as elutriant.
With this universal method preparation following compound: N-[(1S, 2R)-1-benzyl-2-hydroxyl-3-[isobutyl-[(4-p-methoxy-phenyl) alkylsulfonyl] amino] propyl group] carboxylamine tertiary butyl ester (14); N-[(1S, 2R)-1-benzyl-2-hydroxyl-3-[isobutyl-[(4-nitrophenyl) alkylsulfonyl]-amino] propyl group] carboxylamine tertiary butyl ester (15); N-[(1S, 2R)-3-[[(benzo-[1,3]-dioxole-5-alkylsulfonyl)] (isobutyl-) amino]-1-benzyl-2-hydroxypropyl] carboxylamine tertiary butyl ester (16); N-[(1S, 2R)-1-benzyl-3-[[(3-fluoro-4-p-methoxy-phenyl) alkylsulfonyl] (isobutyl-) amino]-the 2-hydroxypropyl]-carboxylamine tertiary butyl ester (17); N-[(1S, 2R)-1-benzyl-2-hydroxyl-3-[isobutyl-[[(4-three fluoro-methoxyl groups) phenyl] alkylsulfonyl] amino] propyl group] carboxylamine tertiary butyl ester (18); N-[(1S, 2R)-1-benzyl-2-hydroxyl-3-[isobutyl-[(3-p-methoxy-phenyl) alkylsulfonyl] amino] propyl group] carboxylamine tertiary butyl ester (19); N-[(1S, 2R)-1-benzyl-3-[(cyclopropyl methyl) [(3-p-methoxy-phenyl) alkylsulfonyl]-amino]-the 2-hydroxypropyl] carboxylamine tertiary butyl ester (32); N-[(1S, 2R)-1-benzyl-2-hydroxyl-3-[[(3-p-methoxy-phenyl) alkylsulfonyl] (2-thio-phenyl methyl)] amino] propyl group] carboxylamine tertiary butyl ester (33); N-[(1S, 2R)-1-benzyl-2-hydroxyl-3-[(2-thio-phenyl methyl) [(2,4, the 5-trifluorophenyl) alkylsulfonyl]-amino] propyl group] carboxylamine tertiary butyl ester (34); And N-[(1S, 2R)-and 1-benzyl-2-hydroxyl-3-[[(3-p-methoxy-phenyl) alkylsulfonyl] [(R)-(tetrahydrochysene-2-furyl) methyl] amino] propyl group] carboxylamine tertiary butyl ester (35).
Embodiment 6
The universal method of coupled reaction
Excessive oxalul chloride is added in solid phenyl oxazolidinones-5-carboxylic acid (0.5mmols), stir the mixture overnight that is generated under the room temperature.Oxalyl chloride is removed in decompression distillation down, and dried residue is 30 minutes under high vacuum.Anhydrous THF (5mL) solution of the acyl chlorides that generates is used for coupled reaction.
In the mixture of anhydrous THF (5mL), add Et to the de-protected amine of ice-cooled Boc (0.5mmols) 3N (1.1mmols) slowly adds solution of acid chloride subsequently.After 15 minutes, the reacting by heating mixture stirs up to react completely (through the tlc monitoring) to room temperature.Add less water and ethyl acetate, separate each layer.Organic extract is through saturated NaCl solution washing, dry (Na 2SO 4), filter and evaporation.As elutriant, obtain the solid target compound with ethyl acetate and hexanes mixtures (methyl alcohol/chloroform mixture in some cases) through flash chromatography on silica gel.
Embodiment 7
The universal method of reduction nitro
Under 80 ℃, add nitro-compound (0.4mmols) and SnCl in the hot ethyl acetate (10mL) 2.2H 2O (0.45g, 2mmols) mixture 2-3 hour.Reaction mixture is used saturated NaHCO to envrionment temperature 3The aqueous solution (10mL) is handled.Through the ethyl acetate dilution, separate each layer, further use ethyl acetate extraction waterbearing stratum (2 *).With the organic extract that saturated NaCl solution washing merges, dry (Na 2SO 4) and evaporation, obtain foam solid.Carbinol mixture in the employing chloroform through flash chromatography on silica gel, obtains the solid target compound as elutriant.
Embodiment 9
The biological assessment of HIV-1 proteinase inhibitor
With FRET (fluorescence resonance energy transfer) (FRET) method (Matayoshi, E. D.; Wang, G.T.; Krafft, G.A.; Erickson, J. 954-958), determines the HIV-1 protease inhibitory activity with the new fluorophore substrate .Science 1990,247 of resonance energy transfer analysis retroviral Protease.(Arg-Glu (EDANS)-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-Lys (DABCYL)-Arg) is available from Molecular Probe for protease substrate.Carry out FRET at its two auspicious mark energy transfer donator (EDANS) and acceptor (DABCYL) respectively.Under 30 ℃, (PhotonTechnology International) carries out fluorescence measurement with the PTI spectrophotofluorometer.Excite with emission wavelength and be set at 340nm and 490nm respectively.The about 10min of each reaction of record.Wild-type HIV-1 proteolytic enzyme (Q7K) and MDR mutant M1 (L10I, G48V, I54V, L63P, V82A) thereof, M2 (D30N, L63P, N88D) and M3 (L10I, L63P, A71V, G73S, I84V, L90M) are through PD-10 post (Amersham Biosciences) desalination.With sodium-acetate (20mM, pH 5) as elution buffer.At 280nm, estimate that with UV spectrophotometer (Shimadzu) surperficial protease concentration is about 50nM.Make all inhibitor be dissolved in DMSO and be diluted to suitable concentration.Before causing the substrate scission reaction, hatching is 20-30 minute under mixing protease (2 μ L) and inhibitor (2 μ L) or DMSO and the room temperature.During this running, adopt 150 μ L, 1 μ M substrate.Substrate buffer solution is mixed by the 0.1M sodium-acetate that is adjusted to pH 4.7,1M sodium-chlor, 1mM ethylenediamine tetraacetic acid (EDTA) (EDTA), 1mM dithiothreitol (DTT) (DTT), 2% methyl-sulphoxide (DMSO) and 1mg/mL bovine serum albumin (BSA).According to the Morrison equation, the figure that initial velocity is done as the function of inhibitor concentration carries out nonlinear regression and fitting method (GraFit5, Erithacus software), and the agent that is inhibited is in conjunction with dissociation constant (Ki) (Greco, W.R.; The combine closely evaluation .J.Biol.Chem.1979 of evaluation method of enzyme inhibitors dissociation constant of Hakala, M.T., 254,12104-12109).The linearity range of initial velocity autoreaction curve derives.
Embodiment 10
Proteinase inhibitor synthetic that contains oxyethylamine (HEA) nuclear
Can be in 4 steps of starting raw material with the chiral epoxy thing (1S, 2S enantiomorph) 12 that can commercially availablely obtain, the designed inhibitor of anamorphic zone oxyethylamine (HEA) nuclear isostere.To epoxide 12 open loops, obtain compound 13 with various primary and secondary amine.13 obtain compound 14 with the reaction of various SULPHURYL CHLORIDE.After going to protect the Boc group, make the amine that generated 15 and activating carboxy acid's (R) or (S) isomer coupling, obtain designed inhibitor 16 (Fig. 7 A).
Embodiment 11
Proteinase inhibitor synthetic that contains cyclic carbamate: HE series
Contain proteinase inhibitor synthetic to examine 17 synthetic beginning of hydroxyalkyl vinyl (HE) isostere, it derives from the acid of L-phenylpropylamine with 5 steps.At R 4X 2CO 2After H is coupled to 17, remove the dibenzyl protection, make unhindered amina 19 be coupled to activated acids, the agent 20 that is inhibited (Fig. 7 B).
Embodiment 12
Proteinase inhibitor synthetic that contains cyclic carbamate: azepine-HEA series
Contain azepine-oxyethylamine (synthetic Fig. 8 of being summarized in of the proteinase inhibitor of isostere of azepine-HEA).22 pairs of chirality epoxide of hydrazine derivative (1S, 2R enantiomorph), 21 open loops with the CBz protection obtain compound 23.CBz goes protection, subsequently with R 4X 2CO 2The H coupling obtains compound 24.Remove Boc protection and and R 3X 1CO 2The H coupling, the inhibitor 27 that obtains wanting.
Be attached to this paper by reference
The content of all reference of quoting (comprising the patent of document, mandate, disclosed patent application and the GenBank searching number of being quoted in full as the application) all ad hoc is attached to herein by reference.When the definition of the term in the document that is incorporated into this paper by reference and used herein when discrepancy is arranged, be as the criterion with definition used herein.
Equivalent
Only adopt normal experiment, those skilled in the art should be appreciated that the many Equivalents that maybe can understand fully particular of the present invention as herein described.Be intended to this class Equivalent is included in the following claim.

Claims (107)

1. formula I compound or its pharmacy acceptable salt:
Figure F2008800167017C00011
Wherein, when occurring at every turn independently,
X 1For do not exist ,-O-,-S-,-NR-or
X 2For do not exist ,-O-,-S-,-NR-or
Figure F2008800167017C00013
R 1Be-OH ,-SH or-NHR;
R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl group;
R 2Be hydrogen, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 3Be hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 4Be alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 5Be hydrogen, alkyl, (cycloalkyl) alkyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
The three-dimensional chemical configuration at any three-dimensional center is R, S, or the mixture of these configurations;
Prerequisite is to work as X 1When not existing; R 3Be not
Figure F2008800167017C00014
R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
Prerequisite is X 1Be Or X 2Be
Figure F2008800167017C00022
Or R 3Be amino,
Figure F2008800167017C00023
Figure F2008800167017C00024
Figure F2008800167017C00025
Or R 6Be
Figure F2008800167017C00026
2. the compound of claim 1, wherein X 1Do not exist.
3. the compound of claim 1, wherein X 1Be
4. the compound of claim 1, wherein X 2Do not exist.
5. the compound of claim 1, wherein X 1Do not exist; And X 2Do not exist.
6. the compound of claim 1, wherein R 1Be OH.
7. the compound of claim 1, wherein R 2Be aralkyl or heteroaralkyl.
8. the compound of claim 1, wherein R 2It is aralkyl.
9. the compound of claim 1, wherein R 3Be alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl.
10. the compound of claim 1, wherein R 3Be aryl or heteroaryl.
11. the compound of claim 1, wherein R 4Be alkyl, aryl or heteroaryl.
12. the compound of claim 1, wherein R 5Be alkyl, (cycloalkyl) alkyl, amino, (amino) alkyl, amido, (amido) alkyl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl.
13. the compound of claim 1, wherein R 5Be alkyl, (cycloalkyl) alkyl or (heterocyclic radical) alkyl.
14. formula II compound or its pharmacy acceptable salt:
Figure F2008800167017C00031
Wherein, when occurring at every turn independently,
X 1Do not exist, for-O-or
Figure F2008800167017C00032
R 3Be alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 4Be aryl, heteroaryl, aralkyl or heteroaralkyl; With
R 6Be alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl or heteroaralkyl;
Prerequisite is to work as X 1When not existing; R 3Be not
Figure F2008800167017C00033
R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
Prerequisite is X 1Be Or R 3Be amino,
Figure F2008800167017C00035
Figure F2008800167017C00036
Figure F2008800167017C00037
Or R 6Be
Figure F2008800167017C00038
15. the compound of claim 14, wherein X 1Do not exist.
16. the compound of claim 14, wherein X 1Be
Figure F2008800167017C00041
17. the compound of claim 14, wherein R 3Be alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl.
18. the compound of claim 14, wherein R 3Be aryl or heteroaryl.
19. the compound of claim 14, wherein R 4Be alkyl, aryl or heteroaryl.
20. the compound of claim 14, wherein R 6Be alkyl, (cycloalkyl) alkyl, amino, (amino) alkyl, amido, (amido) alkyl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl.
21. the compound of claim 14, wherein R 6Be alkyl, (cycloalkyl) alkyl or (heterocyclic radical) alkyl.
22. the compound of claim 14, wherein R 3Be
Figure F2008800167017C00042
23. the compound of claim 14, wherein R 3Be
Figure F2008800167017C00052
Figure F2008800167017C00053
24. the compound of claim 14, wherein R 4Be
Figure F2008800167017C00061
Figure F2008800167017C00062
25. the compound of claim 14, wherein R 6Be
Figure F2008800167017C00063
Figure F2008800167017C00064
26. the compound of claim 14, wherein R 6Be
Figure F2008800167017C00065
27. the compound of claim 14, wherein X 1Do not exist; And R 3Be
Figure F2008800167017C00066
Figure F2008800167017C00071
28. one kind is selected from following compound, or its pharmacy acceptable salt
Figure F2008800167017C00072
Figure F2008800167017C00081
Figure F2008800167017C00091
Figure F2008800167017C00101
Figure F2008800167017C00111
Figure F2008800167017C00121
Figure F2008800167017C00131
Figure F2008800167017C00141
Figure F2008800167017C00151
Figure F2008800167017C00161
Figure F2008800167017C00171
Figure F2008800167017C00181
Figure F2008800167017C00191
Figure F2008800167017C00201
Figure F2008800167017C00211
29. formula III compound or its pharmacy acceptable salt:
Wherein, when occurring at every turn independently,
X 1For do not exist ,-O-,-S-,-NR-or
Figure F2008800167017C00213
X 2For do not exist ,-O-,-S-,-NR-or
Figure F2008800167017C00214
R 1Be-OH ,-SH or-NHR;
R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl group;
R 2Be hydrogen, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 3Be hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 4Be alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 5Be hydrogen, alkyl, aralkyl, heteroaralkyl or acyl group;
R 7Be hydrogen, alkyl, (cycloalkyl) alkyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
The three-dimensional chemical configuration at any three-dimensional center is R, S, or the mixture of these configurations;
Prerequisite is to work as X 1When not existing; R 3Be not
Figure F2008800167017C00221
R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
Prerequisite is to work as X 2When not existing; R 4Be not
Figure F2008800167017C00222
R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
Prerequisite is X 1Be Or X 2Be
Figure F2008800167017C00224
R 3Be amino,
Figure F2008800167017C00225
Figure F2008800167017C00227
Or R 4Be
Figure F2008800167017C00228
Figure F2008800167017C00229
30. the compound of claim 29, wherein X 1Do not exist.
31. the compound of claim 29, wherein X 2Do not exist.
32. the compound of claim 29, wherein X 1Do not exist; And X 2Do not exist.
33. the compound of claim 29, wherein R 1Be OH.
34. the compound of claim 29, wherein R 2Be aralkyl or heteroaralkyl.
35. the compound of claim 29, wherein R 2It is aralkyl.
36. the compound of claim 29, wherein R 3Be alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl.
37. the compound of claim 29, wherein R 3Be aryl or heteroaryl.
38. the compound of claim 29, wherein R 3Be
Figure F2008800167017C00232
39. the compound of claim 29, wherein R 4Be alkyl, aryl or heteroaryl.
40. the compound of claim 29, wherein R 4Be
Figure F2008800167017C00233
Figure F2008800167017C00234
41. the compound of claim 29, wherein R 5Be hydrogen.
42. the compound of claim 29, wherein R 7Be alkyl, (cycloalkyl) alkyl, amino, (amino) alkyl, amido, (amido) alkyl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl.
43. formula IV compound or its pharmacy acceptable salt:
Figure F2008800167017C00241
Wherein, when occurring at every turn independently,
X 1Do not exist or be-O-;
R 3Be alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 4Be aryl, amino, (amino) alkyl, amido, (amido) alkyl, heterocyclic radical, (heterocyclic radical) alkyl, heteroaryl, aralkyl or heteroaralkyl; With
R 7Be alkyl, cycloalkyl, (cycloalkyl) alkyl or aralkyl;
Prerequisite is to work as X 1When not existing; R 3Be not
Figure F2008800167017C00242
R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
Prerequisite is to work as X 2When not existing; R 4Be not
Figure F2008800167017C00243
R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
Prerequisite is X 1Be
Figure F2008800167017C00244
Or X 2Be
Figure F2008800167017C00245
R 3Be amino,
Figure F2008800167017C00246
Figure F2008800167017C00248
Or R 4Be
Figure F2008800167017C00249
Figure F2008800167017C00251
44. the compound of claim 43, wherein X 1Do not exist.
45. the compound of claim 43, wherein R 3Be amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl.
46. the compound of claim 43, wherein R 3Be
Figure F2008800167017C00252
47. the compound of claim 43, wherein R 4Be aryl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl (heterocyclic radical) alkyl or heterocyclic radical.
48. the compound of claim 43, wherein R 4Be
Figure F2008800167017C00254
Figure F2008800167017C00255
49. the compound of claim 43, wherein R 7Be alkyl, cycloalkyl or (cycloalkyl) alkyl.
50. the compound of claim 43, wherein X 1Do not exist; And R 3Be amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl.
51. the compound of claim 43, wherein R 3Be
Figure F2008800167017C00261
52. the compound of claim 43, wherein R 4Be
Figure F2008800167017C00263
Figure F2008800167017C00264
Figure F2008800167017C00271
53. the compound of claim 43, wherein R 7Be
Figure F2008800167017C00272
Figure F2008800167017C00273
54. the compound of claim 43, wherein R 7Be
Figure F2008800167017C00274
55. one kind is selected from following compound, or its pharmacy acceptable salt
Figure F2008800167017C00275
Figure F2008800167017C00281
Figure F2008800167017C00291
Figure F2008800167017C00301
56. formula V compound, or its pharmacy acceptable salt:
Figure F2008800167017C00302
Wherein, when occurring at every turn independently,
X 1For do not exist ,-O-,-S-,-NR-or
X 2For do not exist ,-O-,-S-,-NR-or
Figure F2008800167017C00304
R 1Be-OH ,-SH or-NHR;
R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl group;
R 2Be hydrogen, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 3Be hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 4Be alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 5Be hydrogen, alkyl, (cycloalkyl) alkyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
The three-dimensional chemical configuration at any three-dimensional center is R, S, or the mixture of these configurations;
Prerequisite is to work as X 1When not existing; R 3Be not R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
Prerequisite is to work as X 2When not existing; R 4Be not
Figure F2008800167017C00312
R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
Prerequisite is X 1Be
Figure F2008800167017C00313
Or X 2Be
Figure F2008800167017C00314
Or R 3Be amino.
57. the compound of claim 56, wherein X 1Do not exist.
58. the compound of claim 56, wherein X 1Be-O-.
59. the compound of claim 56, wherein X 2Do not exist.
60. the compound of claim 56, wherein X 1Do not exist or-O-; And X 2Do not exist.
61. the compound of claim 56, wherein R 1Be OH.
62. the compound of claim 56, wherein R 2Be aralkyl or heteroaralkyl.
63. the compound of claim 56, wherein R 2It is aralkyl.
64. the compound of claim 56, wherein R 3It is heterocyclic radical.
65. the compound of claim 56, wherein R 4It is (heterocyclic radical) alkyl.
66. the compound of claim 56, wherein R 5It is alkyl.
67. the compound of claim 56, wherein X 1Do not exist or be-O-; X 2Do not exist;
R 1Be OH; R 2It is aralkyl; R 3It is heterocyclic radical; R 4Be alkyl, aryl or heteroaryl; And R 5It is alkyl.
68. formula VII compound, or its pharmacy acceptable salt:
Wherein, when occurring at every turn independently,
X 1For do not exist ,-O-,-S-,-NR-or
Figure F2008800167017C00322
X 2For do not exist ,-O-,-S-,-NR-or
R 1Be-OH ,-SH or-NHR;
R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl group;
R 2Be hydrogen, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 3Be hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 4Be alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 5Be hydrogen, alkyl, (cycloalkyl) alkyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
The three-dimensional chemical configuration at any three-dimensional center is R, S, or the mixture of these configurations;
Prerequisite is to work as X 1When not existing; R 3Be not
Figure F2008800167017C00324
R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
Prerequisite is to work as X 2When not existing; R 4Be not
Figure F2008800167017C00331
R wherein 3ABe hydrogen, alkyl, alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl; With
Prerequisite is X 1Be Or X 2Be
Figure F2008800167017C00333
Or R 3Be amino.
69. the compound of claim 68, wherein X 1Do not exist.
70. the compound of claim 68, wherein X 2Do not exist.
71. the compound of claim 68, wherein X 1Do not exist; And X 2Do not exist.
72. the compound of claim 68, wherein R 1Be-OH or-NH 2
73. the compound of claim 68, wherein R 2Be aralkyl or heteroaralkyl.
74. the compound of claim 68, wherein R 2It is aralkyl.
75. the compound of claim 68, wherein R 3Be alkenyl, amino, (amino) alkyl, amido, (amido) alkyl, (ketone group) alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl.
76. the compound of claim 68, wherein R 3Be (amido) alkyl or heterocyclic radical.
77. the compound of claim 68, wherein R 4Be (amido) alkyl or heterocyclic radical.
78. the compound of claim 68, wherein R 5It is alkyl or aryl.
79. formula XII compound, or its pharmacy acceptable salt:
Figure F2008800167017C00334
Wherein, when occurring at every turn independently,
R 3Be
Figure F2008800167017C00335
Figure F2008800167017C00336
Figure F2008800167017C00341
R 4Be
Figure F2008800167017C00342
Figure F2008800167017C00343
Wherein, independently, W is selected from-NHR at every turn when occurring 7Or-NHR (CH 2) pN (R 7) 2R 7Be selected from hydrogen, alkyl, aralkyl, heteroaralkyl and acyl group; With p be 1-10; With
R 6Be
Figure F2008800167017C00351
80. the compound of claim 79, wherein R 3Be
Figure F2008800167017C00352
81. the compound of claim 79, wherein R 4Be
Figure F2008800167017C00354
Figure F2008800167017C00355
82. the compound of claim 79, wherein R 6Be
83. the compound of claim 79, wherein R 6Be
Figure F2008800167017C00363
84. one kind is selected from following compound, or its pharmacy acceptable salt:
Figure F2008800167017C00364
Figure F2008800167017C00371
Figure F2008800167017C00391
Figure F2008800167017C00401
Figure F2008800167017C00411
Figure F2008800167017C00421
Figure F2008800167017C00431
Figure F2008800167017C00441
Figure F2008800167017C00451
Figure F2008800167017C00471
Figure F2008800167017C00481
Figure F2008800167017C00501
Figure F2008800167017C00511
85. formula XII compound or its pharmacy acceptable salt:
Figure F2008800167017C00512
Wherein, when occurring at every turn independently,
R 3Be
Figure F2008800167017C00513
Figure F2008800167017C00514
R 4Be
Figure F2008800167017C00522
Figure F2008800167017C00523
Wherein, independently, W is selected from-NHR at every turn when occurring 7Or-NHR (CH 2) pN (R 7) 2R 7Be selected from hydrogen, alkyl, aralkyl, heteroaralkyl and acyl group; With p be 1-10; With
R 6Be
Figure F2008800167017C00524
Figure F2008800167017C00525
86. the compound of claim 85, wherein R 3Be
Figure F2008800167017C00526
Figure F2008800167017C00527
87. the compound of claim 85, wherein R 3Be
Figure F2008800167017C00531
Figure F2008800167017C00532
88. the compound of claim 85, wherein R 3Be
Figure F2008800167017C00534
89. the compound of claim 85, wherein R 4Be
Figure F2008800167017C00535
90. the compound of claim 85, wherein R 6Be
Figure F2008800167017C00537
91. one kind is selected from following compound, or its pharmacy acceptable salt:
Figure F2008800167017C00538
Figure F2008800167017C00541
Figure F2008800167017C00561
Figure F2008800167017C00571
Figure F2008800167017C00581
Figure F2008800167017C00591
Figure F2008800167017C00601
92. different (the iso)-XII of formula compound, or its pharmacy acceptable salt:
Figure F2008800167017C00611
Different-XII
Wherein, when occurring at every turn independently,
R 3Be alkyl, (amino) alkyl, (amido) alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, (heterocyclic radical) alkyl, aralkyl or heteroaralkyl;
R 4Be aryl, heteroaryl, aralkyl or heteroaralkyl; With
R 6Be alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl or heteroaralkyl.
93. a medicinal compositions, it comprises each compound among the claim 1-92 of pharmaceutical carrier and treatment significant quantity.
94. treat the method that HIV infects for one kind, the medicinal compositions that it comprises among the claim 1-92 of the Mammals treatment significant quantity that needs are arranged each compound or treats the claim 93 of significant quantity.
95. the method for claim 94, wherein said compound gives as the part of high reactivity antiretroviral therapy (HAART) scheme.
96. the method for claim 94, wherein said medicinal compositions gives as the part of high reactivity antiretroviral therapy (HAART) scheme.
97. also comprising, each method among the claim 94-96, this method give second kind of therapeutical agent.
98. the method for claim 97, second kind of therapeutical agent wherein are non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI), nucleotide reverse transcriptase inhibitors, entry inhibitor, integrase inhibitor, fusion inhibitor, proteinase inhibitor or metabolic enzyme inhibitor.
99. the method for claim 97, second kind of therapeutical agent wherein is selected from efavirenz (Sustiva TM), nevirapine (Viramune TM), Delavirdine (Rescriptor TM), AZT (zidovudine, Retrovir TM)/3TC (lamivudine, Epivir TM), d4T (stavudine, Zerit TM)/3TC, ddI (didanosine, Videx TM/ VidexEC TM), ddC (zalcitabine, HiVid TM), d4T, tynofovir (Viread TM) and En Fuwei peptide (Fuzeon TM).
100. the method for claim 97, second kind of therapeutical agent wherein be selected from amprenavir (
Figure F2008800167017C00621
APV), tipranavir (
Figure F2008800167017C00622
TPV), Indinavir ( IDV), Saquinavir (
Figure F2008800167017C00624
SQV), rltonavir and ritonavir (
Figure F2008800167017C00625
LPV), fosamprenavir (
Figure F2008800167017C00626
FPV), ritonavir (
Figure F2008800167017C00627
RTV), Reyataz R (
Figure F2008800167017C00628
ATZ), viracept see nelfinaivr (
Figure F2008800167017C00629
NFV), Bu Ruinawei and Da Lunawei.
101. the method for claim 97, second kind of therapeutical agent wherein be ritonavir (
Figure F2008800167017C006210
LPV).
102. the method for claim 97, second kind of therapeutical agent wherein is selected from zidovudine (AZT; Zidovodine;
Figure F2008800167017C006211
), didanosine (didanosine; DdI;
Figure F2008800167017C006212
), zalcitabine (zalcitabine; DdC;
Figure F2008800167017C006213
), lamivudine (3TC; ), stavudine (2 ', 3 '-two dehydrogenations-3 '-deoxythymidine; D4T;
Figure F2008800167017C006215
), abacavir succinate (1592U89 succinate;
Figure F2008800167017C006216
ABC),
Figure F2008800167017C006217
(La Mifuding ﹠amp; Zidovudine; (-)-3TC ﹠amp; AZT) and
Figure F2008800167017C006218
(A Bakawei ﹠amp; La Mifuding ﹠amp; Zidovudine; ABC ﹠amp; (-)-3TC ﹠amp; AZT).
103. the method for claim 97, second kind of therapeutical agent wherein is selected from nevirapine (BI-RG-587;
Figure F2008800167017C006219
), Delavirdine (BHAP; U-90152;
Figure F2008800167017C006220
) and (efavirenz; DMP-266;
Figure F2008800167017C006221
).
104. the method for claim 97, second kind of therapeutical agent wherein be T-20 (
Figure F2008800167017C006222
The En Fuwei peptide; DP-178; Pentafuside; GP41 127-162 AA).
105. the method for claim 97, second kind of therapeutical agent wherein is TMCC114.
106. the method for claim 97, it also comprises and gives reverse transcriptase inhibitors.
107. the method for claim 97, second kind of therapeutical agent wherein is rltonavir (lupinavir).
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