CN101084231B - Phosphoindoles as HIV inhibitors - Google Patents

Phosphoindoles as HIV inhibitors Download PDF

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CN101084231B
CN101084231B CN2005800392187A CN200580039218A CN101084231B CN 101084231 B CN101084231 B CN 101084231B CN 2005800392187 A CN2005800392187 A CN 2005800392187A CN 200580039218 A CN200580039218 A CN 200580039218A CN 101084231 B CN101084231 B CN 101084231B
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alkyl
compound
optional
hiv
independently
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CN101084231A (en
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理查德·斯托勒
西里尔·多森
弗兰西斯-雷内·亚历山大
阿琳·罗兰
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Idenix Pharmaceuticals LLC
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Idenix Pharmaceuticals LLC
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Abstract

3-phosphoindole compounds for the treatment of retroviral infections, and particularly for HIV, are described. Also included are compositions comprising the 3-phosphoindole derivatives alone or in combination with one or more other anti-retroviral agents, processes for their preparation, and methods of manufacturing a medicament incorporating these compounds.

Description

Phosphoric acid-indoles as hiv inhibitor
The cross reference of related application
The application requires the 60/611st of submission on September 16th, 2005, the 60/711st of submission on August 25th, No. 061 1, submit in No. 445 and on August 26th, 2005 the 60/711st, No. 565 U.S. Provisional Application No., all these application titles are " as the phosphoric acid-indoles of hiv inhibitor ".
Invention field
The invention provides new human immunodeficiency virus (HIV) reversed transcriptive enzyme inhibition compound and their pharmacy acceptable salt, prodrug, analogue and derivative.Also comprise with these compound preventions and treatment HIV and infecting and the method for AIDS and the pharmaceutical composition that contains this compound.
Background of invention
Synthesized chemical compound lot and tackled human immunodeficiency virus (HIV), because just have been found that as far back as nineteen eighty-three this virus is to cause the cause of disease of acquired immunodeficiency syndrome (AIDS).The focus of AIDS research once was and still was exploit person immunodeficiency virus (HIV-1) reverse transcriptase inhibitors, this kind of enzyme be responsible for from retrovirus RNA to proviral DNA reverse transcription (W.C.Greene, New England Journalof Medicine(1991), 324:308-17; Mitsuya etc., Science(1990), 249:1533-44; E.J.DeClercq, Retrovirus(1992), 8:119-34).Inhibitor comprises non-nucleosides type reverse transcriptase inhibitors, or be called the NNRTI class, they are attached near the specific other structure site of the hiv reverse transcriptase the polysaccharase site and disturb reverse transcription by the conformation or the reactivity that change reversed transcriptive enzyme, thereby cause the noncompetitive of enzyme to suppress (Kohlstaedt etc. Science(1992), 256:1783-90).
The compound of some kinds has been accredited as the NNRTI class of HIV.Their example comprises:
1) methyl 1-[(2-hydroxyl-oxethyl)]-6-(thiophenyl) thymus pyrimidine (HEPT) (Tanaka etc., J.Med.Chem.(1991), 34:349-57; Pontikis etc., J.Med.Chem.(1997), 40:1845-54; Danel etc., J.Med.Chem.(1996), 39:2427-31; Baba etc., Antiviral Res.(1992), 17:245-64);
2) two (heteroaryl) piperazine (BHAP) (Romero etc., J.Med.Chem.(1993), 36:1505-8);
3) dihydro alkoxybenzyl oxygen pyrimidine (DABO) (Danel etc., Acta Chemica Scandinavica(1997), 51:426-30; Mai etc., J.Med.Chem.(1997), 40:1447-54);
4) 2 ', 5 '-two-O-(t-butyldimethylsilyl)-3 '-spiral shell-5 " (4 "-amino-1 ", 2 " oxathiole-2 ", 2 " and dioxide) pyrimidine (TSAO) (Balzarini etc., PNAS USA(1992), 89:4392-96);
5) phenylethyl thiazolyl thiocarbamide (PETT) derivative (Bell etc., J.Med.Chem.(1995), 38:4929-36; Cantrell etc., J.Med.Chem.(1996), 39:4261-74);
6) tetrahydrochysene-imidazo [4,5,1-jk] [1,4]-benzodiazepine
Figure G05839218720070518D000021
-2 (1H)-ketone and-thioketones (TIBO) derivative (Pauwels etc., Nature (1990), 343:470-4);
7) imdazole derivatives of phosphorus replacement (Gilead Sciences, the open No.WO 03/091264A2 of the PCT of Inc.);
8) α-anilino phenyl-acetamides (derivative of α-APA) (Pauwels etc., PNAS USA(1993), 90:1711-15); With
9) indole derivatives (Merck ﹠amp; Co. U.S. Patent No. 5,527,819 and the open No.WO 94/19321 of corresponding PCT).
Merck ﹠amp; It is the inhibitor of hiv reverse transcriptase that the indole derivatives of describing in No. the 5th, 527,819, the United States Patent (USP) Co. shows.In these compounds some are to the IC of hiv reverse transcriptase 50Concentration value is 3-35 η M.Merck ﹠amp; Co. also developed by between ketone and Iodoaniline (iodoaniline), carry out the palladium catalytic cyclization synthesize the method for the optional indoles that replaces (Chen etc., J.Org.Chem.(1997), 62 (9): 2676-77).
Disclosed compound is represented with following general formula (III) usually in the patent of ' 819:
Wherein, variable X, Y, Z, R and R 6Extensively limited.
Merck ﹠amp; Co. U.S. Patent No. 5,124,327 discloses the optional alkylsulfonyl Phenylindole compounds that replaces of a class.This patent claims that this compound has the reverse transcriptase inhibitors activity and can be used in treatment HIV infection and AIDS.
Idenix Pharmaceuticals, the United States Patent (USP) of Ltd. discloses a class Phenylindole the 6th, 710, No. 068, and one of two ring or both are replaced by the group outside at least two hydrogen.Can WO be disclosed No. 02/083126 referring to PCT also.
The PCT of Idenix Pharmaceuticals discloses WO and discloses the another kind of active Phenylindole of enhanced anti-HIV that demonstrates for No. 2004/014364.One of two of these compounds rings or two rings are also replaced by two groups outside the hydrogen at least.In addition, these compounds have many different substituting groups with methane amide functionality 2 of indoles, and this position is expressed as " Z " in above-mentioned formula (II).Substituent exemplary position be 4 of 3 " and 5 " position of phenyl ring and indoles part benzo ring ' and 5 ', 5 ' and 6 ' or 5 ' and 7 ' position.
Open and PCT discloses indoles, azaindole, piperazine and the tetramethyleneimine of the optional replacement of various HIV of being used for the treatment of and/or AIDS in open to Bristol Myers Squibb in some United States Patent (USP)s and the U.S..Referring to US publication 2004/0006090; 2004/0063746; 2003/0096825; 2003/0236277; With WO 03/068221.
The WO 01/02388 of SmithKline Beecham S.P.A discloses and it is said the Phenylindole with the substituent optional replacement of carbamyl that can be used for the treatment of HIV, AIDS, osteoporosis, cancer and degenerative brain disorder.
Warner-Lambert Company is at U.S.5, and 424,329; U.S.5,565,446; U.S.5,703,069; With the indole-3-sulphur that discloses the various HIV of being used for the treatment of among the WO 96/29077 for azepine ketone (thiazepinone), oxa-azepine ketone (oxazepinone), diazepinone (diazepinone), thionaphthene, cumarone and indoles-2-methane amide.
Shinogi ﹠amp; Co. disclose No. 2002/0019434 and United States Patent (USP) the 6th, 716,605 and 6,506 in the U.S., claim in No. 787, can be used as the anti-HIV medicine as the indole derivatives of the optional replacement of viral integrase enzyme inhibitors.
The United States Patent (USP) the 5th of Kleinschroth etc., the indole carbazole acid amides that one class is used for the treatment of the various diseases that comprises cancer, virus disease (comprising HIV), heart and vascular disease, bronchopneumopathy, inflammatory diseases, degenerative disease of the central nervous system and other disease is disclosed for 945, No. 440.
The United States Patent (USP) of Gunasekera etc. has disclosed some for the 4th, 866, No. 084 and has had antiviral and two indole alkaloid compounds anti-tumor activity, comprising HSV (hsv).The United States Patent (USP) 5,935,982 of Dykstra etc. has been reported another kind of two indoles, and it can be used for resisting retroviral infection, especially HIV.
The United States Patent (USP) of Matsunaga etc. discloses a class for the 5th, 852, No. 011 by the indole derivatives of heteroaryl functional group and amide functional group replacement.It is said that this compound has antitumor, antiviral and antimicrobial characteristic.
The United States Patent (USP) of Dykstra etc. discloses a class two indoles for the 5th, 935, No. 982, and they specifically are used for the treatment of retroviral infection, and especially HIV infects.
The United States Patent (USP) of Domagala etc. discloses a class aryl sulfo-and dithio diaryl amide compound for the 5th, 929, No. 114, comprises indole derivatives, it is said that they have antibiotic and antiviral activity.
The United States Patent (USP) of Pevear etc. discloses a class three azino indole derivativeses for the 5th, 830, No. 894, the anti--pestivirus activity that it is said that they have, and the most significant is the BVDV activity.
Come in the disease for the treatment of outside the HIV with indoles.The United States Patent (USP) of Farina etc. discloses the bewildering array that is used for the treatment of osteoporotic indoles the 5th, 981, No. 525, and this is based on them can suppress osteoclast H +Thereby-ATP enzyme reduces bone resorption.The U.S. Patent No. 6,025,390 that belongs to Farina etc. equally discloses another group indole derivatives, is called the heteroaromatic pentadienoic acid derivates, also is used for the treatment of osteoporosis.The U.S. Patent No. 5,489,685 of Houpis etc. discloses a series of compounds, and they are that (2,3-b) (furo (2,3-b) pyridine carboxylic acid) it is said to be used for the treatment of HIV the pyridine carboxylic acid ester furans.
As time goes on known, the anti-virus formulation with HIV (human immunodeficiency virus)-resistant activity can induced mutation in virus, thereby reduces efficacy of drugs.This obviously is a United States Patent (USP) the 5th, 527, the problem that Merck indoles described in No. 819 exists (Williams etc., J.Med.Chem., 1993,36 (9), 1291-94).Resistance takes place owing to the encoding gene sudden change of the enzyme that is used for virus replication usually, and modal for HIV is reversed transcriptive enzyme, proteolytic enzyme or DNA intergrase.Verified, with second kind, if possible the third, antiviral compound associating or alternately give the effect that certain compound can prolong, strengthens or recover the anti-HIV infection of medicine, described antiviral compound inductive suddenlys change and is different from this mainly drug-induced sudden change.Perhaps, can change in the pharmacokinetics, body of medicine by this combination or rotational therapy and decompose or other parameter.Usually, combination treatment is better than rotational therapy, because combination treatment can cause the multiple pressure to virus simultaneously.Yet which kind of sudden change our unpredictable certain medicine will induce in the HIV-1 genome, and this sudden change is permanent or temporary transient, and which kind of reaction the cells infected that perhaps has the HIV-1 sequence of sudden change will produce to combination or other reagent that is used alternatingly.Long-term cell culture medicine patience dynamics data with modern antiretroviral agent treatment is few, thereby has further increased the weight of these factors.
Therefore, the Compounds and methods for of new treatment HIV need be provided.
Therefore, an object of the present invention is to provide new compound, composition and the methods and applications that are used for the treatment of HIV patient.
Another object of the present invention provides new composition and the method that is used for the treatment of HIV patient, and described composition and method have activity to the resistance form of virus.
Summary of the invention
3-phosphoric acid benzazolyl compounds has antiviral activity to HIV, especially to other anti-HIV medicine being produced the HIV bacterial strain of intersection patience.The method of the compound, composition and the treatment HIV infection that comprise 3-phosphoric acid benzazolyl compounds is disclosed.Described 3-phosphoric acid indoles can have various forms, comprising but be not limited to: phosphoric acid ester or salt, phosphonic acid ester or salt, thiophosphatephosphorothioate or salt, comprise thiophosphatephosphorothioate or salt, Thiophosphonate or salt, phosphoric acid ester or salt and phosphoramidate or salt (phosphoramidate) comprise imino-phosphoric acid ester or salt (immiophosphate) and imino-phosphonic acid ester or salt.
In one embodiment, have the active compound of anti-HIV and have following formula (A).These compounds contain the substituting groups that phosphorus connects 3 of indoles, and 2 of indoles specific substituting group are arranged, and at the R of benzo ring 5 'The place is single to be replaced or at R 4 'And R 5 ', R 5 'And R 6 'Or R 5 'And R 7 'The position is two to be replaced.
Figure G05839218720070518D000061
In one specific embodiments, substituting group " X " representative phenyl ring unsubstituted or that replaced by one or more halogens or low alkyl group such as methyl or ethyl.The specified substituent that the indoles part is 2 comprises, for example, and hydrogen, hydroxyl, halogen, alkyl, aryl, heteroaryl, and especially have with the methane amide of " Z " expression in the formula (A) or the substituting group of methane amide part.The substituting group of the benzo ring of indoles part includes but not limited to chlorine, fluorine, bromine, iodine, CF 3, CN, NO 2And methoxyl group.
Described active compound can be salt or prodrug, and they can directly or indirectly provide parent compound or itself promptly to have required activity after administration.In another embodiment, the compound with formula A comprises charged heteroatoms, and in one embodiment, described compound comprises the N-oxide groups.Here also comprise the modification that influences the The compounds of this invention biologic activity, promptly produce any variation of the parent compound of increased activity.
The accompanying drawing summary
Fig. 1 has shown three (3) the kind formulas of the present invention with formula (A), formula (B) and formula (C) expression.
Fig. 2 has shown the compound (I)-(X) with general formula (A) and phosphorylation (B).
Fig. 3 has shown the compound (XI)-(XX) of 9-with general formula (C) and 10-unit dicyclo phosphorylation.
Detailed Description Of The Invention
Composition, using method and the pharmaceutical composition of material are provided, have been used for the treatment of mammiferous retroviral infection, be particularly useful for treating human HIV.The present invention includes following feature:
3-phosphoric acid indoles described here and pharmacy acceptable salt and prodrug, optional other chemical entities (entity) that is substantially free of;
3-phosphoric acid indoles with formula A-C and pharmacy acceptable salt and prodrug described here, optional other chemical entities that is substantially free of;
3-phosphoric acid indoles described here and pharmacy acceptable salt thereof and prodrug can effectively be resisted HIV in the host;
3-phosphoric acid indoles described here and pharmacy acceptable salt thereof and prodrug can effectively be resisted the HIV persister in the host, in certain embodiments, the HIV persister is owing to the reversed transcriptive enzyme sudden change produces as Methionin 103 → l-asparagine and/or tyrosine 181 → halfcystine;
3-phosphoric acid indoles described here and pharmacy acceptable salt thereof and prodrug are used for infecting in host's treatment or prevention HIV, or the medicine that is used for being manufactured on host's treatment or prevents the HIV infection, be particularly useful for being diagnosed as the individuality that is infected or have infected risk by HIV;
3-phosphoric acid indoles described here and pharmacy acceptable salt thereof and prodrug are used for infecting in host's treatment or prevention HIV, or the medicine that is used for being manufactured on host's treatment or prevents the HIV infection, described HIV has resistance to one or more reverse transcriptase inhibitors;
3-phosphoric acid indoles described here and pharmacy acceptable salt thereof and prodrug are used for infecting in host's treatment or prevention HIV with the form of remedying therapy, or be used for making with the form of remedying therapy at the medicine that host's treatment or prevention HIV infect, be particularly useful for being diagnosed as the individuality that is infected or have infected risk by HIV;
3-phosphoric acid indoles described here and pharmacy acceptable salt thereof and prodrug are used in host's treatment or prevention HIV infection or are used to make the medicine for the treatment of or preventing HIV to infect, described HIV is particularly useful for being diagnosed as the individuality that is infected or have infected risk by HIV because reversed transcriptive enzyme sudden change has patience as Methionin 103 → l-asparagine and/or tyrosine 181 → halfcystine to one or more reverse transcriptase inhibitors;
Make the optional method that is substantially free of the 3-phosphoric acid indoles of other chemical entities;
Contain the 3-phosphoric acid indoles of anti-HIV treatment significant quantity or the pharmaceutical composition of its pharmacy acceptable salt or its prodrug and pharmaceutically acceptable carrier or thinner;
Contain 3-phosphoric acid indoles or its pharmacy acceptable salt or its prodrug and the optional pharmaceutical composition that contains pharmaceutically acceptable carrier or thinner for the treatment of significant quantity with the anti-HIV of one or more other anti-HIV preparation combinations;
Treatment or prevention have the pharmaceutical composition of the HIV infection of patience to one or more reverse transcriptase inhibitors in the host, it contains 3-phosphoric acid indoles or its pharmacy acceptable salt or the prodrug of anti-HIV treatment significant quantity, optional and at least a other anti-HIV preparation combination, and optional pharmaceutically acceptable carrier or the thinner of containing;
The pharmaceutical composition that in the host, infects with the form of therapy of remedying therapy or prevention HIV, it contains 3-phosphoric acid indoles or its pharmacy acceptable salt or the prodrug of anti-HIV treatment significant quantity, optional and at least a other anti-HIV preparation combination, and optional pharmaceutically acceptable carrier or the thinner of containing;
Treatment or prevention in the host are because reversed transcriptive enzyme sudden change as Methionin 103 → l-asparagine and/or tyrosine 181 → halfcystine and one or more reverse transcriptase inhibitors are had the pharmaceutical composition of the HIV infection of patience, it contains 3-phosphoric acid indoles or its pharmacy acceptable salt or the prodrug of anti-HIV treatment significant quantity, optional and at least a other anti-HIV preparation combination, and optional pharmaceutically acceptable carrier or the thinner of containing;
The method that treatment or prevention HIV infect in the host, wherein said HIV can have patience to one or more reverse transcriptase inhibitors, described method comprises 3-phosphoric acid indoles or its pharmacy acceptable salt or the prodrug that gives described host's anti-HIV treatment significant quantity, optional and at least a other anti-HIV preparation combination gives or alternately gives, and optional with contain pharmaceutically acceptable carrier or thinner and make up;
The method that in the host, infects with the form of therapy of remedying therapy or prevention HIV, described method comprises 3-phosphoric acid indoles or its pharmacy acceptable salt or the prodrug that gives described host's anti-HIV treatment significant quantity, optional and at least a other anti-HIV preparation combination gives or alternately gives, and optional and pharmaceutically acceptable carrier or thinner combination;
Treatment or prevention in the host are because reversed transcriptive enzyme sudden change as Methionin 103 → l-asparagine and/or tyrosine 181 and one or more reverse transcriptase inhibitors are had the method for the HIV infection of patience, described method comprises 3-phosphoric acid indoles or its pharmacy acceptable salt or the prodrug that gives described host's anti-HIV treatment significant quantity, optional and at least a other anti-HIV preparation combination gives or alternately gives, and optional and pharmaceutically acceptable carrier or thinner combination;
The also optional and pharmaceutically acceptable carrier that optional and at least a other anti-HIV preparation combination gives or alternately gives or the 3-phosphoric acid indoles of thinner combination or its pharmacy acceptable salt or prodrug are used in host's treatment or prevent HIV to infect;
The 3-phosphoric acid indoles of that optional and at least a other anti-HIV preparation combination gives or alternately gives and optional and pharmaceutically acceptable carrier or thinner combination or its pharmacy acceptable salt or prodrug are used for infecting in host's treatment or prevention HIV, or be used to make treatment or prevention may be because reversed transcriptive enzyme sudden change as Methionin 103 → l-asparagine and/or tyrosine 181 → halfcystine and one or more reverse transcriptase inhibitors are had the medicine of the HIV infection of patience.This application can be a form of remedying therapy; With
In above-mentioned any or all situation, described host is the people.
I. active compound of the present invention
In general embodiment of the present invention, 3-phosphoric acid indoles or its pharmacy acceptable salt, prodrug, N-oxide compound, quaternary amine, steric isomer or tautomer are provided.The form of described 3-phosphoric acid indoles can be phosphoric acid ester or salt, phosphonic acid ester or salt, thiophosphatephosphorothioate or salt, Thiophosphonate or salt, imino-phosphoric acid ester or salt or imino-phosphonic acid ester or salt.
In first embodiment of the present invention, described compound is represented with following chemical formula (A) usually:
Or its pharmacy acceptable salt, prodrug, N-oxide compound, quaternary amine, steric isomer or tautomer, wherein:
X and Y are independently of one another:
a)H；
B) halogen (F, Cl, Br or I) is typically F;
c)R 3；
d)CF 3；
E) C 1-6Alkyl;
F) C 2-6Thiazolinyl;
G) C 2-6Alkynyl;
H) alkyl heterocycle;
I) 3-14 unit carbocyclic ring, aryl, heterocycle, wherein any one can contain monocycle, dicyclo, three ring or spirane structures;
j)OH；
k)OR 2；
L) O-alkyl;
M) O-thiazolinyl;
N) O-alkynyl;
O) O-alkylaryl;
P) O-aryl;
Q) O-heterocycle;
R) O-aralkyl;
S) O-carbocyclic ring;
t)SH；
u)SR 2；
V) S-alkyl;
W) S-thiazolinyl;
X) S-alkynyl;
Y) S-alkylaryl;
Z) S-aryl;
Aa) S-heterocycle;
Bb) S-aralkyl;
Cc) S-carbocyclic ring;
dd)NH 2；
ee)NHR 2；
ff)NR 2R 2；
Gg) NH-alkyl;
Hh) N-dialkyl group;
Ii) NH-aryl;
Jj) N-alkaryl;
Kk) N-aralkyl;
Ll) NH-heterocycle;
Mm) N-alkyl-heterocycle;
Nn) N-thiazolinyl-heterocycle;
Oo) N-alkynyl-heterocycle; Or
Perhaps, X and Y can be in conjunction with forming optional dicyclo or the three cyclic phosphoric acid heterocycles that replace, and wherein each ring contains 3-7 ring members;
Z is:
a)H；
b)CN；
c)NO 2；
D) C 1-6Alkyl;
E) C 2-6Thiazolinyl;
F) C 2-6Alkynyl;
G) alkaryl;
H) aralkyl;
I) heterocycle;
J) alkyl-heterocycle;
K) aryl;
L) alkoxyl group;
m)OR 2；
n)SR 2；
o)S(O) nR 2；
p)S(O) n-NR 2R 3；
q)N(R 2)(R 3)；
R) formamido-;
S) amido;
T) acyl group;
u)C(＝W)-R 3；
v)C(＝W)NH-C(R 3)(R 3)-C(＝W)-N(R 2)(R 2)；
w)C(＝W)NH-P(＝W)(R 3)-A-R 3；
x)C(＝W)NH-A-S(O) n-NR 2；
y)C(＝W)NH-CR 3R 3-S(O) n-NR 2R 2；
z)C(＝W)-NH-A-C(＝W)-N(R 2)(R 2)；
aa)C(＝W)-N(R 2)(R 2)；
bb)C(＝W)-NH-A-R 3；
cc)C(＝W)-NH-NH-R 3；
dd)C(＝W)-NH-C(R 3)(R 3)-C(＝W)NH-C(R 3)(R 3)C(＝W)-N(R 2)(R 2)；
ee)C(＝W)-NH-R 2；
ff)C(＝W)-NH-A-C(＝W)-NH-A-C(＝W)-NH 2；
gg)C(R 2)(R 3)(R 3)；
hh)C(R 2)(R 3)-NH-R 2；
ii)A-S(O) n-R 3；
jj)C(＝W)-A-C(＝W)-A-C(＝W)R 3；
kk)A-R 3；
ll)C(＝W)-(O)R 2；
mm)C(＝W)-A-C(＝W)-NH 2；
Nn) amino-acid residue;
Oo) C (=W)-N (R 2)-A-(amino-acid residue);
Pp) C (=W)-N (R 2)-A-(amino-acid residue)-C (=W)-R 3
Qq) C (=W)-amino-acid residue;
Rr) C (=W)-N (R 2)-A-(amino-acid residue)-A-C (=W)-R 3
ss)C(＝W)-OR 2；
tt)C(＝W)-S(R 2)；
uu)C(＝W)-NH-NH-R 2；
vv)C(＝W)-NH-N(R 2)-A-C(＝W)R 3；
ww)C(＝W)-N(R 2)-C(＝W)-R 3；
xx)C(＝W)-A-NH-C(＝W)R 3；
yy)C(＝W)-A-NH-C(＝W)OR 2；
zz)C(＝W)-A-R 3；
aaa)C(＝W)-NH-NH-CH 2-C(＝W)R 3；
Bbb) P (=W) (R 3) (R 3); Or
ccc)A-P(＝W)(R 3)(R 3)；
Ddd) C (=W)-NH-C 1-10Alkyl-heteroaryl
Eee) C (=W)-NH-C 1-4Alkyl-heteroaryl
Fff) C (=W)-NH-CH 2-heteroaryl
Wherein, in embodiment (ddd), (eee) with (fff), described heteroaryl can be chosen wantonly and comprise charged heteroatoms, and especially can comprise the N-oxide compound
Wherein, above-mentioned X, Y and Z are unsubstituted independently of one another or are replaced by one or more following substituting groups: C 1-6Alkyl; Alkoxyl group; OH; Oxo; Halogen (F, Cl, Br or I); NR 2R 2The optional aryl that replaces; The optional heterocycle that replaces; O-C (=W)-alkyl; C (=W)-OR 2CN; NO 2NH-C (=W)-alkyl; NH-S (O) n-alkyl; NH-S (O) n-NR 2R 2Or C 3-6Cycloalkyl;
Each W is independently:
a)O；
b)S；
c)NH；
d)N-N(R 2)(R 2)；
e)N(R 2)；
f)N-OH；
G) N-O-alkyl; Or
h)N-O-R 2；
R 1Be:
a)H；
b)R 2；
c)C(＝W)-R 3；
d)C(＝W)-O(R 2)；
e)C(＝W)-S(R 2)；
f)C(＝W)-NH-R 2；
g)C(＝W)-N(R 2)(R 2)；
H) C (=W)-NH-A-(amino-acid residue);
I) A-(amino-acid residue)-R 3
J) S (O) n-R 3Or
k)S(O) 2-N(R 2)(R 2)；
Wherein any one can be chosen wantonly by one or more following substituting groups and replace: C 1-6Alkyl; OH; Alkoxyl group; Aryl; Halogen; CN; NO 2Or N (R 2) (R 2);
Each R 2Be independently:
a)H；
b)CF 3；
c)CN；
D) optional that replace, branch or not ramose alkyl are as C 1-6Alkyl;
E) optional that replace, branch or not ramose, thiazolinyl is as C 2-6Thiazolinyl;
F) optional that replace, branch or not ramose, alkynyl is as C 2-6Alkynyl;
G) 3-14 unit carbocyclic ring;
H) the optional aryl that replaces;
I) the optional aralkyl that replaces;
J) the optional alkylaryl that replaces;
K) the optional heterocycle that replaces;
L) the optional alkyl heterocycle that replaces;
M) the optional heterocycle-alkyl that replaces;
N) A-heterocycle;
O) acyl group;
P) alkoxyl group;
q)CH 2-S(O) nR 3；
R) C (alkyl) 2-S (O) nAlkyl;
S) CH (alkyl)-S (O) nAlkyl;
t)CH 2NH 2；
U) CH 2NH (alkyl);
V) CH 2N (alkyl) 2
W) CH (alkyl)-NH 2
X) CH (alkyl)-NH (alkyl);
Y) CH (alkyl)-N (alkyl) 2
Z) C (alkyl) 2-NH 2
Aa) C (alkyl) 2-NH (alkyl);
Bb) C (alkyl) 2-N (alkyl) 2
cc)CH 2-C(＝W)H；
Dd) CH 2-C (=W) alkyl;
Ee) A-alkyl;
Ff) C (alkyl) 2-C (=W) alkyl;
gg)CH 2-C(＝W)H；
Hh) CH 2-C (=W) thiazolinyl;
Ii) CH (thiazolinyl)-C (=W) H;
Jj) A-S (O) alkyl;
Kk) CH (NH)-S (O) nAlkyl; Or
Ll) A-N (NH) alkyl;
mm)C(R 3)(R 3)-S(O) nNH 2；
nn)C(R 3)(R 3)-S(O) nCF 3；
oo)C(R 3)(R 3)-NH 2；
Each R 3Be independently:
a)H；
b)OH；
C) halogen (F, Cl, Br or I);
d)CF 3；
e)CN；
F) optional that replace, branch or not ramose alkyl are as C 1-6Alkyl;
G) optional that replace, branch or not ramose, thiazolinyl is as C 2-6Thiazolinyl;
H) optional that replace, branch or not ramose, alkynyl is as C 2-6Alkynyl;
I) 3-14 unit carbocyclic ring;
J) the optional aryl that replaces;
K) the optional aralkyl that replaces;
L) the optional alkylaryl that replaces;
M) the optional heterocycle that replaces;
N) the optional alkyl heterocycle that replaces;
O) the optional heterocycle-alkyl that replaces;
P) A-heterocycle;
Q) acyl group;
R) formamido-;
S) carbamyl;
T) alkoxyl group;
u)OH
v)OR 2；
W) O-alkyl;
X) O-thiazolinyl;
Y) O-alkynyl;
Z) O-alkaryl;
Aa) O-aralkyl;
Bb) O-carbocyclic ring;
Cc) O-heterocycle;
Dd) O-aryl;
ee)SH
ff)SR 2；
Gg) S-alkyl;
Hh) S-thiazolinyl;
Ii) S-alkynyl;
Jj) S-alkaryl;
Kk) S-aralkyl;
Ll) S-carbocyclic ring;
Mm) S-heterocycle;
Nn) S-aryl;
oo)S(O) n-R 2；
Pp) amino;
qq)NH 2；
rr)NHR 2；
ss)N(R 2)(R 2)；
tt)NH-S(O) n-R 2；
Uu) NHC (=W)-aryl;
Vv) NHC (=W)-alkyl;
Ww) NH-C (=W)-heterocycle;
xx)CH 2-S(O) nR 2；
yy)C(＝W)R 2；
zz)C(＝W)-N(R 2)-R 2；
Aaa) C (alkyl) 2-S (O) nR 2
Bbb) CH (alkyl)-S (O) nR 2
Ccc) C (alkyl) 2-NH 2
Ddd) CH (alkyl)-N (alkyl) R 2
eee)C(R 2)(R 2)-NR 2R 2；
Fff) CH 2N (alkyl) R 2
Ggg) CH (alkyl)-NHR 2
Hhh) C (alkyl) 2-NHR 2
Iii) C (alkyl) 2-N (alkyl) R 2
Kkk) CH 2-C (=W) alkyl;
lll)CR 2R 2-C(＝W)R 2；
mmm)A-R 2；
nnn)C(R 2) 2-C(＝W)R 2；
ooo)CH 2-C(＝W)H；
Ppp) CH 2-C (=W) thiazolinyl;
Qqq) CH (thiazolinyl)-C (=W) H;
rrr)A-S(O)R 2；
Sss) CH (NH)-S (O) nR 2Or
ttt)A-N(NH)R 2；
uuu)C(R 2)(R 2)-S(O) nNH 2；
vvv)C(R 2)(R 2)-S(O) nCF 3；
www)C(R 2)(R 2)-NH 2；
Wherein, described optional substituting group comprises following one or more:
A) replacement or unsubstituted heterocycle;
B) C (=W) O-aryl;
C) C (=W) O-alkyl;
d)C(＝W)NH 2；
E) C (=W) NH-alkyl;
F) C (=W) NH-aryl;
G) C (=W) n-two-alkyl;
H) C (=W) N (alkyl)-aryl;
I) a-amino acid;
J) alpha-amino group ester;
K) alpha-amino group-methane amide;
L) beta-amino acids;
M) beta-amino ester; Or
N) beta-amino-methane amide;
Wherein, this heterocyclic substituent is selected from when described optional substituting group contains the heterocycle of replacement:
A) C (=W) O-aryl;
B) C (=W) O-alkyl;
c)C(＝W)NH 2；
D) C (=W) NH-aryl;
E) C (=W) NH-alkyl;
F) C (=W) n-two-alkyl;
G) C (=W) N (alkyl)-aryl;
H) a-amino acid;
I) alpha-amino group ester;
J) alpha-amino group-methane amide;
K) beta-amino acids;
L) beta-amino ester; With
M) beta-amino-methane amide;
N) halogen; Or
O) cyano group,
Can occur separately or occur with arbitrary combination;
I is 0,1 or 2 independently;
Each A is independently for being selected from down dibasic spacer of group:
A) C 1-6Alkylidene group, branch or ramose not, and optional containing or optional one or more heteroatomss, aryl, cycloalkyl or the heterocyclic radical functional group of connecting of chain in its chain;
B) C 2-12Alkenylene, branch or ramose not, and optional containing or optional one or more heteroatomss, aryl, cycloalkyl or the heterocyclic radical functional group of connecting of chain in its chain;
C) C 2-12Alkynylene, branch or ramose not, and optional containing or optional one or more heteroatomss, aryl, cycloalkyl or the heterocyclic radical functional group of connecting of chain in its chain;
D) the optional arylidene that replaces;
E) O-alkylidene group, branch or ramose not, and optional containing or optional one or more heteroatomss, aryl, cycloalkyl or the heterocyclic radical functional group of connecting of chain in its chain;
F) arylmethylene alkyl, branch or ramose not, and optional containing or optional one or more heteroatomss, aryl, cycloalkyl or the heterocyclic radical functional group of connecting of chain in its chain;
G) the optional cycloalkyl that replaces; With
H) the optional heterocycle that replaces;
Wherein, " A " can pass through any required bonding (linkage) as ether, thioether, amino, formamido-, ester or carbon-to-carbon bonding, or any of required bonding is connected;
Each R 4 ', R 5 ', R 6 'And R 7 'Be independently:
a)H；
B) halogen (F, Cl, Br, I);
c)NO 2；
d)CN；
e)CF 3；
f)OH
g)OR 2；
h)SH
i)SR 2；
j)NR 2R 2；
k)NHS(O) nR 2；
L) NHCO-C 1-3Alkyl;
m)S(O) nR 2；
N) aryl;
O) heterocycle;
P) C 1-6Alkyl;
Q) C 2-6Thiazolinyl;
R) C 2-6Alkynyl;
s)C(＝W)-S(O) nR 2；
t)C(＝W)-S(O) n-NR 2R 2；
U) C (=W)-aryl;
V) C (=W)-alkyl;
W) C (=W)-heterocycle; Or
x)C(＝W)-NR 2R 2；
Wherein can choose wantonly separately by one or more following substituting groups and replace:
a)OR 2；
b)S(O) nR 2；
c)C(＝W)-S(O) nR 2；
d)C(＝W)-S(O) n-NR 2R 2；
E) C (=W)-aryl;
F) C (=W)-alkyl;
G) C (=W)-heterocycle;
h)C(＝W)NR 2R 2；
i)NO 2；
j)CN；
k)CF 3；
L) halogen (F, Cl, Br, I);
m)NHS(O) nR 2；
N) NHCO-C 1-3Alkyl;
O) aryl;
P) heterocycle;
Q) C 1-6Alkyl;
R) C 2-6Thiazolinyl;
S) C 2-6Alkynyl; Or
t)NR 2R 2。
In an embodiment of formula (A), X is the optional phenyl that replaces; Y is its any definition; R 1, R 4 ', R 6 'And R 7 'All be hydrogen; R 5 'It is halogen; Z is the methane amide part.
In another embodiment, R 1Be acyl group, alkyl, aryl, alkaryl or aralkyl.
Again in another embodiment, R 4 'Be fluorine, nitro or cyano group, W is an oxygen, and Y is the O-alkyl.
In second embodiment of formula (A), X is the optional phenyl that replaces; Y is its any definition; R 1, R 4 ', R 6 'And R 7 'All be hydrogen; R 5 'Be chlorine; Z is methane amide or formamido--heterocyclic radical part.
In another embodiment of formula (A), X is a tolyl again, thiazolyl or pyridyl; Y is H, OH or O-alkyl; R 1, R 4 ', R 6 'And R 7 'All be hydrogen; R 5 'It is halogen; Z is formamido-, acyl group, alkyl-alkylsulfonyl or carboxylic acid derivative.
In a variation of above-mentioned embodiment, X, Y, R 1, R 4 ', R 6 ', R 7 'And R 5 'All as top definition, Z is formamido--alkylidenyl-heterocyclic, especially formamido--alkylidene group-pyridyl; Amido-pyridyl, pyridyl wherein are unsubstituted or are replaced by OH, OMe or low alkyl group; Imino--nitrile; Or alkyl sulphonyl-aryl.
Again in another embodiment, Z is formamido--alkylidenyl-heterocyclic, and heterocycle wherein comprises at least one N-oxide groups.
In second embodiment, the invention provides the Phenylindole of the following general formula of the usefulness that is used for the treatment of HIV (B) expression:
Figure G05839218720070518D000271
Or its pharmacy acceptable salt, prodrug, N-oxide compound, quaternary amine, steric isomer or tautomer, wherein:
W, Y, Z, R 1, R 2, R 3, A, n, R 4 ', R 5 ', R 6 'And R 7 'Separately as mentioned to the definition of formula (A); With
Each R 2 ", R 3 ", R 4 ", R 5 "And R 6 "Be independently:
a)H；
B) halogen;
c)NO 2；
d)CN；
e)OR 2；
f)SR 2；
g)NH 2；
h)NR 2R 3；
I) N (R 2)-C (=W)-C 1-4Alkyl;
J) N (R 2)-SO 2-C 1-4Alkyl;
K) C 1-6Alkyl;
L) C 2-6Thiazolinyl;
M) C 2-6Alkynyl;
N) aryl;
o)CF 3；
P)CR 2R 2-S(O) n-R 3；
q)CR 2R 2NR 2R 3；
r)C-OH；
s)CR 2R 2-C(＝W)R 2；
T) acyl group;
u)C(＝W)R 2；
v)C(＝W)OR 2；
W)C(＝W)SR 2；
x)C(＝W)-NR 2R 3；
Y) C (=W) NH (CH 2) p-(amino-acid residue);
Z) amino residue; Or
Aa) A-(amino-acid residue);
Wherein, above-mentioned any one optional can being substituted; Or
Alternatively, R 2 "Or R 6 "Can combine with Y and form optional dicyclo or the three cyclic phosphoric acid heterocycles that replace, wherein each ring contains 3-14 ring members.
Below be the non-limitative example of the embodiment of formula (B):
A) Y is an alkyl; W is O, S (O) nOr NH; R 1, R 4 ', R 6 ', R 7 ', R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All be hydrogen; R 5 'It is halogen; Z is a methane amide;
B) Y is an aryl; W is O, S (O) nOr NH; R 1, R 4 ', R 6 ', R 7 ', R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All be hydrogen; R 5 'Be amino-alkyl, sulfo-amino-alkyl or aminocarboxyl-alkyl; Z is a methane amide;
C) Y be-OH or-SR 2W is O, S (O) nOr N-NH 2R 1, R 4 ', R 6 ', R 7 ', R 2 ", R 4 "And R 6All be hydrogen; R 5 'It is halogen; R 3 "And R 5 "It is methyl; Z is a methane amide;
D) Y is-OH; W is O, S (O) nOr NH; R 1, R 6 ', R 7 ', R 2 ", R 4 "And R 6 "All be hydrogen; R 4 'And R 5 'It is halogen; R 3 "And R 5 "It is methyl; Z is a methane amide;
E) Y is-OH; W is O, S (O) nOr N-NR 2R 2R 1, R 4 ', R 6 ', R 7 ', R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All be hydrogen; R 5 'It is halogen; Z is a methane amide;
F) Y is a thiazolinyl; W is O, S (O) nOr NH; R 1, R 4 ', R 6 ', R 7 ', R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All be hydrogen; R 5 'It is halogen; Z is methane amide or methane amide-heterocycle;
G) Y be alkynyl or-NR 2R 3W is O, S (O) nOr N-O-alkyl; R 1, R 4 ', R 6 ', R 7 ', R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All be hydrogen; R 5 'It is halogen; Z is a methane amide;
H) Y is an alkenylene; W is O, S (O) nOr NH; R 1, R 4 ', R 6 ', R 7 ', R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All be hydrogen; R 5 'It is halogen; Z is a methane amide;
I) Y is an ethyl; W is O, S (O) nOr N-OH; R 1, R 4 ', R 6 ', R 7 ', R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All be hydrogen; R 5 'Be chlorine; Z is a methane amide;
J) Y is-the O-methyl; W is O, S (O) nOr NH; R 1, R 4 ', R 6 ', R 7 ', R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All be hydrogen; R 5 'It is halogen; Z is a methane amide;
K) Y is-the O-ethyl; W is O, S (O) nOr N-NH 2R 1, R 4 ', R 6 ', R 7 ', R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All be hydrogen; R 5 'It is halogen; Z is methane amide-heterocycle;
L) Y is-the O-ethyl; W is O, S (O) nOr NH; R 1, R 4 ', R 6 ', R 7 ', R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All be hydrogen; R 5 'Be chlorine; Z is a methane amide;
M) Y is-O-H; W is O, S (O) nOr NH; R 1, R 4 ', R 6 ', R 7 ', R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All be hydrogen; R 5 'It is halogen; Z is unsubstituted or by one or more-NO 2,-NH-C (=O)-alkyl or-NH-S (O) nThe methane amide alkyl that-alkyl replaces;
N) Y is-O-H; W is O, S (O) nOr N-NH 2R 1, R 4 ', R 6 ', R 7 ', R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All be hydrogen; R 5 'It is halogen; Z is amide group-alkylidenyl-heterocyclic base, and wherein, described heterocycle is imidazoles, thiazole, pyridyl or furans, and wherein said heterocycle be unsubstituted or by one or more halogens, oxo ,-OH ,-NO 2,-MeOH ,-NH-C (=O)-alkyl or-NH-S (O) n-alkyl further replaces;
O) Y is-O-H; W is O, S (O) nOr NH; R 1, R 4 ', R 6 ', R 7 ', R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All be hydrogen; R 5 'It is halogen; Z is methane amide-cyclopropyl or methane amide-cyclobutyl;
P) Y is-the O-methyl; W is O, S (O) nOr NH; R 1, R 4 ', R 6 ', R 7 ', R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All be hydrogen; R 5 'It is halogen; Z is methane amide-ethyl, methane amide-ethanol or methane amide-ethyl-methoxyl group;
Q) Y be-OH or-NR 2R 3W is O, S (O) nOr N-O-alkyl; R 1, R 4 ', R 6 ', R 7 ', R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All be hydrogen; R 5 'It is halogen; Z is the methane amide alkyl-phenyl, phenyl wherein by one or more halogens, oxo ,-OH ,-OCH 3,-NO 2,-MeOH or-NH-C (=O)-alkyl further replaces;
R) Y be-OH or-SR 2W is O, S (O) nOr N-NR 2R 2R 1, R 4 ', R 6 ', R 7 ', R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All be hydrogen; R 5 'It is halogen; Z is a Virahol methane amide part; With
S) Y is-OH; W is O, S (O) nOr N-OH; R 1, R 4 ', R 6 ', R 7 ', R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All be hydrogen; R 5 'It is halogen; Z is the thioacetyl amido.
In the 3rd embodiment, the invention provides the dicyclo 3-of 9-11 unit phosphoric acid indoles with the optional replacement that is used for the treatment of HIV of following general formula (C) expression:
Figure G05839218720070518D000311
Or its pharmacy acceptable salt, prodrug, N-oxide compound, quaternary amine, steric isomer or tautomer, wherein:
W, Z, R 1, R 2, R 3, A, n, R 4 ', R 5 ', R 6 'And R 7 'Separately as mentioned to the definition of formula (A);
R 3 ", R 4 ", R 5 "And R 6 "Separately as mentioned to the definition of formula (B);
Figure G05839218720070518D000312
Expression exists singly-bound or two key, wherein:
When
Figure G05839218720070518D000313
When there was two key in expression, Y and T were independently of one another:
a)CR 3；
B) N; Or
c)S(＝W)；
At this moment, one of Y and T are CR at least 3With
When
Figure G05839218720070518D000321
When there was singly-bound in expression, Y and T were independently of one another:
a)CHR 3；
b)C(R 3)(R 3)；
c)O；
D) S; Or
e)NR 2；
At this moment, one of Y and T are C (R at least 3) (R 3); With
M is 1 or 2, and prerequisite is, as T or Y=CR 2The time m can only be 2.
Below be the non-limitative example of the embodiment of formula (C):
A) W is O, and Y is CR 2, T is (CH 2) 2, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be halogen, Z is a methane amide;
B) W is S, and Y is O, and T is CH 2, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be halogen, Z is amide group-heterocycle, and wherein, described heterocycle is optional furans, imidazoles, thiazole or the pyridyl that replaces;
C) W is S, and Y is NR 2, T is CH 2, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be halogen, Z is a methane amide;
D) W is O, and Y is SR 2, T is CH 2, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be halogen, Z is alkyl-methane amide;
E) W is S, and Y is SR 2, T is CH 2, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be halogen, Z is a methane amide;
F) W is O, and Y is CR 2, T is C-C (=W) R 3, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be halogen, Z is methoxymethyl-methane amide;
G) W is S, and Y is O, and T is C-C (=W) R 3, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be halogen, Z is methane amide-cyclobutyl;
H) W is O, and Y is SR 2, T is C-C (=W) R 3, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be chlorine, Z is an alkyl formamides, wherein, alkyl optional by one or more halogens, oxo ,-OH ,-NO 2,-MeOH ,-NH-C (=O) alkyl or-NH-S (O) n-alkyl replaces;
I) W is S, and Y is NR 2, T is CC (=W) R 3, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be chlorine, Z is a methane amide;
J) W is S, and Y is N, and T is C-C (=W) R 3, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be fluorine, Z is a methane amide;
K) W is NH, and Y is CR 2, T is NR 2, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be amino-alkyl, Z is a methane amide;
L) W is NR 2, Y is O, T is (CH 2) 2, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be chlorine, Z is a methane amide;
M) W is N-OH, and Y is O, and T is CH 2, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be sulfo-amino-alkyl, Z is an alkyl formamides;
N) W is S, and Y is SR 2, T is CH 2, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be halogen, Z is methane amide-heterocyclic radical, and wherein, described heterocycle is optional pyridine, thiazole, imidazoles or the furans that replaces;
O) W is the N-O-alkyl, and Y is NR 2, T is CH 2, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be halogen, Z is methane amide-alkyl, and wherein, described alkyl is by one or more-NO 2,-NH 2,-NH-C (=W) alkyl or-NH-S (O) n-alkyl is optional to be replaced;
P) W is NH, and Y is SR 2, T is (CH) 2, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be halogen, Z is methane amide-alkyl-phenyl, and wherein, described phenyl is by one or more halogens, oxo, OH, NO 2, MeOH ,-NH-C (=O) alkyl or-NH-S (O) n-alkyl is optional to be replaced;
Q) W is NR 2, Y is (CH 2) 2, T is NR 2, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be halogen, Z is methane amide-cyclopropyl;
R) W is N-OH, and Y is CH, and T is O, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be halogen, Z is methane amide-cyclopropyl;
S) W is the N-O-alkyl, and Y is O, and T is (CH 2) 2, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5Be chlorine, Z is methane amide-methoxy ethyl;
T) W is O, and Y is N, and T is CH 2, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be halogen, Z is methane amide-ethanol;
U) W is N-NR 2R 2, Y is NR 2, T is CH 2, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5Be halogen, Z is a methane amide; With
V) W is O, and Y is CR 2, T is CH 2, R 1, R 4 ', R 6 ', R 7 ', R 3 ", R 4 ", R 5 "And R 6 "All be H; R 5 'Be aminocarboxyl-alkyl, Z is a methane amide.
In one group of embodiment of formula A, B or C, Z be C (=W)-R 3C (=W)-NH-A-C (=W)-N (R 2) (R 2); C (=W)-NH-A-R 3C (=W)-NH-R 2Or C (=W)-A-R 3
In the embodiment of formula A, B or C, described compound comprises charged heteroatoms.Specifically, for example become a compound part by the charged nitrogen of N-oxide compound.Described charged heteroatoms can be positioned at and is connected to (by C (O) NH-alkyl, perhaps specifically is by C (O) NH-CH for example 2) on the hetero-aromatic ring of indoles.
In the specific embodiments of formula A, B or C, Z be C (=O)-NH-R 2, wherein, R 2Be the optional alkyl heterocycle that replaces, wherein said heterocycle has following formula
Wherein, each Rx is CH or N independently +-O -In one embodiment, one of Rx is N +-O -Described alkyl can be C 1-10Alkyl or C 1-4Alkyl perhaps specifically can be methylene radical or ethylidene.In one embodiment, R 2Has following formula
Figure G05839218720070518D000352
Wherein, n is 0,1 or 2.
In the specific embodiments of formula A, B or C, described compound is:
Figure G05839218720070518D000361
Figure G05839218720070518D000371
Or
Figure G05839218720070518D000373
Other example of the N-oxide compound embodiment of the compound of formula A, B or C is:
Figure G05839218720070518D000374
Figure G05839218720070518D000381
Arbitrary substituting group on the phenyl ring can be replaced by CN, Me, halogen, alkyl, thiazolinyl, alkynyl, alkyl-CN or thiazolinyl-CN, as the at present the most normal N-oxide compound that synthesizes and test.
II. concrete secondary embodiment of the present invention (Sub-Embodiment)
In first embodiment of the present invention, described compound is used formula (A) expression usually:
Figure G05839218720070518D000382
Or its pharmacy acceptable salt, prodrug, N-oxide compound, quaternary amine, steric isomer or tautomer, wherein:
X and Y are independently of one another:
A) 3-14 unit carbocyclic ring, aryl, heterocycle, wherein any one can contain monocycle, dicyclo, three ring or spirane structures, or optional the replacement;
b)H；
c)OH；
d)Cl、Br、I、F；
e)CF 3；
F) C 1-6Alkyl;
G) C 2-6Thiazolinyl;
H) C 2-6Alkynyl;
I) alkyl heterocycle;
j)NH 2；
K) NH-alkyl;
L) N-dialkyl group;
M) NH-aryl;
N) N-alkaryl;
O) N-aralkyl;
P) NH-heterocycle;
Q) N-alkyl-heterocycle;
R) N-thiazolinyl-heterocycle;
S) N-alkynyl-heterocycle;
T) O-alkyl;
U) O-thiazolinyl;
V) O-alkynyl;
W) O-alkylaryl;
X) O-aryl;
Y) O-heterocycle;
Z) O-aralkyl;
Aa) O-carbocyclic ring;
Bb) SR 2Or
cc)NR 2R 3；
Alternatively, X and Y can be in conjunction with forming optional dicyclo or the three cyclic phosphoric acid heterocycles that replace, and wherein each ring contains 3-7 ring members;
Z is:
a)H；
B) alkoxyl group;
c)NO 2；
d)N(R 2)(R 3)；
e)OR 2；
F) formamido-;
G) amido;
H) acyl group;
i)S(O) nR 2；
j)S(O) n-NR 2R 3；
K) C 1-6Alkyl;
L) C 2-6Thiazolinyl;
M) C 2-6Alkynyl;
N) alkaryl;
O) aralkyl;
P) heterocycle;
Q) alkyl-heterocycle;
R) aryl;
s)CN；
t)C(＝W)-R 2；
u)C(＝W)NH-C(R 2)(R 2)-C(＝W)-N(R 2)(R 2)；
v)C(＝W)NH-P(＝W)(R 2)-A-R 2；
w)C(＝W)NH-A-S(O) n-NR 2；
x)C(＝W)NH-CR 2R 3-S(O) n-NR 2R 3；
y)C(＝W)-NH-A-C(＝W)-N(R 2)(R 3)；
z)C(＝W)-N(R 2)(R 3)；
aa)C(＝W)-NH-A-R 2；
bb)C(＝W)-NH-NH-R 2；
cc)C(＝W)-NH-C(R 2)(R 2)-C(＝W)NH-C(R 2)(R 3)C(＝W)-N(R 2)(R 3)；
dd)C(＝W)-NH-R 2；
ee)C(＝W)-NH-A-C(＝W)-NH-A-C(＝W)-NH 2；
ff)C(R 2)(R 2)(R 3)；
gg)C(R 2)(R 2)-NH-R 2；
hh)A-S(O) n-R 2；
ii)C(＝W)-A-C(＝W)-A-C(＝W)R 3；
jj)A-R 2；
kk)C(＝W)-(O)R 2；
ll)C(＝W)-A-C(＝W)-NH 2；
Mm) amino-acid residue;
Nn) C (=W)-N (R 2)-A-(amino-acid residue);
Oo) C (=W)-N (R 2)-A-(amino-acid residue)-C (=W)-R 2
Pp) C (=W)-amino-acid residue;
Qq) C (=W)-N (R 2)-A-(amino-acid residue)-A-C (=W)-R 2
rr)C(＝W)-OR 3；
ss)C(＝W)-S(R 2)；
tt)C(＝W)-NH-NH-R 2；
uu)C(＝W)-NH-N(R 2)-A-C(＝W)R 2；
vv)C(＝W)-N(R 2)-C(＝W)-R 3；
ww)C(＝W)-A-NH-C(＝W)R 2；
xx)C(＝W)-A-NH-C(＝W)OR 3；
yy)C(＝W)-A-R 3；
zz)C(＝W)-NH-NH-CH 2-C(＝W)R 2；
Aaa) P (=W) (R 2) (R 2); Or
bbb)A-P(＝W)(R 2)(R 2)；
Wherein, above-mentioned X, Y and Z are unsubstituted independently of one another or are replaced by one or more following substituting groups:
a)H；
B) C 1-6Alkyl;
C) alkoxyl group;
d)OH；
E) oxo;
F) halogen;
g)NR 2R 2；
H) the optional aryl that replaces;
I) the optional heterocyclic radical that replaces;
J) O-C (=W)-alkyl;
k)C(＝W)-OR 2；
l)CN；
m)NO 2；
N) NH-C (=W) alkyl;
O) NH-S (O) n-alkyl;
P) NH-S (O) n-NR 2R 2Or
Q) C 3-6Cycloalkyl;
W is:
a)O；
b)S；
c)NH；
d)N-N(R 2)(R 2)；
e)N(R 2)；
F) N-OH; Or
G) N-O-alkyl;
R 1Be:
a)H；
b)R 2；
c)C(＝W)-R 2；
d)C(＝W)-O(R 2)；
e)C(＝W)-S(R 2)；
f)C(＝W)-NH-R 2
g)C(＝W)-N(R 2)(R 2)；
H) C (=W)-NH-A-(amino-acid residue);
I) A-(amino-acid residue)-R 2
J) S (O) n-R 3Or
k)S(O) 2-N(R 2)(R 2)；
Wherein any one can be chosen wantonly by one or more following substituting groups and replace:
A) C 1-6Alkyl;
b)OH；
C) alkoxyl group;
D) aryl;
E) halogen;
f)CN；
G) NO 2Or
h)N(R 2)(R 2)；
R 2Be:
a)H；
b)OH；
C) halogen;
D) optional that replace, branch or not ramose alkyl;
E) optional that replace, branch or not ramose thiazolinyl;
F) optional that replace, branch or not ramose alkynyl;
G) 3-14 unit carbocyclic ring;
H) alkyl heterocycle;
I) acyl group;
J) formamido-;
K) carbamyl;
L) alkoxyl group;
M) the optional aryl that replaces;
N) the optional aralkyl that replaces;
O) the optional alkylaryl that replaces;
P) O-alkyl;
Q) O-thiazolinyl;
R) O-alkynyl;
S) O-alkaryl;
T) O-aralkyl;
U) O-carbocyclic ring;
V) O-heterocycle;
W) O-aryl;
x)CF 3；
y)CN；
z)S(O) n-R 3；
aa)N(R 3)(R 3)；
bb)NH-S(O) n-R 3；
Cc) NHC (=W)-aryl;
Dd) NHC (=W)-alkyl;
Ee) NHC (=W)-heterocycle;
ff)CH 2-S(O) nR 3；
gg)C(＝W)R 3；
hh)C(＝W)NR 3R 3；
Ii) C (alkyl) 2-S (O) nR 3
Jj) CH (alkyl)-S (O) nR 3
Kk) C (alkyl) 2-NH 2
Ll) CH (alkyl)-N (alkyl) R 3
mm)CR 3R 3-NR 3R 3；
Nn) CH 2N (alkyl) R 3
Oo) CH (alkyl)-NHR 3
Pp) C (alkyl) 2-NHR 3
Qq) C (alkyl) 2-N (alkyl) R 3
rr)CH 2-C(＝W)H；
Ss) CH 2-C (=W) alkyl;
tt)CR 3R 3-C(＝W)R 3；
uu)A-R 3；
vv)C(R 3) 2-C(＝W)R 3；
ww)CH 2-C(＝W)H；
Xx) CH 2-C (=W) thiazolinyl;
Yy) CH (thiazolinyl)-C (=W) H;
zz)A-S(O)R 3；
Aaa) CH (NH)-S (O) nR 3Or
bbb)A-N(NH)R 3；
Wherein, described optional substituting group comprises one or more:
A) replacement or unsubstituted heterocycle;
B) C (=W) O-aryl;
C) C (=W) O-alkyl;
d)C(＝W)NH 2；
E) C (=W) NH-alkyl;
F) C (=W) NH-aryl;
G) C (=W) n-two-alkyl;
H) C (=W) N (alkyl)-aryl;
I) a-amino acid;
J) alpha-amino group ester;
K) alpha-amino group-methane amide;
L) beta-amino acids;
M) beta-amino ester; Or
N) beta-amino methane amide;
R 3Be:
a)H；
b)OH；
C) C 1-6Alkyl;
D) C 2-6Thiazolinyl;
E) C 2-6Alkynyl;
F) alkoxyl group;
g)CF 3；
h)CN；
I) amino;
j)NR 2R 2；
K) O-alkyl;
L) O-thiazolinyl;
M) O-alkynyl;
n)C(R 2)(R 2)-S(O) nNH 2
o)C(R 2)(R 2)-S(O) nCF 3；
p)C(R 2)(R 2)-NH 2；
Q) A-heterocycle;
r)C(R 2)(R 2)-NR 2R 2；
s)C(R 2)(R 2)-C(＝W)R 2；
T) aryl;
U) carbocyclic ring;
V) heterocycle;
W) cycloalkyl;
X) alkaryl;
Y) alkyl heterocycle;
Z) aralkyl; Or
Aa) heterocycle-alkyl;
Wherein any one can be that unsubstituted or arbitrarily combined one or more following substituting group replaces:
A) halogen;
b)OH；
c)OR 2；
d)SR 2；
e)COOH；
F) carboxylicesters;
g)C(＝W)R 2；
h)C(＝W)OR 2；
i)C(＝W)OR 3；
j)C(＝W)SR 2；
k)A-C(＝W)NH 2；
l)C(＝W)NR 2R 3；
m)NR 2R 2；
n)NR 2R 3；
o)NR 2-S(O) nR 3；
P) NR 2-C (=W)-C 1-6Alkyl;
q)S(O) nR 3；
R) C 1-6Alkoxyl group;
S) C 1-6Thioether;
T) amino-acid residue;
U) NH-A-(amino-acid residue);
V) C (=W) NH-A-(amino-acid residue); With
Wherein, when described optional substituting group contained the heterocycle of replacement, this substituting group was selected from:
A) C (=W) O-aryl;
B) C (=W) O-alkyl;
c)C(＝W)NH 2；
D) C (=W) NH-aryl;
Al e) C (=W) NH-alkyl;
F) C (=W) n-two-alkyl;
G) C (=W) N (alkyl)-aryl;
H) a-amino acid;
I) alpha-amino group ester;
J) alpha-amino group-methane amide;
K) beta-amino acids;
L) beta-amino ester; Or
M) beta-amino-methane amide;
N) halogen; Or
O) cyano group,
Can occur separately or occur with arbitrary combination;
N is 0,1 or 2 independently;
Each A is independently for being selected from down dibasic spacer of group:
A) C 1-6Alkylidene group, branch or ramose not, and optional containing or optional one or more heteroatomss, aryl, cycloalkyl or the heterocyclic radical functional group of connecting of chain in its chain;
B) C 2-12Alkenylene, branch or ramose not, and optional containing or optional one or more heteroatomss, aryl, cycloalkyl or the heterocyclic radical functional group of connecting of chain in its chain;
C) C 2-12Alkynylene, branch or ramose not, and optional containing or optional one or more heteroatomss, aryl, cycloalkyl or the heterocyclic radical functional group of connecting of chain in its chain;
D) the optional arylidene that replaces;
E) O-alkylidene group, branch or ramose not, and optional containing or optional one or more heteroatomss, aryl, cycloalkyl or the heterocyclic radical functional group of connecting of chain in its chain;
F) arylmethylene alkyl, branch or ramose not, and optional containing or optional one or more heteroatomss, aryl, cycloalkyl or the heterocyclic radical functional group of connecting of chain in its chain;
G) the optional cycloalkyl that replaces; With
H) the optional heterocycle that replaces;
Wherein, " A " can pass through any required bonding such as ether, thioether, amino, amide group, ester or carbon-to-carbon bonding, or any of required bonding is connected;
Each R 4 ', R 5 ', R 6 'And R 7 'Be independently:
a)H；
B) halogen;
c)NO\ 2；
d)CN；
e)CF 3；
f)OR 2；
g)NR 2R 2；
h)NHS(O) nR 2；
I) NHCO-C 1-3Alkyl;
j)S(O) nR 2；
K) aryl;
L) heterocycle;
M) C 1-6Alkyl;
N) C 2-6Thiazolinyl;
O) C 2-6Alkynyl;
p)C(＝W)-S(O) nR 2；
q)C(＝W)-S(O) n-NR 2R 2；
R) C (=W)-aryl;
S) C (=W)-alkyl;
T) C (=W)-heterocycle; Or
u)C(＝W)-NR 2R 2；
Wherein each can be chosen wantonly by one or more following substituting groups and replace:
a)OR 2；
b)S(O) nR 2；
c)C(＝W)-S(O) nR 2；
d)C(＝W)-S(O) n-NR 2R 2；
E) C (=W)-aryl;
F) C (=W)-alkyl;
G) C (=W)-heterocycle;
h)C(＝W)NR 2R 2；
i)H；
j)NO 2；
k)CN；
l)CF 3；
M) halogen;
n)NHS(O) nR 2；
O) NHCO-C 1-3Alkyl;
P) aryl;
Q) heterocycle;
R) C 1-6Alkyl;
S) C 2-6Thiazolinyl;
T) C 2-6Alkynyl; Or
u)NR 2R 2。
In an embodiment of formula (A), X is the optional phenyl that replaces; Y is its any definition; R 1, R 4 ', R 6 'And R 7 'All be hydrogen; R 5 'It is halogen; Z is the methane amide part.
In another embodiment, R 1Be acyl group, alkyl, aryl, alkaryl or aralkyl.
Again in another embodiment, R 4 'Be fluorine, nitro or cyano group, W is an oxygen, and Y is the O-alkyl.
In second embodiment of formula (A), X is the optional phenyl that replaces; Y is its any definition; R 1, R 4 ', R 6 'And R 7 'All be hydrogen; R 5 'Be chlorine; Z is methane amide or amide group-heterocyclic radical part.
In another embodiment of formula (A), X is tolyl, thiazolyl or pyridyl again; Y is H, OH or O-alkyl; R 1, R 4 ', R 6 'And R 7 'All be hydrogen; R 5 'It is halogen; Z is amide group, acyl group, alkyl-alkylsulfonyl or carboxylic acid derivative.
In a variation of above-mentioned embodiment, X, Y, R 1, R 4 ', R 6 ', R 7 'And R 5 'All as top definition, Z is formamido--alkylidenyl-heterocyclic, and wherein said heterocycle typically is optional imidazoles, furans, pyridine, pyrimidine or the thiazole that replaces; The thioamides pyridine, wherein pyridine is not substituted or by OH, and OMe or low alkyl group replace; Nitrilimine, or alkyl sulphonyl-aryl.
Provided first group of secondary embodiment of the present invention, wherein, formula (A) is provided as mentioned, and W, X and Y are defined as:
A) W is O, and X is an alkyl, and Y is-the O-alkyl;
B) W is O, and X is-the O-aryl that Y is an alkyl;
C) W is O, and X is-the O-aryl that Y is-NR 2R 3
D) W is O, and X is-the O-alkyl that Y is an alkyl;
E) W is O, and X is-the O-alkyl that Y is a halogen;
F) W is O, and X is-the O-heterocycle that Y is an alkyl;
G) W is O, and X is an aryl, and Y is-the O-alkyl;
H) W is O, and X is a heterocyclic radical, and Y is-the O-aryl;
I) W is O, and X is an alkyl, and Y is-the O-heterocyclic radical;
J) W is-NR 2R 2, X is a heterocyclic radical, Y is-the O-aryl;
K) W is-NR 2R 2, X is an alkyl, Y is a halogen;
L) W is S, and X is an alkyl, and Y is-the O-alkyl;
M) W is S, and X is an alkyl, and Y is-NR 2R 3
N) W is S, and X is-the O-aryl that Y is an alkyl;
O) W is S, and X is-the O-aryl that Y is the C-halogen;
P) W is S, and X is-the O-alkyl that Y is an alkyl;
Q) W is S, and X is-the O-heterocycle that Y is an alkyl;
R) W is S, and X is an aryl, and Y is-the O-alkyl;
S) W is S, and X is a heterocyclic radical, and Y is-the O-aryl;
T) W is S, and X is an alkyl, and Y is-the O-heterocyclic radical;
U) W is O, and X is an aryl, and Y is-the O-aryl;
V) W is-NR 2, X is-the O-alkyl that Y is-NR 2R 3
W) W is O, and X is-the O-aryl that Y is-the O-aryl;
X) W is O, and X is an alkyl, and Y is an alkyl; With
Y) W is-NR 2, X is-the O-alkyl that Y is an alkyl.
Provided second group of secondary embodiment of the present invention, wherein, formula (A) is given as mentioned, R 1Be H, alkyl, acyl group, aryl, aralkyl or alkaryl; Z is defined as follows:
A)-C (=W) NR 2R 3, R 2Be H, R 3Be NR 2R 2
B)-C (=W) NR 2R 3, R 2Be H, R 3Be NR 2R 2, perhaps R 2Be the optional C that is replaced by OH 1-5Alkyl, R 3Be-NH 2
C)-C (=W) NR 2R 3, R 2Be H, R 3Be (CH 2) mC (=W) NR 2R 2
D)-C (=W) NR 2R 3, R 2Be H, R 3Be the aryl that is optionally substituted or the alkyl of heterocyclic substituted;
E)-C (=W) R 3, R 3Be amino-acid residue or-NH (CH 2) p-(amino-acid residue);
f)-C(＝W)NHNHC 2H 5OH；
g)-C(＝W)NHCH 2C(＝W)NH 2；
h)-C(＝W)NHCH 2CONHNH 2；
I)-C (=W) NHCH 2CH 2-(2-NO 2, the 5-Methylimidazole);
j)-C(＝W)NHCH 2NHCH(CH 3)C(＝W)OH；
k)-C(＝W)NHCH＝CHC(＝W)NH 2；
L)-C (=W) NR 2R 5NR 2R 3, R 5Be (=O), R 2And R 3As hereinbefore defined;
M)-C (=W) NR 2NR 2-C (=W) R 3, R 2Be H or alkyl, R 3It is aryl;
N)-C (=W) NC-NR 2R 3)-N (NR 2R 3) R 3, R 2Be H, R 3Be R 2Or alkoxyl group;
O)-C (=W) NHR 2C (=W)-and Q, Q is a heterocycle, R 2As hereinbefore defined;
P)-C (=W) NR 2R 3, R 2As hereinbefore defined, R 3Be-OH;
Q)-COR 2R 3, R 2Be amino, R 3It is heterocycle;
R)-C (=W) NHNHC (=W) R 2, R 2Be NH 2
S)-C (=W)-R 2-CH-A-C (=W) NH 2, R 2Be NH;
T)-C (=W)-R 2-CH-A-C (=W) H, R 2Be NH;
U)-C (=W)-R 2-CH-A-C (=W) OH, R 2Be NH;
V)-C (=W)-R 2-CH-A-R 3, R 2Be NH, R 3Be CH 3
W)-C (=W) NHR 2C (=W) NH 2, R 2It is the optional branched-chain alkyl that replaces;
X)-C (=W) R 2R 3, R 2Be NH or alkyl, R 3Be NH 2
Y)-C (=W) R 2-C (=W) OR 3, R 2And R 3As hereinbefore defined;
Z)-C (=W) R 2-NH-C (=W) C 1-4Alkoxyl group, R 2As hereinbefore defined;
Aa)-C (=W) R 2C (=W) C 1-4Alkoxyl group, R 2As hereinbefore defined;
Bb)-C (=W) R 2, R 2Be NH 2
Cc)-C (=W) R 2-NH-C (=W) OR 3, R 2And R 3As hereinbefore defined;
Dd)-C (=W) R 2-C (=W) R 2, R 2As hereinbefore defined;
Ee)-C (=W) NHR 2, R wherein 2Be optional aryl, cycloalkyl or the heterocyclic ring that replaces;
Ff)-C (=W) R 2-W-R 3, R wherein 2And R 3As hereinbefore defined;
Gg)-C (=W)-NH-CH (R 2)-C (=W)-NH 2, R 2As hereinbefore defined;
hh)-C(＝(W)-NH-NH 2；
Ii)-C (=W)-NH-NH (R 2), R 2As hereinbefore defined;
Jj)-C (=W)-and NH-CH (C[=W] NH 2) (CH 2-C[=W]-the O-aryl);
kk)-C(＝W)-NH-CH(-[CH 2] 4-NH-C[＝W]-t-BuO)C-C[＝W]-NH 2)；
ll)-C(＝W)-NH-CH(-CH 2-CH 2-C[＝W]-t-BO)C[＝W]-NH 2)；
Mm)-C (=W)-NH-CH (R 3) (C[=W]-NH 2), R 3As hereinbefore defined;
Nn)-C (=W)-NH-CH (CH 2-R 3) (C[=W]-NH 2), R 3As hereinbefore defined;
oo)-C(＝W)-NH-CH(-CH 2OH)(-C[＝W]-NH 2)；
pp)-C(＝W)-NH-CH(C[＝W]-NH 2)(C[＝W]-NH 2)；
Qq)-C (=W)-NHR 2-C[=W] NH 2, R 2As hereinbefore defined;
Rr)-C (=W)-NH-CH ([CH 2] 4-NH-C[=W]-O-CH 2-R 3) (C[=W]-NH 2), R 3As hereinbefore defined;
ss)-C(＝W)-NH-CH(-CH 2-C[＝W]-NH 2)(-C[＝W]-NH 2)；
Tt)-C (=W)-NH-CH (CH 2-R 3) (C[=W]-NH 2), R wherein 3As hereinbefore defined;
uu)-C(＝W)-NH-CH(-[CH 2] 4-NH 2)(-C[＝W]-NH 2)；
Vv)-C (=W)-NH-CH (CH[R 2] [OH]) (C[=W]-NH 2), R 2As hereinbefore defined;
Ww)-C (=W)-NH-CH (R 2) (C[=W]-NH 2), R 2As hereinbefore defined;
Xx)-C (=W)-NH-CH (R 2-C[=W]-NH 2) (C[=W]-NH 2), R 2As hereinbefore defined;
Yy)-C (=W)-NH-CH (R 2-SCH 3) (C[=W]-NH 2), R 2As hereinbefore defined;
zz)-C(＝W)-NH-CH(-C[＝N]-NH 2)(-C[＝W]-NH 2)；
Aaa)-C (=W)-NH-CH (R 3) (C[=W]-NH 2), R 3As hereinbefore defined;
Bbb)-C (=W)-NH-CH (CH 2-R 3) (C[=W]-NH 2), R 3As hereinbefore defined;
Ccc)-C (=W)-NH-CH (R 2) (C[=W]-NH 2), R 2As hereinbefore defined;
Ddd)-C (=W)-NH-R 2-C[=W] R 3, R 2Be alkylidene group, R 3Be aryl or heteroaryl;
Eee)-C (=W)-NH-R 2-R 3-C[=W]-NH 2, R wherein 7Be alkylidene group, R 3Be ryl or heteroaryl;
Fff)-C (=W)-NH-NB-R 2-R 3-C (=W) NH 2, R wherein 2Be alkylidene group, R 3Be aryl or heteroaryl;
Ggg)-C (=W)-NH-NH-CH (R 3)-C (=W) R 2, R 2Be NH 2, R 3Be optional aryl or the heteroaryl that replaces;
Hhh)-C (=W) NHR 2(R 3)-C (=W) NH 2, R wherein 2Be alkylidene group, R 3Be optional alkyl, aryl or the heteroaryl that replaces;
Iii)-C (=W) NHR 2(R 3)-C (=W) NH-R 2-C (=W) OH, wherein R 2Be alkylidene group, R 3Be optional alkyl, aryl or the heteroaryl that replaces;
Jjj)-C (=W) NHR 2(R 3)-C (=W) NH-R 2-NH 2, R wherein 2Be alkylidene group, R 3Be optional alkyl, aryl or the heteroaryl that replaces;
Kkk)-C (=W) NHR 2(R 3)-C (=W) NH-R 3, R wherein 2Be alkylidene group, R 3Be optional alkyl, aryl or the heteroaryl that replaces;
Lll)-C (=W)-R 2-(CH 2) p-A-C (=W)-NH 2, R wherein 2Be-NH, p is 0-10, and A is divalence bonding radical (linker) or optional aryl or the heteroaryl that replaces, and W is O or S;
Mmm)-C (=W) NH-R 3, R wherein 3It is the optional heterocycle that replaces;
Nnn)-C (=W)-NH-R 2-R 5-R 3, wherein W is O or S, R 2Be alkylidene group, alkenylene or alkynylene, R 5Be-SO 2, R 3Be-NH 2
Ooo)-C (=W)-NH-NH-R 2(R 3)-R 5-NH 2, wherein W is O or S, R 2Be alkylidene group, alkenylene or alkynylene, R 3Be aryl, arylidene or heteroaryl, R 5Be-SO 2
Ppp)-C (=W)-NH-R 3(R 5-NH 2), wherein W is O or S, R 3Be aryl, arylidene or heteroaryl, R 5Be SO 2
Qqq)-C (=W)-NH-R 2-R 3(R 5-NH 2), wherein W is O or S, R 2Be alkylidene group, alkenylene or alkynylene, R 3Be aryl, arylidene or heteroaryl, R 5Be SO 2
Rrr)-C (=W)-NH-R 3(R 2R 5-NH 2), wherein W is O or S, R 2Be alkylidene group, alkenylene or alkynylene, R 3Be aryl, arylidene or heteroaryl, R 5Be SO 2
Sss)-C (=W)-NHR 2(R 3)-C (=W) NH-R 2-C (=W) OH, wherein R 2Be optional alkylidene group, alkenylene or the alkynylene that replaces, R 3It is its any definition as providing above;
Ttt)-C (=W)-NHR 2(R 3)-C (=W) NH-R 2-C (=W) NH 2, R wherein 2Be optional alkylidene group, alkenylene or the alkynylene that replaces, R 3It is its any definition as providing above;
Uuu)-C (=W)-NHR 2-C (=W) NH-R 2-C (=W) OH, wherein R 2Be optional alkylidene group, alkenylene or the alkynylene that replaces, R 3It is its any definition as providing above; Or
Vvv)-C (=W)-NHR 2-C (=W) NH-R 2-C (=W) NH 2, R wherein 2Be optional alkylidene group, alkenylene or the alkynylene that replaces, R 3It is its any definition as providing above; With
Wherein, R 2, R 3With A respectively as before definition.
Formula provided above (A) the 3rd group of secondary embodiment of the present invention, wherein R have been provided 4 ', R 5 ', R 6 'And R 7 'Be defined as:
A) R 6 'And R 7 'All be hydrogen, R 4 'And R 5 'Be halogen independently;-NO 2-N;-OR 2,-NR 2R 2-NH-R 5-C 1-3Alkyl;-NHCO-C 1-3Alkyl; Oxime; Hydrazine;-H (SO 2) C 1-3Alkyl;-NH-O-C 1-3Alkyl;-NHOH; Or optional by one or more-OH ,-SR ,-C (=W) H ,-C (=W) OH, halogen ,-NR 2R 2, C 1-3Alkoxyl group or C 1-3The C that thioether replaces 1-3Alkyl or alkenyl;
B) R 4 'And R 7 'All be hydrogen, R 5 'And R 6 'Be halogen independently;-NO 2-N;-OR 2-NR 2R 2-NHSO 2-C 1-6Alkyl;-NHCO-C 1-6Alkyl; Oxime; Hydrazine;-H-O-C 1-6Alkyl;-NH-OH; Or optional by one or more-OH ,-SR ,-C (=W) H ,-(=W) OH, halogen ,-NR 2R 2, C 1-3Alkoxyl group or C 1-3The C that thioether replaces 1-3Alkyl or alkenyl;
C) R 4 'And R 6 'All be hydrogen, R 5 'And R 7 'Be halogen independently;-NO 2-N;-OR 2-NR 2R 2-NHSO 2-C 1-6Alkyl;-NHCO-C 1-6Alkyl; Oxime; Hydrazine;-H-O-C 1-6Alkyl;-NH-OH; Or optional by one or more-OH ,-SR ,-C (=W) H ,-(=W) OH, halogen ,-NR 2R 2, C 1-3Alkoxyl group or C 1-3The C that thioether replaces 1-6Alkyl or alkenyl;
D) R 4 'And R 7 'All be hydrogen, R 5 'And R 6 'Be halogen independently;-NO 2-N;-OR 2-NR 2R 2-NH-O-C 1-6Alkyl;-NHOH; Or optional by one or more-OH ,-SR ,-C (=W) H ,-C (=W) OH, halogen or-NH 2The C that replaces 1-6Alkyl or alkenyl;
E) R 4 'And R 6 'All be hydrogen, R 5 'And R 7 'Be halogen independently;-NO 2-N;-OR 2-NR 2R 2-NH-O-C 1-3Alkyl;-NHOH; Or optional by one or more-OH ,-SR ,-C (=W) H ,-C (=W) OH, halogen or-NH 2The C that replaces 1-6Alkyl or alkenyl;
F) R 6 'And R 7 'All be hydrogen, R 4 'And R 5 'Be halogen independently; Optional by one or more halogens replace-C 1-6Alkyl, alkenyl or alkynyl;
G) R 4 'And R 7 'All be hydrogen, R 5 'And R 6 'Be halogen independently; Optional by one or more halogens replace-C 1-6Alkyl, alkenyl or alkynyl;
H) R 4 'And R 6 'All be hydrogen, R 5 'And R 7 'Be halogen independently; Optional by one or more halogens replace-C 1-6Alkyl, alkenyl or alkynyl;
I) R 6 'And R 7 'All be hydrogen, R 4 'And R 5 'Be Cl, F, Br, I, methyl independently, ethyl or CF 3
J) R 4 'And R 7 'All be hydrogen, R 5 'And R 6 'Be Cl, F, Br, I, methyl independently, ethyl or CF 3
K) R 4 'And R 6 'All be hydrogen, R 5 'And R 7 'Be Cl, F, Br, I, methyl independently, ethyl or CF 3With
Wherein, A as hereinbefore defined.
Defined the 4th group of secondary embodiment of formula (A), wherein W, X and Y are as the definition in first group of secondary embodiment, and Z is as the definition in second group of secondary embodiment.
Defined the 5th group of secondary embodiment of formula (A), wherein W, X and Y are as the definition in first group of secondary embodiment, R 4 ', R 5 ', R 6 'And R 7 'As the definition in the 3rd group of secondary embodiment.
Defined the 6th group of secondary embodiment of formula (A), wherein Z is as the definition in second group of secondary embodiment, R 4 ', R 5 ', R 6 'And R 7 'As the definition in the 3rd group of secondary embodiment.
Defined the non-limiting kind of first embodiment that provides by above-mentioned formula (A), wherein:
1) Z is-C (=W) NHNHC 2H 5OH, R 4 ', R 6 'And R 7 'Be H, R 5 'Be Cl, X is H, and Y is H;
2) Z is-C (=W) NHCH 2C (=W) NH 2, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is H, and Y is OH;
3) Z is-C (=W) NHCH 2CONHNH 2, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is H, and Y is-the O-alkyl;
4) Z is-C (=W) NHCH 2CH 2-(2-NO 2, the 5-Me-imidazoles), R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is H, and Y is-the O-thiazolinyl;
5) Z is-C (=W) NHCH 2NHCH (CH 3) C (=W) OH, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is H, and Y is-the O-alkynyl;
6) Z is-C (=W) CH=CHC (=W) NH 2, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is H, and Y is-the O-alkaryl;
7) Z is-C (=W) NHNHCH 2C (=W) NH 2, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is H, and Y is-the O-aryl;
8) Z is-C (=W) NHCH 2C (=W) R 2, R wherein 2Be NH 2, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is H, and Y is-the O-heterocycle;
9) Z is-C (=W) NHCH 2-A-C (=W) NH 2, wherein A is the divalence spacer, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is H, and Y is C 1-6Alkyl;
10) Z is-C (=W) R 2(=W) H, wherein A is the divalence spacer to CH-A-C, R 2Be NH, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is H, and Y is C 2-6Alkynyl;
11) Z is-C (=W) R 2(=W) OH, wherein A is the divalence spacer to CH-A-C, R 2Be NH, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is H, and Y is C 2-6Alkynyl;
12) Z is-C (=W) R 2-CH-A-R 3, wherein A is the divalence spacer, R 2Be NH, R 3Be CH 3, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is H, and Y is an aryl;
13) Z is-C (=W) NHR 2-C (=W) R 2, R wherein 2Be optional branched alkylidene or the NH that replaces, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is H, and Y is a heterocycle;
14) Z is-C (=W) R 2, R wherein 2Be NH, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is OH, and Y is H;
15) Z is-C (=W) R 2R 3-heterocycle, wherein R 2Be NH, R 3Be CH 2, heterocycle is optional morpholine, imidazoles or the pyrroles who replaces, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is C 1-6Alkyl, Y are H;
16) Z is-C (=W) R 2C (=W)-O-R 3, R wherein 2Be the optional alkyl that replaces, R 3Be benzyloxy, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is-the O-alkyl that Y is H;
17) Z is-C (=W) R 2-NH-C (=W)-C 1-4Alkoxyl group, wherein R 2Be the optional alkyl that replaces, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is-the O-thiazolinyl that Y is H;
18) Z is-C (=W) R 3-C (=W) R 2, R wherein 2Be C 1-4Alkoxyl group, R 3Be the optional alkyl that replaces, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is-the O-alkynyl that Y is H;
19) Z is-C (=W) R 2R 3, R wherein 2Be the optional alkyl that replaces, R 3Be the optional phenyl that replaces, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is-the O-alkaryl that Y is H;
20) Z is-C (=W) R 2-NH-C (=W)-O-R 3, R wherein 2Be the optional alkyl that replaces, R 3Be benzyl, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is-the O-aralkyl that Y is H;
21) Z is-C (=W) R 2C (=W)-NH 2, R wherein 2Be the optional alkyl that replaces, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is-the O-aryl that Y is H;
22) Z is-C (=W) R 2-W-R 3, R wherein 2And R 3Be the optional alkyl that replaces, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is-the O-heterocycle that Y is H;
23) Z is-C (=W) R 2C (=W)-O-R 3, R wherein 2Be the optional alkyl that replaces, R 3Be benzyloxy, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is-C 2-6-thiazolinyl, Y are H;
24) Z be-C (=W)-NH-CH (R 2)-C (=W)-NH 2, R wherein 2Be NH 2, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is-C 2-6-alkynyl, Y are H;
25) Z be-C (=W)-NH-NH 2, R wherein 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is an aryl, and Y is H;
26) Z be-C (=W)-NH-NH (R 2), R wherein 2Be NH 2, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, X is a heterocycle, and Y is H;
27) Z be-C (=W)-NH-CH (C[=W] NH 2) (CH 2-C[=W]-O-CH 2-aryl), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is a carbocyclic ring, and Y is H;
28) Z be-C (=W)-NH-CH ([CH 2] 4-NH-C[=W]-t-BuO) (C[=W]-NH 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-the O-alkaryl that Y is C 1-6Alkyl;
29) Z be-C (=W)-NH-CH (CH 2-CH 2-C[=WJ-t-BuO) (C[=W]-NH 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-the O-aryl that Y is-the O-alkyl;
30) Z be-C (=W)-NH-CH (CH 2R 3) (C[=W]-NH 2), R wherein 3Be CF 3, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-C 2-6Thiazolinyl, Y are-OH;
31) Z be-C (=W)-NH-CH (CH 2R 3) (C[=W]-NH 2), R wherein 3As the definition in first embodiment, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-C 2-6Alkynyl, Y are H;
32) Z be-C (=W)-NH-CH (CH 2OH) (C[=W]-NH 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-the O-alkylaryl that Y is-the O-alkyl;
33) Z be-C (=W)-NH-CH (C[=W]-NH 2) (C[=W]-NH 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-heterocycle that Y is-OH;
34) Z be-C (=W)-NH-CH (R 3) (C[=W]-NH 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-the O-thiazolinyl that Y is-the O-alkyl;
35) Z be-C (=W)-NH-CH ([CH 2] 4-NH-C[=W]-O-CH 2-R 3) (C[=W]-NH 2), R wherein 3As the definition in first embodiment, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-OH that Y is-the O-alkylidene group;
36) Z be-C (=W)-NH-CH (CH 2-C[=W]-NH 2) (C[=W]-NH 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-carbocyclic ring that Y is-the O-alkyl;
37) Z be-C (=W)-NH-CH (CH 2-R 3) (C[=W]-NH 2), R wherein 3As the definition in first embodiment, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-the O-alkyl that Y is-heterocycle;
38) Z be-C (=W)-NH-CH ([CH 2] 4-NH 2) (C[=W]-NH 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-the O-thiazolinyl that Y is-OH;
39) Z be-C (=W)-NH-CH (CH[R 2] [OH]) (C[=W]-NH 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-the O-alkynyl that Y is-the O-alkyl;
40) Z be-C (=W)-NH-CH (R 2) (C[=W]-NH 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-OH that Y is-the O-alkylidene group;
41) Z be-C (=W)-NH-CH (R 2-C[=W]-NH 2) (C[=W]-NH 2), R wherein 2Be NH 2, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-C 2-6Alkylidene group, Y are-OH;
42) Z be-C (=W)-NH-CH (C[=NH]-NH 2) (C[=W]-NH 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-carbocyclic ring that Y is-the O-alkyl;
43) Z be-C (=W)-NH-CH (C[=NH]-NH 2) (C[=W]-NH 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-OH that Y is-the O-alkylidene group;
44) Z be-C (=W)-NH-CH (R 3) (C[=W]-NH 2), R wherein 3As the definition in first embodiment, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-the O-aryl that Y is-C 1-6Alkyl;
45) Z be-C (=W)-NH-CH (CH 2-R 3) (C[=W]-NH 2), R wherein 3As the definition in first embodiment, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-OH that Y is-the O-alkylidene group;
46) Z be-C (=W)-NH-CH (R 2) (C[=W]-NH 2), R wherein 2Be NH 2, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-C 1-6Alkynyl, Y are-the O-aryl;
47) Z be-C (=W)-NH-NH-CH (R 3)-C[=W] R 2, R wherein 2Be-NH 2, R 3Be optional aryl or the heterocycle that replaces, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-the O-alkylaryl that Y is-OH;
48) Z be-C (=W)-NHR 2(R 3)-C[=W] NH 2, R wherein 2Be-alkylidene group R 3Be optional alkyl, aryl or the heterocycle that replaces, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-the O-alkynyl that Y is-OH;
49) Z is-C (=W) NHR 2(R 3)-C (=W) NH-R 2-C (=W) OH, wherein R 2Be alkylidene group, R 3Be optional alkyl, aryl or the heterocycle that replaces, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-the O-thiazolinyl that Y is-the O-alkyl;
50) Z is-C (=W) NHR 2(R 3)-C (=W) NH-R 2-NH 2, R wherein 2Be alkylidene group, R 3Be optional alkyl, aryl or the heterocycle that replaces, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is H, and Y is-the O-alkyl;
51) Z is-C (=W) NHR 2(R 3)-C (=W) NH-R 3-C (=W) OH, wherein R 2Be alkylidene group, R 3Be optional alkyl, aryl or the heterocycle that replaces, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-OH that Y is-the O-alkylidene group;
52) Z is-C (=W) R 2(CH 2) p-A-C (=W) NH 2j, R wherein 2Be-NH, p is 0-10, and A is optional aryl or the heterocycle that replaces of divalence, R 3Be optional alkyl, aryl or the heterocycle that replaces, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-C 1-6Alkyl, Y are-the O-thiazolinyl;
53) Z is-C (=W) NH-R 3, R wherein 3Be the optional heterocycle that replaces, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-the O-alkyl that Y is-OH;
54) Z is-C (=W) NH-R 2-R 5-R 3, R wherein 2Be alkylidene group, alkenylene or alkynylene, R 5Be-SO 2, R 3Be-NH 2, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-the O-aryl that Y is-the O-alkyl;
55) Z is-C (=W) NH-NH-R 2(R 3)-R 5-NH 2, R wherein 2Be alkylidene group, alkenylene or alkynylene, R 3Be aryl, arylidene or heterocyclic radical, R 5Be-SO 2, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-the O-alkynyl that Y is-OH;
56) Z is-C (=W) NH-R 3(R 5-NH 2), R wherein 3Be aryl, arylidene or heterocyclic radical, R 5Be-SO 2, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-heterocyclic radical that Y is-the O-alkyl;
57) Z is-C (=W) NH-R 2R 3(R 5-NH 2), R wherein 2Be alkylidene group, alkenylene or alkynylene, R 3Be aryl, arylidene or heterocyclic radical, R 5Be-SO 2, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-aryl that Y is-the O-thiazolinyl;
58) Z is-C (=W) NH-R 3(R 2R 5-NH 2), R wherein 2Be alkylidene group, alkenylene or alkynylene, R 3Be aryl, arylidene or heterocyclic radical, R 5Be-SO 2, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-OH that Y is-the O-alkylaryl;
59) Z is-C (=W) NHR 2(R 3)-C (=W) NH-R 2-C (=W) OH, wherein R 2Be optional alkylidene group, alkenylene or the alkynylene that replaces, R 3Be any definition that provides in first general embodiment, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-C 2-6Alkynyl, Y are-the O-thiazolinyl;
60) Z is-C (=W) NHR 2(R 3)-C (=W) NH-R 2-C (=W) NH 2, R wherein 2Be optional alkylidene group, alkenylene or the alkynylene that replaces, R 3Be any definition that provides in first general embodiment, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-C 2-6Thiazolinyl, Y are-H;
61) Z is-C (=W) NHR 2-C (=W) NH-R 2-C (=W) OH, wherein R 2Be optional alkylidene group, alkenylene or the alkynylene that replaces, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-C 1-6Alkyl, Y are-H;
62) Z is-C (=W) NHR 2-C (=W) NH-R 2-C (=W) NH 2, R wherein 2Be optional alkylidene group, alkenylene or the alkynylene that replaces, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, X is-H that Y is-the O-alkyl;
63) Z is-C (=W) NH-R 3, wherein W is O, R 3Being heterocycle, more specifically is the optional pyridyl that is replaced by one or more halogens, cyano group, alkyl, thiazolinyl, alkynyl or cyano group alkyl, pyrimidyl or imidazolyl; R 4 'And R 5 'Be H, F or Cl independently, R 6 'And R 7 'Be H, X is the optional phenyl that replaces, and Y is-the O-alkyl; With
Wherein, W is as the definition to formula (A).
In second embodiment, the invention provides the Phenylindole that is used for the treatment of HIV with following general formula (B) expression:
Figure G05839218720070518D000671
Or its pharmacy acceptable salt, prodrug, N-oxide compound, quaternary amine, steric isomer or tautomer, wherein:
W, Y, Z, R 1, R 2, R 3, A, n, R 4 ', R 5 ', R 6 'And R 7 'Respectively as mentioned to the definition of formula (A); And
Each R 2 ", R 3 ", R 4 ", R 5 "And R 6 "Be independently:
a)H；
B) halogen;
c)NO 2；
d)CN；
e)OR 2；
f)SR 2；
g)NH 2；
h)NR 2R 3；
I) N (R 2)-C (=W)-C 1-4Alkyl;
J) N (R 2)-SO 2-C 1-4Alkyl;
K) C 1-6Alkyl;
L) C 2-6Thiazolinyl;
M) C 2-6Alkynyl;
N) aryl;
o)CF 3；
p)CR 2R 2-S(O) n-R 3；
q)CR 2R 2NR 2R 3；
r)C-OH；
s)CR 2R 2-C(＝W)R 2；
T) acyl group;
u)C(＝W)R 2；
v)C(＝W)OR 2；
w)C(＝W)SR 2；
x)CO＝W)-NR 2R 3；
Y) C (=W) NH (CH 2) p-(amino-acid residue);
Z) amino residue; Or
Aa) A-(amino-acid residue);
Bb) cyano group alkyl;
Cc) cyano group thiazolinyl; Or
Dd) cyano group alkynyl,
Wherein, above-mentioned any one optional can being substituted; Or
Perhaps, R 2 "Or R 6 "Can combine with Y and form optional dicyclo that contains 4-14 ring members or the three cyclic phosphoric acid heterocycles that replace.
First group of secondary embodiment of formula (B) comprises all secondary embodiments of above-mentioned formula (A).
For the embodiment of the formula (B) that provides above provides second group of secondary embodiment, wherein R of the present invention 2 ", R 3 ", R 4 ", R 5 "And R 6 "Be defined as:
A) R 2 ", R 4 "And R 6 "Be hydrogen, R 3 "And R 5 "Be halogen independently of one another;-NO 2-CN;-OR 2-NH-R 5-C 1-6Alkyl;-NHCO-C 1-6Alkyl; Oxime; Hydrazine;-N (OH) C 1-6Alkyl; C 1-6Alkoxyl group;-OH;-NR 2R 2Or by one or more-OH ,-SR ,-CN ,-halogen ,-C (=W) H ,-C (=W) OH, halogen, NR 2R 2,-C 1-6Thioether or-C 1-6The optional replacement of alkoxyl group-C 1-6Alkyl, alkenyl or alkynyl;
B) R 2 ", R 4 "And R 6 "Be hydrogen, R 3 "And R 5 "Be halogen independently of one another or replaced-C by one or more halogens are optional 1-6Alkyl, thiazolinyl, alkynyl;
C) R 2 ", R 3 ", R 4 ", R 5 "And R 6 "Be hydrogen;
D) R 2 ", R 4 "And R 6 "Be hydrogen, R 3 "And R 5 "It is methyl;
E) R 2 ", R 4 "And R 6 "Be hydrogen, R 3 "And R 5 "Be chlorine;
F) R 2 ", R 4 "And R 6 "Be hydrogen, R 3 "And R 5 "It is fluorine;
G) R 2 ", R 4 "And R 6 "Be hydrogen, R 3 "Be iodine, R 5 "It is bromine;
H) R 2 ", R 4 "And R 6 "Be hydrogen, R 3 "Be methyl, R 5 "Be chlorine; With
I) R 2 ", R 4 "And R 6 "Be hydrogen, R 3 "Be chlorine, and R 5 "It is methyl.
For the embodiment of the formula (B) that provides above provides the 3rd group of secondary embodiment, wherein W, Y, R of the present invention 2 ", R 3 ", R 4 ", R 5 "And R 6 "Be defined as:
A) W is O, and Y is-the O-alkyl R 2 ", R 4 "And R 6 "Be hydrogen, R 3 "And R 5 "Be halogen independently of one another;-NO 2-CN;-OR 2-NH-R 5-C 1-6Alkyl;-NHCO-C 1-6Alkyl; Oxime; Hydrazine;-N (OH) C 1-6Alkyl; C 1-6Alkoxyl group;-OH;-NR 2R 2Or quilt-OH ,-SR ,-C (=W) H ,-C (=W) OH, halogen, NR 2R 2,-C 1-6Thioether or-C 1-6One or more optional replacements in the alkoxyl group-C 1-6Alkyl, alkenyl or alkynyl;
B) W is S, and Y is OH, R 2 ", R 4 "And R 6 "Be hydrogen, R 3 "And R 5 "Be halogen independently of one another or replaced-C by one or more halogens are optional 1-6Alkyl, thiazolinyl, alkynyl;
C) W is O, and Y is C 1-6Alkyl, R 2 ", R 3 ", R 4 ", R 5 "And R 6 "Be hydrogen;
D) W is S, and Y is C 1-6Alkylidene group, R 2 ", R 4 "And R 6 "Be hydrogen, R 3 "And R 5 "It is methyl;
E) W is NH, and Y is-the O-alkyl R 2 ", R 4 "And R 6 "Be hydrogen, R 3 "With
F) R 5 "Be chlorine;
G) W is S, and Y is-the O-thiazolinyl R 2 ", R 4 "And R 6 "Be hydrogen, R 3 "With
H) R 5 "It is fluorine;
I) W is O, and Y is an aryl, R 2 ", R 4 "And R 6 "Be hydrogen, R 3 "And R 5 "It is fluorine;
J) W is NH, and Y is-the O-alkynyl R 2 ", R 4 "And R 6 "Be hydrogen, R 3 "And R 5 "It is fluorine;
K) W is S, and Y is S, R 2 ", R 4 "And R 6 "Be hydrogen, R 3 "And R 5 "It is fluorine;
L) W is O, and Y is-the O-alkyl R 2 ", R 4 "And R 6 "Be hydrogen, R 3 "Be iodine, R 5 "It is bromine;
M) W is O, and Y is-the O-alkaryl R 2 ", R 3 ", R 5 "And R 6 "Be hydrogen, R 4 "Be-OH;
N) W is S, and Y is-NR 2R 3, R 2 ", R 3 ", R 5 "And R 6 "Be hydrogen, R 4 "Be-NH 2
O) W is S, and Y is-SR 2, R 2 ", R 3 ", R 5 "And R 6 "Be hydrogen, R 4 "Be-NO 2With
P) W is O, and Y is-the O-aralkyl R 2 ", R 4 "And R 6 "Be hydrogen, R 3 "Be chlorine, R 5 "It is methyl.
Defined the 4th group of secondary embodiment, wherein, Z is suc as formula any one definition in (A) second group of secondary embodiment, R 4 ', R 5 ', R 6 'And R 7 'Suc as formula the definition in (A) the 3rd group of secondary embodiment, R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All in second group of secondary embodiment of formula (B), define.
Defined the 5th group of secondary embodiment, wherein, W and Y are suc as formula the definition in (A) first group of secondary embodiment, and Z is suc as formula any one definition in (A) second group of secondary embodiment, R 4 ', R 5 ', R 6 'And R 7 'Suc as formula the definition in (A) the 3rd group of secondary embodiment, R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All in the 3rd group of secondary embodiment of formula (B), define.
Defined the 6th group of secondary embodiment, wherein, Z is suc as formula any one definition in (A) second group of secondary embodiment, R 4 ', R 5 ', R 6 'And R 7 'Suc as formula the definition in (A) the 3rd group of secondary embodiment, W, Y, R 2 ", R 3 ", R 4 ", R 5 "And R 6 "All in the 3rd group of secondary embodiment of formula (B), define.
Defined the non-limiting kind of second embodiment that provides by above-mentioned formula (B), wherein:
A) Z is-C (=W) NHNHC 2H 5OH, R 4 ', R 6 'And R 7 'Be H, R 5 'Be Cl, Y is H, R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
B) Z is-C (=W) NHCH 2C (=W) NH 2, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is OH, R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
C) Z is-C (=W) NHCH 2CONHNH 2, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is-the O-alkyl R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
D) Z is-C (=W) NHCH 2CH 2-(2-NO 2, the 5-Me-imidazoles), R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is-the O-thiazolinyl R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
E) Z is-C (=W) NHCH 2NHC (=W) OH, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is-the O-alkynyl R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
F) Z is-C (=W) CH=CHC (=W) NH 2, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is-the O-alkaryl R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
G) Z is-C (=W) NHNHCH 2C (=W) NH 2, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is-the O-aryl R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
H) Z is-C (=W) NHCH 2C (=W) R 2, R wherein 2Be NH 2, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is-the O-heterocycle R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
I) Z is-C (=W) NHCH 2-A-C (=W) NH 2, wherein A is the divalence spacer, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is C 1-6Alkyl, R 2 ", R 3 ", R 5 "And R 6 "Be H, R 4 "Be-NH 2
J) Z is-C (=W) R 2(=W) H, wherein A is the divalence spacer to CH-A-C, R 2Be NH, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is C 2-6Alkynyl, R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5It is methyl;
K) Z is-C (=W) R 2(=W) OH, wherein A is the divalence spacer to CH-A-C, R 2Be NH, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is C 2-6Alkynyl, R 2 ", R 3 ", R 5 "And R 6 "Be H, R 4 "Be-NO 2
L) Z is-C (=W) R 2-CH-A-R 3, wherein A is the divalence spacer, R 2Be NH, R 3Be CH 3, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is an aryl, R 2 ", R 3 ", R 5 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
M) Z is-C (=W) NHR 2-C (=W) R 2, R wherein 2Be optional branched alkylidene or the NH that replaces 3, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is a heterocycle, R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
N) Z is-C (=W) R 2, R wherein 2Be NH 3R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is H, R 2 ", R 3 ", R 5 "And R 6 "Be H, R 4 "Be-OH;
O) Z is-C (=W) R 2R 3-heterocycle, wherein R 2Be NH, R 3Be CH 2, heterocycle is optional morpholine, imidazoles or the pyrroles who replaces, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is H, R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
P) Z is-C (=W) R 2NH-C (=W)-O-R 3, R wherein 2Be the optional alkyl that replaces, R 3Be benzyloxy, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is H, R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
Q) Z is-C (=W) R 2-NH-C (=W)-C 1-4Alkoxyl group, wherein R 2Be the optional alkyl that replaces, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is H, R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
R) Z is-C (=W) R 3-C (=W) R 2, R wherein 2Be C 1-4Alkoxyl group, R 3Be the optional alkyl that replaces, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is H, R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
S) Z is-C (=W) R 2R 3, R wherein 2Be the optional alkyl that replaces, R 3Be the optional phenyl that replaces, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is H, R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
T) Z is-C (=W) R 2-NH-C (=W)-O-R 3, R wherein 2Be the optional alkyl that replaces, R 3Be benzyl, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is H, R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
U) Z is-C (=W) R 2C (=W)-NH 2, R wherein 2Be optional alkyl, the R that replaces 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is H, R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
V) Z be-C (=W)-A-R 3, R wherein 3Be the optional alkyl that replaces, A is the alkylidene group bonding radical, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is H, R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
X) Z is-C (=W) R 2C (=W)-O-R 3, R wherein 2Be the optional alkyl that replaces, R 3Be benzyloxy, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is H, R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
Y) Z be-C (=W)-NH-CH (R 2)-C (=W)-NH 2, R wherein 2Be NH 2, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is H, R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
Z) Z be-C (=W)-NH-NH 2, R wherein 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is H, R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
AA) Z be-C (=W)-NH-NH (R 2), R wherein 2Be NH 2, R 4 'Be F or Cl, R 6 'And R 7 'Be H, R 5 'Be F or Cl, Y is H, R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
BB) Z be-C (=W)-NH-CH (C[=W] NH 2) (CH 2-C[=W]-O-NR 2R 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, R 2Be alkyl or aryl, Y is H, R 2 ", R 3 ", R 5 "And R 6 "Be H, R 4 "Be-NH 2
CC) Z be-C (=W)-NH-CH ([CH 2] 4-NH-C[=W]-t-BuO) (C[=W]-NH 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is C 1-6Alkyl, R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
DD) Z be-C (=W)-NH-CH (CH 2-CH 2-C[=W]-t-BuO) (C[=W]-NH 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-the O-alkyl R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
EE) Z be-C (=W)-NH-CH (CH 2R 3) (C[=W]-NH 2), R wherein 3Be CF 3, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-OH R 2 ", R 4 "And R 6 "Be H, R 3 "With R be methyl;
FF) Z be-C (=W)-NH-CH (CH 2R 3) (C[=W]-NH 2), R wherein 3As the definition in first embodiment, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is H, R 2 ", R 3 ", R 5 "And R 6 "Be H, R 4 "Be-NO 2
GG) Z be-C (=W)-NH-CH (acyl group) (C[=W]-NH 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-the O-alkyl R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
HH) Z be-C (=W)-NH-CH (C[=W]-NH 2) (C[=W]-NH 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-OH R 2 ", R 3 ", R 5 "And R 6 "Be H, R 4 "Be-OH;
II) Z be-C (=W)-NH-CH (R 3) (C[=W]-NH 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-the O-alkyl R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
JJ) Z be-C (=W)-NH-CH (CH 2-R 3) (C[=W]-NH 2), R wherein 3As the definition in first embodiment, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-heterocycle R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
KK) Z be-C (=W)-NH-CH ([CH 2] 4-NH 2) (C[=W]-NH 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-OH R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
LL) Z be-C (=W)-NH-CH (CR 2R 2) (C[=W]-NH 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-the O-alkyl R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
MM) Z be-C (=W)-NH-CH (R 2) (C[=W]-NH 2), R wherein 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-the O-alkylidene group R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
NN) Z be-C (=W)-NH-CH (R 3) (C[=W]-NH 2), R wherein 3As the definition in first general embodiment, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-C 1-6Alkyl, R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
OO) Z be-C (=W)-NH-CH (CH 2-R 3) (C[=W]-NH 2), R wherein 3As the definition in first general embodiment, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-the O-alkylidene group R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
PP) Z be-C (=W)-NH-CH (R 2X-C[=W]-NH 2), R wherein 2Be NH 2, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-the O-aryl R 2 ", R 3 ", R 5 "And R 6 "Be H, R 4 "Be-NH 2
UU) Z be-C (=W)-NH-NH-CH (R 3)-C[=W] R 2, R wherein 2Be-NH 2, R 3Be optional aryl or the heterocycle that replaces, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-OH R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
VV) Z be-C (=W)-NHR 2(R 3)-C[=W] NH 2, R wherein 2Be-alkylidene group R 3Be optional alkyl, aryl or the heterocycle that replaces, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-OH R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
WW) Z is-C (=W) NHR 2(R 3)-C (=W) NH-R 2-C (=W) OH, wherein R 2Be alkylidene group, R 3Be optional alkyl, aryl or the heterocycle that replaces, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-the O-alkyl R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
XX) Z is-C (=W) NHR 2(R 3)-C (=W) NH-R 2-NH 2, R wherein 2Be alkylidene group, R 3Be optional alkyl, aryl or the heterocycle that replaces, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-the O-alkyl R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
YY) Z is-C (=W) NHR 2(R 3)-C (=W) NH-R 3-C (=W) OH, wherein R 2Be alkylidene group, R 3Be optional alkyl, aryl or the heterocycle that replaces, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-the O-alkylidene group R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
ZZ) Z is-C (=W) R 2(CH 2) p-A-C (=W) NH 2, R wherein 2Be-NH, p is 0-10, and A is optional aryl or the heterocycle that replaces of divalence, R 3Be optional alkyl, aryl or the heterocycle that replaces, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-the O-thiazolinyl R 2 ", R 3 ", R 5 "And R 6 "Be H, R 4 "Be-NO 2
AAA) Z is-C (=W) NH-R 3, R wherein 3Be the optional heterocycle that replaces, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-OH R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
BBB) Z is-C (=W) NH-A-S (O) n-R 2, wherein A is alkylidene group, alkenylene or alkynylene, R 2Be-NH 2, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-the O-alkyl R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
CCC) Z is-C (=W) NH-NH-R 2(R 3)-A-C (=W) NH 2, R wherein 2Be alkyl, A is alkylidene group, alkenylene or alkynylene, R 3Be aryl, arylidene or heterocyclic radical, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-OH R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
DDD) Z is-C (=W) NH-A-[S (O) 2-NH 2], wherein A is alkylidene group, alkenylene or alkynylene, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-the O-thiazolinyl R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
EEE) Z is-C (=W) NH-A-C (=W) NH-R 2-C (=W) OH, wherein R 2And R 3Be any definition that provides in first general embodiment, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-the O-thiazolinyl R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
FFF) Z is-C (=W) NHR 2(R 3)-C (=W) NH-R 2-C (=W) NH 2, R wherein 2Be optional alkylidene group, alkenylene or the alkynylene that replaces, R 3Be any definition that provides in first general embodiment, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-H R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
GGG) Z is-C (=W) NHR 2-C (=W) NH-R 2-C (=W) OH, wherein R 2Be optional alkylidene group, alkenylene or the alkynylene that replaces, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-H R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl;
HHH) Z is-C (=W) NHR 2-C (=W) NH-R 2-C (=W) NH 2, R wherein 2Be optional alkylidene group, alkenylene or the alkynylene that replaces, R 4 'And R 5 'Be F or Cl independently, R 6 'And R 7 'Be H, Y is-the O-alkyl R 2 ", R 4 "And R 6 "Be H, R 3 "And R 5 "It is methyl; With
Wherein, W is as the definition to formula (A).
In the 3rd embodiment, the invention provides the dicyclo 3-of 9-11 unit phosphoric acid indoles with the optional replacement that is used for the treatment of HIV of following general formula (C) expression:
Figure G05839218720070518D000781
Or its pharmacy acceptable salt, prodrug, N-oxide compound, quaternary amine, steric isomer or tautomer, wherein:
W, Z, R 1, R 2, R 3, A, n, R 4 ', R 5 ', R 6 'And R 7 'Separately as mentioned to the definition of formula (A);
R 3 ", R 4 ", R 5 "And R 6 "Separately as mentioned to the definition of formula (B);
Figure G05839218720070518D000782
Expression exists singly-bound or two key, wherein:
When
Figure G05839218720070518D000783
When there was two key in expression, Y and T were independently of one another:
a)CR 2；
B) N; Or
c)SR 2；
Be noted that one of Y and T must be CR 2
When
Figure G05839218720070518D000784
When there was singly-bound in expression, Y and T were independently of one another:
a)CR 2；
b)O；
C) NR 2Or
d)SR 2；
Be noted that one of Y and T must be CR 2With
M is 1 or 2, and prerequisite is, as T or Y=CR 2The time m can only be 2.
First group of secondary embodiment of formula (C) comprises all secondary embodiments of above-mentioned formula (A), and wherein, substituting group " X " is aryl, heterocyclic radical, O-aryl and O-heterocyclic radical.
For the embodiment of the formula (C) that provides above provides second group of secondary embodiment of the present invention, wherein Y and T are defined as:
J) T is-CH 2, Y is-O-;
K) T be-C-C (=O)-OCH 3, Y is-O-;
L) T is-O, and Y is-CR 2
M) T is (CH 2) 2, Y is-NR 2
N) T is-CH 2, Y is-SR 2
O) T is-O, and Y is-the C-aryl;
P) T is-NR 2, Y is-the C-halogen;
Q) T is-SR 2, Y is-the C-heterocycle;
R) T is-C-C 1-6Alkyl, Y are-O-;
S) T is-C-C (=S) CH 2, Y is-CH 2-;
T) T is-CH-OCH 3, Y is-SR 2
U) T is-C-OH, and Y is-CH 2-;
V) T is-C-O-C 1-6Alkyl, Y are-CH 2-;
W) T is-C-NH 2, Y is-CH 2-;
X) T is-C-NH-C 1-6Alkyl, Y are-CH 2-; With
Y) T is (CH 2) 2, Y is (CH 2) 2
For the embodiment of the formula (C) that provides above provides the 3rd group of secondary embodiment, wherein R of the present invention 3 ", R 4 ", R 5 "And R 6 "Be defined as:
A) R 4 "And R 6 "Be hydrogen, R 3 "And R 5 "Be halogen independently of one another;-NO 2-CN;-OR 2-NH-R 5-C 1-6Alkyl;-NHCO-C 1-6Alkyl; Hydrazine;-N (OH) C 1-6Alkyl; C 1-6Alkoxyl group;-OH;-NR 2R 2Or by one or more-OH ,-SR ,-C (=W) H ,-C (=W) OH, halogen, NR 2R 2,-C 1-6Thioether or-C 1-6The optional replacement of alkoxyl group-C 1-6Alkyl, alkenyl or alkynyl;
B) R 4 "And R 6 "Be hydrogen, R 3 "And R 5 "Be halogen independently of one another or replaced-C by one or more halogens are optional 1-6Alkyl, thiazolinyl, alkynyl;
C) R 3 ", R 4 ", R 5 "And R 6 "Be hydrogen;
D) R 4 "And R 6 "Be hydrogen, R 3 "And R 5 "It is methyl;
E) R 4 'And R 6 "Be hydrogen, R 3 "And R 5 "Be chlorine;
F) R 4 "And R 6 "Be hydrogen, R 3 "And R 5 "It is fluorine;
G) R 4 "And R 6 "Be hydrogen, R 3 "Be iodine, R 5 "It is bromine;
H) R 3 ", R 4 "And R 6 "Be hydrogen, R 5 "Be chlorine;
I) R 4 "And R 6 "Be hydrogen, R 3 "Be chlorine, R 5 "It is methyl.
I) R 3 ", R 5 "And R 6 "Be hydrogen, R 4 "It is halogen;-NO 2-CN;-OR 2-NH-R 5-C 1-6Alkyl;-NHCO-C 1-6Alkyl; Hydrazine;-N (OH) C 1-6Alkyl; C 1-6Alkoxyl group;-OH;-NR 2R 2Or quilt-OH ,-SR ,-C (=W) H ,-C (=W) OH, halogen, NR 2R 2,-C 1-6Thioether or-C 1-6One or more optional replacements in the alkoxyl group-C 1-6Alkyl, alkenyl or alkynyl;
J) R 3 ", R 5 "And R 6 "Be hydrogen, R 4 "Be-NO 2
K) R 3 ", R 5 "And R 6 "Be hydrogen, R 4 "Be-OR 2
L) R 3 ", R 5 "And R 6 "Be hydrogen, R 4 "It is halogen; With
M) R 3 ", R 5 "And R 6 "Be hydrogen, R 4 "Be-NH 2
Defined the 4th group of secondary embodiment of formula (C), wherein, Z is suc as formula any one definition in (A) second group of secondary embodiment, R 4 ', R 5 ', R 6 'And R 7 'Suc as formula the definition in (A) the 3rd group of secondary embodiment, R 3 ", R 4 ", R 5 "And R 6 "All in the 3rd group of secondary embodiment of formula (C), define.
Defined the 5th group of secondary embodiment of formula (C), wherein, Z is suc as formula any one definition in (A) second group of secondary embodiment, R 4 ', R 5 ', R 6 'And R 7 'Suc as formula the definition in (A) the 3rd group of secondary embodiment, Y and T are suc as formula the definition in (C) second group of secondary embodiment.
Defined the 6th group of secondary embodiment of formula (C), wherein, Z is suc as formula any one definition in (A) second group of secondary embodiment, R 4 ', R 5 ', R 6 'And R 7 'Suc as formula the definition in (A) the 3rd group of secondary embodiment, R 3 ", R 4 ", R 5 "And R 6 "All in second group of secondary embodiment of formula (B), define.
Defined the kind of the 3rd embodiment that provides by above-mentioned formula (C), wherein:
A) Z is-C (=W) N (R 2R 3) C (=W) NH 2, R wherein 2Be NH, R 3It is alkyl; R 1, R 4 ', R 6 'And R 7 'Be H; R 5 'Be halogen or-NO 2R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently-OH or-NR 2R 2Y is O; T is CH 2
B) Z be-C (=W)-NH-CH (C[=W] NH 2) (CH 2-C[=W]-O-CH 3-aryl); R 1, R 4 ', R 6 'And R 7 'Be H; R 5 'Be halogen or-CN; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently-C 1-5Alkoxyl group or quilt-C 1-5The optional replacement of alkoxyl group-C 1-5Alkyl; Y is SR 2T is CH 2
C) Z is-C (=W) NHNH 2R 1, R 4 ', R 6 'And R 7 'Be H; R 5 'Be halogen or-NR 2R 2R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently-NO 2Or-CN; Y is CH 2T-R 2-R 3Be CH 2
D) Z is-C (=W) NH-CH 2-C (=W) NHNH 2R 1, R 4 ', R 6 'And R 7 'Be H; R 5 'Be halogen or-NH-R 5-C 1-6Alkyl, wherein R 5Be-C (O) or-S (O) n, n is 0,1 or 2; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently-OR 2Or-CN; Y is C-C 1-6Alkyl; T is N;
E) Z is-C (=W) NH-CH 2-C (=W) NHNH 2R 1, R 4 ', R 6 'And R 7 'Be H; R 5 'Be halogen or-NH-R 5-C 1-6Alkyl, wherein R 5Be-C (O) or-S (O) n, n is 0,1 or 2; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently-OR 2Or-CN; Y is C-C 1-6Alkyl; T is SR 2, R 2As definition to formula (A);
F) Z is-C (=W) NH-CH (R 2)-C (=W) NH 2, R wherein 2Be-NH 2Or alkyl; R 1, R 4 ', R 6 'And R 7 'Be H; R 5 'Be halogen or-NHCO-C 1-6Alkyl; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently-NHOH; Y is the C-thiazolinyl; T is (CH 2) 2
G) Z is-C (=W) NR 2-C (=W) R 3, R wherein 2Be optional alkyl, the alkenyl or alkynyl that replaces; R 3Be NH 2R 1, R 4 ', R 6 'And R 7 'Be H; R 5 'Be halogen or oxime; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-NH-R 5-C 1-6Alkyl, wherein R 5Be-C (O) or-S (O) n, n is 0,1 or 2; Y is the C-alkynyl; T is-O;
H) Z is-C (=W) NH-R 2-SR 2, R wherein 2Be optional alkyl, the alkenyl or alkynyl that replaces; R 1, R 4 ', R 6 'And R 7 'Be H; R 5 'Be halogen or hydrazine; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-NHCO-C 1-6Alkyl; Y is the C-carbocyclic ring; T is NR 2, R wherein 2As definition to formula (A);
I) Z be-C (=W)-NH-N (R 3) (R 2), R wherein 2Be hydroxyl or alkoxyl group, R 3Be H or alkyl; R 1, R 4 ', R 6 'And R 7 'Be H; R 5Be halogen or quilt-OH ,-SR ,-C (=W) H ,-C (=W) OH, halogen ,-NR 2R 2, C 1-3Alkoxyl group or C 1-3The C of the one or more optional replacements in the thioether 1-6Alkyl or alkenyl; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-CN; Y is the C-aryl; T is N;
J) Z is-C (=W) NH-CH 2NH-CH (CH 3) C (=W) OH; R 1, R 4 ', R 6 'And R ' 'Be H; R 3Be halogen or CF 3R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-NH-O-C 1-3Alkyl; Y is O; T is CH 2
K) Z be-C (=W)-NH-N (R 2)-CH (R 2)-C (=W) R 2, R wherein 2Be H or NH 2R 1, R 4 ', R 6 'And R 7 'Be H; R 5 'Be halogen or H; R 4 "And R 6 "Be H; R 3 "And R 5 "Be H or halogen independently; Y is-NR 2, T is CR 2, R wherein 2Define as first general embodiment;
L) Z be-C (=W)-N (R 2)-C (=W) R 3, R wherein 2Be NH, R 3Be CH 3R 1, R 4 ', R 6 'And R 7 'Be H; R 5 'Be halogen or H; R 4 "And R 6 "Be H; R 3 "And R 5 "Be H or halogen independently; Y is-O; T is (a C-O-alkyl);
M) Z be-C (=W)-NH-CH=CH-C (=W) R 2, R wherein 2Be NH 2R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be halogen or H; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-OR 2, R wherein 2Define as first general embodiment; Y is-O; T is (C-CH 2-CH 3);
N) Z be-C (=W)-NH-CH=CH-C (=W) R 2, R wherein 2Be-NH 2R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be halogen or-NO 2R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-NHOH; Y is-O that T is C-CH 3
O) Z is-C (=W) R 2(CH) 2-C (=W) R 2, R wherein 2Be NH or NH 2R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be halogen or-OR 2, R wherein 2Define as first general embodiment; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or quilt-OH ,-SR ,-C (=W) OH, halogen or-NH 2In one or more optional replacements-C 1-3Alkyl or alkenyl; Y is-SR 2T is CH 2
P) Z be-C (=W)-R 2-CH 2-A-C (=W) R 2, R wherein 2Define as first general embodiment, A is the divalence bonding radical that defines as in first general embodiment; R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be halogen or-CN; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-C 1-3Alkoxyl group; Y is-NR 2, R wherein 2Define as first general embodiment; T is (CH 2) 2
Q) Z be-C (=W)-R 2-CH 2-A-C (=W) R 2, R wherein 2Be alkyl or-NH 2, A is the divalence bonding radical; R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be halogen or-NR 2R 2, R wherein 2Define as first general embodiment; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-OH; Y is-CH 2, T is (CH 2) 2
R) Z be-C (=W)-A-R 2-C (=W) OR 3, R wherein 2Be-NH R 3Be-H or alkyl; R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be halogen or-NHR 5-C 1-3Alkyl, wherein R 5Define as first general embodiment; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-NR 2R 2, R wherein 2Define as first general embodiment; Y is-C-C 1-6Alkyl; T is CH 2
S) Z be-C (=W)-NH-C (=W) OR 3, R wherein 3As definition to formula (A); R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be halogen or-NHCO-C 1-3Alkyl; R 4 "And R 6 "Be H; R 3 "And R 5 "Be halogen or H independently; Y is-the C-thiazolinyl; T is O;
T) Z is-C (=W) R 3-NH-C (=W)-R 2, R wherein 2Be-NH 2, R 3Be-NH; R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be halogen or oxime; R 4 "And R 6 "Be H; R 3 "And R 5 "Be H independently or replaced-C by one or more halogens are optional 1-3Alkyl or alkenyl; Y is-the C-alkynyl; T is (CH 2) 2
U) Z be-C (=W)-N (C=O)-N (R 2)-R 3, R wherein 2Be H or alkyl, R 3Be-NH 2, R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be halogen or hydrazine; R 4 "And R 6 "Be H; R 3 "And R 5 "Be H independently; Y is-the C-aryl; T is (CH 2) 2
V) Z be-C (=W)-N (R 2)-N (R 2)-C (=W) R 3, R wherein 2Be H or alkyl, R 3Be NH 2R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be halogen or-NHS (O) 2-C 1-3Alkyl; R 4 "And R 6 "Be H; R 3 "And R 5Be independently H or-methyl; Y is-the C-heterocycle; T is O;
W) Z be-C (=W)-N (N[R 2] [R 3])-R 3, R wherein 2Be H or alkyl, R 3Be NH 2R 1, R 6 'And R 7 'Be H; R 4And R 5Be halogen or quilt-OH ,-SR ,-C (=W) H ,-C (=W) OH, halogen, NR 2R 2, C 1-3Alkoxyl group or C 1-3One or more optional replacements in the thioether-C 1-6Alkyl or alkenyl, wherein R 2Define as first general embodiment; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-NR 2R 2, R wherein 2Define as first general embodiment; Y is-the C-carbocyclic ring; T is NR 2, R wherein 2As hereinbefore defined;
X) Z is-C (=W) R 2-C (=W) NH 2, R wherein 2It is alkyl; R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be halogen or-H; R 4 "And R 6 "Be H; R 3 "And R 5 "Be H or chlorine independently; Y is-SR 2, T is CH 2
Y) Z is-C (=W) R 2-SR 2, R wherein 2Be-NH or alkyl; R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be halogen or-CF 3R 4 "And R 6 "Be H; R 3 "And R 5 "Be H or fluorine independently; Y is-O; T is (CH 2) 2
Z) Z be-C (=W)-CH (R 2)-C (=NH) R 2, R wherein 2Be H or NH 2R 1, R 4 'And R 7 'Be H; R 5 'And R 6 'Be halogen or-H; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-CF 3Y is-NR 2T is CR 2R wherein 2As definition to formula (A);
Aa) Z be-C (=W)-NH-A-NH-C (=W)-A-C-(=W)-R 2, R wherein 2Be NH 2, A is the divalence bonding radical; R 1, R 4 'And R 7 'Be H; R 5 'And R 6 'Be-CN or-NO 2R 4 "And R 6 "Be H; R 3 "And R 5Be independently H or-NO 2Y is-CH 2T is NR 2, R wherein 2As definition to formula (A);
Bb) Z be-C (=W)-R 2-CH-(A-C[=W] R 2) (C[=W]-NH 2), R wherein 2Be H, alkyl or NH; A connects as the divalence spacer to formula (A) definition; R 1, R 4 'And R 7 'Be H; R 5And R 6 'Be H or-NHCO-C 1-6Alkyl; R 4 "And R 6 "Be H; R 3 "And R 5 "Be H or diazanyl independently; Y is (CH 2) 2T is N;
Cc) Z be-C (=W)-NH-A (C[=W]-NH 2), wherein A is that alkylidene group or arylidene divalence spacer connect; R 1, R 4 'And R 7 'Be H; R 5 'And R 6 'Be H or-NH (SO 2) C 1-6Alkyl; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-NHOH; Y is-the C-thiazolinyl; T is N;
Dd) Z be-C (=W)-NH-CH (A-R 3) (C[=W]-NH 2), wherein A is alkylidene group or alkenylene spacer; R 3Be OH; R 1, R 4 'And R 7 'Be H; R 5 'And R 6 'Be H or CF 3R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-NR 2R 2, R wherein 2As definition to formula (A); Y is-the C-carbocyclic ring; T is SR 2
Ee) Z be-C (=W)-NH-CH (R 2) (R 3), R wherein 2And R 3C (=W) NH respectively does for oneself 2R 1, R 6 'And R 7 'Be H; R 5 'And R 4 'Be H or halogen; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-C 1-5Alkoxyl group; Y is-O; T is CH 2
Ff) Z be-C (=W)-A-CH (R 2-C[=W]-NH 2) (C[=W]-NH 2), wherein A connects as the spacer to formula (A) definition; R 2Be NH; R 1, R 6 'And R 7 'Be H; R 5 'And R 4 'Be H or-NO 2R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-OH; Y is-N; T is CH 2
Gg) Z be-C (=W)-NH-CH-(CH-R 2-OH) (C[=W]-NH 2), R wherein 2Be NH or alkylidene group; R 1, R 6 'And R 7 'Be H; R 5 'And R 4 'Be H or-halogen; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-halogen; Y is-SR 2T is CH-OCH 3
Hh) Z be-C (=W)-NH-CH (R 2) (C[=W]-NH 2), R wherein 2It is alkyl; R 1, R 6 'And R 7 'Be H; R 5 'And R 4 'Be H or-NO 2R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-CN; Y is-the C-aryl; T is N;
Ii) Z be-C (=W)-NH-CH (R 2) (C[=W]-NH 2), R wherein 2It is alkyl; R 1, R 6 'And R 7 'Be H; R 5 'And R 4 'Be H or-OH; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-CN; Y is-the C-heterocycle; T is (CH 2) 2
Jj) Z be-C (=W)-NH-CH (R 2-C[=W]-NH 2) (C[=W]-NH 2, R wherein 2It is alkylidene group; R 1, R 6 'And R 7 'Be H; R 4 'And R 5Be H or-NO 2R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-NHOH; Y is-O that T is CH 2
Kk) Z be-C (=W)-NH-CH (R 2) (C[=W]-NH 2), R wherein 2Be-S (O) R 3, R 3As definition to formula (A); R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be H or-OR 2, R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-C 1-3Alkoxyl group; Y is-NR 2, R wherein 2Define as first general embodiment, T is CH 2
Ll) Z be-C (=W)-NH-CH (C[=NH]-NH 2) (C[=W]-NH 2); R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be H or-NR 2R 2, R wherein 2Define as first general embodiment; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-OH; Y is-SR 2, T is (CH 2) 2
Mm) Z be-C (=W)-NH-NH-CH (R 3)-C[=W] R 2, R wherein 2Be-NH 2, R 3Be optional aryl or the heteroaryl that replaces; R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be H or-CN; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-NR 2R 2, R wherein 2Define as first general embodiment; Y is-C-C 1-6Alkyl; T is N;
Nn) Z be-C (=W)-NHR 2(R 3)-C[=W] NH 2, R wherein 2Be alkyl, R 3Be optional alkyl, aryl or the heteroaryl that replaces; R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be H or-NH-R 5-C 1-3Alkyl, wherein R 5Define as first general embodiment; R 4 "And R 6 "Be H; R 3 "And R 5Be independently H or quilt-OH ,-SR ,-C (=W) OH, halogen or NH 2In one or more optional replacements-C 1-6Alkyl or alkenyl; Y is-the C-thiazolinyl; T is SR 2, R wherein 2As definition to formula (A);
Oo) Z be-C (=W)-NHR 2(R 3)-C[=W] NH-R 2-C (=W) OH, wherein R 2Be alkyl, R 3Be optional alkyl, aryl or the heteroaryl that replaces; R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be H or-NHCO-C 1-3Alkyl; R 4 "And R 6 "Be H; R 3 "And R 5 "Be H independently or replaced-C by one or more halogens are optional 1-6Alkyl or alkenyl; Y is-the C-alkynyl; T is CH 2
Pp) Z be-C (=W)-NHR 2(R 3)-C[=W] NH-R 2NH 2, R wherein 2Be alkyl, R 3Be optional alkyl, aryl or the heteroaryl that replaces; R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be H or-oxime; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-halogen; Y is-CH 2T is-NR 2, R wherein 2As definition to formula (A);
Qq) Z be-C (=W)-NHR 2(R 3)-C (=W) NH-R 3, R wherein 2Be alkyl, R 3Be optional alkyl, aryl or the heteroaryl that replaces; R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be H or-hydrazine; R 4 "And R 6 "Be H; R 3 "And R 5 "Be H independently; Y is-NR 2, R wherein 2Define as first general embodiment; T is (CH 2) 2
Rr) Z be-C (=W)-R 2-A-C (=W)-NH 2, R wherein 2Be-NH, A is that the divalence spacer connects, and described connection is optional aryl or the heteroaryl that replaces; R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be H or-NH (SO 2) C 1-6Alkyl; R 4 "And R 6 "Be H; R 3 "And R 5 "Be H or methyl independently; Y is-C-C 1-6Alkyl; T is N;
Ss) Z is-C (=W) NH-R 3, R wherein 3It is the heterocycle of choosing wantonly; R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be H or quilt-OH ,-SR, C (=W) H, CO=W) OH, halogen, NR 2R 2, C 1-3Alkoxyl group or C 1-3One or more optional replacements in the thioether-C 1-6Alkyl or alkenyl; R 4 "And R 6 "Be H; R 3 "And R 5 "Be H or chlorine independently; Y is-the C-thiazolinyl; T is NR 2, R wherein 2As definition to formula (A);
Tt) Z is-C (=W) NH-A-S (O) 2-R 3, wherein A is alkylidene group, alkenylene or alkynylene divalence spacer bonding, R 3Be-NH 2, and R 5Be-SO 2R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be H; R 4 "And R 6 "Be H; R 3 "And R 5 "Be H or fluorine independently; Y is-(CH 2) 2T is (CH 2) 2
Uu) Z is-C (=W) NH-NH-A-(R 3)-S (O) 2-NH 2, wherein A is alkylidene group, alkenylene or alkynylene divalence spacer bonding, R 3Be aryl, arylidene or heteroaryl, and R 5Be-SO 2R 1, R 6 'And R 7 'Be H; R 4 'And R 5 'Be H or-CF 3R 4 "And R 6 "Be H; R 3 "And R 5 "Be H or CF independently 3Y is-O; T is CH 2
Vv) Z is-C (=W) NH-R 3(SO 2-NH 2), R wherein 3Be aryl, arylidene or heteroaryl; R 1, R 4 'And R 7 'Be H; R 5 'And R 6 'Be H or-halogen; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-NO 2Y is-O; T is CR 2, R wherein 2As definition to formula (A);
Ww) Z is-C (=W) NH-A-(NH 2), wherein A is alkylidene group, alkenylene or alkynylene divalence spacer bonding; R 1, R 4 'And R 7 'Be H; R 5 'And R 6 'Be H or-NO 2R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-halogen; Y is-O-; T is the C-carbocyclic ring;
Xx) Z is-C (=W) NH-R 3(A-SO 2-NH 2), wherein A is alkylidene group, alkenylene or alkynylene divalence spacer bonding; R 3Be aryl, arylidene or heteroaryl; R 1, R 4 'And R 7 'Be H; R 5 'And R 6 'Be H or-CN; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-NH-R 5-C 1-3Alkyl, wherein R 5Define as first general embodiment; Y is-the C-carbocyclic ring; T is NR 2, R wherein 2As definition to formula (A);
Yy) Z is-C (=W) NH (R 3)-C (=W) NH-A-C (=W) OH, wherein A is optional alkylidene group, alkenylene or the alkynylene divalence spacer bonding that replaces, R 3Define as first general embodiment; R 1, R 4 'And R 7 'Be H; R 5And R 6Be H or-OR 2, R wherein 2Define as first general embodiment; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-CN; Y is-the C-aryl; T is CH 2
Zz) Z is-C (=W) NH (R 3)-C (=W) NH-A-C (=W) NH 2, wherein A is as the divalence spacer bonding to the defined optional replacement of formula (A); R 3Define as first general embodiment; R 1, R 4 'And R 7 'Be H; R 5 'And R 6 'Be H or-NR 2R 2, R wherein 2Define as first general embodiment; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-NH-R 5-C 1-6Alkyl, wherein R 5Define as first general embodiment; Y is-the C-heterocycle; T is SR 2
Aaa) Z is-C (=W) NHR 2-C (=W) NH-R 2-C (=W) OH, wherein R 2As definition to formula (A); A is the optional divalence spacer bonding that replaces; R 1, R 4 'And R 7 'Be H; R 5 'And R 6 'Be H or-NHSO 2-C 1-6Alkyl; R 4 "And R 6 "Be H; R 3 "And R 5 "Be H or hydrazine independently; Y is-O that T is (CH 2) 2With
Bbb) Z is-C (=W) NHR 2-C (=W) NH-R 2-C (=W) NH 2, R wherein 2As definition to formula (A); A is the optional divalence spacer bonding that replaces; R 1, R 4 'And R 7 'Be H; R 5 'And R 6 'Be H or-NHCO-C 1-6Alkyl; R 4 "And R 6 "Be H; R 3 "And R 5 "Be independently H or-OH; Y is-NR 2, R wherein 2Define as first general embodiment, T is CH 2
Wherein, W is as mentioned to the definition of first general embodiment of formula (A).
All embodiments have been defined secondary embodiment, wherein:
1) Z be-C (=W)-NH-R 2-C (=W)-NR 2R 3-C-R 2R 3-CR 2-C (=W) R 3-R 2-C (=W) R 3-R 2-C (=W) R 2-R 2R 3R 3Or C (=W)-NH-CR 2R 2-C (=W)-NH-CR 2R 3-C (=W)-NR 2R 3
2) R 4 ', R 6 'And R 7 'Be H, R 5 'Be i) halogen, especially chlorine; Ii) hydrazine; Iii) C 1-6Alkyl, thiazolinyl, alkynyl, amino-alkyl, sulfo-amino-alkyl or aminocarboxyl-alkyl, wherein optional separately can by one or more-OH ,-C (=W) H ,-C (=W) OH ,-NR 2R 3,-C 1-3Alkoxyl group or-C 1-3Thioether replaces; One of or following combination:
A) R 5 ', R 6 'And R 7 'Be hydrogen, R 4 'It is halogen;
B) R 4 ', R 5 'And R 7 'Be hydrogen, R 6 'It is halogen;
C) R 4 ', R 5 'And R 6 'Be hydrogen, R 7 'It is halogen;
D) R 5 ', R 6 'And R 7 'Be hydrogen, R 4 'Be CF 3
E) R 4 ', R 5 'And R 7 'Be hydrogen, R 6 'Be CF 3With
F) R 4 ', R 5 'And R 6 'Be hydrogen, R 7 'Is CF 3
III. definition
Unless have describedly in addition, be defined as to give a definition and terminological interpretation.
The scope of listed group, substituting group and derivative, occurrence and representative value only are used for illustrative purposes, never get rid of the value of other qualification that is used for described group, substituting group and derivative or the value in institute's limited range.No matter where this paper has mentioned scope, this scope independently comprises each member (member) of this scope.As exemplary embodiment, when mentioning C 1-6During-alkyl, these clauses and subclauses independently comprise C 1-alkyl, C 2-alkyl, C 3-alkyl, C 4-alkyl, C 5-alkyl and C 6-alkyl.
" halogen " is fluorine, chlorine, bromine or iodine.
" alkyl ", " alkoxyl group ", " thiazolinyl ", " alkynyl " and etc. comprise straight chain and branched group.But separate base only comprises straight chain group as " propyl group ", and branched chain isomer is as " sec.-propyl " then name in addition.
Unless have describedly in addition, " alkyl " used herein is saturated straight chain, side chain or cyclic primary, the second month in a season or tertiary hydrocarbon, for example C 1-10And specifically comprise methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, butyl, isobutyl-, t-butyl, amyl group, cyclopentyl, isopentyl, neo-pentyl, hexyl, isohexyl, cyclohexyl, cyclohexyl methyl, 3-methyl amyl, 2,2-dimethylbutyl and 2, the 3-dimethylbutyl.When the context of this article allows alkyl to be substituted; the described part that is used for substituted alkyl includes but not limited to hydroxyl; amino; alkylamino; arylamino; alkoxyl group; aryloxy; aryl; heterocyclic radical; halogen; carboxyl; acyl group; acyloxy; amido; nitro; cyano group; sulfonic acid; sulfuric acid; phosphonic acids; phosphoric acid salt or phosphonate; on demand can be protected or not protected; known as those skilled in the art; and as for example; Greene etc. are at " protecting group of organic synthesis " (Protective Groups in Organic Synthesis; John Wiley and Sons; the third edition, 1999) told about in.
Unless have describedly in addition, term used herein " low alkyl group " comprises C 1-4Saturated straight chain, side chain or the cycloalkyl (for example, cyclopropyl) when suitable comprise replacing and unsubstituted form.Unless the application particularly points out, when alkyl was suitable part (moiety), low alkyl group was typical.Similarly, when alkyl or low alkyl group were suitable part, unsubstituted alkyl or low alkyl group were typical.
Term " thiazolinyl " and " alkynyl " are meant at least one saturated C-C key by two keys or the displaced moieties of triple bond, comprise replacement and unsubstituted form.Like this, C 2-6Thiazolinyl can be vinyl, allyl group, 1-propenyl, 2-propenyl, 1-butylene base, crotyl, 3-butenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl.Similarly, C 2-6Alkynyl can be ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base or 5-hexin base.
Term " alkylidene group " be meant general formula-(CH 2) n-shown in the saturated straight chain divalent alkyl, wherein " n " can be the arbitrary integer of 1-10.
Exception unless otherwise indicated, in this article, " aryl " is meant any stable monocycle, dicyclo or three ring carbocyclic rings, 8 members at the most in each ring, wherein, at least one ring is the defined aromatic ring of Huckel 4n+2 rule.The example of aromatic ring system comprises phenyl, naphthyl, tetralyl and xenyl.Described aryl can be replaced by one or more parts; described part includes but not limited to hydroxyl; amino; alkylamino; arylamino; alkoxyl group; aryloxy; alkyl; heterocyclic radical; halogen; carboxyl; acyl group; acyloxy; amido; nitro; cyano group; the semi-annular jade pendant amido; sulfonic group; sulfuric acid; phosphonic acids; phosphoric acid salt or phosphonate; on demand can be protected or not protected; known as those skilled in the art; and as for example; Greene etc. are at " protecting group of organic synthesis " (John Wiley and Sons; the third edition, 1999) told about in.
Exception unless otherwise indicated, in this article, term " heterocycle " or " heterocyclic " be meant stable 5 yuan to 7 yuan monocycles or 8 yuan of stable heterocycles to 11 yuan of dicyclos, it can be saturated or unsaturated, comprise heteroaryl, and form by carbon atom and 1-4 heteroatoms, described heteroatoms includes but not limited to O, S, N and P; Wherein, described nitrogen-atoms and sulfur heteroatom can be chosen wantonly oxidized, and/or described nitrogen heteroatom is by quaternized, and comprise bicyclic radicals arbitrarily, and wherein, any above-mentioned heterocycle can condense into phenyl ring.Described heterocycle can connect in any heteroatom or carbon atom place, forms stable structure.If need the partially or completely hydrogenation of described hetero-aromatic ring.For example, can use dihydropyridine to replace pyridine.If necessary or when needing, can protect function oxygen and nitrogen groups on the heteroaryl.The appropriate protection group that is used for oxygen or nitrogen comprises trityl, alkyl, methylsulfonyl, p-toluenesulfonyl or acyl group such as the ethanoyl and the propionyl of trimethyl silyl, dimethyl hexyl silyl, t-butyldimethylsilyl, tertiary butyl xenyl silyl, trityl, replacement.
The non-limitative example of heteroaryl and heterocyclic radical comprises furyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, piperidyl (piperidinyl), piperazinyl (piperazinyl), thienyl, pyrryl, pyrrolinyl, pyrrolidyl, imidazolyl, tetrazyl, triazolyl, triazinyl, thiazinyl, oxazolyl, purine radicals, carbazyl, quinolyl, pyrazolyl, morpholinyl, benzimidazolyl-etc.Heteroaromatic and heterocyclic moiety can be chosen replacement wantonly arbitrarily; as above described during at aryl; comprise and have one or more hydroxyls; amino; alkylamino; arylamino; alkoxyl group; aryloxy; alkyl; heterocyclic radical; halogen; carboxyl; acyl group; acyloxy; amido; nitro; cyano group; sulfonic group; sulfuric acid; phosphonic acids; the substituted radical of phosphoric acid salt or phosphonate on demand can be protected or not protected; known as those skilled in the art; and as for example; Greene etc. are at " protecting group of organic synthesis " (John Wiley and Sons; the third edition, 1999) told about in.
Term " acyl group " be meant the compound shown in the formula " RC (O)-", wherein R be replace or unsubstituted alkyl or aryl, as described herein.
Term " carboxyl " be meant the compound shown in the formula " RCOOH ", wherein R be replace or unsubstituted alkyl or aryl, as described herein.
Unless have in addition described, term used herein " aralkyl " be meant by abovementioned alkyl and be connected to above-mentioned aryl on the molecule.
Unless have in addition described, term used herein " alkaryl " be meant by above-mentioned aryl and be connected to abovementioned alkyl on the molecule.
Unless have in addition described, term used herein " alkoxyl group " be meant the part shown in the structure " O-alkyl ", wherein alkyl is as hereinbefore defined.
Unless have in addition described, term used herein " amino " be meant structure " NR 2" shown in part, comprise optional primary amine, secondary amine and the tertiary amine that is replaced by alkyl, aryl, heterocyclic radical and/or alkylsulfonyl.Like this, R 2Can represent two hydrogen, two moieties or a hydrogen or a moieties.
Unless have in addition described, term used herein " amido (amido) " be meant structure " C (O) NR 2" shown in part, R wherein 2Be H, alkyl, aryl, acyl group, heterocyclic radical and/or alkylsulfonyl.
In the literary composition, " amino acid " or " amino-acid residue " is to be the natural amino acid of D or L shaped formula or its some parts (promptly, Ala, Arg, Asn, Asp, Cys, GIu, GIn, GIy, His, HyI, Hyp, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Tip, Tyr and VaI), or for example having valent alpha-non-natural amino acid of one or more free time, tertiary butyl glycine, ornithine, urobenzoic acid and phosphorus are for Threonine (phosphothreonine).Other alpha-non-natural amino acid is formula " NH 2(CH 2) yCOOH " shown in those, wherein, y is 2-12, comprises amino-alkane acid, as epsilon-amino caproic acid (H 2N-(CH 2) 5-COOH).Described term also comprises the natural and alpha-non-natural amino acid with amino protecting group, described amino protecting group such as acyl group, trifluoroacetyl group and benzyloxycarbonyl; And carboxylic moiety with protecting group (as C 1-6Alkyl, phenyl or benzyl ester and acid amides, and protecting group well known by persons skilled in the art) protection natural and alpha-non-natural amino acid.Comprise under all situations of one or more chiral centres at natural and alpha-non-natural amino acid, this paper comprises all possible three-dimensional chemical configuration, comprises " D " and " L " form and their mixture, comprises racemic mixture.
In this article, term " quaternary amine " comprise quaternary ammonium salt with positive charge nitrogen-atoms.Their basic nitrogens (basic nitrogen) by compound of interest and suitable quaternizing agent such as the reaction between methyl-iodide or the benzyl iodide form.Follow the suitable counter of quaternary amine to comprise acetate moiety, trifluoroacetic acid root, chlorion, bromide anion and iodide ion.
In the literary composition, term " the N-oxide compound " be meant that one or more nitrogen-atoms in the The compounds of this invention are by the state of Sauerstoffatom oxidation.
In the literary composition, " retrovirus " comprises the virus of any expression reversed transcriptive enzyme.Retroviral example includes but not limited to: HTV-1, HTV-2, HTLV-I, HTLV-II, FeLV, FIV, SIV, AMV, MMTV and MoMuLV.
In the literary composition, " reversed transcriptive enzyme " or " RT " refers to have the enzyme that the non-nucleosides that is similar to HIV-1RT suppresses binding site, on these enzymes also will in conjunction with the compound binding pocket bonded part of The compounds of this invention.The active a kind of tolerance of RT is virus replication.A kind of measuring method of HIV-1 virus replication is to utilize the automatic assay method of MTT, and this method was described in this manual.Another kind of measuring method is a p24 cAg enzyme immunoassay, for example, and available from Coulter Corporation/Immunotech, Inc.
Figure G05839218720070518D000941
(Westbrook, assay method MI).The active method of another kind of measure R T is to measure Recombinant HIV-I reverse transcriptase activity, for example adopts available from Amersham (Arlington Heights, Quan-T-RT IL) TMThe mensuration system, this system also is described in Bosworth etc., Nature, 1989,341:167-168.
In the literary composition, the compound of " HIV inhibiting (HIV) duplicates " refers to that (for example cell by being infected by HIV) can make the amount of HIV-1 compare the compound that untreated control reduces when contacting with HIV-1.Can for example measure the inhibition that HIV-1 is duplicated by being proficient in any method known to those skilled in the art by above-mentioned p24 assay method.
The reagent that in synthetic schemes, is called as " mCPBA " be between-the chloro-benzoyl hydroperoxide.
Term " is remedied therapy " and referred in the text can be with any scheme administered compound after patient's initial treatment plan failure.
In the literary composition, term " host " refers to the unicellular or multicellular organism that virus can be duplicated therein.Therefore, " host " comprises clone, Mammals, and people preferably.Perhaps, host's portability part HIV genome, described genomic duplicate or function can be changed by The compounds of this invention.The cell that the term host especially refers to infect, by all or part of HIV genome cells transfected and Mammals, especially comprise chimpanzee and people's primates.In most of Mammalss of the present invention were used, described host was a human patients.Yet the present invention obviously also can be used for the animal doctor to use, as is used for chimpanzee.
IV. pharmacy acceptable salt, prodrug, steric isomer and tautomer
The active compound that gives as salt or prodrug can directly or indirectly provide parent compound after giving acceptor, perhaps they itself promptly demonstrate activity.Nonrestrictive example comprises pharmacy acceptable salt, perhaps is called " physiologically acceptable salt ".In addition, its biological activity can be influenced, its active parent compound that surpasses can be made in some cases the modification of compound.Can prepare the salt of compound or prodrug forms estimating this activity, and detect its antiviral activity by method described here or other method known to the skilled of being proficient in the NNRTI field.
Phrase " pharmacy acceptable salt or prodrug " is used for describing any pharmaceutically acceptable form (as the salt of ester, acid amides, ester, the salt or the relevant group of acid amides) of certain compound in whole specification sheets, they can provide active compound of the present invention after giving the patient.Term " steric isomer " and " tautomer " comprise any possible stereoisomeric forms in any ratio and the tautomeric form of The compounds of this invention here, and they quaternary amine, salt, solvate, prodrug, derivative and N-oxide form.When general formula (I) and compound (II) contain one or more chiral centre, comprise all possible mapping and diastereomeric form formula.
Term " pharmacy acceptable salt " refers to a kind of state of compound, wherein, described compound carries pharmaceutically acceptable gegenion, and wherein, and described salt keeps here that the required biological activity of institute's compounds identified demonstrates the unwanted toxic effect of minimum simultaneously.This salt be The compounds of this invention nontoxic, the treatment on useful form.Kept the required biological activity of the compound that is comprised here and demonstrate minimum or do not have any salt of unwanted effect or toxic effect all to be included.Pharmacy acceptable salt comprises those salt derived from pharmaceutically acceptable organic or inorganic bronsted lowry acids and bases bronsted lowry.Also can use non-pharmaceutically acceptable acid or alkali, for example be used for synthetic and/or purifying compound of interest.Therefore, all " salt " are all included.
The nonrestrictive example of suitable salt comprises those derived from mineral acid and organic acid salt, described mineral acid for example, salt solution, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, heavy carbonic, carbonic acid; Described organic acid for example, formic acid, acetate, oxalic acid, tartrate, succsinic acid, oxysuccinic acid, propanedioic acid, xitix, citric acid, phenylformic acid, tannic acid, palmitinic acid, Lalgine, polyglutamic acid, tosic acid, methanesulfonic, naphthene sulfonic acid, naphthalene disulfonic acid, α-Tong Wuersuan, α-Phosphoric acid glycerol esters and polygalacturonic acid.Suitable salt comprises the salt derived from basic metal such as lithium, potassium and sodium; The salt of other alkali of knowing derived from the salt of alkaline-earth metal such as magnesium and derived from the technician who is proficient in pharmacy field.Other suitable salt comprises those salt derived from metallic cation such as zinc, bismuth, barium or aluminium, or contains the positively charged ion that formed by amine such as ammonium, NN-Dibenzylethylenediamine, D-glycosamine, the salt of triethylammonium tetrakis or quadrol.In addition, suitable salt comprises those salt derived from the combination of bronsted lowry acids and bases bronsted lowry, as the tannic acid zinc salt.
Pharmaceutically acceptable prodrug refers to form at host's intracellular metabolite (i.e. for example hydrolysis or oxidation) compound of The compounds of this invention.The exemplary of prodrug is included in the compound that has the biological instability protecting group on the funtion part of active compound.Prodrug comprises can be oxidized, reduction, ammonification, deaminizatingization, dehydroxylation, hydrolysis, dehydration, alkylation, dealkylation, acidylate, deacylation, phosphorylation and/or dephosphorylation and form the compound of active compound.
Compound of the present invention has the antiviral activity at retrovirus especially HIV, perhaps can be metabolized to have this active compound.
Any oxo-pyrimidine compound described here can be used as prodrug and gives the characteristic that is improved activity, bioavailability, stability or change oxo-pyrimidine.Known many prodrug parts, heteroatomic acidylate, alkylation or other lipotropy are modified the stability that will improve compound usually on oxygen-pyrimidine.Can replace that the substituent example of one or more hydrogen includes but not limited on the heterocycle: alkyl, aryl, steroid, carbohydrate comprise carbohydrate, 1,2-DG, phosphatide, phosphatidylcholine, phosphorylcholine and/or ethanol.Any can being used in combination to obtain required effect in these with disclosed oxo-pyrimidine compound.
V. methods of treatment
In the embodiment, provide the method for the treatment of or preventing HIV to infect in the host, described method comprises the host of these needs 3-phosphoric acid benzazolyl compounds.In a specific embodiments, this compound is in oral, parenteral, the intestines, intravenously, intracutaneous, subcutaneous, in skin, transdermal, nose, local or give by anapnotherapy.Described compound can give to be diagnosed as the host that HIV infects by the viral load of measuring host's blood or tissue.In other embodiments, can diagnose the host by the anti-HIV antibody titer of measuring in the blood.In other embodiments, can give compound in the host, to reduce or to prevent the symptom of AIDS (acquired immunodeficiency syndrome).The host that compound of the present invention can be had again in another embodiment, the infected by HIV risk.
In another embodiment, described active compound demonstrates the activity of inverase patience form, and the antiviral therapy of therefore ratifying relatively at present demonstrates the intersection patience of reduction.Phrase " to the activity of HIV medicine patience form " refers to that compound (or its prodrug or pharmacy acceptable salt) has activity to mutant strain, its EC 50Concentration is less than about 50,25,10 or 1 micromole.In one embodiment, non-nucleoside reverse transcriptase inhibitors (NNRTI) is to the EC of HIV mutant strain 50(representing with volumetric molar concentration) is less than about 5,2.5,1 or 0.1 micromole.In a non-limiting embodiments, the HIV mutant strain has the reversed transcriptive enzyme sudden change on Methionin 103 → l-asparagine and/or tyrosine 181 → halfcystine.
Can be according to the ability of standard screening method prediction 3-phosphoric acid indoles at the vitro inhibition reverse transcriptase activity.By the described assay method of this specification sheets or other attested assay method assessing compound known to the skilled of being proficient in anti-HIV compound field to determine the activity profile of specific compound.The EC of compound 50Usually less than 10-15 μ M.
In one embodiment, measure the effect of 3-phosphoric acid indoles by HIV specific enzymes linked immunosorbent assay method p24ELISA.Efficacy of drugs be expressed as HIV p24 antigen this fast and the inhibition percentage ratio in the sensitive assay method.Be used for the relevant embodiment of special test, the effect of anti-HIV compound is by " have a liking for bacterial plaque and reduce test " decision, this experimental measurement is had a liking for the necessary compound concentrations of bacterial plaque number in external minimizing virus, according to the method for specifically listing in the literary composition, measurement be that 50% inhibition concentration (is the EC of compound 50).In some embodiments, compound is at external EC 50Less than 15, or less than 10 micromoles to the nmole order of magnitude.
VI. make up or rotational therapy
In some embodiment, 3-phosphoric acid benzazolyl compounds and one or more other anti-retroviral virus or anti-HIV preparation make up and/or alternately give.In one embodiment, make up and/or alternately give two or more this medicament and duplicate the generation synergistic effect for suppressing HIV.In other embodiments, make up and/or alternately give two or more this medicament and duplicate the generation additive effect for suppressing HIV.
In combination treatment, give two or more medicaments of effective dose simultaneously, and in rotational therapy, give every kind of medicament of effective dose continuously.Dosage will depend on absorption, inactivation and the metabolic rate of medicine and be proficient in other factors known to those skilled in the art.Dose value will change according to the seriousness for the treatment of relief of symptoms.For any particular individual, will regulate particular dosage regimen in time and arrange to satisfy the professional judgement of individual need and individual medication or supervision medication.
Medicine patience is the most normal owing to the encoding gene sudden change that is used for virus replication round-robin enzyme takes place, and specifically is pol gene or proteinase gene for HIV.Verified, with second kind, if possible the third, antiviral compound associating or alternately give the effect that certain compound can prolong, strengthens or recover the anti-HIV infection of medicine, described antiviral compound inductive suddenlys change and is different from mainly drug-induced sudden change.This drug regimen has reduced the possibility and any relevant toxic action that any single medicine is produced patience simultaneously.Perhaps, can change in the pharmacokinetics, body of medicine by this combination or rotational therapy and decompose or other parameter.Required dosage when for example, using drug regimen can make the dosage of single medicine in the combination be lower than this medicine of independent use.Equally, when with the medicament mixed of target virus life cycle different steps, just there is the possibility that prolongs drug effect.In addition, use the combination of medicine can reduce or eliminate the unwanted side effect of a kind of medicine and still can produce antiviral activity simultaneously.Usually, combination treatment is better than rotational therapy, because combination treatment can be simultaneously to the multiple pressure of virus induction.
The second kind of anti-virus formulation that is used for the treatment of HIV can be, for example, proteinase inhibitor, HIV-integrase inhibitor, CFI or reverse transcriptase inhibitors (" RTI "), the latter can be synthetic nucleoside reverse transcriptase inhibitor (" NRTI ") or non-nucleoside reverse transcriptase inhibitors (" NNRTI ").In other embodiments, second kind or the third compound can be pyrophosphate analogs or fusion-binding inhibitors.Collected the tabulation visible Schinazi of patience data in the external and body of some antiviral compound etc., " sudden change of the reverse transcription virus gene relevant " (Mutations in retroviral genes associatedwith drug resistance) with medicine patience, International Antiviral News, 1997,5 (8).
In certain embodiments, described benzazolyl compounds makes up with following compound and/or alternately gives: FTC (2 ', 3 '-two deoxidations-3 '-sulfo--5-fluorine cytidine); 141W94 (amprenavir, Glaxo Wellcome, Inc.); Viramune (nevirapine); Rescriptor (Delavirdine); DMP-266 (efavirenz); DDI (2 ', 3 '-dideoxyinosine); 3TC (3 '-sulfo--2 ', 3 '-dideoxycytidine); DDC (2 ', 3 '-dideoxycytidine), Abacavir (1592U89), promptly (1S, 4R)-4-[(2-amino-6-cyclopropyl-amino)-9H-purine-9-yl]-2-cyclopentenes-1-methyl alcohol succinate, tenofovir DF (Viread), D4T, or AZT.
The example of other anti-virus formulation that can make up with compound described here and/or be used alternatingly includes but not limited to: phosphorylcholine calcium; Carbovir; Acycloguanosine; Interferon, rabbit; Fusion inhibitor such as enfuvirtide; With enantiomerically pure beta-d-dioxolane nucleosides with selective such as β-D-dioxolanyl guanine (DXG), β-D-dioxolanyl-2,6-diaminopurine (DAPD) and β-D-dioxolanyl-6-chloropurine (ACP).Does operable Interferon, rabbit comprise the Interferon Alpha-2b product of Schering-Plough, Intron? A and PEG-Intron TMAnd the Co-Pegasus of HoffmanLa Roche and PEGASYS (PEGization Intederon Alpha-2a).The combination that can give 3-phosphoric acid indoles comprises Epzicom (ABC+3TC), Trizivir (ABC+3TC+AZT), Truvada (FTC+Viread) and Combivir (AZT+3TC).
The example of the proteinase inhibitor that can make up with compound described here and/or alternately give includes but not limited to: indinavir ({ 1 (1S, 2R), 5 (S) }-2,3,5-three '-deoxy-ns-(2,3-dihydro-2-hydroxyl-1H-indenes-1-yl)-and 5-[2-[[(1, the 1-dimethyl ethyl) amino] carbonyl]-4-(3-pyridylmethyl)-1-piperazinyl]-2-(phenyl methyl)-D-is red-valeramide vitriol; Merck ﹠amp; Co., Inc.); Nelfinavir (Agouron); Ritonavir (Abbott Labs), Saquinavir (Roche); Amprenavir; Atazanavir; Fosamprenavir; Kaletra; And DMP-450{[4R-4 (r-a, 5-a, 6-b, 7-6)-six hydrogen-5,6-two (hydroxyl)-1,3-two (3-amino)-phenyl] methyl-4,7-two (phenyl methyl)-2H-1,3-diazepine-2-ketone }-dimethanesulfonate (TrianglePharmaceuticals, Inc.).
Can or comprise alternately for other compound that is strengthened its ntiviral characteristic with the Phenylindole combination: (1S, 4R)-4-[2-amino-6-cyclopropyl-amino-9H-purine-9-yl]-2-cyclopentenes-1-methyl alcohol succinate (1592U89, the Carbovir analogue is from GlaxoSmithKline); BILA 1906 (N-{1S-[[[3-[2S-{ (1, the 1-dimethyl ethyl) amino] carbonyl }-4R-] the 3-pyridylmethyl) sulfo-]-piperidino]-2R-hydroxyl-1S-phenyl methyl) propyl group]-amino] carbonyl]-the 2-methyl-propyl }-2-quinoline formyl amine) (BioMega/Boehringer Ingelheim); BILA 2185 (N-(1, the 1-dimethyl ethyl)-1-[2S-[[[2-2,6-dimethyl-phenoxy group]-1-oxygen ethyl] amino]-2R-hydroxy-4-phenyl butyl] 4R-pyridylthio-2-piperidines-methane amide) (Bio Mega/Boehringer Ingelheim); BM+51.0836 (triazole different-dihydroindolone (triazoloiso-indolinone) derivative) and BMS 186,318 (aminodiol deutero-HIV-1 proteinase inhibitor) (Bristol-Myers Squibb); D4API (9-[2,5-dihydro-5-(phosphono methoxyl group)-2-furyl]-VITAMIN B4) (Gilead); HBY097 (S-4-isopropoxy carbonyl-6-methoxyl group-3-[methylthio group-methyl]-3,4-Er Qing quinoxaline-2 (1H)-thioketones); HEPT (1-[(2-hydroxyl-oxyethyl group) methyl] the 6-[thiophenyl]-thymus pyrimidine); KNI-272 (contain (2S, 3S)-3-amino-butyro-tripeptides of 2-hydroxy-4-phenyl); L-697,593 (5-ethyl-6-methyl-3-(2-phthalimido-ethyl) pyridines-2 (1H)-ketone); L-732,524 (hydroxyl-aminopentane acid amides HIV-1, proteinase inhibitor) (Merck ﹠amp; Co.); L-697,661 (3-{[(-4,7-two chloro-1,3-benzoxazole-2-yl) methyl] amino }-5-ethyl-6-methyl-pyridine-2 (1H)-ketone); L-FDDC ((-)-β-1-5-fluoro-2 ', 3 '-dideoxycytidine); L-FDOC ((-)-β-1-5-fluoro-dioxolane cytosine(Cyt)); PFA (phosphonoformate; " phosphorylcholine calcium "; Astra); PMEA (9-(2-phosphonium mesitoyl methoxy ethyl) VITAMIN B4) (Gilead); PMPA ((R)-9-(2-phosphonium mesitoyl methoxy-propyl group)-VITAMIN B4) (Gilead); Ro 31-8959 (oxyethylamine deutero-HIV-1 proteinase inhibitor) (Roche); RPI-3121 (peptide acyl proteinase inhibitor, 1-[(3S)-3-(n-α-benzyloxy-carbonyl)-1-asparginyl)-amino-2-hydroxy-4-phenyl butyryl]-the n-tertiary butyl-1-proline(Pro) acid amides); 2720 (6-chloro-3,3-dimethyl-4-(pseudoallyl oxygen base carbonyl)-3,4-dihydro-quinoxalines-2 (1H) thioketones); SC-52151 (hydroxyethyl urea isostere proteinase inhibitor) (G.D.Searle); SC-55389A (hydroxyethyl-urea isostere proteinase inhibitor (G.D.Searle); TIBO R82150 ((+)-(5S)-4,5,6,7-tetrahydrochysene-5-methyl-6-(3-methyl-2-butene base)-imidazo-[4,5,1-jk]-[1,4]-benzodiazepines-2 (1H)-thioketones) (Janssen Pharmaceuticals); TIBO 82913 ((+)-(5S)-4,5,6,7-tetrahydrochysene-9-chloro-5-methyl-6-(3-methyl-2-butene base) imidazo [4,5,1-jk]-[1,4]-benzo-diazepine-2 (1H)-thioketones (JanssenPharmaceuticals); TSAO-m3T ([2 ', 5 '-two-O-(t-butyldimethylsilyl)-3 '-spiral shell-5 '-(4 '-amino-1 ', 2 '-Evil thiophene-2 ', 2 '-dioxide)]-β-D-penta furyl glycosyl-N3-methyl-thymus pyrimidine); U90152 (1-[3-[(1-methylethyl-amino] the 2-pyridyl]-the 4-[[5-[(methyl sulphonyl)-amino]-1H-indoles-2-yl]-carbonyl]-piperazine); UC (sulfo--carboxanilide derivative) (Uniroyal); UC-781 (N-[4-chloro-3-(3-methyl-2-butene base oxygen base) phenyl]-2-methyl-3-furans carbonyl thioamides); UC-82 (N-[4-chloro-3-(3-methyl-2-butene base oxygen base) phenyl]-2-methyl-3-thiophene carbonyl thioamides); VB 11,328 (hydroxyethyl-sulfonamide proteinase inhibitor) (Vertex/Glaxo Wellcome); XM 323 (ring urea proteinase inhibitor) (Dupont Merck); And Penciclovir.Again in another embodiment, benzazolyl compounds of the present invention and proteinase inhibitor LG 1350 combinations give.
Following medicine has obtained FDA approval or to be ready carrying out or to carry out clinical trial, is used for the treatment of HIV and infects, and therefore, in one embodiment, they can and/or be used alternatingly with compound combination of the present invention.
Figure G05839218720070518D001021
Figure G05839218720070518D001031
Figure G05839218720070518D001051
Can comprise with combination of 3-phosphoric acid indoles and/or the other medicines that are in the clinical trial that are used alternatingly:
The I phase The II phase The III phase
GW5634(GSK) MIV-150(Medivir/Chiron) Tipranavir *(B-I)
RO033-4649(Roche) TMC125(Tibotec) ?
GW640385(GSK/Vertex) TMC114(Tibotec) ?
Elvucitabine(Achillion?Ph.) Aovudine (FLT) (B-I) ?
MIV-210(GSK/Medivir) Racivir(Pharmasset) ?
SPD754(Shire?Pharm.) Reverset(Incyte?Corp.) ?
FP21399(Fuji?Pharm.) AMD070(AnorMed) ?
GW873140(GSK) BMS-488043(BMS) ?
Schering?C/D(417690) PRO?542(Progenics?Pharm) ?
? TAK-220(Takeda) ?
? TNX-355(Tanox) ?
? UK-427,857(Pfizer) ?
Following medicine can be used for treating HIV through the FDA approval to be infected and the AIDS complication, and they can make up with the compound of this ring and/or be used alternatingly.
Trade(brand)name Popular name Purposes Manufacturers's title
?Abelcet，?Ambisome Amphotericin B, ABLC Antimycotic, be used for aspergillosis How tame
?Bactrim，Septra Sulfamethoxazole and trimethoprim Protozoacide antibiotic is used for the treatment of and prevents pneumocystosis How tame
?Biaxin，Klacid Clarithromycin Antibiotic is used for the treatment of and prevents mycobacterium avium Abbott Laboratories
?Cytovene Ganciclovir, DHPG Antiviral, be used for the CMV retinitis Roche
?DaunoXome Mycocet The chemotherapy that is used for Kaposi sarcoma Gilead
?Diflucan Fluconazole Antimycotic, be used for moniliosis, cryptococcal meningitis Pfizer
?Doxil Hydrochloric doxorubicin liposome The chemotherapy that is used for Kaposi sarcoma Ortho?biotech
?Famvir Famciclovir Antiviral, be used for bleb Novartis
?Foscarnet Trisodium phosphonoformate hexahydrate Antiviral, be used for bleb, the CMV retinitis Astra Pharmaceuticals
?Gamimune?N Immunoglobulin (Ig), gamma Globulin, IGIV Reinforced immunological is with prevention children infectation of bacteria Bayer?Biologicals
?Intron?A Interferon Alpha-2b Kaposi sarcoma, third liver Schering
?Marinol Dronabinol The treatment appetite stimulator Roxane?Laboratories
?Megace Magace Treat appetite stimulator, lose weight Bristol?Myers-Squibb
Mepron Atovaquone Protozoacide antibiotic is used for the treatment of and prevents pneumocystosis GlaxoSmithKline
Mycobutin， Ansamycin Mycobutin Mycobacteria antibiotic is used to prevent mycobacterium avium Adria Pharmaceuticals
NebuPent Pentamidine Protozoacide antibiotic is used to prevent pneumocystosis Fujisawa
Neutrexin Trimetrexate and formyl tetrahydrofolic acid Protozoacide antibiotic is used for the treatment of pneumocystosis MedImmune
Panretin?gel 0.1% alitretinoin gel The AIDS Kaposi sarcoma of being correlated with Ligand Pharmaceuticals
Procrit，Epogen Erythropoietin, EPO Treatment and the relevant anaemia of AZT treatment Amgen
Roferon?A Intederon Alpha-2a The Kaposi sarcoma and third liver Roche
Serostim Tethelin rDNA Treatment loses weight Serono
Sporanox Itraconazole Antimycotic, be used for blastomycosis, histoplasmosis, aspergillosis and moniliosis Janssen Pharmaceuticals
Taxol Taxol Kaposi sarcoma Bristol?Myers-Squibb
Valcyte Valganciclovir Antiviral, be used for the CMV retinitis Roche
Vistide West polyfluoro Wei, HPMPC Antiviral, be used for the CMV retinitis Gilead
Vitrasert?implant The ganciclovir inset Antiviral, be used for the CMV retinitis Bausch?&?Lomb
Vitravene intravitreal injectable The Fomivirsen sodium injection Antiviral, be used for the CMV retinitis Isis?Pharmaceuticals
Zithromax Azythromycin Antibiotic is used for mycobacterium avium Pfizer
Some products are continued as treating the new drug (IND) that HIV infects and the clinical study of AIDS complication is used by the FDA approval.Therefore, following medicine can and/or be used alternatingly with compound combination of the present invention.
Trimetrexate is used for the treatment of the AIDS patient's that can not tolerate the standard care form pneumocystosis.
Ganciclovir is used for the treatment of AIDS patient's the cytomegalovirus retinitis.
Pentamidine (pentamidine) aerosol is used to prevent AIDS patient's pneumocystosis.
Erythropoietin is used for the treatment of the relevant anaemia of zidovudine.
Atovaquone is used for the treatment of the AIDS patient who suffers from pneumocystosis, and this patient does not tolerate trimethoprim-sulfamethoxazole or be reactionless.
Mycobutin is used in AIDS patient's prevention mycobacterium avium composite bacteria group microbemia.
Vistide (Vistide) is though be used to suffer from the HIV infected individuals (Hoffmann-La Roche) of recurrent cytomegalovirus (CMV) retinitis of still making progress through treatment.
Serostim, the recombinant human somatropin in Mammals source is used for the treatment of AIDS relevant become thin (Serono Laboratories).
Usually, in rotational therapy, give all ingredients of significant quantity continuously.In combination treatment, give two or more reagent of significant quantity together.The dosage that gives depends on multiple factor, as decomposition, metabolism and excretion rate in the absorption of various medicines, the body and be proficient in other factors known to those skilled in the art.It should be noted that dosage will change according to the seriousness for the treatment of relief of symptoms, the age of accepting the object of medicine, body weight and general health situation.Should be further understood that,, will regulate particular dosage regimen and arrangement in time to the reaction of medicine, the needs of object and the professional judgement of individual medication or supervision medication according to object for any particular individual.The anti-HIV compound comprises that the suitable dose scope of nucleoside derivates (as D4T, DDI and 3TC) or proteinase inhibitor (as nelfinavir and indinavir) can find in scientific literature and " doctor's desk reference " (Physicians ' Desk Reference).The suggested range of relevant The compounds of this invention effective dose just conduct instructs, and is not to limit the scope or application of this invention.
Known combination and alternate scheme can be used for treatment and prevention retroviral infection and other related symptoms, for example, AIDS-related complex (ARC), persistent generalized lymphadenopathy (PGL), acquired immune deficiency syndrome (AIDS) related neural symptom, anti-HIV antibody position and HIV-positive symptom, Kaposi sarcoma, thrombopenic purpura and opportunistic infection.In addition, preventability uses these compounds or preparation with prevention or postpone anti-HIV antibody or HIV-antigen is positive or the progress of the individual clinical disease of contacted HIV.
VII. pharmaceutical composition
Benzazolyl compounds of the present invention can be chosen wantonly with the combination of other other anti-HIV preparation or anti-retroviral virus formulation or alternately, and/or the object that has this to need with pharmaceutically acceptable carrier, thinner or vehicle.In one embodiment, indole derivatives, its salt, prodrug, steric isomer or tautomer that can be by the object significant quantity that gives to be infected by HIV and pharmaceutically acceptable carrier or thinner are treated this object.For the object that multiple medicine is produced patience, can give oxygen-pyrimidine compound individually or with one or more other anti-retroviral viral agents or the combination of anti-HIV preparation.Described active compound can give by any suitable pathways, for example, in oral, parenteral, the intestines, intravenously, intradermal, subcutaneous, in skin, transdermal, nose, local or give by anapnotherapy, and can solid, liquid or gas form give.
Described active compound is contained in pharmaceutically acceptable carrier, thinner or the vehicle, its content is enough to active compound to patient's delivery treatments significant quantity to suppress virus replication in vivo, especially HIV duplicates, and can not cause serious toxic effect in treatment target." amount of suppression " is meant that the amount of activeconstituents is enough to stop virus replication, and virus replication can be measured by method for example described here.
For all symptoms of mentioning here, a kind of dosage range of described benzazolyl compounds is about every kg body weight 0.1-100 milligram every day, perhaps is about every kg body weight 1-75 milligram every day, more typical every kg body weight 1-20 milligram every day that is about.Can calculate the effective dosage ranges of pharmaceutically acceptable derivates according to the weight of the parent indole derivatives that will send.If itself has activity derivative, then the weight of available derivative is estimated effective dose as stated above or by being proficient in other method known to those skilled in the art.
Described compound gives with the unit of any dosage forms usually, and the per unit formulation contains the 7-3000mg that has an appointment, or about 70-1400mg, even more typical about 25-1000mg activeconstituents, but is not limited thereto.For example, oral dosage is about 50-1000mg usually.
Ideally, give activeconstituents to obtain about 0.02-70 μ M, more to be typically the peak plasma concentration of 0.5-10 μ M active compound.For example, this can or inject activeconstituents and realize by intravenous injection 0.1-25% active ingredient solution (randomly being salt brine solution).Should be understood that for any particular patient, should regulate particular dosage regimen at any time to satisfy individual demand.Here the concentration of listing is not the scope or the practice that will limit desired compound as an example just.Activeconstituents can once all give, and perhaps can be divided into many times smaller dose so that give with the variable timed interval.
A kind of form of medication of described active compound is oral.Oral compositions contains inert diluent or edible carrier usually.Can be packaged in them in the gelatine capsule, be pressed into tablet or send with liquid form.For the oral administration administration, can or make solid dispersion or solid solution with described active compound and mixed with excipients, and use with tablet, lozenge or capsular form." solid dispersion " refers to contain the solid state of at least two kinds of components, and wherein a kind of component evenly or unevenly is dispersed in other component." solid solution " refers to contain the solid state of at least two kinds of components, and these components are at chemistry and physically be combined to form uniform product.Solid solution is better than solid dispersion usually, because its easier formation liquor behind contact suitable liquid medium, thereby improve bioavailability of medicament.Compatible wedding agent and/or Adjuvanting material also can be used as the part of this composition in the pharmacy.
The compound that tablet, pill, capsule, lozenge etc. can contain any following composition or have similarity: tackiness agent, as Microcrystalline Cellulose, tragacanth gum or gelatin; Vehicle is as starch or lactose; Decomposition agent is as Lalgine, Primogel or W-Gum; Lubricant is as Magnesium Stearate or hydrogenated vegetable oil; Glidant is as silicon-dioxide; Sweeting agent is as sucrose or asccharin; And seasonings, as peppermint, wintergreen oil or orange seasonings.When unit dosage is capsule, remove the material of any kind that provides above, it also can contain liquid vehicle, as fatty oil.In addition, unit dosage can contain various other materials of the physical form that can modify dose unit, as sugar-coat, shellac or other intestines inner absorbent.
The composition that described benzazolyl compounds can be used as elixir, suspension agent, syrup, cachet, chew gel etc. gives.Remove active compound, syrup can contain sucrose as sweeting agent, sanitas, dyestuff, tinting material and seasonings.
Described active compound or its pharmacy acceptable salt or prodrug can with do not damage required active other active material and mix, or with additional required active material mixing, described material such as microbiotic, antifungal drug, antiphlogiston, proteinase inhibitor or other nucleosides or non-nucleoside anti-virus formulation.Parenteral, intradermal, solution or suspension subcutaneous or local use can contain following component: sterile diluent, as water for injection, salt solution, expressed oil, polyoxyethylene glycol, glycerine, propylene glycol or other synthetic agent; Antiseptic-germicide is as benzylalcohol or ethyl p-hydroxybenzoate; Antioxidant is as xitix or sodium bisulfite; Sequestrant is as ethylenediamine tetraacetic acid (EDTA); Buffer reagent, as acetate, Citrate trianion or phosphoric acid salt, and tonicity contributor, as sodium-chlor or glucose.Parenteral administration contains sterilized water usually, and can be contained in the multiple doses medicine bottle of ampoule, disposable needle tubing or glass or plastics.
If intravenous administration, typical carrier is physiological saline, phosphate-buffered saline (PBS), glucose solution or the mixing solutions that contains g/s.If percutaneous dosing pastes or the ointment administration as using transdermal, relevant carrier can comprise penetration enhancers and/or suitable wetting agent that can injured skin.If required route of administration is to suck or be blown into, composition then of the present invention contains the compound of solution, suspension or the dry powder form that can send by oral cavity and/or nostril.
The liposome suspension that contains the liposome (it has the monoclonal antibody of virus antigen) of target infected cell also is the pharmaceutically acceptable carrier of using always.Can make the liposome suspension according to being proficient in method known to those skilled in the art, for example, these methods are described in United States Patent (USP) the 4th, 522, and No. 811, this patent is included this paper by reference in full in.For example, suitable lipid such as stearyl phosphatidylethanolamine, stearyl phosphatidylcholine, arachidonic acyl (arachadoyl) phosphatidylcholine and cholesterol can be dissolved in organic solvent, evaporating solvent forms the film of dried lipid at vessel surface then.The aqueous solution with active compound or its salt or prodrug adds this container then.The vortex stirred vessel so that matrix material discharge and disperse the lipid aggregation from its sidewall, thereby form the liposome suspension.
VIII. the method for preparing active compound
General scheme
Scheme 1:
Figure G05839218720070518D001121
Scheme 2:
Figure G05839218720070518D001131
Scheme 3:
Figure G05839218720070518D001141
Scheme 4:
Figure G05839218720070518D001142
Scheme 5:
Figure G05839218720070518D001143
Scheme 6:
Scheme 7:
Figure G05839218720070518D001152
Scheme 8:
Figure G05839218720070518D001153
Scheme 9:
Figure G05839218720070518D001161
Scheme 10:
Figure G05839218720070518D001162
Concrete scheme
Scheme 11:N-branch heterocycle
Figure G05839218720070518D001171
Scheme 12: phosphinate (Phosphinate) heterocycle
Figure G05839218720070518D001181
Scheme 13: alkyl/thiazolinyl/alkynyl phosphinate
Figure G05839218720070518D001182
Scheme 14: alkyl sub-phosphonate
Figure G05839218720070518D001183
Scheme 15: alkyl methyl methane amide
Figure G05839218720070518D001191
Scheme 16: phosphonic acids
Figure G05839218720070518D001192
Method
Below be to describe at the method for using in the following proposal.The digital compound that has been designated as mark among the digital corresponding scheme 1-16 of runic.Method A, B, C, D, F, L, N, T, U and AA are known to the skilled for making in this compounds field those, but have been used to prepare particular compound of the present invention.This point also is like this to method H, I, J, M, P, Q, Y, Z, AB and AC.Method E, G, K, O, R, S, W, V and X are the novel methods of preparation The compounds of this invention.
Method A
In penstock, stir bromobenzene 1 (1 equivalent), diethyl phosphite (1.1 equivalent) and triethylamine (1.1 equivalent), described mixture N 2Outgased about 15 minutes.Then, add tetramethyl-palladium (palladiumtetrakis) (0.05 equivalent), described mixture spends the night in about 85 ℃ of stirrings under pressurized conditions.In morning next day, in reactant, add Et 2O, and with described mixture filtration.The evaporation filtrate, crude product is by chromatography (elutriant: the purifying of sherwood oil/EtOAc:8/2-6/4) on silica gel.Perhaps, described reaction can be used 1 of 10 volumes, and the 2-diethoxyethane carries out under the same conditions.
Method B
All reaction reagents (1 equivalent phosphonic acids diethyl ester 2 or phosphonic acids dimethyl esters 19,6 Equivalent Hydrogen sodium oxides and ethanol or methyl alcohol (3ml/mmol)) are stir about 5 hours at room temperature.Then, ethanol evaporation (or methyl alcohol) in a vacuum, described mixture is acidified to pH=1 with the HCl of 2.5N.Described then mixture is saturated with NaCl, and uses ethyl acetate extraction.The blended organic layer is at Na 2SO 4Last dry, filter and concentrate, make required product 3 or 20.
Method C
At N 2Down, at room temperature about 5 hours of agitate compounds 20 or 3 (1.2 equivalent) and thionyl chloride (3.6 equivalent), methylene dichloride (5ml/mmol) and several dimethyl formamide acid amides.Take out equal portions, and place anhydrous methanol and Et 3Among the N, monitor described reaction.After described reaction was finished, methylene dichloride and thionyl chloride (with the toluene coevaporation) were evaporated in a vacuum, make oily matter, and it is stored in N 2Down.
Method D
Under about 0 ℃, toward aryl phosphine acyl group dichloro 21 (1mL, 6.35mmol) in the solution of anhydrous methylene chloride (25mL), drip ethanol or methyl alcohol (1,12mL, 19.04mmol), add afterwards triethylamine (2,65mL, 19.04mmol).Described reaction mixture is stir about 2 hours at room temperature, uses the solution washing of the HCl (50mL) of 1N then.The water layer dichloromethane extraction.The organic phase of dry mixed, and under reduced pressure, concentrate.Crude product oil is by chromatography (elutriant: C on silica gel 6H 12/ EtOAc6/4) purifying makes arylphosphonic acid dimethyl esters 19 or aryl phenyl phosphonic acids diethyl ester 2.
Method E
At N 2At room temperature, stirred arylphosphonic acid diethyl ester 2 (1 equivalents) and bromo trimethyl silane (10 equivalent) and methylene dichloride (5ml/mmol) about 5 hours down.Evaporate bromo trimethyl silane and methylene dichloride then, make yellow oil.Then, at N 2Under add oxalyl chloride, dimethyl formamide and methylene dichloride, described mixture at room temperature stirs and spends the night, afterwards, evaporation oxalyl chloride and solvent.Stir the oily matter in the dichloromethane solution, and be cooled to about 0 ℃, and at N 2Under add ethanol or methyl alcohol (1,12mL 19.04mmol), drip triethylamine afterwards.Then, described mixture is warming up to room temperature.Evaporating solvent, products therefrom is by chromatography (elutriant: CH on silica gel 2Cl 2/ EtOAc:8/2) purifying makes compound 14.
Method F
At N 2At room temperature, in methylene dichloride (5ml/mmol) solution of the arylphosphonic acid diethyl ester 2 (1 equivalent) that stirs, add bromo trimethyl silane (5 equivalent) down.At room temperature after the stir about 3 hours, evaporating solvent, and add methylene dichloride (5ml/mmol), several dimethyl formamides and oxalyl chloride (2,5eq).This mixture at room temperature stirs and spends the night, and evaporating solvent, makes oily matter.Stir the solution of oily matter (1.2 equivalent) in Anaesthetie Ether (3ml/mmol), and be cooled to-17 ℃ approximately, afterwards, drip anhydrous methanol (1.2 equivalent) and remove component and the triethylamine that secondary adds.The gained mixture is warming up to room temperature, and stir about 1 hour is then at N 2Automatically removing by filter triethylamine salt on the cup (autocup) down.Evaporating solvent makes compound 15.
Method G
At N 2Down, H-BuLi (2.5M in hexane, 1.2 equivalents) is added drop-wise to stir and anhydrous THF (10ml/mmol) solution of the bromo indoles 11 (1 equivalent) of cooling (to-90 ℃ approximately) in.Afterwards solution is maintained at about-90 ℃ and descended about 5 minutes, under uniform temp, suitable chlorine phosphorus phosphine (chorophosphosphorus) reagent 15,4 or diphenyl phosphonyl chloride (1.2 equivalent) are added drop-wise in this solution.Described sluggish is warming up to-40 ℃ approximately (TLC monitoring, elutriant CH 2Cl 2/ ETOAc:9/1).Add entry then.Use ethyl acetate extraction, dry and evaporation makes crude product oily matter, and it makes compound 16,5 or 26 by chromatography purifying on silica gel.
Method H
In penstock, use NH 3About 10 minutes of the compound 5,16,26,28 of saturated stirring of gas and cooling (to about 0 ℃) or 30 methanol solution.Described then mixture stirs down at about 50 ℃ and spends the night, and carries out the TLC monitoring afterwards, and excess of ammonia and methyl alcohol evaporate in a vacuum, and crude product makes methane amide 6,7,27,29 or 31 by chromatography purifying on silica gel.
Method I
Lithium hydroxide (14 equivalent) is joined in the solution of the compound 1 of stirring or 5 tetrahydrofuran (THF) (20ml/mmol) and water (20ml/mmol).Then this mixture at room temperature stirs, and monitors by TLC.If necessary, add normal lithium hydroxide, finish up to described reaction.Evaporate THF then, and add HCL (1N), up to pH1.The water layer ethyl acetate extraction, blended organic phase drying is filtered and concentrated compound 17 or 8 of making under reduced pressure.
Method J
With compound 17 or 8 (1 equivalent) and methylene dichloride (20ml/mmol) or DMF stirring, and add I-hydroxybenzotriazole (1 equivalent), add EDCI (1 equivalent) afterwards, add amine (1 equivalent) afterwards.This mixture at room temperature stirs and spends the night.In morning next day, described mixture washes (to pH=5-6) with water, and the organic layer drying is filtered and concentrated under reduced pressure.Gained oily matter is by chromatography (elutriant: CH on silica gel 2Cl 2/ EtOAc) purifying makes powder 18 or 9.
Method K
In microwave tube, agitate compounds 5 or 6 (1 equivalent) and DMF (5ml/mmol), and add TMSBr (5 equivalent).Under pressurized conditions, under about 60 ℃, this pipe heated about 50 minutes down in microwave radiation (peak power input 100W, CEM video picture).DMF evaporates in a vacuum, and described mixture is put into penstock.Add trimethyl phosphite (4ml/mmol), stir described mixture, and in about 90 ℃ of heated overnight.Then, described mixture cools off in ice-water bath, and drips HCl (1N).Described mixture ethyl acetate extraction, the blended organic layer is with HCl (1N) washing, up to there not being HP (OMe) 2Then carry out drying, filter and concentrate under reduced pressure, make oily matter, gained oily matter makes compound 16 or 7 by chromatography purifying on silica gel.
Method L
At N 2Down, toward stir and DMF (2ml/mmol) solution of the ethylindole-2-carboxylicesters 10 (1 equivalent) of cooling (extremely about 0 ℃) in add NaH (60%, in oily matter, 1.2 equivalents) in batches.When gaseous volatilization stops, adding benzene sulfonyl chloride (1.2 equivalent).Described reaction mixture stir about 1 hour (TLC monitoring, elutriant: methylene dichloride); Carefully add less water then, and evaporation DMF.The crude product residue is dissolved in the ethyl acetate, and water and salt water washing.Dry afterwards, and evaporating solvent, compound is by chromatography (elutriant: C on silica gel 6H 12/ EtOAc:9/1-7/3) purifying makes 1-phenyl sulfonyl Ethyl indole-2-carboxylate.
At N 2In the 1-phenyl sulfonyl Ethyl indole-2-carboxylate's (1 equivalent) who stirs DMF (2.5ml/mmol) solution, add the solution of bromine (4 equivalent) in DMF (0.5ml/mmol) down.This reaction mixture is stir about 4 hours at room temperature, adds entry afterwards, and described mixture is with methylene dichloride (* 3) extraction.Organic layer Na 2SO 5The saturated solution washing, dry and evaporation makes the crude product yellow oil.By chromatography (elutriant: C on silica gel 6H 12/ EtOAc:9/1) purifying makes 3-bromination indoles 11.
Method M
In penstock, under microwave radiation, stir and heated 5 or 16 (1 equivalents), vinyl cyanide (10 equivalent), acid chloride (20%mol), triethylamine (1 equivalent) and three-neighbour-tolylphosphine (equivalent) mixture in the acetonitrile (30mL/mmol) that outgases about 45 minutes.Then, add entry, the water layer dichloromethane extraction.The organic layer of dry mixed, concentrate and by chromatography on silica gel (elutriant: the purifying of sherwood oil/EtOAc:8/2), make compound 32, be the mixture (separating) of enantiomorph E and Z by preparation HPLC.
Method N
With bromobenzene 1 (1 equivalent), dimethyl formamide (1ml/mmol), triethylamine (3 equivalent) and aniline salt *(1.25 equivalent) is placed in the penstock, and uses N 2Outgased about 15 minutes.Add the tetramethyl-palladium then, this mixture spends the night in about 85 ℃ of stirrings, and evaporating solvent adds entry afterwards, reaches pH=and is about 5-6.Described mixture NaHCO 3Alkalization extracts with Anaesthetie Ether then up to pH8.Water layer up to pH=1, and is used ethyl acetate extraction with HCl (1N) acidifying.The organic layer of dry mixed filters and concentrates under reduced pressure, makes compound 14.
Aniline salt according to Montchamp etc. (J.Am.Chem.Soc, 2001,123,510-511) program described in is synthetic.
Method O
At N 2Adjacent quanmethyl silicate (1.2 equivalent) is added in toluene (4ml/mmol) solution of the compound 14 (1.2 equivalent) that stirs down.This mixture heating up refluxed about 1.5 hours, was cooled to room temperature then.Then, adding triethylamine (3.3 equivalent), bromo indoles 11 (1 equivalent) and tetramethyl-palladium (0.05 equivalent) before, described mixture N 2The degassing.Described mixture stirs a weekend (about 48 hours) at about 100 ℃, and afterwards, described reactant is cooled to room temperature, and adds entry, and making pH is about 8-9.Then, described mixture ethyl acetate extraction, organic phase saturated KHSO through NaCl 4(1N) washing.Dry then, filter and under reduced pressure, concentrate, make oily matter, it is by chromatography (elutriant: CH on silica gel 2Cl 2/ MeOH) purifying makes compound 12.
Method P
At N 2At room temperature, in methyl alcohol (25ml/mmol) solution of the compound 12 (1 equivalent) that stirs, divide several parts to add trimethyl silyl diazo methane (13 equivalent) down.This mixture stirs and spends the night, and afterwards, adds entry, and evaporation under reduced pressure methyl alcohol.Then, add NaHCO 3, up to pH8, described mixture ethyl acetate extraction.Dry organic phase is filtered and is concentrated under reduced pressure.Crude product is by chromatography (elutriant: C on silica gel 6H 12/ EtOAc) purifying makes compound 16.
Method Q
At room temperature, under agitation condition, compound 18 is dissolved in chloroform (or CH 2Cl 2) in; Add the m-chloroperoxybenzoic acid, described reactant stirs spend the night (about 15 hours).Described then mixture dilutes with methylene dichloride, and with saturated K 2CO 3/ H 2O (1/3) mixture extraction.Water layer dichloromethane extraction three times.The blended organic layer is at Na 2SO 4Last dry, filter and under reduced pressure, concentrate (TLC: methylene chloride=9/1).Crude product makes compound 22 by chromatography purifying on silica gel.
Method R
In the microwave seal pipe, compound 11 (1 equivalent) and 23 (1.1 equivalents) are joined in toluene (8ml/mmol) and the triethylamine (3.3 equivalent), and use N 2Outgased about 10 minutes.Add Pd (PPh then 3) 2, under about 120 ℃, this pipe heated about 30 minutes down in microwave radiation (peak power input 200W, CEM display unit) under pressurized conditions.Described reaction is monitored with TLC, if necessary, about 30 minutes of this pipe heating.Evaporating solvent, crude product is by chromatography (elutriant: C on silica gel 6H 12/ EtOAc:8/2) purifying makes compound 5.
Method S
In the microwave seal pipe, compound 11 (1 equivalent) and 24 (2 equivalents) are joined in the toluene (8ml/mmol), use N then 2Outgased about 10 minutes.Then, add about 20% Pd (OAc) 2, this pipe is in pressurized conditions, about 150 ℃, microwave radiation (peak power input 200W, CEM display unit) about 45 minutes down.Described reaction is monitored by TLC, if having any raw material, about 45 minutes of 170 ℃ of following reheat of this Guan Zaiyue.Then, add HCl (1N) (8ml/mmol), the solution ethyl acetate extraction.Blended organic layer drying is filtered and is concentrated under reduced pressure.(elutriant: sherwood oil/EtOAc:1/1) purifying makes compound 5 or 16 to crude product on silica gel by chromatography.
Perhaps, described being reflected at carried out in dimethylbenzene under about 150 ℃ about 5 hours.
Method T
At room temperature, pyridine (1 equivalent) is carefully joined in the solution of alkyl chloroformate (1 equivalent) and the vigorous stirring of aryl phosphate ester (1 equivalent) in methylene dichloride (2ml/mmol).In case stop boiling, described solution refluxed about 15 minutes, was cooled to room temperature then.Pour solution into 0.1M hydrochloric acid (1ml/mmol), and separate organic layer.Wash with water afterwards, and at Na 2SO 4Last dry, described solvent is removed in a vacuum, makes compound 23.
Method U
At N 2Under the atmosphere, under about 50 ℃, alkyl or aryl bromide (0.15mol) is added drop-wise in the mixture of magnesium (3.6g) and anhydrous tetrahydro furan (40mL).After the adding, described reaction mixture finished described reaction at about 50 ℃ of following restir 1-2 hours.Then at N 2In the atmosphere, under 40-50 ℃, described mixture is added drop-wise in the solution of triethyl-phosphite (0.1mol) and THF (25mL), and about 50 ℃ of following stir abouts 3 hours.Except that after desolvating, crude product distills from semisolid residue in a vacuum, makes compound 24 under reduced pressure.
Method V
In penstock, at N 2Down, under about 90 ℃, heating compound 6 or 7 in toluene (10ml/mmol) (1 equivalent) and Lawesson reagent (4 equivalent).Described reaction is monitored by TLC, and continues heating up to there not being raw material (about 5.5 hours).Filter crude product in solution, and with the filtrate evaporate to dryness, and by chromatography purifying on silica gel make compound 25 and compound 25 '.
Method W
At N 2In bromo indoles 11 (1 equivalent) solution of stirring and cooling (to-90 ℃ approximately), drip n-Butyl Lithium (1.2 equivalent) down.After about 10 minutes, drip the phosphniline acyl group dichloro 21 (1.1 equivalent) in tetrahydrofuran (THF) (15ml/mmol) under about-70 ℃ temperature, described then temperature rises to-90 ℃ approximately, and keeps about 15 minutes.Add methylmagnesium-bromide (1.1 equivalent) subsequently afterwards, described mixture is warming up to-40 ℃ approximately, kept about 1 hour, after the water quenching, use ethyl acetate extraction, use dichloromethane extraction then.Organic layer is at Na 2SO 4Last dry, filter and under reduced pressure, concentrate.Crude product is by chromatography (elutriant: CH on silica gel 2Cl 2/ AcOEt:9/1-7/3) purifying makes compound 28.
Method X
In Anaesthetie Ether (1.5ml/mmol) solution of the dichloro-phenyl phosphate 21 (1 equivalent) of stirring that dimethylamine (1 equivalent) is added drop-wise to and cooling (to-55 ℃ approximately).Then, add triethylamine (1 equivalent), described mixture is warming up to room temperature.Then, filter described mixture, and the evaporation filtrate, make oily matter/mixture.In order to remove dichloro-phenyl phosphate (phenylphosphonicdichlorid) oily matter/mixture, described oily matter/mixture is dissolved among the EtOAc, and with twice of the HCl solution washing of pH4-5.Organic phase Na 2SO 4Drying is filtered and the concentrated oily matter that makes under reduced pressure.Then, at N 2Down n-Butyl Lithium (1.2 equivalent) is added drop-wise to stir and tetrahydrofuran (THF) (5ml/mmol) solution of the bromo indoles 11 (1 equivalent) of cooling (to-80 ℃ approximately) in.When adding end, described mixture is warming up to-60 ℃ approximately, and with tetrahydrofuran (THF) (1.2 equivalents; 3ml/mmol) be added drop-wise in the oily matter.Described then mixture slowly is warming up to-10 ℃ approximately, and water (8ml/mmol) makes described reaction all standing.Add HCl (1N), make pH reach about 5, and evaporating solvent in a vacuum.Described water ethyl acetate extraction, the salt water washing of blended organic layer is at Na 2SO 4Last dry, filter and under reduced pressure, concentrate.Crude product is by chromatography (elutriant: C on silica gel 6H 12/ EtOAc:9/1-0/10) purifying makes compound 30.
Method Y Suzuki cross-coupling
At N 2Down, with Pd (PPh 3) 4(10%mol), Na 2CO 3(6 equivalent) is at H 2Solution among the O (2M) and boric acid aryl ester, boric acid alkyl ester or the solution of boric acid heteroaryl ester (2 equivalent) in EtOH (0.3M) join in the solution of 5 or 16 (having halogen or triflate substituting group) in the toluene of the degassing of stirring.Described then reaction tubes is under following microwave radiation, in about 110 ℃ of heating down, up to there not being the raw material residue.Add entry, and extract described reaction medium with EtOAc, dry and concentrated.The crude product residue makes 37 by column chromatography (PE/EtOAc8/2) purifying on silica gel.
Method Z
In nitrogen atmosphere, in the anhydrous response pipe, add Red copper oxide (10%mol), part (20%mol), nucleophilic reagent (1.5 equivalent), cerous carbonate (2 equivalent) and aryl halide 5 or 16 (having halogen or triflate substituting group) (1 equivalent), add acetonitrile (0.6mL/mol aryl halide) anhydrous and the degassing afterwards.Seal this pipe, and, finish up to described reaction stirring down at about 80 ℃.Then, described reaction mixture is cooled to room temperature, and with the tert-butyl methyl ether dilution, and by the plug of celite filtration, filter cake is again with the washing of butyl methyl ether.Filtrate concentrates in a vacuum, removes acetonitrile, and is dissolved in the tert-butyl methyl ether once more.This organic layer filtrate washes twice with water, and with the salt water washing once, afterwards at Na 2SO 4Last dry and filtration.Solvent is removed in a vacuum, makes crude product, and it makes compound 42 by chromatography purifying on silica gel.
Method AA
Alkyl halide in trimethyl phosphite (10mL/mmol) in about 90 ℃ of following heated overnight.Described reaction medium is cooled to about 0 ℃ in ice bath, and carefully adds HCl (1N) solution.Water layer extracts with EtOAc.The blended organic layer is with HCl (1N) and water washing, and is dry then and concentrated, makes compound 53, is colorless oil.
Method AB
In the microwave seal pipe, compound 17 (1 equivalent), formaldehyde (37 weight %, in water, 1 equivalent) and morpholine (1 equivalent) are joined in the trimethyl carbinol (4ml/mmol).This pipe heated about 60 minutes down at about 170 ℃ under pressurized conditions under microwave radiation (peak power input 200W, CEM display unit).Described reaction is monitored by TLC, if residual any raw material, this Guan Zaiyue heated about 45 minutes down for 170 ℃.The residue of evaporating solvent, and crude product in a vacuum makes compound 18 by chromatography (MeOH/EtOAc:2/98) purifying on silica gel.
Method AC
In microwave tube, agitate compounds 5 or 6 (1 equivalent) and DMF (5ml/mmol), and add TMSBr (5 equivalent).This pipe under pressurized conditions, heated about 50 minutes down at about 60 ℃ under microwave radiation (peak power input 100W, CEM display unit).After the cooling, add entry, and collect compound 60 by filtering.
IX. the representative example of active compound
Table 1 and 2 comprises can be according to the non-limiting tabulation of the scheme 1-16 that provides above by the representative compounds of described method preparation.
Table 1
Figure G05839218720070518D001301
Figure G05839218720070518D001311
Figure G05839218720070518D001321
Figure G05839218720070518D001331
Figure G05839218720070518D001341
Figure G05839218720070518D001351
Figure G05839218720070518D001361
Figure G05839218720070518D001371
Figure G05839218720070518D001381
Table 2
Figure G05839218720070518D001411
Figure G05839218720070518D001421
Figure G05839218720070518D001431
Figure G05839218720070518D001441
Figure G05839218720070518D001451
Figure G05839218720070518D001461
Figure G05839218720070518D001491
Figure G05839218720070518D001501
Figure G05839218720070518D001511
Figure G05839218720070518D001521
Figure G05839218720070518D001531
Figure G05839218720070518D001541
Figure G05839218720070518D001551
Figure G05839218720070518D001561
Figure G05839218720070518D001571
Figure G05839218720070518D001581
Figure G05839218720070518D001591
Figure G05839218720070518D001611
Figure G05839218720070518D001621
Figure G05839218720070518D001641
Figure G05839218720070518D001651
Figure G05839218720070518D001671
Figure G05839218720070518D001691
Figure G05839218720070518D001711
Figure G05839218720070518D001721
Figure G05839218720070518D001731
Figure G05839218720070518D001751
Figure G05839218720070518D001761
Figure G05839218720070518D001771
Figure G05839218720070518D001781
Figure G05839218720070518D001801
Figure G05839218720070518D001811
Figure G05839218720070518D001821
Figure G05839218720070518D001831
Figure G05839218720070518D001841
Figure G05839218720070518D001871
Figure G05839218720070518D001881
Figure G05839218720070518D001891
Figure G05839218720070518D001901
Figure G05839218720070518D001911
Figure G05839218720070518D001921
Figure G05839218720070518D001931
Figure G05839218720070518D001941
Figure G05839218720070518D001951
Figure G05839218720070518D001961
Figure G05839218720070518D001971
Figure G05839218720070518D001981
Figure G05839218720070518D001991
Figure G05839218720070518D002001
Figure G05839218720070518D002011
Figure G05839218720070518D002021
Figure G05839218720070518D002031
Figure G05839218720070518D002051
Figure G05839218720070518D002061
Figure G05839218720070518D002071
Figure G05839218720070518D002081
Figure G05839218720070518D002091
Figure G05839218720070518D002101
Provide following examples to set forth the present invention rather than limit the scope of the invention by any way.
Embodiment
X. compound is synthetic
General synthesis method
Figure G05839218720070518D002102
Compound FW Equivalent amount
CHCl 3(or CH 2Cl 2) ? 75ml/mmol
MCPBA (70%, in water) 172.57 2.5
Experiment:
At room temperature, the pyridine precursor is dissolved in chloroform (or CH under agitation condition 2Cl 2) in; Add metachloroperbenzoic acid, and described reactant is stirred spend the night (about 15 hours).
Described mixture dilutes with methylene dichloride, and with saturated K 2CO 3/ H 2O (1/3) mixture extraction.
Water layer dichloromethane extraction three times.The blended organic layer filters and concentrates under reduced pressure through dried over sodium sulfate.(TLC: methylene chloride=9/1).Then, crude product passes through purification by chromatography.
The synthetic compound:
Figure G05839218720070518D002121
Figure G05839218720070518D002131
Embodiment 1.3-bromo-5-chloro-1-(phenyl sulfonyl)-1H-indoles-1-ethyl formate
A) synthetic 3-bromo-5-chloro-1-(phenyl sulfonyl)-1H-indoles-1-ethyl formate as raw material is (based on the works of SilvestriR., DeMartinoG., LaReginaG., ArticoM., MassaS., VargiuL., MuraM., LoiA.-G., MarcedduT., LaCollaP.; J Med.Chem.2003,46:2482-2493):
Figure G05839218720070518D002141
At N 2Down, toward stir and the 5-chloro-indole-ethyl formate of cooling (0 ℃) (1.052g, add in DMF 4.70mmol) (25mL) solution in batches NaH (60%, in oil, 230mg, 5.64mmol).After gaseous volatilization finishes, and adding phenyl SULPHURYL CHLORIDE (0.72mL, 5.64mmol).Described reaction mixture stirs 1 hour (TLC monitoring, elutriant: methylene dichloride).The careful less water that adds, and evaporation DMF.The crude product residue is dissolved among the EtOAc, and water and salt water washing.Afterwards, drying and evaporating solvent, (elutriant: the purifying of hexanaphthene/EtOAc:9/1-7/3) makes shielded indoles (1.547g, 90% productive rate) to compound on silica gel by chromatography.Off-white solid; 1HNMR (d 6-DMSO) δ 1,30 (t, J=7.2Hz, 3H), 4.35 (q, J=7.2Hz, 2H), 7.37 (s, 1H), 7.53 (dd, J=2.2 and 9.1Hz), 7.62-7.77 (m, 3H), 7.80 (d, J=2.2Hz, 1H), 7.99 (m, 2H), 8.06 (d, J=9.1Hz); MS (ESI, El +) m/z=364 (MH +).
B) synthetic 3-bromo-5-chloro-1-(phenyl sulfonyl)-1H-indole-2-ethyl formate intermediate:
Figure G05839218720070518D002142
At N 2Down, (4.83g adds bromine (1.3mL, 26.54mmol) solution in DMF (10mL) in DMF 13.27mmol) (40mL) solution toward 5-chloro-1-(the phenyl sulfonyl)-1H-indole-2-ethyl formate that stirs.Reaction medium at room temperature stirred 4 hours, added entry (150mL), and (3 * 100mL) extract with methylene dichloride.Organic layer Na 2SO 5The saturated solution washing, dry and evaporation makes crude product, is yellow oil.(elutriant: the purifying of hexanaphthene/EtOAc:9/1) makes 3-bromination indoles (5.548g, 93% productive rate) on silica gel by chromatography.Off-white solid; 1HNMR (d 6-DMSO) δ 1,37 (t, J=12Hz, 3H), 4.48 (q, J=7.2Hz, 2H), 7.59-7.68 (m, 4H), 7.77 (m, 1H), 7.96-8.09 (m, 3H); MS (ESI, El +) m/z=442-444 (MH +).
Method A: synthetic 5-chloro-3-(dialkoxy phosphoryl)-1-(phenyl sulfonyl)-1H-Ethyl indole-2-carboxylate and 5-chloro-3-[alkoxyl group (phenyl) phosphoryl]-exemplary steps of 1-(phenyl sulfonyl)-1H-indole-2-ethyl formate
At N 2Down, toward stir and cool off drip in anhydrous THF (2.5mL) solution of 3-bromo-5-chloro-1-(phenyl sulfonyl)-1H-indole-2-ethyl formate (0.50mmol) of (90 ℃) n-BuLi (2.5M, in hexane, 0.24mL, 0.60mmol).At-90 ℃ after following 5 minutes, under uniform temp, drip suitable chlorine phosphorus phosphonate reagent (0.60mmol).Described being reflected at is warming up to room temperature (TLC monitoring, elutriant: methylene dichloride/EtOAc9/1) in 3 hours.Add entry (5mL) then.(3 * 20mL) extract, and dry and evaporation makes crude product oily matter, and it is by chromatography purifying on silica gel with EtOAc.
Embodiment 2.5-chloro-3-(diethoxy phosphoryl)-1-(phenyl sulfonyl)-1H-indole-2-ethyl formate
Figure G05839218720070518D002161
Method A: (elutriant: the purifying of methylene dichloride/EtOAc:9/1-8/2) makes required indoles (176mg, 71% productive rate) on silica gel by chromatography.White solid; 1HNMR (d 6-DMSO, 300MHz) δ 1,19 (t, J=7.1Hz, 6H), 1,39 (t, J=7.1Hz, 3H), 3.99-4.09 (m, 4H), 4.46 (q, J=7.1Hz, 2H), 7.77 (dd, J=2.1 and 8.7Hz, 1H), 7.67-7.82 (m, 4H), 8.07-8.12 (m, 2H); 31PNMR (d 6-DMSO, 101MHz) δ 9.7; MS (ESI, El +) m/z=500 (MH +).
Embodiment 3.5-chloro-3-[oxyethyl group (phenyl) phosphoryl]-1-(phenyl sulfonyl)-1H-Ethyl indole-2-carboxylate
A) according to Smith A.B. (III, DucryL., Corbett R.M., Hirschmann R.Org.Lett.2000,2:3887-3890) synthetic ethyl-hydrogen-phenyl phosphonic chloromethylated intermediate
I) synthesis of phenyl diethyl phosphonate:
Figure G05839218720070518D002162
Colorless oil; 1HNMR (CDCl 3, 250MHz) δ 1,33 (t, J=7.1Hz, 6H), 4.05-4.25 (m, 4H), 7.46-7.57 (m, 3H), 7.78-7.87 (m, 2H); 31P NMR (CDCl 3, 101MHz) δ 19.3;
Ii) synthesis of phenyl phosphonic acids hydrogen ethyl ester:
Figure G05839218720070518D002171
Colorless oil; 1HNMR (CDCl 3, 300MHz) δ 1,32 (t, J=7.3Hz, 3H), 4.08 (q, J=7.3Hz, 2H), 7.42-7.56 (m, 3H), 7.79-7.86 (m, 2H), 10.67 (brs, 1H); 31PNMR (CDCl 3, 101MHz) δ 21.3;
Iii) synthetic ethyl-hydrogen-Phenylphosphine acyl chlorides with following physical property:
Figure G05839218720070518D002172
31P NMR (CDCl 3, 101MHz) δ 10.20 and 10.24.
B) synthetic final product: 5-chloro-3-[oxyethyl group (phenyl) phosphono]-1-(phenyl sulfonyl)-1H-indole-2-ethyl formate:
Figure G05839218720070518D002173
Method A: by chromatography on silica gel (elutriant: the purifying of methylene dichloride/EtOAc:9/1), make the indoles (318mg) of debrominate, make required indoles (326mg, 41% productive rate) then.Colorless oil; 1HNMR (d 6-DMSO, 300MHz) δ 1,27 (t, J=7.1Hz, 3H), 1,36 (t, J=7.1Hz, 3H), 4.03 (m, 2H), 4.38 (q, J=7.1Hz, 2H), 7.51-7.83 (m, HH), 8.05-8.11 (m, 3H); 31P NMR (d 6-DMSO, 101MHz) δ 23.3; MS (ESI, El +) m/z=532 (MH +).
Embodiment 4.5-chloro-3-[oxyethyl group (3, the 5-3,5-dimethylphenyl)) phosphoryl]-1-(phenyl sulfonyl)-1H-Ethyl indole-2-carboxylate
A) according to HiraoT., MasunagaT., OshiroY., (Synthesis1981,56-57) described method synthesizes 3 to AgawaT., 5-3,5-dimethylphenyl diethyl phosphoric acid intermediate.
Figure G05839218720070518D002181
By chromatography on silica gel (elutriant: the purifying of hexanaphthene/EtOAc:6/4), make product (1.625g, 61% productive rate), be colorless oil; 1HNMR (CDCl 3, 300MHz) δ 1,33 (t, J=7.0Hz, 6H), 2.35 (s, 6H), 4.02-4.18 (m, 4H), 7.18 (s, 1H), 7.40 (s, 1H), 7.45 (s, 1H); 31PNMR (CDCl 3, 101MHz) δ 20.3.
Other intermediate is according to embodiment 3 (i, ii and iii) described synthetic.
B) phosphono synthetic 5-chloro-3-[oxyethyl group (3, the 5-3,5-dimethylphenyl))]-1-(phenyl sulfonyl)-1H-indole-2-ethyl formate:
Method A: by chromatography on silica gel (elutriant: the purifying of methylene dichloride/EtOAc:95/5), make product (750mg, 56% productive rate), be faint yellow solid. 1HNMR (d 6-DMSO, 300MHz) δ 1,27 (t, J=7.1Hz, 3H), 1,36 (t, J=7.1Hz, 3H), 2.30 (s, 6H), 3.94-4.06 (m, 2H), 4.44 (q, J=7.1Hz, 2H), 7.25 (s, 1H), 7.39 (s, 1H), 7.42 (s, 1H), 7.53 (dd, J=2.1 and 9.0Hz, 1H), 7.65-7.71 (m, 2H), and 7.77-7.82 (m, 2H), 8.05-8.11 (m, 3H); 31PNMR (d 6-DMSO, 101MHz) δ 23.6; MS (ESI, El +) m/z=560 (MH +).
Embodiment 5.5-chloro-3-[methoxyl group (phenyl) phosphoryl]-1-(phenyl sulfonyl)-1H-Ethyl indole-2-carboxylate
A) synthesis of phenyl dimethyl phosphonate:
Figure G05839218720070518D002191
Under 0 ℃, toward phosphniline acyl group dichloro (1mL, 6.35mmol) drip in the solution in anhydrous methylene chloride (25mL) ethanol (1,12mL, 19.04mmol), drip afterwards triethylamine (2,65mL, 19.04mmol).Described reaction mixture at room temperature stirred 2 hours.The described reaction mixture solution washing of HCl1N (50mL).The water layer dichloromethane extraction.The organic phase of dry mixed also concentrates under reduced pressure.Crude product oily matter by chromatography on silica gel (elutriant: the purifying of hexanaphthene/EtOAc:6/4), make the phenyl-phosphonic acid dimethyl ester, be colorless oil (1,110g, 82% productive rate). 1HNMR(CDCl 3，300MHz)δ3.76(d，J＝11.1Hz，3H)，7.44-7.58(m，3H)，7.76-7.84(m，2H)； 31P?NMR(CDCl 3，101MHz)δ22.2。
According to embodiment 3 (i, ii and iii) synthetic other intermediate.
B) synthetic final product 5-chloro-3-[methoxyl group (phenyl) phosphono]-1-(phenyl sulfonyl)-1H-indoles-2-ethyl formate:
Figure G05839218720070518D002201
Method A: colorless oil; 1HNMR (CDCl 3, 300MHz) δ 1.45 (t, J=7.2Hz, 3H), 3.80 (d, J=11.4Hz, 3H), 4.54 (q, J=7.2Hz, 2H), 7.36 (dd, J=2.1 and 9.0Hz, 1H), 7.47-7.67 (m, 6H), 7.84-7.96 (m, 4H), 8.09-8.12 (m, 2H); 31P NMR (CDCl 3, 101MHz) δ 26.7; MS (ESI, El +) m/z=518 (MH +).
Embodiment 6.2-(aminocarboxyl)-5-chloro-1H-indol-3-yl-(phenyl) phosphonous acid ethyl ester
Figure G05839218720070518D002202
In penstock, with 5-chloro-3-[oxyethyl group (phenyl) phosphono]-(268mg 0.50mmol) is dissolved in methyl alcohol (5mL) solution of saturated ammonia 1-(phenyl sulfonyl)-1H-Ethyl indole-2-carboxylate.This pipe under pressurized conditions, heated 2 hours down at 65 ℃ under microwave radiation (peak power input 100W, CEM display unit).After the evaporating solvent, (elutriant: the purifying of methylene dichloride/MeOH:95/5-9/1) makes required methane amide indoles (107mg, 81% productive rate) on silica gel by chromatography.White solid; 1HNMR (4-DMSO, 300MHz) δ 1,34 (t, J=7.1Hz, 3H), 4.05 (m, 1H), 4.20 (m, 1H), 7.32 (dd, J=2.1 and 8.7Hz, 1H), 7.49-7.61 (m, 5H), 7.68-7.75 (m, 2H), 8.02 (brs, 1H), 10,27 (brs, 1H), 12.77 (brs, 1H); 31P NMR (d 6-DMSO, 101MHz) δ 31.1; MS (ESI, El +) m/z=363 (MH +).
Embodiment 7.2-(aminocarboxyl)-5-chloro-1H-indol-3-yl-(3, the 5-3,5-dimethylphenyl) phosphinic acid ethyl ester
Figure G05839218720070518D002211
Same steps as described in example 5 above.White solid; 1HNMR (d 6-DMSO, 300MHz) δ 1,32 (t, J=7.0Hz, 3H), 2.26 (s, 6H), 3.90-4.03 (m, 1H), 4.09-4.22 (m, 1H), 7.21 (s, 1H), 7.29-7.33 (m, 3H), 7.57 (dd, J=1.8 and 9.0Hz, 1H), 7.60 (dd, J=1.8Hz, 1H), 7.99 (brs, 1H), 10.3 (brs, 1H), 12.7 (brs, 1H); 31P NMR (d 6-DMSO, 101MHz) δ 31.3; MS (ESI, El +) m/z=391 (MH +).
Embodiment 8.2-(aminocarboxyl)-5-chloro-1H-indol-3-yl-(phenyl) methylphosphinate
Same steps as described in example 5 above.Pale yellow powder; 1HNMR (CDCl 3, 300MHz) δ 3.85 (d, J=11.4Hz, 3H), 6.08 (broad peak, 1H), 7.30 (dd, J=2.0 and 9.0Hz, 1H), 7.36-7.56 (m, 4H), 7.68 (d, J=1.8Hz, 1H), 7.73-7.81 (m, 2H), 10.78 (broad peak, 1H), 10.03 (broad peak, IH); 31P NMR (CDCl 3, 101MHz) δ 33.3; MS (ESI, El +) m/z=349 (MH +).
Embodiment 9: to the biological activity of HIV medicine patience bacterial strain
In one embodiment, by quick, the automatic assay method of sensitive in in-vitro measurements the effect of anti-HIV-1 compounds, this assay method relates to reduction 3-(4,5-dimethylthiazole-2-yl)-2,5-phenylbenzene bromination tetrazolium (MTT).Selection is as target cell system (Koyanagi etc., Int.J.Cancer, 1985,3 (5:445-451) as T-4 clone, MT-4 to the HIV-cell transformed that HIV infects highly permission and highly selection.By the 3-(4,5-dimethylthiazole-2-yl)-2 of spectrophotometric assessment, the in-situ reducing of 5-phenylbenzene bromination tetrazolium (MTT) is used as standard, the viability of the cell that infects by its cell that can measure analog infects and HIV.The inhibition of HIV inductive cytopathic effect is used as terminal point.50% cell toxicant concentration (CC 50, μ M) be defined as the control sample of comparing simulated infection and make and absorb to reduce by 50% compound concentration.Calculate the percentage effect (being expressed as %) of anti-HIV compound with following formula:
(OD The HIV test compounds)-(OD Contrast)/(OD The simulated infection cell)-(OD Contrast)
Wherein, (OD The HIV test compounds) be that concrete measurement the in the HIV-cells infected tried the optical density(OD) that compound records; (OD Contrast) be the optical density(OD) that in the control cells that untreated HIV-infects, records; (OD The simulated infection cell) be the optical density(OD) that the control cells to untreated simulated infection records.Optical density value is measured at 540nm usually.Provide the dosage of the anti-HIV test compounds of 50% protection to be defined as 50% inhibition concentration (IC according to following formula 50, μ M).Selectivity index (SI) is defined as CC 50With IC 50The ratio.
In other embodiments, determine the effect of anti-HIV compound with the p24ELISA assay method.This virus replication immunoassay is measured the antigenic amount of p24 viral capsid (core) that exists, and can be from such as Coulter Corporation/Immunotech, Inc. (Westbrook, source MI) is buied.
Other embodiment comprises again: the reverse transcriptase determination method, wherein adopt homopolymer to gather rA: few dT templa-primer systematic survey virus replication amount, this system can be by (the Southern Research Institute that mixes of tritiate thymidine 5'-monophosphate in the scintillation counting technique quantization cell, University of Alabama, Birmingham, AL); Synplasm suppresses assay method, adopts CEM-SS, HeLa-CD4 or HeLa-CD4-LTR-b-tilactase cell with immunity-fluorescence, chemoluminescence or colorimetric terminal point; And adhere to-and fusion-inhibition assay method, utilize indicating clone and by chemoluminescence, colorimetric or microscopic evaluation quantize (SouthernResearch Institute, University of Alabama, Birmingham, AL).
In one embodiment, Phenylindole compounds of the present invention does not show and the patience of intersecting of other non-nucleoside reverse transcriptase inhibitors (NNRTI), that is to say the EC of The compounds of this invention in the HIV mutant strain 50(representing with volumetric molar concentration) is less than about 50,25,10 or 1 μ M.In a typical embodiment, the EC that NNRTI demonstrates in the HIV mutant strain 50Concentration is less than about 5,2.5,1 or 0.1 μ M.Is EC in the medicine patience virus by assessment requisite oxygen-pyrimidine compound in the target virus of sudden change 50Measure intersection patience degree to HIV medicine patience bacterial strain.
Therefore, in another important embodiment of the present invention, the method that provides treatment to intersect patience HIV patient, this method comprises the benzazolyl compounds that gives effective HIV therapeutic dose, its salt, prodrug, steric isomer or tautomer.
Biological activity to HIV medicine patience bacterial strain
In one embodiment, benzazolyl compounds of the present invention does not show the intersection patience of other non-nucleoside reverse transcriptase inhibitors (NNRTI), that is to say its EC in the HIV mutant strain 50(representing with volumetric molar concentration) is less than about 50,25,10 or 1 μ M.In a typical embodiment, the EC that NNRTI demonstrates in the HIV mutant strain 50Concentration is less than about 5,2.5,1 or 0.1 μ M.Is EC in the medicine patience virus by assessment requisite oxygen-pyrimidine compound in the target virus of sudden change 50Can measure intersection patience degree easily to HIV medicine patience bacterial strain.
Therefore, in another important embodiment of the present invention, the method that provides treatment to intersect patience HIV patient, this method comprises Phenylindole or its prodrug or the salt that gives the effective therapeutic dose of HIV.
Figure G05839218720070518D002251
Figure G05839218720070518D002261
Figure G05839218720070518D002271
Figure G05839218720070518D002281
Figure G05839218720070518D002291
Figure G05839218720070518D002311
Figure G05839218720070518D002321
Figure G05839218720070518D002331
Figure G05839218720070518D002341
Figure 979489DEST_PATH_RE-G05839218720070704D000041
Toxicology
1. depend on the water-soluble of pH
Measure each compound water-soluble of 1mM normal concentration with fask oscillating method commonly used.With flask (bottle) room temperature vibration 3 hours, centrifugal then.By HPLC clear liquid analytically, UV detects solubleness.Usually, drug candidate need be than highly water-soluble.
2. human plasma protein fraction combination
Determine the human plasma protein fraction combination with equilibrium dialysis.Is about 6 hours of the human plasma collected of the medicine dialysis of 1 μ M at 37 ℃ with concentration.When dialysis finishes, collect the buffer sample of dialysis pond damping fluid side and analyze free drug concentration with LC/MS/MS.For NNRTI, lower protein bound is desirable more.
3. two-way CACO-2 permeability
The purpose of this assay method is to determine the two-way permeability classification of test compounds in the Caco-2 cell monolayer system and flow out restriction to absorb potential (efflux-limited absorption potential).This assay method is usually included in the non-specific binding of measuring in the assay buffer of pH7.4 the Transwell device, test compounds is passed the two-way permeability assessment of Caco-2 cell monolayer, the top side is to the assessment of transporting of bottom side, and the bottom side is to the assessment of transporting of top side, and the individual layer integrity.It is not the limiting factor that human oral absorbs that high-permeability and nothing flow out explanation intestines permeability.
4.CYP450 suppress
External CYP450 suppresses screening can predict the potential drug-drug interactions.For determining whether test compounds can suppress the activity of specific P450 enzyme, monitor people's liver microbody to the metabolic change of P450 specific substrate with the test compounds of different concns.Can be by measuring the IC of specific isozyme 50Value is assessed the potential and the rank order of inhibition.For NNRTI, higher IC 50The value explanation suppresses lower, so the possibility of patient's Chinese traditional medicine-drug interaction is lower.
CYP3A4 suppresses with CYP3A4/BFC high-throughput inhibitor screening test kit (BD Biosciences) screening, and CYP2D6 suppresses with CYP2D6/AMMC high-throughput inhibitor screening test kit (BD Biosciences) screening, and uses P450-Glo TMMeasuring test kit (Promega) screening CYP2C9 suppresses.
5. the little intravital external metabolic stability of liver
The metabolic stability assay method is used for the stability of evaluation test compound in bio-matrix.Its data are for understanding and predicting that the eliminating mechanism of test compounds is very useful.The CYP450 dependency metabolism of medicine also has very large variation between species.Use the external metabolism of estimating medicine from the liver microbody of multiple species animal species and people's metabolism can be compared.This also helps to identify maximally related PK and toxicologic study animal model.Metabolic stability in rat, dog, monkey and people's liver microbody inner evaluation test compounds.Containing 5mM MgCl in the time of 37 ℃ 2With the 0.1M Tris damping fluid of 0.1mM EDTA, among the pH 7.4 10 μ M test compounds and 1mg/mL liver microbody were cultivated 5 minutes in advance.Add NADPH (final concentration is 3mM) after pre-the cultivation to start reaction, sample was cultivated 0 and 1 or 2 hour.Reaction finish the back by HPLC-UV or LC/MS/MS analytically clear liquid with the disappearance of understanding parent and the formation of metabolite.The % parent is residual to be 1 or 2 hour sample and the ratio of the peak area of 0 hour sample.Usually, less metabolism (higher % parent value) is desirable more.
6. the external metabolism in the liver micrometabolism approach
This assay method has been estimated the I phase bio-transformation of test compounds.Analyze sample from the metabolic stability test to obtain the metabolite curve and to identify by LC/MS/MS.Illustrate the structure of metabolite based on multiple MS/MS test as full scan, neutral loss scanning (neutral loss scan) and product ion scanning.Suppose pathways metabolism based on the structure of major metabolite then.For the compound of phosphinate series, the N-oxidation of terminal pyridine ring is a main path, is the oxidation of dimethyl-phenyl then, and methyl wherein further is oxidized to aldehyde by hydroxylation, becomes carboxylic acid at last.It is extremely important for the eliminating mechanism of understanding test compounds to illustrate pathways metabolism, and helps to design the recruit with improved DM-PK curve.
Figure G05839218720070518D002391
7. PK of rat and dog and oral administration biaavailability.
The pharmacokinetics of evaluation test compound in Sprague-Dawley rat and beagle.Typical PK research comprises that the IV bullet that carries out a 1mg/kg to 2-3 animal injects, and 3 animals carry out the per os tube feed one time with 5mg/kg in addition.Different time points during 24 hours is collected blood sample.Separated plasma also passes through LC/MS/MS analytical test compound and metabolite thereof.Calculate the PK parameter with noncompartmental method from plasma concentration-time curve.Calculate oral administration biaavailability (F) based on the standardized AUC value of the dosage that obtains from oral and IV administration.Oral administration biaavailability is high more good more.
Figure G05839218720070518D002411

Claims (24)

1. the compound of formula (B),
Figure FSB00000491862100011
Or its pharmacy acceptable salt, wherein:
Y is the O-methyl;
W is O;
R 1Be H;
R 4 ', R 6 'And R 7 'Be H independently of one another;
R 5 'Be chlorine;
Z is C (=O) NH 2
R 2 ", R 4 "And R 6 "Be H independently of one another;
R 3 "And R 5 "Be independently of one another H, halogen ,-CN ,-CF 3, C 1-6Alkyl or the C that is replaced by a CN 2-6Thiazolinyl.
2. the described compound of claim 1, it is
Figure FSB00000491862100012
3. the compound of formula (B),
Figure FSB00000491862100021
Or its pharmacy acceptable salt, wherein:
Y is O-C 1-6Alkyl;
W is O;
R 1Be H;
R 6 'And R 7 'Be H independently of one another;
R 4 'Be F;
R 5 'Be Cl;
Z is-C (=O) NH 2
R 2 ", R 4 "And R 6 "Be H independently of one another;
R 3 "And R 5 "Be independently of one another halogen ,-CN, C 1-6Alkyl or the C that is replaced by one-CN 2-6Thiazolinyl.
4. the compound of claim 3, it is:
Figure FSB00000491862100031
5. pharmaceutical composition, it contains each described compound of claim 1-4 or its pharmacy acceptable salt, randomly with a kind of pharmaceutically acceptable carrier or thinner.
6. pharmaceutical composition, it contains each described compound of claim 1-4 or its pharmacy acceptable salt with at least a other anti-HIV agent combination, randomly with a kind of pharmaceutically acceptable carrier or thinner.
7. the described pharmaceutical composition of claim 6, wherein said other anti-HIV reagent is reverse transcriptase inhibitors.
8. the described pharmaceutical composition of claim 7, wherein said reverse transcriptase inhibitors induce Methionin 103 in the hiv reverse transcriptase to the sudden change to halfcystine of l-asparagine and/or tyrosine 181.
9. each described compound of claim 1-4 or its pharmacy acceptable salt are randomly with a kind of pharmaceutically acceptable carrier or the thinner purposes in the medicine that preparation treatment or prevention host HIV infect.
10. each described compound of claim 1-4 or its pharmacy acceptable salt, randomly with a kind of pharmaceutically acceptable carrier or thinner, with the purposes of at least a other anti-HIV agent combination in the medicine of preparation treatment or prevention host HIV infection.
11. the described purposes of claim 10, wherein said other anti-HIV reagent is reverse transcriptase inhibitors.
12. the described purposes of claim 11, wherein said reverse transcriptase inhibitors induce Methionin 103 in the hiv reverse transcriptase to the sudden change to halfcystine of l-asparagine and/or tyrosine 181.
13. claim 9 or 10 described purposes, wherein said HIV has Methionin 103 to the sudden change to halfcystine of l-asparagine and/or tyrosine 181 in hiv reverse transcriptase.
14. claim 9 or 10 described purposes, wherein said HIV has resistance to one or more reverse transcriptase inhibitors.
15. claim 9 or 10 described purposes are used for rescuing treatment in treatment or prevention host HIV infection.
16. claim 9 or 10 described purposes, wherein said host is the people.
17. the compound of following formula:
Figure FSB00000491862100051
Or its pharmacy acceptable salt.
18. the described compound of claim 17.
19. comprise the compound of following formula or the pharmaceutical composition of its pharmacy acceptable salt,
Figure FSB00000491862100052
20. the compound of following formula or its pharmacy acceptable salt purposes in the medicine of preparation treatment or prevention host HIV infection,
Figure FSB00000491862100053
21. the compound of following formula:
Figure FSB00000491862100061
Or its pharmacy acceptable salt.
22. the described compound of claim 21.
23. comprise the compound of following formula or the pharmaceutical composition of its pharmacy acceptable salt,
Figure FSB00000491862100062
24. the compound of following formula or its pharmacy acceptable salt purposes in the medicine of preparation treatment or prevention host HIV infection,
Figure FSB00000491862100063
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