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CN104628729B - Antimicrobe compound and its preparation and application - Google Patents

Antimicrobe compound and its preparation and application Download PDF

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Publication number
CN104628729B
CN104628729B CN201510018490.2A CN201510018490A CN104628729B CN 104628729 B CN104628729 B CN 104628729B CN 201510018490 A CN201510018490 A CN 201510018490A CN 104628729 B CN104628729 B CN 104628729B
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compound
infection
tautomer
alkyl
optionally
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CN104628729A (en
Inventor
E.M.杜菲
A.巴塔查吉
H.奥多德
M.德维托
Z.F.肯尤
J.G.马蒂诺
I-H.佩克
M.H.谢德曼
S.西尼什塔
B.T.温伯利
Y.吴
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Melinta Subsidiary Corp
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Rib X Pharmaceuticals Inc
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04Ortho-condensed systems
    • C07D491/044Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D519/00Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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  • Nitrogen Condensed Heterocyclic Rings (AREA)
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Abstract

The present invention relates to Antimicrobe compounds and its preparation and application.Present invention accomplishes provide for the active new antimicrobial of drug resistance pathogenic bacteria organism, the especially important development need of antiseptic.These compounds can be effectively used for treatment, prevent the microorganism infection of humans and animals and reduce its danger.

Description

Antimicrobe compound and its preparation and application
The application is application No. is 201080057335.7, and the applying date is on October 15th, 2010, entitled " anti-micro- The divisional application of the application for a patent for invention of biologic artifact and its preparation and application ".
Related application
Patent application claims U.S. Provisional Patent Application 61/252,478 (application on October 16th, 2009), the U.S. are interim Patent application 61/314,287 (application on March 16th, 2010) and U.S. Provisional Patent Application 61/358,201 (June 24 in 2010 Day application) priority.The content of above-mentioned application is fully incorporated herein in a manner of being cited.
Technical field
The present invention broadly relates to Antimicrobe compound field and prepares and use their method.These compounds can Effective for treating, preventing the microorganism infection of humans and animals and reduce its danger.
Background technology
Due to being found that penicillin in nineteen twenties and being found that streptomysin in nineteen forties, institute To be found or be specifically designed as antibiotic medicament there are many noval chemical compound.People once thought, by means of this Kind therapeutic agent can control or eliminate completely infectious diseases.However, due to the resistant cell of current effective therapeutic agent Or the bacterial strain of microorganism continues to evolve, so, this viewpoint has been challenged.Almost each antibiosis developed clinically used Plain medicament, which has eventually encountered, there is the problem of antibiotic-resistant bacteria.For example, having formd the resistant strain of gram-positive bacterium, example Such as the staphylococcus of methicillin-resistant, the streptococcus of resistance to penicillin and the enterococcus of anti-vancocin.Antibiotic-resistant bacteria can be with Serious consequences, even fatal result are caused to infected patient.See, e.g.,Lowry, F.D. “Antimicrobial Resistance: The Example of Staphylococcus aureus”, J. Clin. Invest., vol. 111, no. 9, pp. 1265-1273(2003);And Gold, H.S. and Moellering, R.C., Jr., “Antimicrobial-Drug Resistance”, N. Engl. J. Med., vol. 335, pp. 1445-53 (1996)。
In decades, find and research and develop the principal focal point that new antiseptic has become many drugmakers.Nevertheless, It is exited from the research field and Field of Drug Discovery there are many drugmaker recent years.Due to this exit, only The antibiotic for having minimal amount new enters market.It is especially uneasy to lack new antibiotic, especially in bacterium to Current Therapy Resistance when be all continuously improved in hospital and community environment.
During finding new antibiotic medicament, researcher has tested the various pieces of antibiotic molecule Combination or connection, to be formed multi-functional or to mix type compound.Other researchers have manufactured experimently known antibiotic kind The derivative of class, for example, Ketek (telithromycin), is sold with trade (brand) name Ketek, be the derivative of erythromycin Object.However, the success of these methods is restricted.
The approach for forming new Antimicrobe compound is designing modulators, for example, the inhibitor of bacterial ribosome function. By adjusting or inhibiting bacterial ribosome function, this antimicrobial compound can interfere main process, such as RNA translations and egg White matter synthesizes, and thus provides anti-microbial effect.In fact, some known antibiotic compounds, such as erythromycin, clindamycin With Linezolid (linezolid), combined with ribosomes.
In order to find and develop new antimicrobial, the present invention uses Structure-ba sed drug design approach.In order to set The Antimicrobe compound with specific chemical structures, ribosomes binding characteristic and antimicrobial acivity of new type is counted, This approach originates in ribosomal high-resolution X-ray crystal.The drug based on this structure is described in publication below It was found that approach: Franceschi, F. and Duffy, E.M., " Structure-based drug design meets the ribosome”, Biochemical Pharmacology, vol. 71, pp. 1016-1025(2006)。
Based on the drug design approach based on this structure, the present invention, which describes, can be used for treating the thin of humans and animals The Antimicrobe compound of the new chemical species of bacterium infection.Without being bound by theory, it is believed that these chemical combination Object inhibits bacterial ribosome function by being combined with ribosomes.By using these ribosome bind sites, of the invention is anti- Microbial compounds can provide activity more better than the activity of existing antimicrobial compound, especially for the resistant strain of bacterium.
In order to find and develop new antimicrobial, the present invention uses Structure-ba sed drug design approach.In order to set Count the antimicrobial chemical combination with specific chemical structures, ribosomes binding characteristic and target antimicrobial acivity of New raxa Object, this approach originate in ribosomal high-resolution X-ray crystal.This structure-based medicine is described in publication below Object finds approach: Franceschi, F. and Duffy, E.M., " Structure-based drug design meets the ribosome”, Biochemical Pharmacology, vol. 71, pp. 1016-1025(2006)。
Therefore, present invention accomplishes offers to be directed to the active new antimicrobial of drug resistance pathogenic bacteria organism, The especially important development need of antiseptic.
Invention content
The present invention broadly relates to Antimicrobe compound field and prepares and use their method.These compounds can Effective for treating, preventing the microorganism infection of humans and animals and reduce its danger.The present invention also provides these compounds Officinal salt, ester, N- oxides and pro-drug.
The present invention provides the compounds with having structure:
WhereinIt is to be selected from following chemical part:
,,
, or,
WhereinIndicate condensed 5 to 7 yuan of saturations, insatiable hunger and/or aromatic carbocyclic or heterocyclic ring system,
Wherein T1It is carbon atom or N, works as T1When being N ,-D-E-F is not present,
Wherein T2It is carbon atom or N, works as T2When being N ,-G-H-J is not present,
Wherein T1And T2It is N when two differences,
Wherein V is independently selected from-CR4aOr-N-,
W is O, NR1, NOR1Or S or W=combination or two selected from the HO- and H- both being connect with identical carbon atoms (the C that person connect with identical carbon atoms1-8Alkyl) O- and H- combination;
X---Y indicates singly-bound or double bond, works as X---When Y is singly-bound, X is selected from O, NR2With S (O)n, Y is C-R3, work as X---Y When being double bond, X is N, and Y is carbon atom,
Z is selected from O, NR4, S (O)nOr NH,
R1Selected from H and C1-8Alkyl,
R2Selected from H and C1-8Alkyl,
R3Selected from H and C1-8Alkyl,
R4Selected from H and C1-8Alkyl,
R4aSelected from H and C1-8Alkyl,
N is 0,1 or 2,
Alternatively ,-G-H-J is selected from
,
Wherein each H and J is selected independently,
C-B-A- ,-D-E-F and-G-H-J are chemical parts, wherein
A, D and G independently selected from:
(a) singly-bound, (b)-(C1-8Alkyl)-, (c)-(C2-8Alkenyl)-, (d)-(C2-8Alkynyl)-, wherein
I) 0-4 carbon atom in any one of (b) just mentioned above-(d) is optionally replaced selected from following group Generation:- O- ,-S (O)p,-NR6,-(C=O)-,-S (O)pNR6,-NR6S(O)pAnd-NR6S(O)pNR6,
Ii) any one of (b) just mentioned above-(d) is optionally by one or more R5Group replaces, and
Iii) any one of (b) just mentioned above-(d) is optionally by-(C1-8Alkyl)-R5Group replaces;
(e)-O-, (f)-NR6, (g)-S (O)p, (h)-C (O)-, (i)-C (O) O-, (j)-OC (O)-, k)- OC (O) O-, (l)-C (O) NR6, (m)-NR6CO-, (n) -NR6C(O)NR6, (o)-C (=NR6)-, (p)-C (=NR6) O-, (q) -OC(=NR6)-, (r)-C (=NR6)NR6, (S)-NR6C(=NR6)-, (t)-C (=S)-, (u)-C (=S) NR6, (v)-NR6C (=S)-, (w)-C (O) S-, (x)-SC (O)-, (y)-OC (=S)-, (z)-C (=S) O-, (aa)- NR6(CNR6)NR6, (bb)-CR6R6C (O)-, (cc)-C (O) NR6(CR6R6)t, (dd) is containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycle, the hetero atom are selected from nitrogen, oxygen and sulphur,
(ee) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, and
(ff) -(CR6R6)t-,
Wherein (dd) or (ee) are optionally by one or more R5Group replaces;
B, E and H independently selected from:
(a) singly-bound,
(b) contain one or more heteroatomic 3-14 members saturations, insatiable hunger and/or aromatic heterocycle, the hetero atom to be selected from Nitrogen, oxygen and sulphur,
(c) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic,
Wherein (b) or (c) optionally by one or more R5Group replaces;
(d) -(C1-8Alkyl)-,
(e) -(C2-8Alkenyl)-,
(f) -(C2-8Alkynyl)-, wherein
I) 0-4 carbon atom in any one of (d) just mentioned above-(f) is optionally replaced selected from following part Generation:- O- ,-S (O)p,-NR6,-(C=O)-,-C (=NR6)-,-S (O)pNR6,-NR6S(O)pAnd-NR6S(O)pNR6,
Ii) the just any one of (d)-(f) above is optionally by one or more R5Group replaces, and
Iii) any one of (d) just mentioned above-(f) is optionally by-(C1-8Alkyl)-R5Group replaces;
(g)-(CR6R6)t,
C, F and J independently selected from:
(a) hydrogen, (c) F, (d) Cl, (e) Br, (f) I, (g)-CF3, (h)-CN, (i)-N3(j) -NO2, (k)-NR6 (CR6R6)tR8, (l)-OR8, (m)-S (O)p(CR6R6)tR8, (n)-C (O) (CR6R6)tR8, (o)-OC (O) (CR6R6)tR8, (p) -SC(O)(CR6R6)tR8, (q)-C (O) O (CR6R6)tR8, (r)-NR6C(O)(CR6R6)tR8, (s)-C (O) NR6 (CR6R6)tR8, (t)-C (=NR6)(CR6R6)tR8, (u)-C (=NNR6R6)(CR6R6)tR8, (v)-C (=NNR6C(O)R6) (CR6R6)tR8, (w)-C (=NOR8)(CR6R6)tR8, (x)-NR6C(O)O(CR6R6)tR8, (y)-OC (O) NR6(CR6R6)tR8, (z) -NR6C(O)NR6(CR6R6)tR8, (aa)-NR6S(O)p(CR6R6)tR8, (bb)-S (O)pNR6(CR6R6)tR8, (cc)- NR6S(O)pNR6(CR6R6)tR8, (dd)-NR6R8, (ee)-NR6(CR6R6)R8, (ff)-OH, (gg)-NR8R8, (hh)- OCH3, (ii)-S (O)pR8, (jj)-NC (O) R8, (kk)-NR6C(NR6)NR6R8, (ll) C1-8Alkyl, (mm) C2-8Alkenyl, (nn)C2-8Alkynyl, (oo) contain one or more heteroatomic 3-14 members saturations, insatiable hunger and/or aromatic heterocycle, the hetero atom Selected from nitrogen, oxygen and sulphur, (pp) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (qq)-(CR6R6)tNR6(CR6R6)tR8, (rr)- N[(CR6R6)tR8][C=O(CR6R6)tR8], (ss)-(CR6R6)tN[(CR6R6)tR8][(CR6R6)tR8], (tt)-(CR6R6)tNR6 (C=O)(CR6R6)tR8, (uu)-halogenated alkyl, (vv)-C (O) (CR6)[(CR6R6)tR8]R8, (ww)-(CR6R6)tC(O) NR8R8, (xx)-(CR6R6)tC(O)O(CR6R6)tR8, (yy)-NR6C(O)CR8R8R8, (zz)-N [(CR6R6)tR8]C(O)R8, (aaa)-S (O)pNR8R8
Wherein (ll) to (pp) is optionally by one or more R7Group replaces;
R5It is selected from:(a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i) -NO2, (j) -NR6R6, (k)-OR8, (l)-NR6(CNR6)NR6R6, (m)-C1-8Alkyl, (n)-C1-8Alkenyl, (o)-C1-8Alkynyl, (p) -(C1-8Alkyl)-(contain one or more heteroatomic 3-14 members saturation, insatiable hunger and/or fragrance selected from nitrogen, oxygen and sulphur Heterocycle), (q)-(C1-8Alkyl)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), and (r)-halogenated alkyl, (S)-SR6, (t) Contain one or more heteroatomic -3-14 members saturation, insatiable hunger and/or aromatic heterocycles selected from nitrogen, oxygen and sulphur, and (u) -3-14 Member saturation, insatiable hunger and/or aromatic carbocyclic;Alternatively, two R5Group is combined together, and forms carbocyclic ring;
Wherein (m) to (r) and (t) to (u) is optionally by one or more R8Substitution;
R6Selected from (a) hydrogen, (b)-C1-8Alkyl or two R6Group is combined together to form carbocyclic ring, (c)-alkyl halide Base (d) contains one or more heteroatomic -3-14 members saturation, insatiable hunger and/or aromatic heterocycles selected from nitrogen, oxygen and sulphur, and (e) - 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic;
Wherein (b) to (e) is optionally by one to multiple R8Substitution;
R7It is selected from:(a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i) -NO2, (j) -NR6R6, (k)-OR6, (l)-NR6(CNR6)NR6R6, (m)-C1-8Alkyl, (n)-C1-8Alkenyl, (o)-C1-8Alkynyl, (p) -(C1-8Alkyl)-(contain one or more heteroatomic 3-14 members saturation, insatiable hunger and/or fragrance selected from nitrogen, oxygen and sulphur Heterocycle), (q)-(C1-8Alkyl)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), and (r)-halogenated alkyl, (S)-NR6R8, (t) -OR8, (u)-(CR6R6)tNR6R8, (v)-CR6R8R8, (w)-SR6, (x) contain one or more selected from the miscellaneous of nitrogen, oxygen and sulphur - 3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of atom, (y) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (z) - (CR6R6)tC(O)NR8R8, (aa)-S (O)pR8, (bb)-NR6C(O)NR6R6, (cc)-NR6C(O)R6, and (dd)-C (= NR6)NR6R6
Wherein (m) to (q) and (x) to (y) is optionally by one or more R9Substitution;
R8It is selected from:(a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i) -NO2, (j) -NR6R9, (k)-OR9, (l)-NR6(CNR6)NR6R6, (m)-C1-8Alkyl, (n)-C1-8Alkenyl, (o)-C1-8Alkynyl, (p) -(C1-8Alkyl)-(contain one or more heteroatomic 3-14 members saturation, insatiable hunger and/or fragrance selected from nitrogen, oxygen and sulphur Heterocycle), (q)-(C1-8Alkyl)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), (r) contain one or more selected from nitrogen, oxygen With the heteroatomic -3-14 members of sulphur saturation, insatiable hunger and/or aromatic heterocycle, (S) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (t)-halogenated alkyl, (u)-C (O) (CR6R6)tR9, (v)-SR6, (w)-OC (O) (CR6R6)tR9, (x)-NR6C(O) NR6R9, (y)-NR6C(O)R9, (z)-NR6(CNR9)(NR6R6), (aa)-ONR6(CNR6)NR6R6, (bb)-C (=NR9) NR6R6, (cc)-S (O)pR9, (dd)-(CR6R6)tC(O)NR6R9, (ee)-(CR6R6)tOR9, and (ff)-(CR6R6)tNR6R9
Wherein (m) to (s) is optionally by one to multiple R9Substitution;
R9It is selected from:(a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i) -NO2, (j) -NR6R10, (k)-OR6, (l)-NR6(CNR6)NR6R6, (m)-C (O) (CR6R6)tNR6R6, (n)-C1-8Alkyl, (o)- C1-8Alkenyl, (p)-C1-8Alkynyl (q) contains one or more heteroatomic -3-14 members saturations for being selected from nitrogen, oxygen and sulphur, insatiable hunger And/or aromatic heterocycle, (r) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (S)-halogenated alkyl, (t)-(CR6R6)tOR6, (u) -O(CR6R6)tNR6R10, (v)-C (O) R6, (w)-SR6, (x)-C (O) OR10, (y)-S (O)pR6, (z)-(C1-8Alkane Base)-(containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles selected from nitrogen, oxygen and sulphur), (aa)- (C1-8Alkyl)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), (bb)-O (CR6R6)tOR6, (cc)-C (=NR6)NR6R6, (dd) -ONR6R6, (ee)-NR6C(O)NR6R6, (ff)-O (CR6R6)tOR6, (gg)-NR6C(O)R6, and (hh)- (CR6R6)tNR6R10
Wherein (n) to (r) and (z) to (aa) is optionally by one or more R10Substitution;
R10It is selected from:(a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i) -NO2, (j) -NR6R6, (k)-OR6, (l)-NR6(CNR6)NR6R6, (m)-C (O) (CR6R6)tNR6R6, (n)-C1-8Alkyl, (o)- C1-8Alkenyl, (p)-C1-8Alkynyl (q) contains one or more heteroatomic -3-14 members saturations for being selected from nitrogen, oxygen and sulphur, insatiable hunger And/or aromatic heterocycle, (r) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (S)-halogenated alkyl, (t)-(CR6R6)tOR6, (u) -O(CR6R6)tNR6R6, (v)-C (O) R6, (w)-SR6, (x)-C (O) OR6, (y)-S (O)pR6, (z)-(C1-8Alkane Base)-(containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles selected from nitrogen, oxygen and sulphur), (aa)- (C1-8Alkyl)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), (bb)-O (CR6R6)tOR6, (cc)-C (=NR6)NR6R6, (dd) -ONR6R6, (ee)-NR6C(O)NR6R6, (ff)-O (CR6R6)tOR6, (gg)-NR6C(O)R6, and (hh)- (CR6R6)tNR6R6
Optionally, wherein group-D-E-F or group-G-H-J are not present, but both-D-E-F and-G-H-J cannot simultaneously not In the presence of;
P is 0,1 or 2, and
T is 0,1,2 or 3,
Or its officinal salt, ester, tautomer or pro-drug.
In addition, the present invention provides the methods of synthesis above compound.After synthesis, can by the one of therapeutically effective amount or A variety of compounds are made into preparation with pharmaceutical acceptable carrier, are used as antimicrobial especially antiseptic, for giving human or animal. In certain embodiments, the compound of the present invention can be effectively used for treatment, prevents microorganism infection or reduce its danger, or use Its dangerous drug can be treated, prevents microorganism infection or reduce in preparing.Correspondingly, effective in order to be provided to human or animal The compound of amount, the compound or preparation can be given by following approach:It is oral, parenteral, intravenously, and ear, eyes, Nose or topic route.
It is in terms of the above and other of the present invention can be more fully understood and real with reference to following detailed description and claims Apply scheme.
Specific implementation mode
The present invention provides the chemical families that may be used as antimicrobial, are more specifically used as antiseptic.
The present invention includes its officinal salt, ester, tautomer, N- oxides and pro-drug.
Compounds described herein can have asymmetric center.It can be contained with optically active or racemic form separation There is the compounds of this invention of the atom of Asymmetrical substitute.In this field, optically active form how is prepared to be well-known, For example, racemic form is split, or synthesized with the starting material of optically active.Many geometry of alkene, C=N double bonds etc. Isomers can also exist in compounds described herein, and the isomers of all this stabilizations is included in the present invention In.This document describes the cis and trans geometric isomers of the compounds of this invention, and can be with the form of mixtures of isomers Or individually isomeric form detaches.All chiralitys, diastereomeric, racemic and the geometrical isomerism form of structure are object forms, Unless specifically indicating that specific spatial chemistry or isomeric form.Think all methods for being used to prepare the compounds of this invention and wherein The intermediate of preparation is the part of the present invention.It is additionally considered that all tautomers of indicated or description compound are this hairs A bright part.In addition, the invention also includes the metabolins of compound described herein.
The invention also includes all isotopes for the atom being present among the compounds of this invention.Isotope includes having phase Those of homoatomic ordinal number but mass number difference atom.As Typical examples (but not limited to), the isotope of hydrogen includes tritium and deuterium. The isotope of carbon includes C-13 and C-14.
When any variable is (for example, R6) when occurring more than primary in any component part or formula of compound, every Secondary definition when occurring with its it is any other occur when definition it is unrelated.As a result, for example, if showing group by one or more A R6Group replaces, then R6At each occurrence independently selected from R6Definition.Equally, substituent group and/or variable can combine, But condition is:This combination can generate stable compound within the scope of the atom common fare indicated.
Display indicates that the chemical constitution of the dotted line of chemical bond exists with showing the key option.For example, being located next to solid line singly-bound The dotted line drawn shows that the key can be singly-bound, can also be double bond.
When the key table of substituent group is shown as intersecting with the key of two atoms in connection ring, then this substituent group can on ring Any atomistic binding.When list substituent group without show this substituent group and given chemical formula compound rest part Bonding by atom in the case of, this substituent group can pass through any atomistic binding in this substituent group.Substituent group And/or variable can combine, but condition is:This combination can generate stable compound.
In the compounds of this invention have nitrogen-atoms in the case of, if applicable, by with oxidant (for example, MCPBA and/or hydrogen peroxide) it handles, these nitrogen-atoms can be changed into N- oxides.Thus, it is believed that shown and requirement Nitrogen-atoms includes N- oxides (N → O) derivative (depending on the circumstances) of shown nitrogen and it.
A method for developing improved antiproliferative and anti-infectious agent is to provide the conditioning agent of ribose body function and (such as inhibits Agent).
Ribosomes is ribonucleoprotein, is present in prokaryotes and eucaryote.Ribosomes is responsible for protein conjunction At organelle.During gene expression, the hereditary information encoded in mRNA is translated in albumen by ribosomes (GarrettEt al.(2000)“The Ribosome: Structure, Function, Antibiotics and Cellular Interactions,” American Society for Microbiology, Washington, D.C.)。
Ribosomes includes two non-equivalent ribonucleoprotein subunits.(also known as " large ribosomal is sub- single for larger subunit Position ") size be about compared with twice of little subunit (also known as " small ribosomal subunit ").Small ribosomal subunit combines courier RNA (mRNA), and mediate the phase interaction between mRNA and transfer RNA (tRNA) anticodon (it determines the fidelity of translation) With.Large ribosomal subunit catalysis peptide bond is formed, that is, peptide acyl-transfer enzyme reaction of protein synthesis, and include at least three Different tRNA binding sites (be known as aminoacyl, peptide acyl and exit position).The ammonia introduced is received at aminoacyl site or the positions A Its amino acid can be supplied to the peptide chain of growth by acyl-tRNA.In addition, the intervals A at the positions A are important.Peptidyl site Or P receiving peptide acyl-tRNA compounds, that is, the tRNA with its amino acid is the part for increasing peptide chain.In deacylation After tRNA provides its amino acid to the polypeptide chain increased, exits position or the positions E- and receive deacylated tRNA.
1. definition
" isomerism " refers to having identical molecular formula but in the bonding of property or their atom sequence or their original Different compound in terms of the arrangement of subspace.Different isomers is known as " alloisomerism in terms of their steric arrangement Body ".Be not each other mirror image stereoisomer be known as " diastereoisomer ", be the stereoisomer of non-overlapping mirror image each other Referred to as " enantiomer ", or sometimes referred to as optical isomer.The carbon atom that the substituent group different with four is bonded is known as " in chiral The heart ".
" chiral isomer " refers to the compound for having at least one chiral centre.There are two opposite-handed mappings for its tool Body form, and can exist with individual enantiomers or the form of mixtures of enantiomer.It is right containing the opposite-handed independence of equivalent The mixture for reflecting body form is known as " racemic mixture ".Compound with more than one chiral centre is with 2n-1A mapping Body pair, wherein n are chiral centre numbers.Compound with more than one chiral centre can be with independent diastereomer or non-right The mixture for reflecting body (is known as " mixture of diastereomers ") form presence.When there are a chiral centre, stereoisomer can be with It is characterized by the absolute configuration (R or S) of the chiral centre.Absolute configuration refers to the space for the substituent group being connect with chiral centre Arrangement mode.The substituent group being connect with the chiral centre in consideration is arranged according to the Cahn-Ingold-Prelog sequence rule of Cahn, Ingold and Prelog Sequence (Cahn et al.,Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511;Cahn et al.,Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al.,Experientia 1956, 12, 81; Cahn, J., Chem. Educ. 1964, 41, 116)。
" geometric isomer " refers to that its presence is since around double bond, there is the diastereomers of interrupted rotation.At these Indicate that group exists by prefixes cis and trans- or Z and E to distinguish these configurations, cis and trans or Z and E in the title of configuration The homonymy or offside of double bond in molecule (according to Cahn-Ingold-Prelog rules).
Further, structure discussed herein and other compounds include its all reversions (atropic) isomery Body." reversion isomers " is the different stereoisomeric forms of the space arrangement of the atom of two isomers.Invert isomers In the presence of be due to by hinder center key around macoradical rotation by cause hinder rotation effect.This reversion isomers typically with Mixture form exists, however, due to the development of recent chromatographic technique, it is already possible to two reversions of separation in the case of selected The mixture of isomers.
" tautomer " refers to structure compound dramatically different in terms of atomic arrangement, but it is with easy and quick Equilibrium form exist.It should be understood that the compound of the present invention can be described as to different tautomers.It should also manage Solution, when compound has tautomeric form, all tautomeric forms within the scope of the present invention, and the compound Name be not excluded for any tautomeric form.
Some present invention of the present invention may exist tautomeric form, these tautomeric forms are also included within the present invention In range.
The compound of the present invention, salt and pro-drug can exist with some tautomeric forms, including enol and imines shape Formula and ketone and enamine form and its geometric isomer and mixture.All this tautomeric forms are included in the scope of the invention It is interior.In the solution, tautomer exists in the form of the mixture of one group of tautomer.It is usually a kind of in solid form Tautomer is dominant.Even if a kind of tautomer may only be described, but the present invention includes all of the compounds of this invention Tautomer.
Tautomer is one kind in two or more constitutional isomers, they evenly exist, and is easy from one Kind isomeric form is transformed into another isomeric form.This reaction causes the form of hydrogen atom to migrate, while with adjacent conjugation The conversion of double bond.In it the solution of tautomerization may occur, the chemical balance of tautomer can be reached.Tautomerism The definite ratio of body depends on some factors, including temperature, solvent and pH value.Pass through the change that tautomerization mutually converts The concept of isomers is referred to as tautomerism.
In the various types of possible tautomerism, two kinds of patterns are usually can observe.It mutually makes a variation in keto-enol In structure, while there is the movement of electronics and hydrogen atom.Glucose shows ring-chain tautomerism phenomenon.It is due to sugar chain point Aldehyde radical (- CHO) in son is reacted with a hydroxyl (- OH) in identical molecule, obtains the result of ring (ring-type) form.
Tautomerization can be catalyzed by following substance: alkali: 1. deprotonations;2. formation delocalization anion (such as enolization Object);3. the protonation of the different location of anion;Acid: 1. protonations;2. forming delocalization cation;3. not close to cation With the deprotonation of position.
Common tautomerism is to being: keto-enol, amide-nitrile, lactams-lactim, amide-imines in heterocycle Sour tautomerism (for example, in nucleobase guanine, thymidine and cytimidine), amine-ene amine and enamine-enamine.Below one For illustrative purposes, the present invention is not limited to the embodiment to a embodiment:
Term " crystal polymorph " or " polymorph " or " crystal form " they refer to crystal structure, in this configuration, Compound (or its salt or solvate) can be crystallized in the form of different crystal packing arrangements, and all crystal all have identical Element composition.Different crystal form usually have different X-ray diffractograms, infrared spectrum, fusing point, density hardness, crystalline form, Optical activity and electrical property, stability and solubility.Recrystallization solvent, crystalline rate, storage temperature and other factors can cause A kind of crystal habit is dominant.It can be by crystallizing the crystal polymorph come prepare compound at different conditions.
Terms used herein " substitution " refer to:On specified atom (be typically carbon, oxygen or nitrogen-atoms) any one or Multiple hydrogen are replaced selected from specified group, and condition is to be no more than the normal chemical valence of specified atom, and the substitution generates surely Fixed compound.When substituent group is ketone group (that is,=O), then 2 hydrogen on the atom are substituted.Ring double bond used herein is The double bond formed between two adjacent cyclic atoms (for example, C=C, C=N, N=N etc.).
Terms used herein " anomeric carbon " refer to the acetal carbon of glucosides.
Terms used herein " glucosides " are cyclic acetals.
Terms used herein " alkyl " include having specific carbon atom number purpose branch and straight chain saturated fat hydrocarbyl group. For example, C1-6Alkyl includes C1、C2、C3、C4、C5And C6Alkyl.Some examples of alkyl include but is not limited to:Methyl, ethyl, N-propyl, isopropyl, normal-butyl, sec-butyl, tertiary butyl, n-pentyl, sec-amyl, n-hexyl, n-heptyl and n-octyl.
" alkenyl " used herein includes the hydrocarbon chain of straight chain or branched chain and one or more unsaturated carbon-carbon bonds, no Saturation carbon-carbon bond can reside in any stable point along chain, such as vinyl and acrylic.For example, C2-6Alkenyl includes C2、C3、C4、C5And C6Alkenyl.
" alkynyl " used herein includes the hydrocarbon chain of straight chain or branched chain and one or more carbon-carbon triple bonds, carbon-to-carbon Three keys can reside in any stable point along chain, such as acetenyl and propinyl.For example, C2-6Alkynyl includes C2、C3、C4、 C5And C6Alkynyl.
In addition, " alkyl ", " alkenyl " and " alkynyl " includes radical moieties, that is, there are two tie points for tool, in the present invention An example be when D be selected from these chemical groups when.The non-limitative example of this moieties (biradical) is- CH2CH2, that is, pass through the C of each terminal carbon and the rest part covalent bonding of molecule2Alkyl.ALkyl diradicals are also known as " sub- Alkyl " atomic group.Biradical also known as " alkenylene " atomic group of alkenyl.Biradical also known as " alkynylene " atomic group of alkynyl.
Terms used herein " naphthenic base " include saturation cyclic group, such as cyclopropyl, cyclobutyl or cyclopenta.C3-8Ring Alkyl includes C3、C4、C5、C6、C7And C8Naphthenic base.
" counter ion " used herein refers to positively charged or negatively charged existing for ions binding with opposite charges Type.The non-limitative example of counter ion is the ion that balance is provided to the charge on organic compound.Counter ion it is unrestricted Property example includes:Chlorion, bromide ion, hydroxyl, acetate, sulfate radical and ammonium.
" halogen " or " halo " used herein refers to fluorine, chlorine, bromine and iodine substituent group.
" halogenated alkyl " used herein includes branch having specific number carbon atom, being replaced by one or more halogens Chain and straight chain saturated fat hydrocarbyl group (for example,-CvFw, wherein v=1 to 3, w=1 to (2v+1)).The example of halogenated alkyl includes But it is not limited to:Trifluoromethyl, trichloromethyl, pentafluoroethyl group and five chloroethyls.
" alkoxy " used herein refer to connected by oxygen bridge, with the abovementioned alkyl for specifying number carbon atom.C1-6 Alkoxy includes C1、C2、C3、C4、C5And C6Alkoxy.C1-8Alkoxy includes C1、C2、C3、C4、C5、C6、C7And C8Alkoxy.Alkane The example of oxygroup includes but is not limited to:Methoxyl group, ethyoxyl, positive propoxy, iso- propoxyl group, n-butoxy, sec-butoxy, Tert-butoxy, n-pentyloxy, secondary amoxy, positive oxygroup in heptan and n-octyloxy.
" alkylthio group " used herein refer to connected by sulphur bridge, with the abovementioned alkyl for specifying number carbon atom.C1-6 Alkylthio group includes C1、C2、C3、C4、C5And C6Alkylthio group.C1-8Alkylthio group includes C1、C2、C3、C4、C5、C6、C7And C8Alkylthio group.
Unless otherwise noted, " carbocyclic ring " used herein or " carbocyclic ring class ring " refer to any stabilization 3,4,5,6, 7,8,9,10,11 or 12 unit monocycles, bicyclic or tricyclic, any of which one can be saturation, it is unsaturated (including partially and fully It is unsaturated) or aromatic carbocyclic.The example of this carbocyclic ring includes but is not limited to:Cyclopropyl, cyclobutyl, cyclobutane base, cyclopenta, Cyclopentenyl, cyclohexyl, cyclohexenyl group, suberyl, cycloheptenyl, adamantyl, cyclooctyl, cyclo-octene base, cyclo-octadiene base, [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclic decane, [2.2.2] bicyclooctane, fluorenyl, phenyl, naphthalene Base, indanyl, adamantyl and tetralyl.As described above, bridged ring is also included in the definition of carbocyclic ring (for example, [2.2.2] two Cyclooctane).When one or more carbon atoms connect two non-conterminous carbon atoms, there is bridged ring.Preferred bridge is one or two A carbon atom.It will be noted that bridge always makes monocycle be converted into tricyclic.When ring is bridged ring, the substituent group of cited ring It can reside on bridge.Further include condensed ring (such as naphthalene and tetralyl) and loop coil.
Unless otherwise noted, terms used herein " heterocycle " refer to stable 3,4,5,6,7,8,9,10,11 or 12 unit monocycles, bicyclic or tricyclic are saturation, unsaturated (including partially and fully unsaturated) or aromatic heterocycle, by carbon atom It is formed with one or more ring hetero atoms, for example, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 hetero atom, miscellaneous Atom includes any bicyclic or three cyclic groups independently selected from nitrogen, oxygen and sulphur, in this bicyclic or three cyclic groups, is appointed What heterocycle as defined above is condensed or is connect with second ring (for example, phenyl ring).Nitrogen and sulfur heteroatom can be aoxidized optionally (that is, N → O and S (O)p, wherein p=1 or 2).When nitrogen-atoms is included in ring, whether it is connected with the double bond in ring according to it Connect, either N, can also be NH (that is, if necessary to keep nitrogen-atoms three chemical valences, then there is hydrogen).Nitrogen-atoms can To be substituted or unsubstituted (that is, N or NR, wherein R are the other substituent groups of H or defined).Heterocycle can produce It is connected with its side group on any hetero atom or carbon atom of raw rock-steady structure.If obtained compound is stable chemical combination Object, then heterocycle described herein can be substituted on carbon or nitrogen.Miscellaneous nuclear nitrogen can be optionally quaternized.Bridged ring further includes In the definition of heterocycle.When one or more atoms (that is, C, O, N or S) connect two non-conterminous carbon or nitrogen-atoms, occur Bridged ring.Preferably bridge includes but is not limited to:One carbon atom, two carbon atoms, a nitrogen-atoms, two nitrogen-atoms and carbon- Nitrogen groups.When ring is bridged ring, the substituent group of cited ring can also exist on bridge.Further include loop coil and fused rings.
Terms used herein " aromatic heterocycle " or " heteroaryl " refer to 5,6,7,8,9,10,11 or 12 unit monocycles of stabilization Or Bicyclic ring, it is made of carbon atom and one or more hetero atoms, for example, 1 or 1-2 or 1-3 or 1-4 or 1- 5 or 1-6 hetero atom, hetero atom is independently selected from nitrogen, oxygen and sulphur.In the case of bicyclic heterocycle aromatic rings, in two rings Only require that a ring is aromatic rings (for example, 2,3- indoline), but two rings can also all be aromatic rings (for example, quinoline). Second ring, which can also be, condenses or bridges ring defined in heterocycle above.Nitrogen-atoms can be substituted or unsubstituted (that is, N or NR, wherein R are another substituent groups of H or defined).Nitrogen and sulfur heteroatom can be optionally by oxidation (that is, N → O and S (O)p, wherein p=1 or 2).In certain compounds, the sum of S and O atom in aromatic heterocycle are no more than 1.
The example of heterocycle includes but is not limited to:Acridinyl, azabicyclo caprylyl (azabicycleoctanonyl), Nitrogen heterocyclic heptyl, azetidinyl, azocine base, benzimidazolyl, benzofuranyl, benzimidazole thiophanate furyl, benzo thiophene Pheno base, benzoxazolyl, benzoxazole quinoline base, benzothiazolyl, benzotriazole base, benzo tetrazole radical, benzoxazine, benzene And isothiazolyl, benzimidazoline base, benzodioxole group (benzodioxoly), Ben Bing oxadiazolyl, carbazole Base, 4aH- carbazyls, carboline base, Chromanyl, chromene base, cinnoline base, suberyl, decahydroquinolyl, dihydrobenzo bioxin base, 2H, 6H-1,5,2- dithiazine bases, dihydrofuran is simultaneously【2,3-b】Tetrahydrofuran, furyl, furazanyl, imidazolidinyl, imidazolidine Base imines(imidazolidinylimine), imidazolinyl, imidazole radicals, imidazoles ketone group, 1H- indazolyls, indolenyl, indoles Quinoline base (indolinyl), indenes piperazine base(indilizinyl), indyl, 3H- indyls, isatin base (isatinoyl), Isobenzofuran-base, isochroman base, iso indazolyl, isoindolinyl, isoindolyl, isoquinolyl, isothiazole Base, isoxazolyl, methylenedioxyphenyl base, methylbenzotrazole base, methylfuran base, methylimidazolyl, methyl thiazolium oxazolyl, Morpholinyl, naphthyridines base, octahydro isoquinolyl , oxadiazolyls, 1,2,3- oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5- Evil bis- Oxazolyl, 1,3,4- oxadiazolyl, oxazolidine radical, oxazolidine ketone group, oxazolyl, hydroxyindole base, phenanthridinyl, ferrosin base (phenanthrolinyl), phenazinyl, phenothiazinyl (phenothiazinyl), phenoxanthein base(phenoxathinyl), pheno Oxazinyl, phthalazinyl, piperazinyl, piperazine ketone group (piperazinonyl), piperidyl, tetrahydro pyridyl (piperidenyl), Piperidone base, 4- piperidone bases, piperonyl, pteridine radicals, purine radicals, pyranose, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazoles Base, pyridazinyl, Bi Ding Bing oxazolyls, pyridine-imidazole base, pyridothiazole base, pyridyl group, pyriconyl (pyridinonyl), pyridyl group, pyrimidine radicals, pyrrolidone-base(pyrroldionyl), pyrrolidinyl, pyrrolidone-base, pyrroles Quinoline base, 2H- pyrrole radicals, pyrrole radicals, quinazolyl, quinolyl, 4H- quinazinyls, quinoxalinyl, quininuclidinyl, tetrahydrofuran base, Tetrahydro isoquinolyl, tetrahydric quinoline group, tetrazole radical, 6H-1,2,5- thiadiazine bases, 1,2,3- thiadiazolyl group, 1,2,4- thiadiazoles Base, 1,2,5- thiadiazolyl group, 1,3,4- thiadiazolyl group, thianthrene group, thiazolyl, thienyl, thiophene benzothiazolyl, thiophene pheno and oxazole Base, Thienoimidazole base, thienyl (thiophenyl), thiomorpholine base dioxide(thiomorpholinyl dioxidyl), triazine radical, triazolopyrimidinyl, 1,2,3-triazoles base, 1,2,4- triazolyl, 1,2,5- triazolyl, 1,3,4- tri- Oxazolyl and xanthyl.
Terms used herein " pharmaceutically acceptable " refer to:In reliable medical judgment scope, the tissue with patient is suitble to connect Touch but inexcessive toxicity, irritation, allergy or other problems or complication those compounds, raw material, composition and/ Or dosage form, match with rational benefit/hazard ratio.
" officinal salt " used herein refers to that the derivative of disclosed compound, wherein parent compound pass through production Its acid or basic salt and be changed.The example of officinal salt includes but is not limited to:Alkaline residue (such as amine) it is inorganic Or acylate;The alkali metal or organic salt of acidic residues (such as carboxylic acid);Etc..Officinal salt includes the normal of parent compound Nontoxic salts or quaternary ammonium salt are advised, for example, the salt formed by nontoxic inorganic or organic acid.For example, this conventional non-toxic salts include but It is not limited to derived from selected from those of following inorganic and organic acid salt:Aspirin, 2- hydroxyethanesulfonic acids, Acetic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, two carbonic acid, carbonic acid, citric acid, edetic acid(EDTA), ethionic acid, ethanesulfonic acid, fumaric acid, Glucoheptonic acid, gluconic acid, Glutamic Acid, glycol acid, glycollyl Arsanilic Acid(glycollyarsanilic), hexylresorcinol two Phenolic acid (hexylresorcinic), hydrabamic, hydrobromic acid, hydrochloric acid, hydriodate, hydroxymaleic acid, carbonaphthoic acid, hydroxyl Ethanesulfonic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthalene sulfonic acids(napsylic), nitre Acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, secondary acetic acid (subacetic), succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid and toluenesulfonic acid.
Conventional chemical processes can be utilized, by the parent compound containing alkalinity or acidic moiety synthesize it is of the invention can medicine Use salt.In general, this salt can be prepared as follows:In water or organic solvent, or in the mixture of the two, these compounds Free acid or alkali form are reacted with the suitable alkali of stoichiometric or acid;Generally, it is preferred to non-aqueous media, for example, ether, acetic acid Ethyl ester, ethyl alcohol, isopropanol or acetonitrile.The detail list of acceptable acid addition salts can obtain in following:Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, USA, p. 1445(1990)。
Since many desirable quality of drug can be improved (for example, solubility, biological utilisation in known precursors drug Rate, prepare, etc.), so, the compound of the present invention can be delivered with prodrug form.The present invention includes being advocated as a result, The pro-drug of compound delivers its method and the composition containing it." pro-drug " includes any covalently bound load Body discharges the active parent drug of the present invention in vivo when giving this pro-drug to mammalian subject.By repairing The functional group that is present in compound is adornd to prepare the pro-drug of the present invention, method used can make the modification in conventional behaviour In work or fracture in vivo obtains parent compound.Pro-drug include the compounds of this invention hydroxyl, amino or sulfydryl with it is any The compounds of this invention that group combines, when giving the pro-drug of the mammalian subject present invention, this group fracture, respectively Form free hydroxyl group, free amine group or free sulfhydryl groups.The example of pro-drug includes but is not limited to:In the compounds of this invention The acetic acid esters or salt of alkohol and amine functional group, formic acid esters or salt and benzoic acid or salt ester derivant.
" stable compound " and " rock-steady structure " used herein refer to fully firm compound, can be stood from anti- It answers in mixture and detaches to effective purity, and can be formulated as effective therapeutic agent.
Terms used herein " patient " refer to that may perform the operation or the human or animal of invasive medical procedures is (in animal In the case of, more typically mammal) patient.It is considered that this patient or subject need to reduce surgical procedure or invade The dangerous method of entering property method, or the method that prevents the infection caused by surgical procedure or invasive method.It can be with Think that this patient or subject need the prevention in peri-operation period.
Terms used herein " treatment " refer to cure or improve the therapeutic intervention of infection and offer.
Terms used herein " prevention " refer to completely or almost completely terminating infection to occur, for example, working as patient or tested Person tends to infect or when among the risk of infection.Prevent include inhibiting infection, that is, the development to prevent infections.
Terms used herein " reduce dangerous " refer to reduce the possibility or probability that infection occurs, for example, as patient or Subject tends to infect or when among the risk of infection.
" unsaturation " used herein refers to having the compound of at least one degree of unsaturation (for example, at least one multiple Key), and include partially and fully unsaturated compound.
Terms used herein " effective quantity " refer to of the invention when being administered effective alone or in combination as antimicrobial The quantity of the composition of compound or the compounds of this invention.For example, effective quantity refers to being present in give to receive patient or subject Composition, the compound amounts in preparation or medical apparatus, be enough to cause bioactivity, for example, anti-infection activity, example Such as, antimicrobial acivity, antibacterial activity, Antifungal action, antiviral activity or Antiparasitic Activity.
Term " prevention effective dose " refers to the effective quantity of the compounds of this invention to be administered, this effective quantity for prevent by Infection caused by surgical procedure or invasive medical procedures reduces its danger.
It further understands, states " hydrogen bond receptor-hydrogen bond receptor-hydrogen-bond donor " and " hydrogen bond receptor-hydrogen bond receptor-hydrogen bond Receptor " refers to hydrogen bond receptor and the relative orientation of donor, does not imply that this group of limitation is directly linked together, because at this May include other atoms or atomic group between kind group.
In this specification, singulative further includes plural number, unless being clearly dictated otherwise in context.Unless in addition fixed There are those skilled in the art usually to manage for justice, otherwise, all technologies and scientific term used herein The identical meanings of solution.It is subject to the present specification in the case that contradictory." mammal " used herein refers to people and inhuman trouble Person.
Terms used herein " therapeutically effective amount " refer to the compounds of this invention for being supplied to recipient or chemical combination of the present invention The composition quantity of object, which is enough to cause bioactivity, for example, antimicrobial acivity, Antifungal action, antiviral work Property, Antiparasitic Activity, anti diarrhea activity and/or antiproliferative activity.It is preferred that the combination of compound is the combination of synergistic effect. When the effect for the compound that combination is given is more than the additive effect for the compound individually given with single medicine type, for example, The described synergistic effect of Chou and Talalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984) Occur.In general, under the suboptimum concentration of compound, it will act synergistically most apparent from performance.Synergistic effect can reduce thin Cellular toxicity improves antiproliferative and/or anti-infection effect, or some other advantageous effect of combination (compared with one-component).
Terms used herein " the micro- spirals of RNA (microhelix) binding site " refer to shared by the micro- spirals of RNA of formula III According to large ribosomal subunit the position kernel function (ribofunctional).The micro- thread joint locator qualifications of RNA at least one The part sites E- are Chong Die with the positions E-.
Terms used herein " positions A " refer to just participating in its institute before peptide combination forms reaction in aminoacyl tRNA molecules The kernel function position occupied.
Terms used herein " positions E- " refer to deacylated tRNA participate in peptide combine form reaction after occupied by it Kernel function position.
Terms used herein " positions P- " refer to participating in peptide bond in peptidyl tRNA to constitute the when of reacting, by peptide acyl-tRNA institutes The kernel function position occupied.
Terms used herein " intervals A- " refer to the amino acid moiety knot in peptidyl transferase core alanyl t-RNA Together in A site portions therein, or refer to that the oxazolidone ring of Linezolid (linezolid) is incorporated into the positions A therein Part.
When using and refer to herein ribosomes or ribosomal subunit, term " part " or " part for three-dimensional structure " can It is understood as referring to a part for ribosomes or ribosomal subunit's three-dimensional structure, including distribution of charges and hydrophilic/hydrophobic spy Property, by least three, more preferably at least three to ten, and most preferably at least ten amino acid residues and/or ribosomes or core The nucleotide residue of Tang Ti subunits is constituted.Constituting the residue of this part can be, for example, (i) being based on such as rRNA Or the consecutive residue of the primary sequence of ribosomal protein, (ii) constitute the continuous portion of ribosomes or ribosomal subunit's three-dimensional structure The residue divided, or (c) a combination thereof.When using and refer to herein the micro- spirals of RNA, term " part " or " part for three-dimensional structure " Can be regarded as refer to the micro- helix three-dimensional structures of RNA a part, including distribution of charges and hydrophilic/hydrophobic characteristic, by formula III One or more parent nucleus residues at least three, more preferably at least three to ten atomic buildings.Constitute the original of this part Son can be, for example, the inaccessible atom of solvent that (i) the micro- spiral parent nucleus of RNA is embedded in, the solvent of the micro- spirals of (ii) RNA Accessible atom, or (iii) a combination thereof.
All percentages used herein and ratio are by weight unless otherwise stated.
Through the specification, when composition with have including or when being described comprising specific component, or when method is to have Have including or refer to the composition of the present invention also includes the component substantially by enumerating when being described comprising specific method and step Composition, or be grouped as by enumerating group, and the method for the present invention is also substantially made of the processing step enumerated, or by processing step Composition.Further, it should be appreciated that the sequence of step or the sequence for carrying out certain operations are unsubstantialities, as long as the present invention is still It is operable.In addition, two or more steps or operation can be carried out at the same time.
2. the compound of the present invention
The present invention provides the compounds with having structure:
WhereinIt is to be selected from following chemical part:
,,
, or,
WhereinIndicate condensed 5 to 7 yuan of saturations, insatiable hunger and/or aromatic carbocyclic or heterocyclic ring system,
Wherein T1It is carbon atom or N, then works as T1When being N ,-D-E-F is not present,
Wherein T2It is carbon atom or N, then works as T2When being N ,-G-H-J is not present,
Wherein T1And T2It is N when two differences,
Wherein V is independently selected from-CR4aOr-N-,
W is O, NR1, NOR1Or S or W=combination or two selected from the HO- and both H- all being connect with identical carbon atoms The combination for (C1-8 alkyl) O- and H- that person connect with identical carbon atoms;
X---Y indicates singly-bound or double bond, then works as X---When Y is singly-bound, X is selected from O, NR2With S (O)n, Y is C-R3, when X---When Y is double bond, X is N, and Y is carbon atom,
Z is selected from O, NR4, S (O)nOr NH,
R1Selected from H and C1-8Alkyl,
R2Selected from H and C1-8Alkyl,
R3Selected from H and C1-8Alkyl,
R4Selected from H and C1-8Alkyl,
R4aSelected from H and C1-8Alkyl,
N is 0,1 or 2,
Or its officinal salt, ester, tautomer or pro-drug.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, whereinFurther include hydrogen-bond donor part or other hydrogen bond receptors part.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, whereinIt is the chemical part for including at least two hydrogen bond receptor parts and at least one hydrogen-bond donor part.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, wherein hydrogen bond receptor part and hydrogen-bond donor are partially in following direction:
Hydrogen bond receptor-hydrogen bond receptor-hydrogen-bond donor.
The term " direction being in ... " used above, which does not refer to hydrogen-bond donor or acceptor portion, must be connected directly between one It rises, because may exist other atoms or atomic group among hydrogen-bond donor or acceptor portion.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, wherein hydrogen bond receptor part are each other within the scope of 5 and hydrogen-bond donor part is within the scope of the 5 of hydrogen bond receptor part.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, wherein hydrogen bond receptor part are each other within the scope of 3 and hydrogen-bond donor part is within the scope of the 3 of hydrogen bond receptor part.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, wherein hydrogen bond receptor are partly comprised in cyclic structure, wherein the cyclic structure is single ring architecture or condensed polycyclic knot Structure.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, whereinIt is the chemical part for including at least three hydrogen bond receptor parts.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, wherein hydrogen bond receptor are partially in following direction:
Hydrogen bond receptor-hydrogen bond receptor-hydrogen bond receptor.
The term " direction being in ... " used above, which does not refer to hydrogen-bond donor or acceptor portion, must be connected directly between one It rises, because may exist other atoms or atomic group between hydrogen bond receptor.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, wherein each hydrogen bond receptor part is within the scope of about the 5 of at least one other hydrogen bond receptor part.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, wherein each hydrogen bond receptor part is within the scope of about the 3 of at least one other hydrogen bond receptor part.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, wherein at least two hydrogen bond receptor are partly comprised in cyclic structure, wherein the cyclic structure is single ring architecture or condenses Multiring structure.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, wherein the hydrogen bond receptor part is independently selected from carbonyl, thiocarbonyl, imine group, alkyl-substituted imine group, Asia The hydrazone groups of sulfone group, sulfone group, oximido group, alkyl-substituted oximido group, hydrazone groups, monoalkyl or dialkyl group substitution, oxygen ether The amino of (- O-) group, sulfide (also known as sulfide group (- S-)), hydroxyl, alkoxy, amino, monoalkyl or dialkyl group substitution And nitro.
In some embodiments, the present invention relates to compound, its officinal salt, ester, tautomer or pro-drug, The wherein described hydrogen-bond donor part is selected from hydroxyl, mercapto, amino and mono-substituted amino.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, wherein
Including having structure part
Wherein W is O, NR1, NOR1Or S or W=combination selected from the HO- and H- both being connect with identical carbon atoms, Or both the combination of (C1-8 alkyl) O- and H- that is all connect with identical carbon atoms;
X---Y indicates singly-bound or double bond, then works as X---When Y is singly-bound, X is selected from O, NR2With S (O)n, Y is C-R3, when X---When Y is double bond, X is N, and Y is carbon atom,
Z is selected from O, NR4Or S (O)n,
R1Selected from H and C1-8Alkyl,
R2Selected from H and C1-8Alkyl,
R3Selected from H and C1-8Alkyl,
R4Selected from H and C1-8Alkyl,
N is 0,1 or 2.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, wherein W are O, NR1, NOR1Or S;Wherein R4Selected from hydrogen and C1-6Alkyl.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, wherein
Including having structure part
Wherein Z is selected from O, NR4Or S (O)n
R4Selected from hydrogen and C1-6Alkyl,
With
N is 0,1 and 2.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, wherein
Including having structure part
Wherein R4Selected from hydrogen and C1-6Alkyl.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, wherein R4It is hydrogen.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, wherein
Including pyrrolo- cytimidine part or derivatives thereof.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, wherein R4It is hydrogen.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, wherein
Including having structure part
, ,
, ,
,
, or
WhereinIndicate condensed 5 to 7 yuan of saturations, insatiable hunger and/or aromatic carbocyclic or heterocyclic ring system,
Wherein V is independently selected from-CR4aOr-N-,
W is O, NR1, NOR1Or S or W=combination or two selected from the HO- and H- both being connect with identical carbon atoms The combination for (C1-8 alkyl) O- and H- that person connect with identical carbon atoms;
X---Y indicates singly-bound or double bond, then works as X---When Y is singly-bound, X is selected from O, NR2With S (O)n, Y is C-R3, when X---When Y is double bond, X is N, and Y is carbon atom,
Z is selected from O, NR4, S (O)nOr NH,
R1Selected from H and C1-8Alkyl,
R2Selected from H and C1-8Alkyl,
R3Selected from H and C1-8Alkyl,
R4Selected from H and C1-8Alkyl,
R4aSelected from H and C1-8Alkyl,
N is 0,1 or 2.
In some embodiments, the present invention relates to the compounds of following formula:
(I), (II),
(III), or (IV),
WhereinIndicate condensed 5 to 7 yuan of saturations, insatiable hunger and/or aromatic carbocyclic or heterocyclic ring system,
Wherein T1It is carbon atom or N, then works as T1When being N ,-D-E-F is not present,
Wherein T2It is carbon atom or N, then works as T2When being N ,-G-H-J is not present,
Wherein T1And T2It is N when two differences,
Wherein V is independently selected from-CR4aOr-N-,
W is O, NR1, NOR1Or S or W=combination or two selected from the HO- and H- both being connect with identical carbon atoms The combination for (C1-8 alkyl) O- and H- that person connect with identical carbon atoms;
X---Y indicates singly-bound or double bond, then works as X---When Y is singly-bound, X is selected from O, NR2With S (O)n, Y is C-R3, when X---When Y is double bond, X is N, and Y is carbon atom,
Z is selected from O, NR4, S (O)nOr NH,
R1Selected from H and C1-8Alkyl,
R2Selected from H and C1-8Alkyl,
R3Selected from H and C1-8Alkyl,
R4Selected from H and C1-8Alkyl,
R4aSelected from H and C1-8Alkyl,
N is 0,1 or 2,
Or-G-H-J is selected from
,
Wherein each H and J is selected independently,
C-B-A- ,-D-E-F and-G-H-J are chemical parts, wherein
A, D and G independently selected from:
(a) singly-bound, (b)-(C1-8Alkyl)-, (c)-(C2-8Alkenyl)-, (d)-(C2-8Alkynyl)-, wherein
I) 0-4 carbon atom in any one of (b) just mentioned above-(d) is optionally replaced selected from following part Generation:- O- ,-S (O)p,-NR6,-(C=O)-,-S (O)pNR6,-NR6S(O)pAnd-NR6S(O)pNR6,
Ii) any one of (b) just mentioned above-(d) is optionally by one or more R5Group replaces, and
Iii) any one of (b) just mentioned above-(d) is optionally by-(C1-8Alkyl)-R5Group replaces;
(e)-O-, (f)-NR6, (g)-S (O)p, (h)-C (O)-, (i)-C (O) O-, (j)-OC (O)-, k)- OC (O) O-, (l)-C (O) NR6, (m)-NR6CO-, (n) -NR6C(O)NR6, (o)-C (=NR6)-, (p)-C (=NR6) O-, (q) -OC(=NR6)-, (r)-C (=NR6)NR6, (s)-NR6C(=NR6)-, (t)-C (=S)-, (u)-C (=S) NR6, (v)-NR6C (=S)-, (w)-C (O) S-, (x)-SC (O)-, (y)-OC (=S)-, (z)-C (=S) O-, (aa)- NR6(CNR6)NR6, (bb)-CR6R6C (O)-, (cc)-C (O) NR6(CR6R6)t, (dd) is containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycle, the hetero atom are selected from nitrogen, oxygen and sulphur,
(ee) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, and
(ff) -(CR6R6)t,
Wherein (dd) or (ee) are optionally by one or more R5Group replaces;
B, E and H independently selected from:
(a) singly-bound,
(b) contain one or more heteroatomic 3-14 members saturations, insatiable hunger and/or aromatic heterocycle, the hetero atom to be selected from Nitrogen, oxygen and sulphur,
(c) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic,
Wherein (b) or (c) optionally by one or more R5Group replaces;
(d) -(C1-8Alkyl)-, (e)-(C2-8Alkenyl)-, (f)-(C2-8Alkynyl)-, wherein
I) 0-4 carbon atom in any one of (d) just mentioned above-(f) is optionally replaced selected from following part Generation:- O- ,-S (O)p,-NR6,-(C=O)-,-C (=NR6) -,-S(O)pNR6,-NR6S(O)pAnd-NR6S(O)pNR6,
Ii) any one of (d) just mentioned above-(f) is optionally by one or more R5Group replaces, and
Iii) any one of (d) just mentioned above-(f) is optionally by-(C1-8Alkyl)-R5Group replaces;
(g)-(CR6R6)t,
C, F and J independently selected from:
(a) hydrogen, (c) F, (d) Cl, (e) Br, (f) I, (g)-CF3, (h)-CN, (i)-N3(j) -NO2, (k)-NR6 (CR6R6)tR8, (l)-OR8, (m)-S (O)p(CR6R6)tR8, (n)-C (O) (CR6R6)tR8, (o)-OC (O) (CR6R6)tR8, (p) -SC(O)(CR6R6)tR8, (q)-C (O) O (CR6R6)tR8, (r)-NR6C(O)(CR6R6)tR8, (s)-C (O) NR6 (CR6R6)tR8, (t)-C (=NR6)(CR6R6)tR8, (u)-C (=NNR6R6)(CR6R6)tR8, (v)-C (=NNR6C(O)R6) (CR6R6)tR8, (w)-C (=NOR8)(CR6R6)tR8, (x)-NR6C(O)O(CR6R6)tR8, (y)-OC (O) NR6(CR6R6)tR8, (z) -NR6C(O)NR6(CR6R6)tR8, (aa)-NR6S(O)p(CR6R6)tR8, (bb)-S (O)pNR6(CR6R6)tR8, (cc)- NR6S(O)pNR6(CR6R6)tR8, (dd)-NR6R8, (ee)-NR6(CR6R6)R8, (ff)-OH, (gg)-NR8R8, (hh)- OCH3, (ii)-S (O)pR8, (jj)-NC (O) R8, (kk)-NR6C(NR6)NR6R8, (ll) C1-8Alkyl, (mm) C2-8Alkenyl, (nn)C2-8Alkynyl, (oo) contain one or more heteroatomic 3-14 members saturations, insatiable hunger and/or aromatic heterocycle, the hetero atom Selected from nitrogen, oxygen and sulphur, (pp) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (qq)-(CR6R6)tNR6(CR6R6)tR8, (rr)- N[(CR6R6)tR8][C=O(CR6R6)tR8], (ss)-(CR6R6)tN[(CR6R6)tR8][(CR6R6)tR8], (tt)-(CR6R6)tNR6 (C=O)(CR6R6)tR8, (uu)-halogenated alkyl, (vv)-C (O) (CR6)[(CR6R6)tR8]R8, (ww)-(CR6R6)tC(O) NR8R8, (xx)-(CR6R6)tC(O)O(CR6R6)tR8, (yy)-NR6C(O)CR8R8R8, (zz)-N [(CR6R6)tR8]C(O)R8, (aaa)-S (O)pNR8R8
Wherein (ll) to (pp) is optionally by one or more R7Group replaces;
R5It is selected from:(a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i) -NO2, (j) -NR6R6, (k)-OR8, (l)-NR6(CNR6)NR6R6, (m)-C1-8Alkyl, (n)-C1-8Alkenyl, (o)-C1-8Alkynyl, (p) -(C1-8Alkyl)-(contain one or more heteroatomic 3-14 members saturation, insatiable hunger and/or fragrance selected from nitrogen, oxygen and sulphur Heterocycle), (q)-(C1-8Alkyl)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), and (r)-halogenated alkyl, (s)-SR6, (t) Contain one or more heteroatomic -3-14 members saturation, insatiable hunger and/or aromatic heterocycles selected from nitrogen, oxygen and sulphur, and (u) -3-14 Member saturation, insatiable hunger and/or aromatic carbocyclic;Alternatively, two R5Group is combined together, and forms carbocyclic ring;
Wherein (m) to (r) and (t) to (u) is optionally by one or more R8Substitution;
R6Selected from (a) hydrogen, (b)-C1-8Alkyl or two R6Group is combined together to form carbocyclic ring, (c)-alkyl halide Base (d) contains one or more heteroatomic -3-14 members saturation, insatiable hunger and/or aromatic heterocycles selected from nitrogen, oxygen and sulphur, and (e) - 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic;
Wherein (b) to (e) is optionally by one to multiple R8Substitution;
R7It is selected from:(a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i) -NO2, (j) -NR6R6, (k)-OR6, (l)-NR6(CNR6)NR6R6, (m)-C1-8Alkyl, (n)-C1-8Alkenyl, (o)-C1-8Alkynyl, (p) -(C1-8Alkyl)-(contain one or more heteroatomic 3-14 members saturation, insatiable hunger and/or fragrance selected from nitrogen, oxygen and sulphur Heterocycle), (q)-(C1-8Alkyl)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), and (r)-halogenated alkyl, (s)-NR6R8, (t) -OR8, (u)-(CR6R6)tNR6R8, (v)-CR6R8R8, (w)-SR6, (x) contain one or more selected from the miscellaneous of nitrogen, oxygen and sulphur - 3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of atom, (y) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (z) - (CR6R6)tC(O)NR8R8, (aa)-S (O)pR8, (bb)-NR6C(O)NR6R6, (cc)-NR6C(O)R6, and (dd)-C (= NR6)NR6R6;
Wherein (m) to (q) and (x) to (y) is optionally by one or more R9Substitution;
R8It is selected from:(a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i) -NO2, (j) -NR6R9, (k)-OR9, (l)-NR6(CNR6)NR6R6, (m)-C1-8Alkyl, (n)-C1-8Alkenyl, (o)-C1-8Alkynyl, (p) -(C1-8Alkyl)-(contain one or more heteroatomic 3-14 members saturation, insatiable hunger and/or fragrance selected from nitrogen, oxygen and sulphur Heterocycle), (q)-(C1-8Alkyl)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), (r) contain one or more selected from nitrogen, oxygen With the heteroatomic -3-14 members of sulphur saturation, insatiable hunger and/or aromatic heterocycle, (s) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (t)-halogenated alkyl, (u)-C (O) (CR6R6)tR9, (v)-SR6, (w)-OC (O) (CR6R6)tR9, (x)-NR6C(O) NR6R9, (y)-NR6C(O)R9, (z)-NR6(CNR9)(NR6R6), (aa)-ONR6(CNR6)NR6R6, (bb)-C (=NR9) NR6R6, (cc)-S (O)pR9, (dd)-(CR6R6)tC(O)NR6R9, (ee)-(CR6R6)tOR9, and (ff)-(CR6R6)tNR6R9
Wherein (m) to (s) is optionally by one to multiple R9Substitution;
R9It is selected from:(a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i) -NO2, (j) -NR6R10, (k)-OR6, (l)-NR6(CNR6)NR6R6, (m)-C (O) (CR6R6)tNR6R6, (n)-C1-8Alkyl, (o)- C1-8Alkenyl, (p)-C1-8Alkynyl (q) contains one or more heteroatomic -3-14 members saturations for being selected from nitrogen, oxygen and sulphur, insatiable hunger And/or aromatic heterocycle, (r) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (s)-halogenated alkyl, (t)-(CR6R6)tOR6, (u) -O(CR6R6)tNR6R10, (v)-C (O) R6, (w)-SR6, (x)-C (O) OR10, (y)-S (O)pR6, (z)-(C1-8Alkane Base)-(containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles selected from nitrogen, oxygen and sulphur), (aa)- (C1-8Alkyl)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), (bb)-O (CR6R6)tOR6, (cc)-C (=NR6)NR6R6, (dd) -ONR6R6, (ee)-NR6C(O)NR6R6, (ff)-O (CR6R6)tOR6, (gg)-NR6C(O)R6(hh)-(CR6R6)tNR6R10
Wherein (n) to (r) and (z) to (aa) is optionally by one or more R10Substitution;
R10It is selected from:(a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i) -NO2, (j) -NR6R6, (k)-OR6, (l)-NR6(CNR6)NR6R6, (m)-C (O) (CR6R6)tNR6R6, (n)-C1-8Alkyl, (o)- C1-8Alkenyl, (p)-C1-8Alkynyl (q) contains one or more heteroatomic -3-14 members saturations for being selected from nitrogen, oxygen and sulphur, insatiable hunger And/or aromatic heterocycle, (r) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (s)-halogenated alkyl, (t)-(CR6R6)tOR6, (u) -O(CR6R6)tNR6R6, (v)-C (O) R6, (w)-SR6, (x)-C (O) OR6, (y)-S (O)pR6, (z)-(C1-8Alkane Base)-(containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles selected from nitrogen, oxygen and sulphur), (aa)- (C1-8Alkyl)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), (bb)-O (CR6R6)tOR6, (cc)-C (=NR6)NR6R6, (dd) -ONR6R6, (ee)-NR6C(O)NR6R6, (ff)-O (CR6R6)tOR6, (gg)-NR6C(O)R6(hh)-(CR6R6)tNR6R6
Optionally, wherein group-D-E-F or group-G-H-J are not present, but both-D-E-F and-G-H-J cannot simultaneously not In the presence of;
P is 0,1 or 2, and
T is 0,1,2 or 3,
Or its officinal salt, ester, tautomer or pro-drug.
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug, wherein A is:
(a) contain one or more heteroatomic 3-14 members saturations, insatiable hunger and/or aromatic heterocycle, the hetero atom to be selected from Nitrogen, oxygen and sulphur,
(b) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, or
(c) singly-bound,
Wherein (a) or (b) optionally by one or more R5Group replaces.
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug, wherein B is: (a)-(C1-8Alkyl)-, (b)-(C2-8Alkenyl) , (c)-(C2-8Alkynyl)-, or (d) singly-bound, wherein
I) 0-4 carbon atom in any one of (a) just mentioned above-(c) is optionally replaced selected from following part Generation:- O- ,-S (O)p,-NR6,-(C=O)-,-C (=NR6)-,-S (O)pNR6And-NR6S(O)pNR6,
Ii) any one of (a) just mentioned above-(c) is optionally by one or more R5Group replaces, and/or
Iii) any one of (a) just mentioned above-(c) is optionally by-(C1-8Alkyl)-R5Group replaces.
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug, wherein C is: (a) NH2, (b)-NHC (=NH) NH2, or (c) hydrogen.
The present invention relates to the officinal salt of the compound according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa, ester, changes Isomers or pro-drug.
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug, wherein
A is
(a) contain one or more heteroatomic 4-7 members saturations, insatiable hunger and/or aromatic heterocycle, the hetero atom be selected from nitrogen, Oxygen and sulphur,
(b) 4-7 members saturation, insatiable hunger and/or aromatic carbocyclic, or
(c) singly-bound,
Wherein (a) or (b) optionally by one or more R5Group replaces.
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug, wherein A are nitrogen heterocyclic heptyl, cyclobutyl, cyclopenta, hexamethylene Base, suberyl, phenyl, pyridyl group, cyclohexenyl group, cyclohexadienyl, dihydropyridine base, furyl, tetrahydrofuran base, tetrahydrochysene pyrrole Piperidinyl, azetidinyl, pyrrolidinyl, piperidyl or tetrahydro pyridyl (piperidenyl);
Wherein A is optionally by one or more R5Group replaces.
Alternatively, the present invention relates to according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa compound or pharmaceutically acceptable salt thereof, Ester, tautomer or pro-drug, wherein A are singly-bounds.
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug, wherein B are-(C1-8Alkyl)-, wherein
I) 0-4 carbon atom is optionally by selected from following partial alternative:- O- ,-S (O)p,-NR6,-(C=O)-,-S (O) pNR6Or-NR6S(O)pNR6,
Ii) (a) B is optionally by one or more R5Group replaces, and/or
Iii) B is optionally by-(C1-8Alkyl)-R5Group replaces.
Alternatively, the present invention relates to according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa compound or pharmaceutically acceptable salt thereof, Ester, tautomer or pro-drug, wherein B are singly-bounds.
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug, wherein C are-NHC (=NH) NH2
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug, wherein group D-E-F indicate hydrogen.
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug, wherein G are
(a) contain one or more heteroatomic 3-14 members saturations, insatiable hunger and/or aromatic heterocycle, the hetero atom to be selected from Nitrogen, oxygen and sulphur,
(b) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, or
(c) singly-bound;
Wherein (a) or (b) optionally by one or more R5Group replaces.
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug, wherein G is:
(a) contain one or more heteroatomic 4-7 members saturations, insatiable hunger and/or aromatic heterocycle, the hetero atom be selected from nitrogen, Oxygen and sulphur,
(b) 4-7 members saturation, insatiable hunger and/or aromatic carbocyclic, or
(c) singly-bound;
Wherein (a) or (b) optionally by one or more R5Group replaces.
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug, wherein G are nitrogen heterocyclic heptyl, cyclobutyl, cyclopenta, hexamethylene Base, suberyl, phenyl, pyridyl group, cyclohexenyl group, cyclohexadienyl, dihydropyridine base, furyl, tetrahydrofuran base, tetrahydrochysene pyrrole Piperidinyl, azetidinyl, pyrrolidinyl, piperidyl, tetrahydro pyridyl (piperidenyl) or singly-bound.
In some embodiments, the present invention relates to the compounds of following formula:
(I)
Wherein C-B-A- ,-D-E-F ,-G-H-J, W, X, Y, Z, V, T1And T2As defined above or its officinal salt, ester, mutually Tautomeric or pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
,
Wherein C-B-A- ,-D-E-F ,-G-H-J, W, X, Y, Z and V are as described above, or its officinal salt, ester, tautomerism Body or pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
(Ia),
Wherein C-B-A- ,-D-E-F and-G-H-J be as defined above or its officinal salt, ester, tautomer or precursor Drug.
In some embodiments, the present invention relates to the compounds of following formula:
,
Wherein C-B-A- ,-G-H-J, W, X, Y and Z are as described above, or its officinal salt, ester, tautomer or precursor medicine Object.
In some embodiments, the present invention relates to the compounds of following formula:
,
Wherein C-B-A- ,-G-H-J, W, X, Y, Z and V such as Formulas I defined or its officinal salt, ester, tautomer or Pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
,
Wherein C-B-A- ,-D-E-F, W, X, Y, Z and V such as Formulas I defined or its officinal salt, ester, tautomer or Pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
,
Wherein C-B-A- ,-D-E-F ,-G-H-J, W, X, Y, Z and V such as Formulas I defined or its officinal salt, ester, mutually variation Structure body or pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
(II),
Wherein C-B-A- ,-D-E-F ,-G-H-J, W, X, Y, Z, V, T1And T2As Formula II defines above or its is pharmaceutically acceptable Salt, ester, tautomer or pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
,
Wherein C-B-A- ,-D-E-F ,-G-H-J, W, X, Y, Z and V such as Formula II is defined or its officinal salt, ester, change Isomers or pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
(IIa)
Wherein C-B-A- ,-D-E-F and-G-H-J be as defined above or its officinal salt, ester, tautomer or precursor Drug.
In some embodiments, the present invention relates to the compounds of following formula:
,
Wherein C-B-A- ,-G-H-J, W, X, Y and Z such as Formula II is defined or its officinal salt, ester, tautomer or preceding Body drug.
In some embodiments, the present invention relates to the compounds of following formula:
,
Wherein C-B-A- ,-G-H-J, W, X, Y, Z and V such as Formula II defined or its officinal salt, ester, tautomer or Pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
,
Wherein C-B-A- ,-D-E-F, W, X, Y, Z and V such as Formula II defined or its officinal salt, ester, tautomer or Pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
,
Wherein C-B-A- ,-D-E-F, W, X, Y, Z and V such as Formula II defined or its officinal salt, ester, tautomer or Pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
(III),
Wherein C-B-A- ,-D-E-F ,-G-H-J, W, X, Y, Z, V and K such as formula III defined or its officinal salt, ester, mutually Tautomeric or pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
Wherein C-B-A- ,-G-H-J, W, X, Y, Z, V and K such as formula III is defined or its officinal salt, ester, tautomerism Body or pro-drug.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, tautomer or precursor medicines Object, whereinIndicate condensed hexa-atomic saturation, insatiable hunger and/or aromatic carbocyclic or heterocyclic ring system.
In some embodiments, the present invention relates to the compounds of following formula:
Wherein C-B-A- ,-D-E-F ,-G-H-J, W, X, Y, Z, V and K such as formula III is defined;Q1、Q2、Q3And Q4Independently Selected from nitrogen-atoms, carbon atom or CH, wherein in the presence of-D-E-F and-G-H-J, each is connect with carbon atom;
Or its officinal salt, ester, tautomer or pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
(IIIa),
Wherein C-B-A-, D-E-F and-G-H-J such as formula III defines or its officinal salt, ester, tautomer or preceding Body drug.
In some embodiments, the present invention relates to the compounds of following formula:
(IV)
Wherein C-B-A- ,-D-E-F ,-G-H-J, W, X, Y, Z, V and K such as formula IV defined or its officinal salt, ester, mutually Tautomeric or pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
Wherein C-B-A- ,-G-H-J, W, X, Y, Z, V and K such as formula IV is defined or its officinal salt, ester, tautomer Or pro-drug.
In some embodiments, the present invention relates to the compound or pharmaceutically acceptable salt thereofs, ester, tautomer according to formula IV Or pro-drug, whereinIndicate condensed hexa-atomic saturation, insatiable hunger and/or aromatic carbocyclic or heterocyclic ring system.
In some embodiments, the present invention relates to the compounds of following formula:
Wherein C-B-A- ,-D-E-F ,-G-H-J, W, X, Y, Z, V and K such as formula IV is defined;Q1, Q2, Q3 and Q4 are independently Selected from nitrogen-atoms, carbon atom or CH, wherein-D-E-F and-G-H-J, when it is present, each is connect with carbon atom;
Or its officinal salt, ester, tautomer or pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
(IVa)
Wherein C-B-A-, D-E-F and-G-H-J such as formula IV defines;Or its officinal salt, ester, tautomer or precursor Drug.
In some embodiments, the present invention relates to the compounds of following formula:
,
Wherein A is
(a) contain one or more heteroatomic 3-14 members saturations, insatiable hunger and/or aromatic heterocycle, the hetero atom to be selected from Nitrogen, oxygen and sulphur,
(b) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, or
(c) singly-bound,
Wherein (a) or (b) optionally by one or more R5Group replaces;
B is (a)-(C1-8Alkyl)-, (b)-(C2-8Alkenyl)-, (c)-(C2-8Alkynyl)-, or (d) singly-bound, wherein
I) 0-4 carbon atom in any one of (a) just mentioned above-(c) is optionally replaced selected from following part Generation:- O- ,-S (O)p,-NR6,-(C=O)-,-C (=NR6)-,-S (O)pNR6And-NR6S(O)pNR6,
Ii) any one of (a) just mentioned above-(c) is optionally by one or more R5Group replaces, and/or
Iii) any one of (a) just mentioned above-(c) is optionally by-(C1-8Alkyl)-R5Group replaces, and
C is selected from (a) NH2, (b)-NHC (=NH) NH2, and (c) hydrogen,
Or its officinal salt, ester, tautomer or pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
(Ia), (IIa),
(IIIa), or (IVa),
Wherein C-B-A-, D-E-F and-G-H-J such as Formulas I, II, III and IV is defined;Or its officinal salt, ester, mutually variation Structure body or pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
,
Wherein A is nitrogen heterocyclic heptyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, phenyl, pyridyl group, cyclohexenyl group, Cyclohexadienyl, dihydropyridine base, furyl, tetrahydrofuran base, tetrahydro pyridyl, azetidinyl, pyrrolidinyl, piperidines Base or tetrahydro pyridyl (piperidenyl), wherein A is optionally by one or more R5Group replaces;
Or, A is singly-bound;
B is:(a) -(C1-8Alkyl)-, wherein
I) 0-4 carbon atom in (a) just mentioned above is optionally by selected from following partial alternative:- O- ,-S (O)p,-NR6,-(C=O)-,-S (O) pNR6And-NR6S(O)pNR6,
Ii) (a) just mentioned above is optionally by one or more R5Group replaces, and/or
Iii) (a) just mentioned above is optionally by-(C1-8Alkyl)-R5Group replaces;
Or, B is singly-bound;
C is selected from (a) NH2, (b)-NHC (=NH) NH2Or (c) hydrogen.
In some embodiments, the present invention relates to the compounds of following formula:
,
Wherein C-B-A- is selected from:
Or its officinal salt, ester, tautomer or pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
Wherein G is
(a) contain one or more heteroatomic 3-14 members saturations, insatiable hunger and/or aromatic heterocycle, the hetero atom to be selected from Nitrogen, oxygen and sulphur,
(b) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, or
(c) singly-bound;
Wherein (a) or (b) optionally by one or more R5Group replaces or its officinal salt, ester, tautomer or preceding Body drug.
In some embodiments, the present invention relates to the compounds of following formula:
Wherein G is nitrogen heterocyclic heptyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, phenyl, pyridyl group, cyclohexenyl group, Cyclohexadienyl, dihydropyridine base, furyl, tetrahydrofuran base, tetrahydro pyridyl, azetidinyl, pyrrolidinyl, piperidines Base, tetrahydro pyridyl (piperidenyl) or singly-bound;Or its officinal salt, ester, tautomer or pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
Wherein-G-H-J is selected from:
Hydrogen,
Or its officinal salt, ester, tautomer or pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
Hydrogen,
, wherein n is 0,1 or 2 or its officinal salt, ester, tautomer or pro-drug.
In some embodiments, the present invention relates to the compounds of following formula:
,
Wherein-G-H-J is selected from:
Or its officinal salt, ester, tautomer or pro-drug.
In some embodiments, it is related to compound according to the following formula according to invention:
,
Wherein B is C1-8Alkyl, wherein 0-4 carbon atom are optionally replaced by NH,
Wherein each-H-J is independently selected from CF3、OCF3With-(C1-8) alkyl-NH2,
Or its officinal salt, ester, tautomer or pro-drug.
In some embodiments, it is related to compound according to the following formula according to invention:
,
Wherein each-H-J is independently selected from CF3、OCF3With-(C1-8) alkyl-NH2,
Or its officinal salt, ester, tautomer or pro-drug.
In some embodiments, the present invention relates to contain R5Compound, wherein R5It is selected from:(a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3(i) -NO2, (j)-NH2, (k)-OR6, (l)-NHC (=NH) NH2, (m) -C1-8Alkyl, (n)-C1-8Alkenyl, (o)-C1-8Alkynyl, (p)-(C1-8Alkyl)-(containing one or more selected from nitrogen, oxygen With heteroatomic 3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of sulphur), (q)-(C1-8Alkyl)-(3-14 members saturation, unsaturation Or aromatic carbocyclic), (r)-halogenated alkyl, (s)-SR6, (t) contain one or more heteroatomic -3- selected from nitrogen, oxygen and sulphur 14 yuan of saturations, insatiable hunger and/or aromatic heterocycle, and (u) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic;Alternatively, two R5Group It is combined together, forms carbocyclic ring;Or its officinal salt, ester, tautomer or pro-drug.
In some embodiments, the present invention relates to contain R6Compound, wherein R6It is selected from:(a) hydrogen, (b)-C1-8Alkane Base or two R6Group is combined together to form carbocyclic ring, (c)-halogenated alkyl, (d) contains one or more selected from nitrogen, oxygen With heteroatomic -3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of sulphur, and (e) -3-14 members saturation, insatiable hunger and/or aromatic carbon Ring;Or its officinal salt, ester, tautomer or pro-drug.
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug are O, NR wherein in the presence of W1, NOR1Or S.
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug, wherein X---Y is when it is present double bond, and X is N, and Y is carbon original Son.
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug, wherein R5It is OR6, R6It is CF3
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug, wherein R5It is CF3
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug, wherein-G-H-J is selected from
,
Wherein each-H-J is independently selected from-O-CF3With-(C1-8) alkyl-NH2
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug, wherein working as R4aIn the presence of, it is hydrogen.
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug are NR wherein in the presence of Z4
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug, wherein R4It is hydrogen.
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug, it is combined with ribosomes.
In some embodiments, the present invention relates to the compounds according to Formulas I, II, III, IV, Ia, IIa, IIIa, IVa Or its officinal salt, ester, tautomer or pro-drug, it is combined with ribosomes, wherein ribosomes is bacterial ribosome.
In some embodiments, the present invention relates to according to any of table 1 compound compound or pharmaceutically acceptable salt thereof, Ester, tautomer or pro-drug.
In some embodiments, the present invention relates to include the compounds of this invention or its officinal salt, ester, tautomer Or the pharmaceutical composition of pro-drug and pharmaceutical acceptable carrier.
In some embodiments, the present invention relates to the danger of the morbid state for the treatment of human or animal or reduction morbid state Method, this method includes:Give need its a effective amount of the compounds of this invention of human or animal or its officinal salt, ester, mutually Tautomeric or pro-drug.
In some embodiments, the present invention relates to the method for the microorganism infection for the treatment of human or animal, this method includes: Give a effective amount of the compounds of this invention of the human or animal or its officinal salt, ester, tautomer or pro-drug.
In some embodiments, the present invention relates to the compounds of this invention or its officinal salt, ester, tautomers or preceding The purposes of body drug in medicine preparation, the drug are used to treat the microorganism infection of human or animal.
In some embodiments, the present invention relates to treat, prevent the microorganism infection of human or animal or reduce its danger Method, this method includes:It is a effective amount of according to Formulas I, the change of II, III, IV, Ia, IIa, IIIa or IVa to give human or animal Close object or its officinal salt, ester, tautomer or pro-drug or the compounds of this invention or its officinal salt, ester, mutually variation The purposes of structure body or pro-drug in medicine preparation, the drug are used to treat, prevent the microorganism infection or drop of human or animal Its low danger,
Wherein microorganism infection is selected from:
Skin infection, Gram-positive infection, Gram negative infections, Nosocomial Pneumonia, community acquired pneumonia, virus sense Pneumonia after dye, Nosocomial Pneumonia/Ventilator Associated Pneumonia, respiratory tract infection, such as chronic respiratory tract infection (CRTI), acute pelvic infects, concurrent skin and skin structure infection, Skin and soft tissue infection (SSTI), including not simultaneously The Skin and soft tissue infection (uSSTI) of hair and concurrent Skin and soft tissue infection, abdominal infection, the interior infection of concurrent abdomen, Urinary tract infections, bacteremia, septicemia, endocarditis, atrioventricular shunt infection, vascular access infection, meningitis, surgical prophylaxis, Peritoneal infection, infection of bone, the infection of joint, the S. aureus infection of methicillin-resistant, the enterococcus sense of anti-vancocin Dye, the organism infection of anti-Linezolid (linezolid), infection due to Bacillus anthracis, soil draw hot Francisella infection, the plague Yersinia ruckeri infects and pulmonary tuberculosis.
In some embodiments, the present invention relates to infected in the concurrent abdomen for treating, preventing human or animal or reduce it Dangerous method, this method include:It is a effective amount of according to Formulas I, II, III, IV, Ia, IIa, IIIa or IVa to give human or animal Compound or pharmaceutically acceptable salt thereof, ester, tautomer or pro-drug, or be related to the compounds of this invention or its officinal salt, The purposes of ester, tautomer or pro-drug in medicine preparation, the drug be used for treat, prevents human or animal concurrently Its danger is infected or reduced in abdomen,
Infection is selected from polymicrobic infection in wherein concurrent abdomen, for example, due to abscess caused by following:Escherichia coli (Escherichia coli), fusiform bacilarmature (Clostridium clostridioforme), Eubacterium lentum (Eubacterium lentum), Peptostreptococcus (Peptostreptococcus spp.), bacteroides fragilis (Bacteroides fragilis), bacteroides disiens (Bacteroides distasonis), bacteroides ovatus (Bacteroides ovatus), bacteroides thetaiotaomicron (Bacteroides thetaiotaomicron), bacteroides uniformis (Bacteroides uniformis), streptococcus anginosus (Streptococcus anginosus), Streptococcus constellatus (Streptococcus constellatus), enterococcus faecalis (Enterococcus faecalis), proteus mirabilis (Proteus mirabilis) or C.perfringens (Clostridium perfringens)。
In some embodiments, the present invention relates to treatment, the concurrent skins and skin texture sense of prevention human or animal It contaminates or reduces its dangerous method, this method includes:Give human or animal it is a effective amount of according to Formulas I, II, III, IV, Ia, IIa, Compound or pharmaceutically acceptable salt thereof, ester, tautomer or the pro-drug of IIIa or IVa, or be related to the compounds of this invention or its The purposes of officinal salt, ester, tautomer or pro-drug in medicine preparation, the drug is for treating, preventing people or move The concurrent skin and skin structure infection of object reduces its danger,
Wherein concurrent skin and skin structure infection is selected from since diabetic keratopathy feel dye (does not have marrow caused by following It is scorching):Staphylococcus aureus (Staphylococcus aureus) (methicillin-susceptible and drug resistance isolate), agalasisa chain Coccus (Streptococcus agalactiae), micrococcus scarlatinae (Streptococcus pyogenes), Escherichia coli (Escherichia coli), Klebsiella pneumoniae (Klebsiella pneumoniae), proteus mirabilis (Proteus mirabilis), bacteroides fragilis (Bacteroides fragilis), Peptostreptococcus (Peptostreptococcus species), do not understand sugar rufous monad (Porphyromonas asaccharolytica) or two tunnel bacteroids (Prevotella bivia)。
In some embodiments, the present invention relates to treatment, prevent human or animal community acquired pneumonia or reduce it Dangerous method, this method include:It is a effective amount of according to Formulas I, II, III, IV, Ia, IIa, IIIa or IVa to give human or animal Compound or pharmaceutically acceptable salt thereof, ester, tautomer or pro-drug, or be related to the compounds of this invention or its officinal salt, The purposes of ester, tautomer or pro-drug in medicine preparation, the community which is used to treat, prevent human or animal obtains It obtains property pneumonia or reduces its danger,
Wherein community acquired pneumonia (including beta-lactam enzyme positive isolate) is due to streptococcus pneumonia (Streptococcus pneumoniae) (penicillin sensitivity and drug resistance isolate) (including to carry concurrency bacteremic Situation), haemophilus influenzae (Haemophilus influenzae), Moraxella catarrhalis (Moraxella catarrhalis) or atypical bacterium such as mycoplasm hyopneumoniae (Mycoplasma spp.) caused by.
In some embodiments, the present invention relates to treatment, prevent the concurrent urinary tract infections of human or animal or reduce it Dangerous method, this method include:It is a effective amount of according to Formulas I, II, III, IV, Ia, IIa, IIIa or IVa to give human or animal Compound or pharmaceutically acceptable salt thereof, ester, tautomer or pro-drug, or be related to the compounds of this invention or its officinal salt, The purposes of ester, tautomer or pro-drug in medicine preparation, the drug be used for treat, prevents human or animal concurrently Urinary tract infections reduces its danger,
Wherein concurrent urinary tract infections be selected from due to Escherichia coli (Escherichia coli), concurrent bacteremia or gram Thunder Bai Shi bacillus (Klebsiella pneumoniae) caused by pyelonephritis.
In some embodiments, the present invention relates to the acute pelvics for the treatment of, prevention human or animal to infect or reduce its danger The method of danger, this method include:It is a effective amount of according to Formulas I, II, III, IV, Ia, IIa, IIIa or IVa to give human or animal Compound or pharmaceutically acceptable salt thereof, ester, tautomer or pro-drug, or be related to the compounds of this invention or its officinal salt, ester, The purposes of tautomer or pro-drug in medicine preparation, the drug are used to treat, prevent the acute pelvic of human or animal Its danger is infected or reduces,
Wherein acute pelvic infection (including for example, postpartum Endomyometritis, septic abortion and postoperative gynaecology Infection) be due to Streptococcusagalactiae (Streptococcus agalactiae), Escherichia coli (Escherichia coli), it is crisp Weak bacteroid (Bacteroides fragilis), do not understand sugared rufous monad (Porphyromonas asaccharolytica), Peptostreptococcus (Peptostreptococcus spp.) or two tunnel bacteroids (Prevotella bivia) caused by.
In some embodiments, the present invention relates to treatment, Nosocomial Pneumonia/lung ventilator phases of prevention human or animal Closing property pneumonia reduces its dangerous method, and this method includes:Give human or animal it is a effective amount of according to Formulas I, II, III, IV, Compound or pharmaceutically acceptable salt thereof, ester, tautomer or the pro-drug of Ia, IIa, IIIa or IVa, or it is related to chemical combination of the present invention The purposes of object or its officinal salt, ester, tautomer or pro-drug in medicine preparation, the drug is for treating, preventing Nosocomial Pneumonia/Ventilator Associated Pneumonia of human or animal reduces its danger,
Wherein Nosocomial Pneumonia/Ventilator Associated Pneumonia be due to streptococcus pneumonia (Streptococcus pneumoniae) (penicillin sensitivity and drug resistance isolate), Staphylococcus aureus (Staphylococcus aureus) (methicillin-susceptible and drug resistance isolate), Klebsiella pneumoniae (Klebsiella pneumoniae), Pseudomonas aeruginosa (Pseudomonas aeruginosa), acinetobacter (Acinetobacter spp.), stenotrophomonas maltophilia (Stenotrophomonas maltophilia), haemophilus influenzae (Haemophilus influenzae) (including β-is interior Amide enzyme positive isolate) or legionella pneumophilia (Legionella pneumophilia) caused by.
In some embodiments, the present invention relates to treatment, prevent human or animal due to aerobic or facultative gram sun Property microorganism infection caused by microorganism or reduce its dangerous method, this method includes:Give human or animal it is a effective amount of by Compound or pharmaceutically acceptable salt thereof, ester, tautomer or the pro-drug of illuminated I, II, III, IV, Ia, IIa, IIIa or IVa, Or it is related to the purposes of the compounds of this invention or its officinal salt, ester, tautomer or pro-drug in medicine preparation, the medicine Object be used for treat, prevent human or animal due to microorganism infection or reduction caused by aerobic or facultative gram-positive microorganism It is dangerous,
Wherein aerobic or facultative gram-positive microorganism is selected from:
Staphylococcus aureus (Staphylococcus aureus) (methicillin-susceptible and drug resistance isolate), lung Scorching streptococcus (Streptococcus pneumoniae) (penicillin sensitivity and drug resistance isolate), enterococcus (Enterococcus spp.) (vancomycin sensitive and drug resistance isolate), Streptococcusagalactiae (Streptococcus agalactiae), micrococcus scarlatinae (Streptococcus pyogenes) or staphylococcus epidermis (Staphylococcus epidermidis) (methicillin-susceptible and drug resistance isolate).
In some embodiments, the present invention relates to treatment, prevent humans and animals due to aerobic and facultative gram-negative Property microorganism infection caused by microorganism or reduce its dangerous method, this method includes:Give humans and animals it is a effective amount of by Compound or pharmaceutically acceptable salt thereof, ester, tautomer or the pro-drug of illuminated I, II, III, IV, Ia, IIa, IIIa and IVa, Or it is related to the purposes of the compounds of this invention or its officinal salt, ester, tautomer or pro-drug in medicine preparation, the medicine Object be used for treat, prevent humans and animals due to microorganism infection or reduction caused by aerobic and facultative gram-negative micro-organism It is dangerous,
Wherein aerobic and facultative gram-negative micro-organism is selected from:
Escherichia coli ((Escherichia coli) include the isolate that ESBL and KPC is generated), haemophilus influenzae (Haemophilus influenzae) (including beta-lactam enzyme positive isolate), Klebsiella pneumoniae (Klebsiella pneumoniae(isolate for including ESBL and KPC generations)), citrobacter freundii (Citrobacter freundii), production Gas enterobacteria (Enterobacter aerogenes), enterobacter cloacae (Enterobacter cloacae), the root that rubs (family name) bacterium (Morganella morganii), serratia marcescens (Serratia marcescens), Pseudomonas aeruginosa (Pseudomonas aeruginosa), Acinetobacter bauamnnii (Acinetobacter baumanni), Moraxella catarrhalis (Moraxella catarrhalis), proteus mirabilis (Proteus mirabilis), Ke Shi citric acid bacillus (Citrobacter koseri), Hemophilus parainfluenzae (Haemophilus parainfluenzae), klebsiella oxytoca (Klebsiella oxytoca) (isolate for including ESBL and KPC generations), proteus vulgaris (Proteus vulgaris), providencia rettgeri (Providencia rettgeri) and providencia stuartii (Providencia stuartii)。
In some embodiments, the present invention relates to treatment, prevent humans and animals due to micro- caused by anaerobe Biological infection reduces its dangerous method, and this method includes:Give humans and animals it is a effective amount of according to Formulas I, II, III, IV, Compound or pharmaceutically acceptable salt thereof, ester, tautomer or the pro-drug of Ia, IIa, IIIa and IVa, or it is related to chemical combination of the present invention The purposes of object or its officinal salt, ester, tautomer and pro-drug in medicine preparation, the drug is for treating, preventing Humans and animals due to microorganism infection caused by anaerobe or reduce its danger,
Wherein the anaerobe is: bacteroides fragilis (Bacteroides fragilis), bacteroides disiens (Bacteroides distasonis), bacteroides ovatus (Bacteroides ovatus), bacteroides thetaiotaomicron (Bacteroides thetaiotaomicron), bacteroides uniformis (Bacteroides uniformis), fusiform bacilarmature (Clostridium clostridioforme), Eubacterium lentum (Eubacterium lentum), peptostreptococcus (Peptostreptococcus species), do not understand sugar rufous monad (Porphyromonas asaccharolytica), two tunnel bacteroids (Prevotella bivia), lopsided bacterium (Bacteroides vulgates), production Gas capsular clostridium (Clostridium perfringens) or Fusobacterium (Fusobacterium spp.)。
In some embodiments, the present invention relates to treat, prevent the microorganism infection of human or animal or reduce its danger Method, this method includes:It is a effective amount of according to Formulas I, the change of II, III, IV, Ia, IIa, IIIa or IVa to give human or animal Object or its officinal salt, ester, tautomer or pro-drug are closed, or is related to the compounds of this invention or its officinal salt, ester, mutually The purposes of tautomeric or pro-drug in medicine preparation, the drug are used to treat, prevent the microorganism infection of human or animal Or its danger is reduced,
Wherein microorganism be legionella pneumophilia (Legionella pneumophilia)。
In some embodiments, the present invention relates to method or purposes, in this method or on the way, the compounds of this invention or Its officinal salt, ester, tautomer or pro-drug are by ear, eye, nose, oral, parenteral or administer locally to.
In some embodiments, the present invention relates to synthesis the compounds of this invention or its officinal salt, ester, tautomers Or the method for pro-drug.
In some embodiments, the present invention relates to contain the compounds of this invention or its officinal salt, ester, tautomer Or the medical treatment device of pro-drug.
In some embodiments, the present invention relates to the medical treatment devices containing the compounds of this invention, and wherein the device is branch Frame.
3. the synthesis of the compounds of this invention
The present invention provides the methods for preparing the compounds of this invention.Following reaction route 1a-5a briefly describes synthesis The exemplary approach of the compounds of this invention.More specifically chemistry is described in detail and is provided in embodiment.
Reaction route 1a- pyrrolo- cytimidines
Reaction route 2a- pyrrolo- iso-cytosines
Reaction route 3a- triazole iso-cytosines
Reaction route 4a- [6,5,6]-pyrrolo- cytimidine
Reaction route 5a- [6,5,6]-pyrrolo- iso-cytosine
4. the characterization of the compounds of this invention
By above method design, selection and/or optimized compound art technology can be used once preparing It is various known to personnel to test to characterize, so that it is determined that whether the compound has bioactivity.For example, routine test can be used Molecule, experiment including but not limited to as described below are characterized, so that it is determined that whether they have estimated activity, in conjunction with activity And/or binding specificity.
In addition, high flux screening can be used for accelerating the analysis using this experiment.Therefore, this paper institutes can rapidly be screened The activity for describing molecule, for example, as anticancer, antibacterium, antimycotic, anti parasitic or antivirotic.Equally, using this field How known technology can be interacted with test compound with ribosomes or ribosomal subunit, and/or, how effectively to make For the conditioning agent (for example, inhibitor) of albumen synthesis.The conventional method for carrying out high flux screening is described in such as Devlin (1998) in High Throughput Screening, Marcel Dekker and United States Patent (USP) 5,763,263.High throughput test One or more different tests technologies, technology including but not limited to those of as described below can be used.
(1)Surface binding
Various combination experiments can be effectively used for new the having of screening and combine active molecule.A kind of method include surface etc. from Sub-resonance technology (SPR), can be used for evaluating makes one interested molecule for ribosomes, ribosomal subunit or its segment Binding performance.
SPR methods are by generating the surface plasma of quantum mechanics (quntum-mechanical) come the real time measure two Interaction between a or multiple macromoleculars.(BIAcore Biosensor RTM, are obtained from Pharmacia for a kind of device Biosensor, Piscataway, N.J.) to golden film (in the form of disposable biological sensor " dummy slider " provide) and can be by making Interface between the surge chamber that user is adjusted provides heterogeneous light focused beam acts.By " hydrogel " of 100 nm thickness (by carboxy methylation Glucan composition, the covalently fixed matrix for making one interested analyte is provided) be affixed in golden film.When focusing light with When the free electron cloud interaction of golden film, plasma resonance enhancing.Obtained reflected light is in the wave for most preferably sending out the resonance It is exhausted to spectrum in length (spectrally depleted).By the way that the polychromatic light of reflection to be separated into its composition wavelength (by means of prism) and the frequency for exhausting (depleted) is measured, BIAcore forms optical interface, accurately reports institute's shape At surface plasma resonance characteristic (behavior).When according to being designed above, plasma resonance (and thus consume Most spectrum (depletion spectrum)) to the mass-sensitive in evanescent field (it corresponds roughly to the thickness of hydrogel). If a component part of interaction pair is fixed in hydrogel, and provides interaction participant by surge chamber (partner), then it can be measured with quality accumulation and the spectrum by exhausting (depletion spectrum) in evanescent field Carry out the interaction between two component parts of the real time measure based on the correspondence effect of its plasma resonance.This system Any one component can need not be marked quickly with delicately the real time measure intermolecular interaction.
(2) Fluorescence polarization
Fluorescence polarization (FP) is the survey that can be readily used for protein-protein, protein ligand or the interaction of RNA- ligands Technology is determined, to obtain the IC of the association reaction between two molecules50Value and Kds.In this technique, interested one is made one A molecule and fluorophore conjugated.This is typically the relatively small molecule (in this case, being interested compound) in the system. The sample mixture containing ligand-probe conjugate and ribosomes, ribosomal subunit or its segment is excited with orthogonal polarized light. Light is absorbed by fluorescence probe group, and is emitted again after the short time.Measure the degree of polarization of transmitting light.The polarization of transmitting light depends on In some factors, but most significantly depend on the apparent molecular weight of the viscosity and fluorogen of solution.Under suitable control, transmitting The degree of polarization variation of light is solely dependent upon the apparent molecular weight variation of fluorogen, and next depending on probe-ligand conjugate is It is no to keep free state in the solution or combined with receptor.Combination experiment based on FP has many important benefits, including:? IC is measured under the conditions of correct homogeneous equilibrium50Value and Kds, analyze speed and suitable automation, and in cloudy suspension and colour The ability of (screen) is shielded in solution.
(3) Albumen synthesizes
It, can also be with ribosomes or the work(of ribosomal subunit except being characterized except through above-mentioned biochemical test Can active conditioning agent (for example, protein synthesis inhibitor) form characterize interested compound.
Furthermore, it is possible to which carrying out more specific albumen synthesis as follows inhibits experiment:Give entire organism, tissue, organ, Organelle, cell, cell or subcellular extract or the ribosomes product compound of purifying, and by measuring such as its inhibition Inhibition constant (the IC of albumen synthesis50Value) observe its pharmacology and rejection.It, can be in order to study albumen synthesizing activity It carries out3H leucines or35The merging of S methionines or similar experiment.In the presence of making one interested molecule, in cell Albumen synthesis quantity or rate change, if show the molecule be albumen synthesis conditioning agent albumen synthesis rate Or quantity reduces, and shows that the molecule is protein synthesis inhibitor.
(4) Anti-microbial test and other evaluations
Furthermore, it is possible to test the antiproliferative or anti-infection property energy of the compound under cellular level.For example, if targeting has Body is microorganism, then can be by testing sense containing compound or not cultivating the microorganism in the culture medium of compound The activity of the compound of interest.Growth inhibition can indicate that the molecule can serve as protein synthesis inhibitor.More specifically, feel The activity of the compound bacteria resistance pathogen of interest can inhibit the life of identified human pathogen bacterial strain by the compound It grows to prove.For this purpose, strains can be assembled(panel), it includes various targeting pathogenic species to make it, some of them packet Include the Resistance Mechanism characterized.The use of this organism group can measure structure-activity relation, not only consider efficiency and Pedigree, and it is conceived to avoidance resistance mechanism.
According to The Clinical and Laboratory Standards Institute [CLSI;The originally National Committee for Clinical Laboratory Standards (NCCLS)] scheme listed, utilization is micro- Dilution process measures minimum inhibitory concentration (MICs), and final volume is typically 100 microlitres.Referring to CLSI: Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically;The standard-the of approval five editions.Wayne, PA: NCCLS;2000.According to conventional method disclosed in CLSI, also may be used To carry out the experiment in microtiter plates.Referring to CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically;The standard-the of approval seven editions. CLSI Document M7-A7[ISBN 1-56238-587-9] CLSI, 940 West Valley Road, Suite 1400, Wayne Pennsylvania 19087-1898 USA, 2006)。
It can be in various internal mammal experiments, for example, mouse or rat peritoneum inflammation infection model, skin and soft group Organization model (commonly referred to as stock model) or murine pneumonia model, further evaluate the antimicrobial and other Drug of compound Energy.Septicemia also well known by persons skilled in the art or organ infection's model.These effect models may be used as evaluation method A part, and may be used as the guidance of the potential effect in people.Terminal can by the reduction of bacterial load to lethality and It is different.For the terminal of the latter, PD is usually used50Value indicate as a result, or with protection 50% animal from death drug dose come table Show.
In order to further evaluate the class pharmaceutical properties of compound, recombinant people enzyme system or more complicated system can also be used (for example, people's hepatomicrosome) measures the inhibition of cytochrome P 450 enzymes and the second stage of metabolic enzyme activity.It further, can also be with The matrix forms of these metabolic enzymatic activitys evaluates compound.These activity, which can be effectively used for measurement compound, leads to drug- Drug interaction forms metabolin (its reservation(retain)Antimicrobial acivity or not useful antimicrobial acivity) Potentiality.
In order to evaluate the potentiality of compound oral bioavailability, dissolubility and Caco-2 experiments can also be carried out.The latter It is the cell line for being obtained from people's epithelium, uses it to and measure ingestion of medicines and across Caco-2 cell monolayers (usually equipped with 1 Cultivated in the hole of 24 hole microwell plates of micron membranes) pass through.The free drug concentration on the Basolateral face of single layer can be measured, Assessment can pass through the medication amount of intestines single layer.It is required that suitable control, to ensure what the integrality of single layer was connected with gap Compactness.Using this identical system, the outflow of P- glycoprotein mediation can be evaluated.P- glycoprotein is to be located to form polarization list The pump of the cell teleblem of layer.This pump can lead to less medicine with elimination activity or across the Passive intake of Caco-2 cell membranes Object passes through enteric epithelium layer.These results are usually used in combination with solubility test, and the two known factors can be dynamic in lactation Promote oral bioavailability rate in object.Using conventional medicine dynamic experiment, oral bioavailability rate is measured in animal, finally Oral bioavailability rate is measured in people, thus measures absolute oral bioavailability rate.
Test result can be also used for establishing model, and this model can be with aid forecasting to the contributive object of class pharmaceutical properties Reason-chemical parameters.When determining this model, experimental method can be simplified, while increasing the dependence to model prediction.
5. preparation and administration
The compound of the present invention can be effectively used for preventing or treat various people or other animals (including mammal and the non-food in one's mouth Newborn animal) illness, including, for example, bacterium infection, fungal infection, virus infection, diarrhea, parasitic disease and cancer.Once Confirm, it is contemplated that bioactive molecule of the invention can be combined into any suitable carrier, then be used.The dosage of bioactive molecule is given The use of medicine pattern and suitable carrier depends on intended recipient and targeting organism.According to for animals and people of the compounds of this invention The preparation that medical treatment uses typically comprises this compound and is combined with pharmaceutical acceptable carrier.
In terms of with the compatibility of other components of preparation, carrier should be acceptable, and not had to its recipient Harm.In this respect, pharmaceutical acceptable carrier includes any and all solvents matched with administering mode, decentralized medium, coating, resists Bacterium and antifungal agent, etc. blend absorption delay reagent etc..This medium and reagent for pharmaceutically active substances is in ability Domain is known.Any conventional media or reagent, unless it is incompatible with reactive compound, otherwise, they can be used for combining In object.The reactive compound of auxiliary can also (according to present invention confirmation or design and/or reactive compound known in the art) In conjunction with into composition.Preparation can be provided suitably with dosage unit form, and can utilize pharmacy/microbiological art It is prepared by well-known any method.In general, preparing some preparations as follows:Make compound and liquid-carrier or solid fine crushing Carrier or both combines, then, if it is necessary, formed product is made to be target formulation.
The pharmaceutical composition that the present invention should be prepared, to make it be matched with desired for administration approach.The example of administration route Attached bag includes oral, ear, eyes, nose or parenteral administration, for example, intravenous administration, intradermal administration, inhalation are transdermal to give Medicine (part), transmucosal administration and rectally.It can be wrapped for parenteral, intradermal or subcutaneous application solution or suspension Include following component: sterile diluent, such as water for injection, saline solution, expressed oi, polyethylene glycol, glycerine, propylene glycol or The solvent of other synthesis;Antiseptic, such as benzyl alcohol or methyl p-hydroxybenzoate;Antioxidant, such as ascorbic acid or Asia Niter cake;Chelating agent, such as ethylenediamine tetra-acetic acid;Buffer, such as acetate, citrate or phosphate, and adjust and open The reagent of power, such as sodium chloride or glucose.Acid or alkali can be used to adjust pH value, such as with hydrochloric acid or sodium hydroxide.
Useful oral and parenteral administration solution, example can be prepared using the well-known any method of drug field Such as, method of the description in following:Remington'sPharmaceutical Sciences, (Gennaro, A., ed.), Mack Pub., (1990).The preparation of parenteral administration can also include for buccal administration glycocholate, be used for The methoxysalicylate of rectally or citric acid for vagina administration.Parenteral administration can be packed by glass or modeling In bottle, disposable syringe or multi-agent phial made of material.Suppository for rectally can also be prepared as follows:By medicine Object and nonirritant excipient (such as cocoa butter, other glyceride or other compositions, they are solid at room temperature, It is liquid under body temperature) mixing.Preparation can also include, for example, polyglycols, such as polyethylene glycol, vegetable oil and hydrogenated naphthalene.For The preparation of direct administration may include glycerine and other highly viscous compositions.The intestines of other potentially usefuls for these drugs The outer carrier of stomach includes ethylene-vinyl acetate copolymer particle, osmotic pumps, implantable infusion system and liposome.For inhaling The preparation for entering administration may include such as lactose (as excipient), or can be containing such as laureth9, The aqueous solution of glycocholate and dexycholate, or the oil solution being administered in the form of nasal drop or the intranasal gel used.It protects Enema is stayed to can be also used for rectal delivery.
The invention formulation for being suitable for oral medication can be following form: discrete units, such as capsule, gelatin glue Capsule, pouch, tablet, pastille (troches) or lozenge (lozenges), the respectively drug containing predetermined quantity;Pulvis or particle Composition;Solution in liquid, aqueous or on-aqueous liquid or suspension;Or oil in water emulsion or water-in-oil emulsion.It can be with To inject(bolus), paste or paste form give drug.It can be by the way that drug be suppressed or moulded together with one or more auxiliary agents To prepare tablet.Compressed tablets can be prepared as follows:In suitable machinery, by the drug of free-flowing form (such as powder or Particle) squeeze, optionally with adhesive, lubricant, inert diluent, surfactant or dispersant.Molded tablet can be as Lower preparation:In suitable mechanical, the mixture of the powdered drug and suitable carrier that are moistened with inert liquid diluent is moulded.
Orally administered composition generally comprises inert diluent or edible carrier.It is living for oral therapeutic administration purpose Property compound can be combined with excipient.The Orally administered composition (being used as mouthwash) prepared using liquid-carrier is in a liquid carrier It is oral to use including compound, it rustles(swished), and expectoration or swallow.The adhesive of compatible pharmaceutical can be included An and/or part of the adjuvant substance as composition.Tablet, pill, capsule, pastille etc. can include any following component Or the compound of similarity: adhesive, such as microcrystalline cellulose, gum tragacanth or gelatin;Excipient, such as starch or breast Sugar;Disintegrant, such as alginic acid, Primogel or cornstarch;Lubricant, such as magnesium stearate or Sterotes;Glidant, Such as colloidal silicon dioxide;Sweetener, such as sucrose or saccharin;Or flavoring agent, such as peppermint(peppermint), bigcatkin willow Sour methyl esters or orange flavor.
It includes aseptic aqueous solution (water-soluble) or dispersion and sterile powder to be suitable for the pharmaceutical composition that injection uses (extemporaneous preparation of aseptic injectable solution agent or dispersion).For intravenous administration, suitable carrier includes physiological saline, antibacterial Water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS) (PBS).In production and preservation condition Under, should be stable, and should be preserved under conditions of the contamination of antimicrobial such as bacterium and fungi.Carrier Can be solvent or decentralized medium, including, such as water, ethyl alcohol, polyalcohol is (for example, glycerine, propylene glycol and the poly- second of liquid two Alcohol, etc.) and its suitable mixture.By using coating (such as lecithin), in the case of a dispersion by keeping institute It is required that grain size, and by using surfactant, suitable mobility can be kept.In many cases it is preferred to combining Include isotonic reagent in object, for example, sugared, polyalcohol, such as mannitol, D-sorbite or sodium chloride.By wrapping in the composition Reagent containing delayed absorption, for example, aluminum monostearate and gelatin, can be such that injectable composition extends and absorb.
The molten solution of aseptic injection can be prepared as follows:In a suitable solvent, by required amount of reactive compound with The composition of a kind of above-named component or component combines, and is then filtered sterilizing as needed.In general, by will be active Compound, which is attached in sterile excipient, prepares dispersion, and sterile excipient includes basic dispersion medium and above-named required The other components wanted.In the case where being used to prepare the sterile powder of the molten solution of aseptic injection, preparation method includes that vacuum is dry Dry and freeze-drying obtains the pulvis that active component adds any additional object component (being obtained from previous sterilefiltered solutions).
The preparation for being suitable for intra-articular administration can be the sterile aqueous form of drug, and drug can be crystallite shape Formula, for example, aqueous microcrystalline suspension form.Liposomal formulation or biodegradable polymer system also can be used to intra-articular Drug is provided with eyes.
The preparation (including eye therapy) for being suitable for local administration includes liquid or semi-liquid preparations, for example, liniment, is washed Agent, gelling agent, application(applicants), oil-in-water or water-in-oil emulsion, such as cream, ointment or paste;Or solution Agent or suspension, such as drops.Administering locally to the preparation of skin surface can prepare as follows:Drug is acceptable with dermatology Carrier disperses together, such as lotion, cream, ointment or soap.It is applied to position and inhibits to be detached from, it is particularly useful that The carrier of film or layer can be formed on the skin.In order to administer locally to internal tissue surfaces, medicament can be dispersed in liquid tissue In adhesive or known enhancing is in the other materials of tissue surface adsorptivity.For example, in order to advantageous, hydroxypropyl can be used Cellulose or fibrinogen/thrombin solution.Alternatively, tissue-coating solution can be used, for example, the preparation containing pectin.
For inhalation therapy, the powder inhalation of sprayer, atomizer or injector distribution can be used (self-propelled Preparation or spray formulation).This preparation can be the fine powder form from powder inhalation device for pulmonary administration, or Self-propelled powder-dispensing formulations.In the case of self-propelled solution and spray formulation, there is target by selection The valve (that is, the spray with target grain size can be generated) of spray characteristics or the suspended powder shape that grain size is controlled by combining The active component of formula can obtain effect.For inhalation, can also from comprising proper emission agent (for example, gas, such as Carbon dioxide) pressure vessel or distributor or atomizer in the form of aerosol injection deliver compound.
Transmucosal or transdermal methods can also be utilized by being administered systemically.For transmucosal or cutaneous penetration, use in the formulation It is suitable for the bleeding agent of barrier to be penetrated into.This bleeding agent is commonly known in this field, for transmucosal administration, packet It includes, for example, detersive and cholate.Transmucosal administration can be completed by using nose penetrating or suppository.It, will for cutaneous penetration Reactive compound is typically formulated as ointment commonly known in the art, ointment, gelling agent or cream.
Reactive compound, such as controlled release system can be prepared with the carrier that compound can be prevented quickly to be discharged from body Agent, including implantation material and micro-encapsulated delivery system.Biodegradable, bio-compatible polymer, such as second can be used Alkene-vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoester and polylactic acid.The method of this preparation is prepared to ability Field technique personnel are obvious.Liposome suspension is also used as pharmaceutical acceptable carrier.These can be according to this field skill Prepared by method known to art personnel, for example, United States Patent (USP) US 4, the method described in 522,811.
In order to be easy the uniformity of administration and dosage, the oral or parenteral composition of dosage unit form can be prepared. Dosage unit form refers to the physical dispersion unit of the suitable unit dose as treated patient;Each unit contains predetermined number Amount, be computed reactive compound suitable for generating objective response, and combined with required pharmaceutical carrier.Pass through activation It closes the specific characteristic of object and institute's concrete result for the treatment to be achieved and prepares the individual reactive compound field of this treatment and consolidate Some limitations (and directly depending on them) come determine the present invention dosage unit form standard.Furthermore, it is possible to by pushing away The periodic injections liquid of note is administered, or can pass through intravenous, intramuscular or abdomen with external reservoir (for example, bag intravenously) It is administered in film to be administered continuously.
If it is required that adhering on tissue surface, composition may include being dispersed in fibrinogen-thrombin composition Or the drug in other bioadhesive polymers.It is then possible to which compound is applied, spray or is applied on target tissue surface.Alternatively, can With compounding pharmaceutical, for ear, eyes, nose, parenteral or it is oral give people or other mammals, for example, giving treatment has Effect amount, for example, suitable concentration drug can be provided, to target tissue so as to cause the quantity of target effect whithin a period of time.
If reactive compound is used as a part for transplantation method, can be before removing tissue or organ from donor The living tissue or organ to be transplanted provides the reactive compound.The compound can be supplied to donor host.Alternatively, or another Organ or living tissue can be placed on containing the reactive compound by other places once organ or living tissue are removed from donor It preserves in solution.It, can will using being described herein and/or any method and formulation known in the art in all situations The reactive compound directly gives destination organization, can provide to the tissue injection reactive compound or systematically the work Property compound, for example, passing through ear, eyes, nose, oral and parenteral administration method.If drug include a part tissue or Organ preservation solutions, it can be advantageous to use any commercially available preservation solution.For example, useful solution known in the art Including Collins solution, Wisconsin solution, Belzer solution, Eurocollins solution and Lactated Ringer's solution.
The compounds of this invention is used to medical treatment device, which contacts with tissue, thus can by compound directly to It gives to tissue site.The example of medical treatment device is holder, contains or be coated with one or more the compound of the present invention.
For example, reactive compound can be applied on the holder of vascular lesions sites.Holder can use pharmaceutical field It is prepared by well-known any method.See, e.g., Fattori, R. and Piva, T., " Drug Eluting Stents in Vascular Intervention”, Lancet, 2003, 361, 247-249; Morice, M. C., “A New Era in the Treatment of Coronary Disease?” European Heart Journal, 2003, 24, 209-211;And Toutouzas, K. et al., " Sirolimus-Eluting Stents: A Review of Experimental and Clinical Findings," Z. Kardiol., 2002, 91(3), 49-57.It can be with With the intermetallic composite coating holder of stainless steel or other bio-compatibles or it can be made of biocompatible polymer.It can be by work Property compound is combined with rack surface, is embedded in polymer material coated on holder, and from wherein discharging, or is coated Or the carrier of covering holder is wrapped up, and pass through its release.The tissue that holder can be used for giving the close holder is single or multiple Reactive compound.
The reactive compound that method described herein confirms or designs can be given to individual, (prevented to treat illness Or treatment).It is combined with this treatment, it may be considered that pharmacogenomics are (that is, in individual genotype and individual to externalization Close the research of the relationship between object or medicine response).Between dosage and blood concentration by changing active pharmacological agent The metabolism difference of ratio, treatment can lead to serious toxicity or treatment failure.Doctor or clinician can use as a result, Knowledge obtained in relevant pharmacogenomics research, it is determined whether give drug and design the dosage of the drug therapy And/or therapeutic scheme.
It, can be by ear, eye, nose, oral, parenteral in treating or resisting the application of bacterium infection of mammal And/or compound or its pharmaceutical composition are administered locally to, the dosage given should be obtained and be kept in the animal treated The concentration (quantity) or blood level or tissue of the active component of antimicrobial validity are horizontal.In general, active component is effective Dosage in the range of about 0.1 to about 100 mg/kg body weight/days, more preferably from about 1.0 to about 50 mg/kg weight/ It.Quantity is administered possibly also on following variables:For example, the type and extent of the disease or indication treated, specific to suffer from The general health of person, the Relative biological effect of the compound delivered, the preparation of drug, excipient present in preparation and Type and administration route.It should also be understood that in order to rapidly obtain target blood level or tissue level, initial dosages Can be more than above-mentioned higher level or predose can be less than optimal dose, and can be during treatment, according to specific Daily dose is gradually increased in situation.If necessary, daily dose may be divided into multiple dosages, for example, twice daily It is administered to four times.
In people and other mammals, find various morbid states or illness caused by nonsense mutation or ambiguity mutation Or it is mediated by them.These mutation by negatively affect such as albumen synthesis, fold, transport and/or function by cause or Mediated disease state or illness.Think that disease or illness caused by nonsense or ambiguity mutation account for the morbid state of apparent percentage Or the example of illness includes:Hemophilia (factor Ⅷ gene), neurofibroma (NF1 and NF2 genes), retinitis pigmentosa (people USH2A genes), bullous dermatoses, such as pruigo sample epidermolysis bollosa (COL7A1 genes), cystic fibrosis (capsule Property fibrosis transmembrane adjust gene), breast and ovarian cancer (BRCA1 and BRCA2 genes), Duchenne muscular dystrophy (dystrophin gene), colon cancer (mismatch repair gene, mainly in MLH1 and MSH2) and lysosomal storage disease, such as Neimann-Pick diseases (acid sphingomyelinase gene).Referring to Sanders CR, Myers JK. Disease-related misassembly of membrane proteins. Annu Rev Biophys Biomol Struct. 2004;33:25- 51; National Center for Biotechnology Information(U.S.)Genes and disease Bethesda, MD : NCBI, NLM ID: 101138560;With Rask ó, Istv á n; Downes, C SGenes in medicine; molecular biology and human genetic disorders 1st ed. London ; New York : Chapman & Hall, 1995.NLM ID: 9502404.The compound of the present invention can be used for treatment or pre- Anti- mammal is mutated the morbid state for causing or mediating by this nonsense or ambiguity, and this treatment or prevention, which are given, needs it Mammalian effective amount the compound of the present invention, to inhibit be related to the morbid state the nonsense or ambiguity mutation.
6. embodiment
On 500 spectrometer of Bruker Avance 300 or Avance, or GE-Nicolet is used in some cases 300 spectrometers obtain nuclear magnetic resonance (NMR) and compose.Popular response solvent is high performance liquid chromatography (HPLC) grade or american chemical Meeting (ACS) grade, is obtained with anhydrous form from manufacturer, unless otherwise mentioned." chromatography " or " silica gel purification " refers to using silicon The flash column chromatography of glue (EM Merck, Silica Gel 60,230-400 mesh), unless otherwise mentioned.
The compound of the present invention can be prepared using the known chemical conversion for being suitable for inquired into concrete condition.
Some abbreviations used in the experimental detail of embodiment synthesis below are defined as follows: h or hr=hour;Min=point Clock;Mol=mole;Mmol=mM;M=molar concentration;μM=micro-molar concentration;G=gram;Mg=microgram;Rt=room temperature;L=liter;mL =milliliter;Et2O=diethyl ether;THF=tetrahydrofuran;DMSO=dimethyl sulfoxide;EtOAc=ethyl acetate;Et3N=triethylamine;i- Pr2NEt or DIPEA=diisopropylethylamine;CH2Cl2=dichloromethane;CHCl3=chloroform;CDCl3=Deuterated chloroform;CCl4=tetrachloro Change carbon;MeOH=methanol;CD3OD=deuterated methanol;EtOH=ethyl alcohol;DMF=dimethylformamide;BOC=tertbutyloxycarbonyl;CBZ= Benzyloxycarbonyl group;TBS=t-butyldimethylsilyl;TBSCl=tert-butyldimethylsilyl chloride;TFA=trifluoroacetic acid; DBU=diazabicylo endecatylene;TBDPSCl=tert-butyl diphenyl chlorosilane;Hunig's alkali=N, N- diisopropylethylamine; DMAP=4-dimethylaminopyridine;CuI=cupric iodide (I);MsCl=mesyl chloride;NaN3=sodium azide;Na2SO4=sodium sulphate; NaHCO3=sodium bicarbonate;NaOH=sodium hydroxide;MgSO4=magnesium sulfate;K2CO3=potassium carbonate;KOH=potassium hydroxide;NH4OH=hydrogen-oxygen Change ammonium;NH4Cl=ammonium chloride;SiO2=silica;Pd-C=palladium/carbon;Pd(dppf)Cl2=dichloro [bis- (diphenylphosphines of 1,1'- Base) ferrocene] palladium (II).
The illustrative compounds synthesized according to the present invention are listed in Table 1 below.Runic or empty key indicate the specific vertical of chiral centre Body chemistry, and it can be that any one is orientated or the compound is its mixture that corrugated key, which specifies substituent group,.Should also Solution, in order to save space, the chemical constitution of some compounds is divided into two parts, and two tie points are respectively handed over wavy line The key of fork indicates.See, e.g. compound 755, it is classified as two parts and draws:
But it is corresponding with following complete chemical constitution:
The compound of the present invention can be prepared, prepares and delivered with salt, ester and prodrug form.For convenience, lead to Often specific salt, ester or prodrug form are not indicated when display compound.The compound of the present invention is shown in Table 1.If Properly, LCMS (liquid chromatography mass) data are provided.When there is no data, indicated by " NA ".LCMS data use Conventionalm/z, with [M+H]+Form provide, except the case where showing in another manner.
Table 1
In further embodiment, the compound of the present invention does not include the compound for having having structure:
Using synthesising chemical technology well known to those skilled in the art, the compound of the present invention can be prepared.
Embodiment
The synthesis of embodiment 1- compounds 682
{ 3- [(the bromo- benzyls of 4-)-t-butoxycarbonyl-amino]-propyl }-carbamate:
It is with 30 min that the toluene (50 mL) of the bromo- 4- bromomethyls-benzene of 1- (17.79 g, 71.17 mmol) is molten at 80 DEG C Drop be added to (3- amino-propyls)-carbamate (16.1 g, 92.51 mmol), triethylamine (29.6 mL, 213.5 mmol) toluene (200 mL) mixture in.Obtained mixture is additionally heated 2 hours at 80 DEG C, it is then cold But to 0 DEG C.At 0 DEG C, di-tert-butyl dicarbonate (23.5 g, 107.80 mmol) is added.After 2 hours, which is heated It to room temperature, and is stirred overnight, is diluted with EtOAc (500 mL), washed with water (300 mL), brine (300 mL).It will be organic molten Liquid concentrates, and with purification by flash chromatography (10%-25% EtOAc/ heptane), obtains target product (16.15 g, 51%) colorless oil.1NMR(300 MHz, CDCl3): δ 7.44(d, J=8.4 Hz, 2H), 7.01(br, 2H), 5.16(br.s, 0.5H), 4.62(br.s, 0.5H), 4.34(br, 2H), 3.40(m, 2H), 3.10(m, 2H), 1.65(m, 2H), 1.43 (br.s, 18H)。
(3- t-butoxycarbonyl aminos-propyl)-[4- (4,4,5,5- tetramethyls-[1,3,2] dioxaborolan alkane- 2- yls)-benzyl]-carbamate:
In argon atmospher, by { 3- [(the bromo- benzyls of 4-)-t-butoxycarbonyl-amino]-propyl }-carbamate (16.15 g, 36.46 mmol), double pinacol borates (10.20,40.11 mmol), KOAc (10.72 g, 109.38 mmol)、Pd(PPh3)4(0) mixture of (2.03 g, 1.82 mmol) and DMF (80 mL) heat 16 hours at 80 DEG C.It will The reaction mixture is diluted with EtOAc (500 mL), is washed with water (300 mL) and brine (300 mL).Organic solution is dense Contracting, with purification by flash chromatography (10%-30% EtOAc/ heptane), obtains target product (14.15 g, 80%) colorless oil.1NMR (300 MHz, CDCl3): δ 7.76(d, J=8.1 Hz, 2H), 7.01(br.s, 2H), 5.16(br.s, 0.5H), 4.62(br.s, 0.5H), 4.40(br, 2H), 3.28(m, 2H), 3.08(m, 2H), 1.50(m, 2H), 1.43 (br.s, 18H), 1.34(s, 12H)。
2- (4- { [tertbutyloxycarbonyl-(3- t-butoxycarbonyl aminos-propyl)-amino]-methyl }-phenyl) -3- methoxies Base-methyl acrylate:
By (3- t-butoxycarbonyl aminos-propyl)-[4- (4,4,5,5- tetramethyls-[1,3,2] dioxaborolans Alkane -2- bases)-benzyl]-carbamate (6.00g, 12.25 mmol), 2- iodo -3- methoxy-propene acid methyls Ester (4.45 g, 18.38 mmol), K3PO4(7.79 g, 36.75 mmol), Pd (PPh3)4(0) (0.68 g, 0.61 mmol), The mixture of dioxane (60 mL) and water (12 mL) deaerates, and is heated 20 hours in argon atmospher, at 80 DEG C.By the reaction Mixture is diluted with EtOAc (500 mL), is washed with water (300 mL) and brine (300 mL).Organic solution is concentrated, with fast Fast chromatogram purification (0%-30% EtOAc/ heptane), obtains target product (5.35 g, 91%) brown oil.1NMR(300 MHz, CDCl3): δ 7.56(s, 1H), 7.30(d, J=8.1 Hz, 2H), 7.20(br.d, 2H), 5.20(br.s, 0.5H), 4.62(br.s, 0.5H), 4.39(br, 2H), 3.86(s, 3H), 3.74(s, 3H), 3.27(m, 2H), 3.08(m, 2H), 1.62(m, 2H), 1.50(br.d, 9H), 1。43(s, 9H)。LCMS(EI)m/z: 501(M+Na+)。
(3- { tertbutyloxycarbonyl-[4- (7- oxo -1,7- dihydro-imidazols simultaneously [1,2-a] pyrimidine -6- bases)-benzyl]-ammonia Base }-propyl)-carbamate:
To 2- (4- { [tertbutyloxycarbonyl-(3- t-butoxycarbonyl aminos-propyl)-amino]-methyl }-phenyl) -3- first Oxygroup-methyl acrylate (97 mg, 0.2 mmol), 1H- imidazoles -2- base amine sulfate radicals (29 mg, 0.223 mmol) and second Sodium methoxide solution (0.5 mL, 0.5 M, in methyl alcohol, 0.25 mmol) is added in the mixture of alcohol (10 mL).It is mixed by what is obtained Object is closed to flow back 18 hours, and 0.5 mL sodium methoxides of additional addition (0.5M, in methyl alcohol, 0.5 mmol), continue reflux 20 hours.It is dense It contracts the reaction, is diluted with EtOAc (30 mL), water (20 mL), brine (20 mL) be used in combination to wash.Concentrate EtOAc solution.With fast Fast chromatogram purification crude product (10% ethanol/methylene) obtains target product (48 mg, 48%) white solid.1NMR(300 MHz, CD3OD): δ 8.40(s, 1H), 7.59(br.s, 2H), 7.29(m, 4H), 4.46(s, 2H), 3.23(m, 2H), 3.02(m, 2H), 1.68(m, 2H), 1.52(br.d, 9H), 1。42(s, 9H)。LCMS(EI)m/z: 498.1 (M+H+)。
6- { 4- [(3- Amino-propylaminos)-methyl]-phenyl } -1H- imidazos [1,2-a] pyrimidin-7-ones hydrochloride (hydrochloride of compound 563):
It will { (3- { tertbutyloxycarbonyls-[4- (7- oxo -1,7- dihydro-imidazols simultaneously [1,2-a] pyrimidine -6- bases)-benzyl] - Amino }-propyl)-carbamate (48 mg, 0.097 mmol) is dissolved in CH2Cl2In (5 mL), TFA (1 is added ML), and it is stirred at room temperature 2 hours.The reaction mixture is concentrated, 3 mL 0.6N HCl and 2 mL acetonitriles, stirring 0.5 is added Hour, about 3 mL are concentrated into, is freeze-dried, obtains title compound (35 mg, 100%).1NMR(300 MHz, CD3OD): δ 8.90(s, 1H), 7.79(s, 1H), 7.77(d, J=8.2 Hz, 2H), 7.70(d, J=8.2 Hz, 2H), 7.67(s, 1H), 4.33(s, 2H), 3.23(t, J=8.1 Hz, 2H), 3.06(t, J=7.5 Hz, 2H), 2.15 (m, 2H)。LCMS(EI)m/z: 297.1 (M+H+)。
N- { 3- [4- (7- oxo -1,7- dihydro-imidazols simultaneously [1,2-a] pyrimidine -6- bases)-benzylamino]-propyl }-guanidine Hydrochloride (hydrochloride of compound 564):
To compound 563 (26 mg, 0.07 mmol), Hunig's alkali (90 mg, 0.70 mmol) and DMF (10 mL) N, bis--Boc-1- amidino groups of N- are added in mixture(guanyl)Pyrazoles (22 mg, 0.07 mmol).The reaction is stirred at room temperature Mixture is stayed overnight, and is diluted with water (30 mL), is extracted with EtOAc (50 mL x 3).Organic solution is concentrated, purifies (2N with PTLC NH3Methanol/CH2Cl2, 1:4) guanidine, is obtained(guandylated)Product as white solid (30 mg, 80%), is dissolved in 3 mL CH2Cl2In, 1 mL TFA are added.Obtained mixture is stirred overnight, is concentrated.3 mL 0.6N HCl and 2 mL acetonitriles are added, Stirring 0.5 hour, is concentrated into about 3 mL, is freeze-dried, obtains title compound (20 mg, 100%).1NMR(300 MHz, D2O): δ 8.41(s, 1H), 7.60(d, J=8.4 Hz, 2H), 7.53(d, J=8.4 Hz, 2H), 7.46(d, J= 2.1 Hz, 1H), 7.35(d, J=2.1 Hz, 1H), 4.27(s, 2H), 3.25(t, J=6.9 Hz, 2H), 3.12 (m, 2H), 1.96(m, 2H)。LCMS(EI)m/z: 339.7 (M+H+)。
N- (3- { (4- Amino-butyls)-[4- (7- oxo -1,7- dihydro-imidazols simultaneously [1,2-a] pyrimidine -6- bases)-benzyls Base]-amino }-propyl)-guanidine hydrochloride (hydrochloride of compound 616):
To compound 563 (26 mg, 0.07 mmol), Hunig's alkali (90 mg, 0.70 mmol) and DMF (10 mL) N, bis--Boc-1- guanylpyrazoles of N- (22 mg, 0.07 mmol) are added in mixture.The reaction mixture mistake is stirred at room temperature Night is diluted with water (30 mL), is extracted with EtOAc (50 mL x 3).Organic solution is concentrated, purifies (2N NH with PTLC3First Alcohol/CH2Cl2, 1:4) guanidine product as white solid (30 mg, 80%), is obtained.
By the guanidine compound (27 mg, 0.05 mmol), (3- oxo-propylls)-carbamate (9 mg, 0.05 mmol), acetic acid (6 mg, 0.1 mmol) and CH2Cl230 min are stirred at room temperature in the mixture of (5 mL), then add Enter sodium cyanoborohydride (13 mg, 0.2 mmol).Obtained mixture is stirred overnight, CH is used2Cl2(15 mL) dilutes, with full It is washed with sodium bicarbonate solution.Concentrate CH2Cl2Solution purifies (2N NH with PTLC3Methanol/CH2Cl2, 1:9) target uncle, is obtained Amine white solid (13 mg, 37%).
The tertiary amine product (13 mg, 0.0187 mmol) is dissolved in 3 mL CH2Cl2In, and 1 mL TFA are added.It will obtain Mixture be stirred overnight, concentrate.3 mL 0.6N HCl and 2 mL acetonitriles are added, stirs 0.5 hour, is concentrated into about 3 mL, Freeze-drying, obtains title compound (9.4 mg, 100%).1NMR(300 MHz, CD3OD): δ 8.99(s, 1H), 7.86 (d, J=2.1 Hz, 1H), 7.81(br.s, 4H), 7.74(d, J=2.1 Hz, 1H), 4.55(s, 2H), 3.36 (m, 6H), 3.05(m, 2H), 2.22(m, 2H), 2.09(m, 2H).LCMS(EI)m/z: 396.9 (M+H+)。
{ 4- [2- (the bromo- phenyl of 4-) -7- oxo -1,7- dihydro-imidazols simultaneously [1,2-a] pyrimidine -6- bases]-benzyl }-(3- T-butoxycarbonyl amino-propyl)-carbamate:
To 2- (4- { [tertbutyloxycarbonyl-(3- t-butoxycarbonyl aminos-propyl)-amino]-methyl }-phenyl) -3- first Oxygroup-methyl acrylate (5.70 g, 11.92 mmol), 5- (the bromo- phenyl of 4-) -1H- imidazoles -2- bases amine (2.84g, 11.92 mmol) and the mixture of ethyl alcohol (60 mL) in sodium methoxide solution (12 mL, 0.5M, in methyl alcohol, 6 mmol) is added. Obtained mixture is flowed back 18 hours, and 12 mL sodium methoxides of additional addition (0.5M, in methyl alcohol, 6 mmol), continue reflux 20 Hour.The reaction is concentrated, is diluted with EtOAc (300 mL), water (200 mL), brine (200 mL) washing is used in combination.Concentrate EtOAc Solution.With purification by flash chromatography crude product (0%-8% ethanol/methylenes), target product (4.05 g, 52%) brown solid is obtained 。1NMR(300 MHz, CDCl3): δ 7.96(s, 1H), 7.68(d, J=8.1 Hz, 2H), 7.54(m, 2H), 7.35 (s, 1H), 7.27(d, J=8.1 Hz, 2H), 5.25(br.s, 0.5H), 4.70(br.s, 0.5H), 4.44(s, 2H), 3.29(m, 2H), 3.11(m, 2H), 1.67(m, 2H), 1.52(br.d, 9H), 1.44(s, 9H)。LCMS (EI)m/z: 654(M+H+)。
6- { 4- [(3- Amino-propylaminos)-methyl]-phenyl } -2- (the bromo- phenyl of 4-) -1H- imidazos [1,2-a] Pyrimidin-7-ones hydrochloride (hydrochloride of compound 617):
It will { 4- [2- (the bromo- phenyl of 4-) -7- oxo -1,7- dihydro-imidazols simultaneously [1,2-a] pyrimidine -6- bases]-benzyl } - (3- t-butoxycarbonyl aminos-propyl)-carbamate (100 mg, 0.153 mmol) is dissolved in CH2Cl2(5 mL) In, TFA (1 mL) is added, and be stirred at room temperature 2 hours.The reaction mixture is concentrated, 3 mL 0.6N HCl and 2 mL are added Acetonitrile stirs 0.5 hour, is concentrated into about 3 mL, is freeze-dried, obtains title compound (80 mg, 100%).1NMR(300 MHz, CD3OD): δ 8.99(s, 1H), 8.24(s, 1H), 7.75(m, 8H), 4.30(s, 2H), 3.32(t, J= 8.1 Hz, 2H), 3.09(t, J=7.5 Hz, 2H), 2.17(m, 2H)。LCMS(EI)m/z: 454 (M+H+)。
4- [6- (4- { [tertbutyloxycarbonyl-(3- t-butoxycarbonyl aminos-propyl)-amino]-methyl }-phenyl) -7- oxygen Generation -1,7- dihydro-imidazols simultaneously [1,2-a] pyrimidine -2-base]-benzoic acid 2,5- dioxo-pvrrolidin -1- base esters:
It, will { 4- [2- (the bromo- phenyl of 4-) -7- oxos -1,7- dihydro-imidazol simultaneously [1,2-a] pyrimidine -6- in seal pipe Base]-benzyl-(3- t-butoxycarbonyl aminos-propyl)-carbamate (1.50 g, 2.3 mmol), hydroxysuccinimidyl Acid imide (hydroxysuccilimide) (0.40 g, 3.45 mmol), 9,9- dimethyl -4,5- bis- (diphenylphosphino) oxygen Miscellaneous anthracene (67 mg, 0.115 mmol), acid chloride (26 mg, 0.115 mmol), triethylamine (700 mg, 6.9 mmol) and DMSO The mixture of (3 mL) deaerates, and carbon monoxide (20 psi) is used in combination to refill.It is small that the reaction mixture is heated at 80 DEG C to 16 When.After being cooled to room temperature, which is diluted with water (30 mL), uses CH2Cl2(50 mL x 3) is extracted.By CH2Cl2 Solution concentrates, with purification by flash chromatography (0-10% methanol/CH2Cl2), obtain Acibenzolar brown solid (1.0 g, 61%).1NMR (300 MHz, CDCl3): δ 8.14(d, J=8.4 Hz, 2H), 8.01(d, J=8.4 Hz, 2H), 7.96(s, 1H), 7.64(d, J=9.1 Hz, 2H), 5.59(s, 1H), 7.45(d, J=9.1 Hz, 2H), 5.25(br.s, 0.5H), 4.69(br.s, 0.5H), 4.45(s, 2H), 3.29(m, 2H), 3.11(m, 2H), 2.92(s, 4H), 1.67(m, 2H), 1.52(br.d, 9H), 1.44(s, 9H)。LCMS(EI)m/z: 715(M+H+)。
6- { 4- [(3- Amino-propylaminos)-methyl]-phenyl } -2- [4- (piperazine -1- carbonyls)-phenyl] -1H- miaows Azoles simultaneously [1,2-a] pyrimidin-7-ones hydrochloride (682 hydrochlorides):
By 4- [6- (4- { [tertbutyloxycarbonyl-(3- t-butoxycarbonyl aminos-propyl)-amino]-methyl }-phenyl) -7- Oxo -1,7- dihydro-imidazols simultaneously [1,2-a] pyrimidine -2-base]-benzoic acid 2,5- dioxo-pvrrolidin -1- base esters, 1-boc- piperazines Piperazine (229 mg, 1.23 mmol) and CH2Cl2The mixture of (5 mL) is stirred at room temperature overnight, and purification by flash chromatography is used in concentration (0-10% methanol/CH2Cl2), obtain purposed amide white solid (330 mg, 76%).1NMR(300 MHz, CDCl3): δ 8.03(s, 1H), 7.85(d, J=13.8 Hz, 2H), 7.55(d, J=8.4 Hz, 2H), 7.43(d, J=8.4 Hz, 2H), 7.42(s, 1H), 7.26(d, J=13.8 Hz, 2H), 5.35(br.s, 0.5H), 4.95(br.s, 0.5H), 4.44(s, 2H), 3.70(m, 2H), 3.44(m, 6H), 3.20(m, 2H), 3.10(m, 2H), 1.67(m, 2H), 1.52(br.d, 9H), 1.48(s, 9H)1。44(s, 9H)。LCMS(EI)m/z: 786(M+H+)。
The amide product (330 mg) is dissolved in CH2Cl2In (5 mL), TFA (1 mL) is added, and it is small to be stirred at room temperature 2 When.The reaction mixture is concentrated, 4 mL 0.6N HCl and 4 mL acetonitriles are added, stirs 0.5 hour, is concentrated into about 5 mL, it is cold It is lyophilized dry, obtains title compound (250 mg, 100%).1NMR(300 MHz, CD3OD): δ 9.02(s, 1H), 8.34 (s, 1H), 7.98(d, J=8.4 Hz, 2H), 7.81(d, J=8.4 Hz, 2H), 7.74(d, J=8.1 Hz, 2H), 7.71(d, J=8.1 Hz, 2H), 4.35(s, 2H), 3.90(br.s, 4H), 3.34(m, 2H), 3.25(t, J= 7.5 Hz, 2H), 3.12(t, J=7.8 Hz, 2H), 2.17(m, 2H)。LCMS(EI)m/z: 486.1 (M+H+)。
The synthesis of embodiment 2- pyrrolo- cytimidines
The synthesis of compound 3:
Compound 2 (65.0 g, 373 mmol) is dissolved in ethyl alcohol (150 mL).Flask is purged with argon gas.Then it is added Compound 1 (55.93 g, 373 mmol), and the mixture is stirred at room temperature 2 hours.Then, at 0 DEG C, passed through with 20 minutes Funnel is added, the reaction solution is added to NaBH4In toluene (150 mL) suspension of (14.18 g, 373 mmol).It removes Ice bath, and obtained mixture is stirred at room temperature 3 hours.1N HCl (750 mL) are added in the solution, and should 30 min are stirred at room temperature in mixture.By K2CO3(205.9 g, 1.49 mol), Boc2O (81.41 g, 373 mmol) and THF (200 mL) is added in the solution, and is stirred at room temperature 23 hours.By reaction solution in EtOAc and 1:1 brine Between distribute.Water layer is washed with EtOAc (2 x, 300 mL).Combined organic layer is washed with brine (500 mL);Use Na2SO4 It is dry;Filtering, concentration.With Combi purification by flash chromatography crude product (3 part), obtain product as white solid (119.43 g, 78 %)。1H-NMR(300 MHz, CDCl3)δ 1.43(bs, 18H), 1.63(m, 2H), 2.95-3.30(m, 4H), 4.45 (m, 2H), 5.93(bs, 1H), 7.22(bs, 1H), 7.34(bs, 1H), 7.78(d: 8Hz, 1H), 8.19(d: 8Hz, 1H)。
The synthesis of compound 5:
To in the mixture of compound 3 (42.28 g, 103.5 mmol) and compound 4 (24.54 g, 103.5 mmol) MeOH (3 L) and water (750 mL) is added.At room temperature by 30 min of the mixture strong stirring (leading to air).Then it is added Cu(OAc)2•H2TMEDA (18.63 mL, 124.3 mmol) is then added in O (20.67g, 103.5 mmol).At room temperature will The solution stirs 5 hours (leading to air).Once reaction is completed, which is concentrated into 0.7 L, then in CH2Cl2(700 ) and 20% NH mL4OH/ water (uses NH4Cl (500 mL) be saturated) between distribute.Use CH2Cl2(500 mL, 200 mL) washings Layer.By combined organic layer MgSO4It is dry, it filters, concentration.With Combi purification by flash chromatography crude products: A: CH2Cl2, B: 15:1 CH2Cl2/2N NH3/ MeOH, 0-100% B, 85 min (two 330g columns).Obtain product as white solid (35.52 g, 58%). LCMS(ESI): m/e 600(M+H)+
The synthesis of compound 6:
Compound 5 (10.0 g, 16.68 mmol) is dissolved in THF (40 mL).Flask is purged with argon gas.Then it is added BzCl (3.10 mL, 26.69 mmol) is then added in pyridine (40 mL).By the solution at room temperature, 3 are stirred in argon atmospher Hour.MeOH (4 mL) is added, 10 min of the mixture is stirred at room temperature, then by it in EtOAc (200 mL), heptane (100 mL) and 5% KHCO3It is distributed between/water (200 mL).Water layer is washed with EtOAc (100 mL, 50 mL).By merging 5% KHCO of organic layer3/ water (300 mL) washs;Use Na2SO4It is dry;Filtering, concentration.With Combi purification by flash chromatography crude products : 0-100% EtOAc/ heptane, 55 min (330 g columns).Obtain product off-white powder (9.81 g, 84%).LCMS(ESI):m/e 704(M+H)+
The synthesis of compound 8:
3,5- dibromobenzoic acids 7 (3.35 g, 11.97 mmol) are dissolved in DMF (30 mL).TBTU (O- benzos are added Triazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid ester, 5.38 g, 16.76 mmol), and by the solution in argon gas, 22 DEG C of 5 min of stirring.Diisopropyl ethyl amine (4.95 mL, 29.92 mmol) is added, thia piperazine is then added immediately (thiapiperazine) S, S- dioxide (2.26 g, 16.76 mmol).The mixture is stirred at 22 DEG C 24 hours, and Afterwards by it in EtOAc (200 mL) and 3% KHCO3/H2It is distributed between O (300 mL).With water (200 mL), then brine (100 ML organic phase) is washed, Na is used2SO4It is dry, it filters, concentration.With silica gel (200 g) purification by flash chromatography crude product, 3% (2.5M is used NH3/MeOH)/CH2Cl2.Obtain (1.72 g of compound 8;36%) solid.1H-NMR(300 MHz, DMSO-d6)δ 3.10- 3.30(m, 4H), 3.64(m, 2H), 3.98(m, 2H), 7.75(d: 2.0 Hz, 2H), 7.97(t: 2.0Hz, 1H)。
The synthesis of compound 9:
By compound 8 (1.72 g, 4.33 mmol), N-Boc- piperazines (931 mg, 5.0 mmol), K2CO3(1.26 g, 9.1 mmol), CuI (83 mg, 0.43 mmol) and L-PROLINE (100 mg, 0.87 mmol) be suspended in dimethyl sulfoxide (15 ML in).The mixture is purged with argon gas, is then stirred 20 hours in argon atmosphere, at 85 DEG C.After being cooled to room temperature, by this Mixture distributes between water (150 mL) and EtOAc (200 mL), washs organic phase with water (100 mL), uses Na2SO4It is dry, Concentration.With silica gel (200 g) purification by flash chromatography crude product, 2% (2.5M NH are used3/MeOH)/CH2Cl2.Obtain compound 9 (0.65 g;30%) solid.1H-NMR(300 MHz, DMSO-d6)δ 1.42(s, 9H), 3.12-3.28(m, 8H), 3.44(m, 4H), 3.64(m, 2H), 4.00(m, 2H), 7.02(bs, 2H), 7.17(bs, 1H)。
The synthesis of compound 10:
Compound 9 (0.63 g, 1.25 mmol) is dissolved in THF (10 mL).The solution is placed on and is purged with argon gas In pressure vessel, CuI (60 mg, 0.313 mmol), Pd (PPh is then added3)4(145 mg, 0.125 mmol), Et3N (1.40 mL, 10 mmol) and trimethylsilyl acetylene (0.353 mL, 2.5 mmol).The container is sealed, and this is mixed Object is closed to stir at 45-50 DEG C.After 3 hours, the mixture is diluted with EtOAc (30 mL), is concentrated, silica gel (120 is then used G) purification by flash chromatography uses 70% EtOAc-30% heptane.Semisolid (1.2 g) is obtained, is dissolved in MeOH (70 mL). The solution is purged with argon gas, K is added2CO3(1.0 g), and the mixture is stirred to 30 min in argon atmosphere, at 45 DEG C.It crosses The mixture is filtered, concentrates, with silica gel (120 g) purification by flash chromatography, uses 75% EtOAc-25% heptane.Obtain compound 10 (0.425 g, 76%) solid white foam.LCMS(ESI):m/e 448(M+H)+
The synthesis of compound 11:
Compound 6 (669 mg, 0.95 mmol) and compound 10 (425 mg, 0.95 mmol) are placed on pressure vessel In, and anhydrous DMF (15 mL) is added.The solution is purged with argon gas, CuI (46 mg, 0.24 mmol), Pd is then added (PPh3)4(110 mg, 0.095 mmol) and Et3N (1.06 mL, 7.6 mmol), seals the container, and by the mixture 22 15 min are stirred at DEG C.Then, temperature is risen to 80-85 DEG C, and the mixture is stirred 14 hours.Room temperature is cooled to, MeOH (10 mL) is added, seals the container, and the mixture is stirred 3 hours at 90 DEG C.After being cooled to room temperature, this is mixed Object is closed in saturation KH2PO4It is distributed between/water (250 mL) and EtOAc (200 mL), organic phase is washed with brine (150 mL), used Na2SO4It is dry, it filters, concentration.With silica gel (150 g) purification by flash chromatography crude product, 5% (2.5M NH are used3/MeOH)/ CH2Cl2.Obtain (490 mg of compound 11;56%) yellow solid.LCMS(ESI):m/e 920(M+H)+
The synthesis of compound 12A and 12B:
Compound 11 (490 mg, 0.533 mmol) is dissolved in CH2Cl2In (20 mL), trifluoroacetic acid (20 mL) is added, And the mixture is stirred into 40 min at 22 DEG C.CH is added2Cl2(30 mL), and the mixture is concentrated in vacuo to viscous oil. Water (3 mL) and EtOH (70 mL) is added, concentrates the mixture, obtains crude Compound 12A solid residues.By the residue It is dissolved in [(10% MeOH-90% water)+0.15% TFA] (40 mL).Aliquot sample (10 mL) is injected at Dynamax 41.4 Mm C-18 are prepared on HPLC devices (protective cover+column), are washed with the Solvent Gradient of 10%-55% (+0.15% TFA of MeOH/H2O) De- (40 min).Pure fraction is merged, is concentrated to dryness together with EtOH.By the sample 1N HCl/ water (5 mL) and EtOH (70 ML it) handles, and concentrates.Repeat the operation;By thus obtained solid from H2O-MeCN(4:1) freeze-drying, obtains chemical combination in Object 12B (78 mg) yellow powder.LCMS(ESI):m/e 619(M+H)+
The synthesis of compound 13:
By compound 12A above-mentioned solvent [(10% MeOH-90% water)+0.15%TFA] mixture (30 mL, 0.40 Mmol the solution in) is concentrated into viscous oil together with EtOH.The sample is dissolved in DMF (10 mL) and diisopropyl ethyl amine In the mixture of (0.53 mL, 3.20 mmol).Addition N, bis--Boc-1- guanylpyrazoles of N'- (149 mg, 0.48 mmol), and The mixture is stirred 15 hours at 22 DEG C.Be added EtOH (80 mL), and by the mixture be concentrated in vacuo (<1 mm Hg, 45 DEG C) to viscous oil, by its CH2Cl2In the mixture of (25 mL) and trifluoroacetic acid (30 mL).The mixture is stirred 2 at 22 DEG C Hour, CH is then added2Cl2(70 mL), concentrates the solution, and residue is dissolved in MeOH (30 mL), Amberslyst is used in combination A26 (OH) resin (10 g) processing.The mixture is stirred 1 hour, filtering, and concentrates the filtrate to semisolid.With preparation HPLC (41.4 mm C-18 of Dynamax prepare HPLC devices (protective cover+column)) purifies the sample, with 10%-55% (MeOH/ H2+ 0.15% TFA of O) solvent gradient elution (40 min).Pure fraction is merged, is concentrated to dryness together with EtOH.By the sample Product 1N HCl/ water (5 mL) and EtOH (70 mL) processing, and concentrate.Repeat the operation;By thus obtained solid from H2O- MeCN(4:1) freeze-drying, obtains compound 13 (122 mg) yellow powder in.LCMS(ESI):m/e 661(M+H)+
The synthesis of embodiment 3- compounds 2009a (" a " series) and 2029a (" b " series)
The synthesis of 2a and 2b:
In argon atmosphere, by phosphonium salt 12 (5.24 g, 9.88 mmol), 1a (or 1b) (2.65 g, 9.88 mmol), K2CO3The mixture heated at reflux overnight of (1.36 g, 9.88 mmol) and 18- crown-s 6 (catalytic quantity) in toluene (50 mL). Once completing, which is cooled to room temperature, and water is added.Water layer is extracted with ethyl acetate (3 x, 75 mL), and will be merged Organic matter Na2SO4It is dry, then concentrate.With silica gel chromatography residue (2:1 heptane/ethyl acetate).By compound 2a is thoroughly separated (3.78 g, 87% yield) with the mixture of E and Z isomers.
The synthesis of 3a and 3b:
It is added 10% into the flask containing phthalimide 2a (3.78 g, 8.58 mmol) (or 2b)/ethyl acetate Pd/C (0.76 g, 20% w/w).The flask is evacuated into gas, and hydrogen is full of by sacculus assembly.Continue to stir at room temperature 45 minutes, at this point, purging content with argon gas.After the mixture is filtered by diatomite, solvent is evaporated, with quantitative yield Target product 3a (3.77 g) is provided.
The synthesis of 4a and 4b:
In screw-cap pressure pipe, 3a (3.70 g, 8.37 mmol) (or 3b) is dissolved in absolute ethyl alcohol.By one water of hydrazine It closes object (1.62 mL, 33.5 mmol) to be added in the solution, and is heated 8 hours at 65 DEG C.After being cooled to room temperature, filtering should Slurries remove white solid side-product, and obtained solution are concentrated to dryness.Water is added, and aqueous layer with ethyl acetate is extracted Three times.Then the organic matter for using water and salt water washing to merge, uses Na2SO4It is dry.Solvent is evaporated, limpid colorless oil is provided (2.32 g, 89% yield) is re-dissolved in dichloromethane (75 mL), and 0 DEG C with benzyl chloroformate (1.27 mL, 8.94 mmol) and triethylamine (2.07 mL, 14.9 mmol) processing.After stirring 1 hour, water, and collected organic layer is added, uses Na2SO4It is dry, concentration.With silica gel chromatography crude residue (2:1 heptane/ethyl acetate), 4a viscous oils (3.06 are provided G, 92% yield).
The synthesis of 5a and 5b:
By the identical two steps Sonogashira- deprotections sequence synthesis of alkynes 10 (be used for), prepare compound 5a (and 5b).From 1.5 g 4a startings, target product (0.69 g) is obtained with 53% yield.
The synthesis of 7a and 7b:
Pyrrolo- born of the same parents are prepared by the coupling with alkynes 5a (and 5b) respectively of common intermediate 6 according to the method for above-mentioned synthesis 11 Pyrimidine 7a (and 7b).From 690 mg 5a startings, the 1.23 orange-brown solids of g target compounds (81%) are obtained.LCMS(ESI)m/e 863.4(M+1)+
The synthesis of 8a and 8b:
Method (agent notes: Provisional Application No) described in preparation according to 12A, it is complete with trifluoroacetic acid It is deprotected at the Boc- of 7a (0.60 g, 0.69 mmol) (and 7b).Alternatively, at 50 DEG C, with 8 mL 6N HCl and anhydrous EtOH (30 mL) handles starting material (2 hours), carries out the conversion.After evaporation of the solvent, crude residue (is obtained from any one Approach) just it can be used in next step without being further purified.LCMS(ESI)m/e 663.3(M+1)+
The synthesis of 9a and 9b:
Guanidine is carried out according to scheme used in prepare compound 13 (agent notes: Provisional Application No) to be formed, Only starting material 8a (~0.48 g, 0.65 mmol) (and 8b) is used with crude product oil or semi-solid form, rather than MeOH- aqueous solution forms.The guanidine intermediate of protection is dissolved in 35 mL absolute ethyl alcohols, 10 mL 6N HCl are then added, is promoted Into the removing of Boc groups.The solution is heated to 70 DEG C, is kept for 3 hours.Once it is cooling, concentrate the mixture, by with it is additional Absolute ethyl alcohol azeotropic be further dried.Brown solid, which does not have to be further purified, directly to be used in next step.
The synthesis of 11a and 11b:
In argon atmosphere, guanidine 9a (or 9b) is dissolved in 30 mL trifluoroacetic acids.Thioanisole (0.5 is added dropwise ML it), and by the solution is stirred at room temperature 3-4 hours.Once completing, solvent is evaporated, obtains oil or semisolid.Diethyl is added Ether, and the liquid layer containing most of residual thioanisole is decanted.Then crude product 10a is dissolved in [(20% MeOH-90% water)+ 0.15% TFA] in (20 mL).Aliquot sample (10 mL) is injected at 41.4 mm C-18 of Dynamax and prepares HPLC devices On (protective cover+column), with 10%-65% (MeOH/H2+ 0.15% TFA of O) solvent gradient elution (45 min).By pure fraction Merge, is concentrated to dryness together with EtOH.Sample 1N HCl/ water (5 mL) and EtOH (70 mL) are handled, and concentrated.Weight The multiple operation;By thus obtained solid from H2O-MeCN (4:1) freeze-drying, obtains compound 11a (171 mg) yellow in Powder.LCMS(ESI)m/e 571.2(M+1)+; 1H NMR(300 MHz, D2O)δ 1.50-1.61(m, 4H), 1.87- 1.97(m, 2H), 2.56(bs, 2H), 2.87(bs, 2H), 3.08(t, J=6.9 Hz, 2H), 3.20(t, J=6.9 Hz, 2H), 4.25(s, 2H), 6.60(s, 1H), 7.02(s, 1H), 7.21(s, 1H), 7.32(s, 1H), 7.41(d, J=8.7, 2H), 7.57(d, J=8.7 Hz, 2H), 8.28(s, 1H)
The data of 11b: LCMS(ESI)m/e 555.3(M+1)+; 1H NMR(300 MHz, D2O)δ 1.33-1.46 (m, 4H), 1.72-1.80(m, 2H), 2.44-2.47(m, 2H), 2.70-2.75(m, 2H), 2.84(t, J=8.0 Hz, 2H), 3.03(t, J=8.0 Hz, 2H), 4.09(s, 2H), 6.51(s, 1H), 7.25-7.27(m, 3H), 7.40-7.44(m, 3H), 7.51(s, 1H), 8.13(s, 1H). 。
The synthesis of embodiment 4- triazolopyrimidones
Representative embodiment:
6- { 4- [(3- Amino-propylaminos)-methyl]-phenyl } -2- (4- fluoro-phenyls) -3H- [1,2,4] triazol [1,5-a] pyrimidine -5- ketone
To 2- (4- { [tertbutyloxycarbonyl-(3- t-butoxycarbonyl aminos-propyl)-amino]-first in 10 mL methanol Base }-phenyl) middle addition 5- (4- the fluorophenyls) -3- amino-of -3- methox ,-acrylic acids methyl ester (1.13 g, 2.16 mmol) 1,2,4- triazole (0.50 g, 2.81 mmol).The methanol solution (5.6 mL, 2.81 mmol) of 0.5M sodium methoxides is added dropwise, And the orange mixture is gradually heated to 50 DEG C, it is kept overnight in this condition.Once completing, methanol is removed in vacuum, and will Residue distributes between 100 mL dichloromethane and 100 mL water.Collected organic layer uses Na2SO4Dry, concentration obtains orange Color precipitates.Crude product is loaded on silicagel column, elution is as follows: 5 minutes, 40 mL/min, with 100:0 CH2Cl2/MeOH;15 points Clock, 40 mL/min, with 95:5 CH2Cl2/MeOH;15 minutes, 40 mL/min, with 90:10 CH2Cl2/ MeOH, at this time from column Middle collection target product.Solvent is evaporated, pale yellow precipitate is provided, it is ground together with ether, obtains 560 mg white powders (44% yield).Then solid is dissolved in 10 mL dichloromethane, 3 mL trifluoroacetic acids is then added, remove BOC- protections Base.At room temperature after 1 hour, observe that conversion is completed.It is added after dichloroethanes (10 mL), volatile matter is removed under reduced pressure.Add Enter about 3 mL aq 1N HCl, then evaporates water, promote the formation of HCl salt.It is freeze-dried (aq 1N HCl/ acetonitriles), provides 396 mg (90%, be obtained from the compound of BOC protections) target product white powder.1H NMR(300 MHz, DMSO)δ 1.99-2.09(m, 2H, CH2), δ 2.90-3.02(m, 4H, NCH2), δ 4.17(bs, 2H, CH2Ar), δ 7.38 (t, J=8.9 Hz, 2H, Ar), δ 7.66(d, J=8.4 Hz, 2H, Ar), δ 7.76(d, J=8.4 Hz, 2H, Ar), δ 8.07-8.12(m, 3H, Ar, NH), δ 8.99(s, 1H, CH=C), δ 9.54(bs, 2H, NH), δ 13.4(bs, 1H, NH); LCMS(ES+)m/z 393.0(MH+)。
N- (3- { 4- [2- (4- fluoro-phenyls) -5- oxo -3,5- dihydros-[1,2,4] triazol [1,5-a] pyrimidine -6- Base]-benzylamino }-propyl)-guanidine
To being suspended in DMF/THF (5:1,5.4 mL) in HCl salt (250 mg, 0.54 mmol) in be added triethylamine (0.301 mL, 2.16 mmol).Then by N, it is molten that bis--Boc-1- guanylpyrazoles of N'- (167 mg, 0.54 mmol) are added to this In liquid, LCMS is used in combination to monitor reaction process.After 5 hours, by (being remained on a small quantity with toluene/EtOH azeotropic to evaporate solvent DMF).Crude product is distributed between dichloromethane and water.Each layer is detached, additional dichloromethane is used in combination to extract water phase twice.With The organic matter that salt water washing merges, uses Na2SO4Dry, concentration provides the crude mixture of oil.By preparing (2000 μm of TLC Plate, 10% MeOH/CH2Cl2) purifying is completed, after removing solvent, obtain white solid.The de- of diamines is carried out according to the method described above The formation of protection and HCl salt, after freeze-drying, provides 145 mg (53% yield).1H NMR(300 MHz, DMSO)δ 1.86-1.93(m, 2H, CH2), δ 2.89-2.95(m, 2H, NCH2), δ 3.20-3.27(m, 2H, NCH2), δ 4.19(bs, 2H, CH2Ar), δ 7.35(t, J=9.0 Hz, 2H, Ar), δ 7.63(d, J=7.8 Hz, 2H, Ar), δ 7.68(d, J=7.8 Hz, 2H, Ar), δ 8.07-8.12(m, 2H, Ar), δ 8.99(s, 1H, CH= C), δ 9.35(bs, 2H, NH), δ 13.4(bs, 1H, NH); LCMS(ES+)m/z 435.3(MH+)。
The synthesis of embodiment 5- compounds 562
3- (2,4- dioxo -3,4- dihydro -2H- pyrimidine -1- bases)-pyrrolidines -1- carboxylates (4)
To DIAD is added dropwise in the tetrahydrofuran suspension of 1 (1g, 5.3mmol) and 2 (1.26g, 5.87mmol) (1.16ml, 5.87mmol), and be stirred at room temperature overnight.The clear solution is concentrated under reduced pressure, thick liquid is obtained.Use silica gel Purification by flash chromatography crude mixture (50-60% ethyl acetate-heptanes), obtains pure 3.LCMS(EI)m/z 408.1(M+Na+). 1H NMR(300 MHz, CDCl3): δ 7.94(2H, d), 7.67(1H, t), 7.50(2H, t), 7.27(1H, d), 5.87(1H, d), 5.14(1H, m), 3.78(1H, dd), 3.54(3H。m), 2.34(1H, m), 2.11(1H, m), 1.49(9H, s).By the 2N NH of 3 (2g)3- MeOH (30mL) solution is stirred at room temperature overnight.It is molten that this is evaporated under reduced pressure Liquid, and thus obtained crude mixture flash chromatography on silica gel is purified (70-100% ethyl acetate-dichloromethanes), it obtains 4 pure white solids.LCMS(EI)m/z 281.1(M+H)+1H NMR(300 MHz, CDCl3): δ 9.41(1H, bs), 7.18(1H, d), 5.78(1H, d), 5.17(1H, m), 3.76(1H, dd), 3.52(3H. m), 2.33(1H, m), 2.07(1H, m), 1.48(9H, s)。
3- (the bromo- 2,4- dioxos -3,4- dihydros -2H- pyrimidines -1- bases of 5-)-pyrrolidines -1- carboxylates (5)
To being added in the mixture of 4 (0.6g, 2.13mmol) and N-bromosuccinimide (0.456g, 2.56mmol) DMF (15ml), and be stirred at room temperature 3-4 hours.By the solution in ethyl acetate (50mL) and 10% Na2S2O3(40mL) it Between distribute.Organic layer is detached, brine (3x50mL) is used in combination to wash, dry (anhydrous Na2SO4), it is concentrated under reduced pressure.With the quick color of silica gel Spectrum purifying crude product (70% ethyl acetate-dichloromethane), obtains pure 5.
1H NMR(300 MHz, CDCl3): δ 9.08(1H, bs), 7.43(1H, s), 5.14(1H, m), 3.78 (1H, dd), 3.53(3H。m), 2.35(1H, m), 2.08(1H, m), 1.49(9H, s)。
3- { 5- (2- tertbutyloxycarbonyls amine-phenyl) -2,4- dioxo -3,4- dihydro -2H- pyrimidine -1- bases }-pyrrolidines - 1- carboxylates (7)
To 5 (0.515g, 1.43mmol), 6 (0.547g, 1.72mmol), Pd (PPh3)4(0.165g, 10mol%) and K2CO3Dioxane (8mL) and water (2mL) are added in the mixture of (0.592g, 4.29mmol).In seal pipe, under vacuum, The suspension is purged with argon gas, and is heated at 90 DEG C.After 15 hours, concentrate the solution, and in ethyl acetate (50mL) and It is distributed between brine (30mL).Organic layer is detached, is washed with brine (2x30mL), dry (anhydrous Na2SO4), silica gel is used in evaporation Purification by flash chromatography (50-70% ethyl acetate-dichloromethanes), obtains title compound 7.LCMS(EI)m/z 495.1(M+Na )+1H NMR(300 MHz, CDCl3): δ 9.28(1H, b), 7.75(1H, d), 7.40(1H, t), 7.28(1H, s), 7.12(1H, t), 7.05(1H, d), 5.23(1H, m), 5.11(1H, dd), 3.45(3H, m), 2.35 (1H, m), 2.11(1H, m), 1.48(9H, s), 1.45(9H, s)。
Three azepines of 3- pyrrolidin-3-yl -3,9- dihydro -1,3,9--fluorenes -2- ketone (9)
To 7 (0.3g, 0.635mmol) and 2- trimethylbenzene chlorides (mesitylenesulfonyl chloride, 0.278g, 1.27mmol) mixture in be added dichloromethane (5mL), then be added triethylamine (0.176ml, 1.27mmol) and N, N dimethyl aminopyridine (0.039g, 0.312mmol).Under an inert atmosphere, which is stirred 3 Hour, DBU (0.191mL, 1.27mmol) is then added, and be stirred at room temperature overnight.It is quenched with cold water, and in acetic acid It is distributed between ethyl ester (50mL) and brine (30mL).Organic layer is detached, brine (3x30mL) is used in combination to wash, drying is (anhydrous Na2SO4), it is evaporated under reduced pressure.Purify thus obtained crude product (70% ethyl acetate-dichloromethane) with flash chromatography on silica gel, obtains 8 。1H NMR(300 MHz, CDCl3): δ 8.11(1H, d), 8.09(1H, s), 7.60(1H, d), 7.42(1H, t), 7.27(1H, t), 5.44(1H, m), 3.86(1H, m), 3.60(1H, m), 2.48(1H, m), 2.25(1H, m), 1.73(9H, s), 1.51(9H, m).At room temperature, dichloromethane (10mL) solution of 8 (0.2g) is handled with TFA (3mL) And it stirs 2 hours.The solution is evaporated under reduced pressure, is dried in vacuo, obtains 9..LCMS(EI)m/z 276.3(M+Na)+.9 TFA Salt does not have to be further purified and just can be used in next step.
2- { 4- [3- (three azepines of 2- oxo -2,9- dihydro -1,3,9--fluorenes -3- bases)-pyrrolidin-1-yl] }-iso-indoles - 1,3- diketone (11)
By 9 tfa salt with triethylamine (0.245mL, 1.762mmol) (in CH3In CN (10mL)) it neutralizes, bromide is used in combination 10 (0.148g, 0.528mmol) processing, is stirred at room temperature.After 3 days, the solution is concentrated, and by the quick color of crude product silica gel Spectrum purifying (10% ethanol/methylene), obtains 11 (0.08g).LCMS(EI)m/z 456.1(M+H)+
{ 4- [3- (three azepines of 2- oxo -2,9- dihydro -1,3,9--fluorenes -3- bases)-pyrrolidin-1-yl] }-carbamic acid Tertiary butyl ester (12)
Excessive hydrazine (0.1mL) is added into ethyl alcohol (8mL) solution of 11 (0.08g, 0.176mmol), and at room temperature Stirring 3 hours, is then heated to 50 DEG C, is in addition kept for 3 hours.The solution is concentrated, and is dissolved in tetrahydrofuran (3mL) and water In (3mL).Then Boc is added2O (0.384g, 1.76mmol) and K2CO3(0.1g, 0.7mmol), and be stirred at room temperature Night.The solution decompression is concentrated, and is distributed between ethyl acetate (30mL) and brine (30mL).Organic layer is detached, second is used in combination Acetoacetic ester (4x10mL) is stripped water layer.All organic layers are merged, dry (anhydrous Na2SO4), it filters, concentration. Purify crude product (10% ethanol/methylene) with flash chromatography on silica gel, obtains 12.LCMS(EI)m/z 426(M+H)+1H NMR (300 MHz, CDCl3): δ 8.93(1H, s), 7.71(2H, dd), 7.38(1H, t), 7.20(1H, t), 5.67 (1H, bt), 4.75(1H, m), 3.29(1H, t), 3.20(2H, d), 3.10(1H, d), 2.60(4H, m), 2.23(1H, q), 1.90(1H, m), 1.62(4H, bs), 1.43(9H, s)。
Guanidine intermediate 13:
TFA (1ml) is added in dichloromethane (4ml) solution of 12 (40mg), and is stirred at room temperature 1 hour.Subtract Pressure evaporates the solution, and is evaporated jointly with dichloromethane (3x3mL).The tfa salt is handled with 0.6N HCl (2mL).2 hours it Afterwards, which is freeze-dried.LCMS(EI)m/z 325.8(M+H)+1H NMR(300 MHz, D2O): δ 8.65(1H, s), 7.69(1H, d), 7.37(1H, dd), 7.28(1H, t), 7.22(1H, t), 5.15(1H, m), 4.05 (1H, d), 4.01(1H, t), 3.60(1H, t), 3.30(3H, m), 3.00(2H, t), 2.98(1H, m), 2.54(1H, m), 1.80(2H, m), 1.72(2H, m).To the hydrochloride (0.03g, 0.0753mmol) and (tertiary butyloxycarbonyl Base imino group-pyrazol-1-yl-methyl)-carbamate, it is added in the mixture of 15 (0.035g, 0.113mmol) Hunig's alkali (0.131mL, 0.753mmol) is then added in DMF (2mL).The solution is stirred at room temperature 2 hours, then uses Ethyl acetate (30mL) dilutes.Ethyl acetate layer, dry (anhydrous Na are washed with brine (3x20mL)2SO4), filtering, decompression is steamed Hair.Purify crude product (10% ethanol/methylene) with flash chromatography on silica gel, obtains 13 (30mg) white solids.LCMS(EI)m/z 568.2(M+H)+1H NMR(300 MHz, CDCl3): δ 8.97(1H, s), 8.41(1H, bt), 7.67(2H, dd), 7.36(1H, t), 7.18(1H, t), 5.67(1H, m), 3.51(2H, q), 3.32(1H, q), 3.15(1H, d), 2.63(4H, m), 2.10(1H, m), 1.99(1H, m), 1.70(4H, m), 1.48(9H, s), 1.47(9H, s)。
N{ 4- [3- (three azepines of 2- oxo -2,9- dihydro -1,3,9--fluorenes -3- bases)-pyrrolidin-1-yl]-butyl }-guanidine (14)
TFA (2mL) is added into dichloromethane (4mL) solution of compound 13 (0.028g), and it is small to be stirred at room temperature 3 When.Then the solution is concentrated, is evaporated jointly with dichloromethane (3x4mL), vacuum drying, and be dissolved in 0.6N HCl (2mL), it is cold It is lyophilized dry, obtains pure 14 hydrochloride (0.028g).LCMS(EI)m/z 368.2(M+H)+1H NMR(300 MHz, D2O): δ 8.67(1H, s), 7.68(1H, d), 7.32(1H, dd), 7.29(1H, t), 7.20(1H, t), 5.14(1H, m), 4.14(1H, d), 3.93(1H, t), 3.50(1H, t), 3.24(2H, m), 3.16(2H, t), 2.70(1H, m), 2.67(1H, m), 2.65(1H, m), 1.70(2H, m), 1.57(2H, m)。
The synthesis of embodiment 6- compounds 602
(3- t-butoxycarbonyl aminos-propyl)-[4- (2- oxos -2,10- dihydros-benzo [4,5] imidazo [1,2-a] Pyrimidin-3-yl)-benzyl]-carbamate (5)
To 2- iodo -3- methox ,-acrylic acids methyl ester (1,1.21 g, 5 mmol), 1H- benzimidazolyl-2 radicals-base amine (2, 0.67 g, 5 mmol) and the mixture of ethyl alcohol (30 mL) in be added sodium methoxide solution (10 mL, 0.5M, in methyl alcohol, 5 mmol).Obtained mixture is flowed back 3 hours, concentration obtains 3- iodo -10H- benzos [4,5] imidazo [1,2-a] pyrimidine - 2- ketone (3).By (3- t-butoxycarbonyl aminos-propyl)-[4- (4,4,5,5- tetramethyls-[1,3,2] dioxaborolans Alkane -2- bases)-benzyl]-carbamate (4,490 mg, 1 mmol), 3 (311 mg, 1 mmol), K2CO3(414 G, 3 mmol), Pd (PPh3)4(0) (41 mg, 0.05 mmol), ethyl alcohol (6 mL), dioxanes (2 mL) and water (2 mL) it is mixed Object degassing is closed, and is heated 20 hours at 80 DEG C, in argon atmospher.The reaction mixture is diluted with EtOAc (500 mL), is used Water (300 mL) and brine (300 mL) washing.Organic solution is concentrated, with purification by flash chromatography (mono- chloromethanes of 0%-6% MeOH/ Alkane), obtain target product 5 (170 mg, 31%) light yellow solid.LCMS(EI)m/z: 570(M+Na+)。
3- { 4- [(3- Amino-propylaminos)-methyl]-phenyl } -10H- benzos [4,5] imidazo [1,2-a] pyrimidine - 2- keto hydrochlorides (601)
Compound 5 (170 mg, 0.31 mmol) is dissolved in CH2Cl2In (5 mL), TFA (1 mL) is added, and at room temperature Stirring 2 hours.The reaction mixture is concentrated, 3 mL 0.6N HCl and 2 mL acetonitriles are added, stirs 0.5 hour, is concentrated into about 3 mL, freeze-drying, obtain title compound (150 mg, 100%).1NMR(300 MHz, CD3OD): δ 9.43(s, 1H), 8.27(d, J=8.2 Hz, 1H), 7.87(d, J=7.8 Hz, 2H), 7.75(d, J=7.8 Hz, 3H), 7.69(t, J=8.2 Hz, 1H), 7.62(t, J=8.2 Hz, 1H), 4.35(s, 2H), 3.25(t, J=8.1 Hz, 2H), 3.10(t, J=7.5 Hz, 2H), 2.18(m, 2H)。LCMS(EI)m/z: 348.1 (M+H+)。
N- { 3- [4- (2- oxos -2,10- dihydros-benzo [4,5] imidazo [1,2-a] pyrimidin-3-yl)-benzyl ammonia Base]-propyl }-guanidine hydrochloride (602)
To RX-6817 (110 mg, 0.16 mmol), Hunig's alkali (720 mg, 5.8 mmol) and acetonitrile (10 mL) N, bis--Boc-1- guanylpyrazoles of N- (50 mg, 0.16 mmol) are added in mixture.The reaction mixture mistake is stirred at room temperature Night is diluted with water (30 mL), is extracted with EtOAc (50 mL x 3).Organic solution is concentrated, with purification by flash chromatography (2N NH3- Methanol/CH2Cl2, 0-10%), 7 white solid of product (60 mg) of guanidine is obtained, 3 mL CH are dissolved in2Cl2In, it is added 1 mL TFA.Obtained mixture is stirred overnight, is concentrated.3 mL 0.6N HCl and 2 mL acetonitriles are added, stir 0.5 hour, it is dense About 3 mL are reduced to, is freeze-dried, obtains title compound (40 mg).1NMR(300 MHz, CD3OD): δ 9.41(s, 1H), 8.25(d, J=8.2 Hz, 1H), 7.87(d, J=7.8 Hz, 2H), 7.74(d, J=7.8 Hz, 3H), 7.68(t, J=8.2 Hz, 1H), 7.60(t, J=8.2 Hz, 1H), 4.34(s, 2H), 3.31(m, 2H), 3.20 (t, J=7.5 Hz, 2H), 2.07(m, 2H)。LCMS(EI)m/z: 390.1 (M+H+)。
Embodiment 7- antimicrobial acivities
Examine the antimicrobial acivity of the compounds of this invention.These data are provided in table 2.For coli strain ATCC25922 operates the compound, using the micro- dilution test of standard, measures minimum inhibitory concentration (MICs).Data are provided, wherein "+" indicates that there is the compound 16 micrograms/ml or smaller MIC values, "-" to indicate that the compound has more than 16 micrograms/ml's MIC value." N/A " refers to that can not obtain data.Those skilled in the art it will be appreciated that can for other bacterial organisms come Compound is evaluated, and the active data for Escherichia coli provided are illustrative data, is not intended to limit this The range of invention.According to the efficiency activity for wishing to collect, a large amount of other microorganisms can be resisted to the compound of the present invention and are carried out It measures.In addition, the boundary value of 16 micrograms/ml of "+", "-" and " N/A " statement and selection is also illustrative, it is not intended to It limits the scope of the invention.For example, "-" does not indicate that compound centainly without activity or application, and only it is for specified micro- The MIC value of biology is more than 16 micrograms/ml.
Table 2
In conjunction with bibliography
For all purposes, by the complete disclosure of each patent document and scientific paper that are mentioned above to be cited Mode is incorporated herein in.
Equivalent
Without departing from the spirit or essential characteristics of the present invention, this hair can be implemented in other specific forms It is bright.It is intended, therefore, that the embodiment above is all illustrative embodiment in all respects, rather than limit described herein The present invention.As a result, the scope of the present invention shown by appended claims rather than shown by description above and All changes in the meaning and scope of the equivalent of claim are included in the present invention.

Claims (28)

1. the compound with following formula:
Wherein each H and J is selected independently,
D and E is singly-bound and F is hydrogen,
C-B-A- and-G-H-J is chemical group, wherein
A is selected from:
(b)-(C1-8Alkyl)-, wherein
I) 0-4 carbon atom in (b) is optionally by-NR6It substitutes;
(ee) 6 yuan of saturations, insatiable hunger and/or aromatic carbocyclic, and
(ff)-(CR6R6)t-;
Wherein (b) or (ee) are optionally by one or more R5Group replaces;
G is selected from:
(ee) 6 yuan of saturations, insatiable hunger and/or aromatic carbocyclic,
Wherein (ee) is optionally by one or more R5Group replaces;
B and H independently selected from:
(b) contain 6 yuan of saturations, insatiable hunger and/or the aromatic heterocycle of one or more nitrogen-atoms,
Wherein (b) is optionally by one or more R5Group replaces;
(d)-(C1-8Alkyl)-, wherein
I) 0-4 carbon atom in (d) is optionally by selected from following partial alternative:- O- ,-S (O)p,-NR6,-(C=O)-,-C (=NR6)-,
Ii) (d) is optionally by one or more R5Group replaces;
(g)-(CR6R6)t,
C and J independently selected from:
(a) hydrogen, (c) F, (d) Cl, (e) Br, (f) I, (l)-OR8, (dd)-NR6R8, (ff)-OH, (gg)-NR8R8, (kk)-NR6C (NR6)NR6R8, (ll) C1-8Alkyl, (oo) contain 5-8 members saturation, insatiable hunger and/or the aromatic heterocycle of one or more nitrogen-atoms, (pp) 5-10 members saturation, insatiable hunger and/or aromatic carbocyclic;
Wherein (ll), (oo) and (pp) is optionally by one or more R7Group replaces;
R5It is selected from:(a) hydrogen and (b) F;
R6It is selected from:(a) hydrogen, (b)-C1-8Alkyl (d) contains -5-6 members saturation, insatiable hunger and/or the fragrance of one or more nitrogen-atoms Heterocycle, and (e) -3-10 members saturation, insatiable hunger and/or aromatic carbocyclic;
Wherein (b), (d) and (e) is optionally by one or more R8Substitution;
R7It is selected from:(a) hydrogen, (b) F, (j)-NR6R6, (k)-OR6, (l)-NR6(CNR6)NR6R6, (m)-C1-8Alkyl, (s)-NR6R8, (t)-OR8, and (dd)-C (=NR6)NR6R6
Wherein (m) is optionally by one or more R9Substitution;
R8It is selected from:(a) hydrogen and (m)-C1-8Alkyl;
Wherein (m) is optionally by one or more R9Substitution;
R9It is selected from:(a) hydrogen, (b) F, (j) NH2, (l) NH (CNH) NH2(n)-C1-8Alkyl;
Wherein (n) is optionally by one or more R10Substitution;
R10It is selected from:(a) hydrogen, (b) F, (j) NH2(l) NH (CNH) NH2
P is 0,1 or 2, and
T is 1,2 or 3,
Or its officinal salt or tautomer.
2. according to the compound of claim 1, wherein
B is:(a)-(C1-8Alkyl)-, wherein
I) 0-4 carbon atom in (a) is optionally by selected from following partial alternative:- O- ,-S (O)p,-NR6And-(C=O)-,
Ii) (a) is optionally by one or more R5Group replaces, and
C is selected from:(a)NH2, (b)-NHC (=NH) NH2, and (c) hydrogen,
Or its officinal salt or tautomer.
3. according to the compound of claim 2, wherein
A is phenyl,
B is:(a)-(C1-8Alkyl)-, wherein
I) 0-4 carbon atom in (a) is optionally by selected from following partial alternative:-NR6And-(C=O)-,
Ii) (a) is optionally by one or more R5Group replaces, and
C is selected from:(a)NH2(b)-NHC (=NH) NH2
Or its officinal salt or tautomer.
4. according to the compound of claim 3, wherein C-B-A- is selected from:
Or its officinal salt or tautomer.
5. according to the compound of claim 1, wherein G is optionally by one or more R5The phenyl of group substitution or its is pharmaceutically acceptable Salt or tautomer.
6. according to the compound of claim 2, wherein R5It is (b) F;Or its officinal salt or tautomer.
7. according to the compound of claim 2, wherein R6It is selected from:(d) -5-6 the members for containing one or more nitrogen-atoms are saturated, no Saturation or aromatic heterocycle, and (e) -3-10 members saturation, insatiable hunger and/or aromatic carbocyclic;Or its officinal salt or tautomer.
8. according to the compound of claim 5, wherein G is unsubstituted phenyl;Or its officinal salt or tautomer.
9. according to the compound of claim 8, wherein-G-H-J is selected from:
Or its officinal salt or tautomer.
10. according to the compound of claim 9, wherein each-G-H-J is selected from:
, wherein n is 0,1 or 2,
Or its officinal salt or tautomer.
11. being selected from following compound or pharmaceutically acceptable salt thereof or tautomer
12. pharmaceutical composition, including according to the compound or pharmaceutically acceptable salt thereof or tautomerism of any one of claim 1-11 Body and pharmaceutical carrier.
13. according to any one of claim 1-11 compound or pharmaceutically acceptable salt thereof or tautomer in medicine preparation Purposes, the drug are used to treat the microorganism infection of human or animal.
14. the purposes of claim 13, wherein microorganism infection are selected from:
Skin infection, Gram-positive infection, Gram negative infections, respiratory tract infection, abdominal infection, urinary tract infections, bacterium blood Disease, septicemia, endocarditis, atrioventricular shunt infection, vascular access infection, meningitis, surgical prophylaxis, infection of bone, joint sense Dye, the organism infection of anti-Linezolid (linezolid) and pulmonary tuberculosis.
15. the purposes of claim 14, wherein respiratory tract infection are chronic respiratory tract infections.
16. the purposes of claim 13, wherein microorganism infection are selected from Nosocomial Pneumonia.
17. the purposes of any one according to claim 13-16, wherein compound or pharmaceutically acceptable salt thereof or tautomer are logical Cross ear, eye, nose, oral, parenteral, part or intravenous administration.
18. the medical treatment of compound or pharmaceutically acceptable salt thereof or tautomer containing any one according to claim 1-11 fills It sets.
19. according to the medical treatment device of claim 18, wherein the device is holder.
20. the purposes of claim 13, wherein microorganism infection are acute pelvic infection.
21. the purposes of claim 13, wherein microorganism infection are concurrent skin and skin structure infection.
22. the purposes of claim 13, wherein microorganism infection are Skin and soft tissue infections.
23. the purposes of claim 22, wherein Skin and soft tissue infection are selected from:Not concurrent Skin and soft tissue infection and simultaneously The Skin and soft tissue infection of hair.
24. the purposes of claim 14, wherein Gram-positive infection are selected from the S. aureus infection of methicillin-resistant, resist The enterococcus of vancomycin infects and infection due to Bacillus anthracis.
25. the purposes of claim 14, wherein Gram negative infections are selected from soil and draw hot Francisella infection and the plague Ademilson Salmonella infects.
26. the purposes of claim 14, wherein respiratory tract infection are selected from community acquired pneumonia, the metainfective pneumonia of virus and doctor Institute's acquired pneumonia/Ventilator Associated Pneumonia.
27. the purposes of claim 14, wherein abdominal infection are peritoneal infections.
28. the purposes of claim 27, wherein peritoneal infection are the interior infection of concurrent abdomen.
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