CN107445976A - Antimicrobe compound and its preparation and application - Google Patents

Antimicrobe compound and its preparation and application Download PDF

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Publication number
CN107445976A
CN107445976A CN201710499688.6A CN201710499688A CN107445976A CN 107445976 A CN107445976 A CN 107445976A CN 201710499688 A CN201710499688 A CN 201710499688A CN 107445976 A CN107445976 A CN 107445976A
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alkyl
compound
optionally
nitrogen
members
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Inventor
E.M.杜菲
A.巴塔查吉
H.奥多德
S.陈
M.德维托
R.罗
B.T.温伯利
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Melinta Subsidiary Corp
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Rib X Pharmaceuticals Inc
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Priority claimed from CN2010800573380A external-priority patent/CN102712657A/en
Publication of CN107445976A publication Critical patent/CN107445976A/en
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Abstract

The present invention relates to a kind of Antimicrobe compound and its preparation and application.Specifically, the present invention broadly relates to Antimicrobe compound field and prepared with using their method.These compounds can be effectively used for treating, preventing the microorganism infection of humans and animals and/or reduce its danger.

Description

Antimicrobe compound and its preparation and application
The application is Application No. 201080057338.0, 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), US provisional patent Apply for 61/314,287 (application on March 16th, 2010) and U.S. Provisional Patent Application 61/358,201 (on June 24th, 2010 Shen Priority please).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 prepared with using their method.These compounds can be effective It is dangerous for treating, preventing the microorganism infection of humans and animals and reduce it.
Background technology
Due to being found that penicillin in nineteen twenties and being found that streptomysin in nineteen forties, so, There are many noval chemical compounds to be found or antibiotic medicament is used as by specific design.People once thought, were controlled by means of this Infectious diseases can be controlled or eliminate completely by treating agent.However, due to current effective therapeutic agent resistant cell or micro- The bacterial strain of biology continues to evolve, so, this viewpoint is challenged.The antibiotic medicament of the almost every kind of development clinically used Eventually encounter and the problem of antibiotic-resistant bacteria occurred.For example, the resistant strain of gram-positive bacteria has been formd, such as anti-first The staphylococcus in oxygen XiLin, the streptococcus of resistance to penicillin and the enterococcus of anti-vancocin.Antibiotic-resistant bacteria can be to infection Patient causes serious consequences, even fatal result.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, Recent years, existing many drugmakers exit from the research field and Field of Drug Discovery.Due to this exit, only There is the new antibiotic of minimal amount to enter market.It is especially uneasy to lack new antibiotic, particularly in bacterium to Current Therapy Resistance when all improved in hospital and community environment.
During new antibiotic medicament is found, 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), it is sold with trade (brand) name Ketek, is the derivative of erythromycin Thing.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 suppressing bacterial ribosome function, this antimicrobial compound can hinder main process, such as RNA translations and egg White matter synthesizes, and thus provides anti-microbial effect.In fact, some known Antibiotique compositions, 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 species is counted, This approach originates in ribosomal high-resolution X ray crystal.This structure-based medicine 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 this Structure-ba sed drug design approach, the present invention is described available for the thin for the treatment 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 Thing suppresses 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 more preferable 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 Thing, this approach originate in ribosomal high-resolution X ray crystal.This structure-based medicine is described in publication below Thing 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 provide for the active new antimicrobial of resistance to the action of a drug malignant bacteria organism The needs of important continuous development, especially antimicrobial.
The content of the invention
The present invention broadly relates to Antimicrobe compound field and prepared with using their method.These compounds can be effective It is dangerous for treating, preventing the microorganism infection of humans and animals and reduce it.Present invention also offers these compounds can medicine With salt, ester, N- oxides and pro-drug.
The invention provides the compound with having structure:
WhereinIt is to be selected from following chemical group:
,,
, or,
Wherein U is selected from CR3R3, O, NR4Or S (O)n, C=O, C=NOR3, or, two R3It is combined together, forms carbonyl,
V is independently selected from-CR4a- or-N-；
WhereinRepresent 5 to 7 yuan of saturations, insatiable hunger and/or the aromatic carbocyclic or heterocyclic ring system of fusion；
W is O, NR1, NOR1Or S, or W=combination selected from the HO- and H- being both connected with identical carbon atoms, or both all (the C being connected with identical carbon atoms1-8Alkyl) O- and H- combination；
X---Y represents 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, work as X---Y When being 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,
R4aSelected from H and C1-8Alkyl,
N is 0,1 or 2,
Or-G-H-J is selected from:
,
Wherein RxSelected from CH2, NH, N (C1-8Alkyl), S or O；RyAnd RzC or CH, each independently by one or more F, CH3、CF3, OH and OCH3Substitution；Or Rx、RyAnd RzIt is each independently selected from CH2Or CRaRb, wherein RaAnd RbIt is combined together, shape Into C1-5Carbocyclic ring；
J is selected from NH2, NH (C1-8Alkyl), N (C1-8Alkyl)2, NHC (=O) CH3, NHC (=O) NH2, NHC (=NH) NH2, NHC (= NH)H；
Wherein n is 0,1 or 2；
Or-G-H-J is selected from:
Wherein RxSelected from CH2, NH, N (C1-8Alkyl), S or O；RzIt is C or CH, it is by one or more CH3Substitution, or RzIt is CRaRb, wherein RaAnd RbIt is combined together, forms C1-5Carbocyclic ring,
Wherein m is 1,2 or 3；
J is selected from NH2, NH (C1-8Alkyl), N (C1-8Alkyl)2, NHC (=O) CH3, NHC (=O) NH2, NHC (=NH) NH2, NHC (= NH)H；
C-B-A- ,-D-E-F and-G-H-J are chemical groups, 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 by selected from following group replacement：- O- ,-S (O)p- ,-NR6- ,-(C=O)-,-S (O)pNR6- ,-NR6S(O)p- and-NR6S(O)pNR6-,
Ii) any one of (b) just mentioned above-(d) is optionally by one or more R5Group substitutes, and
Iii) any one of (b) just mentioned above-(d) is optionally by-(C1-8Alkyl)-R5Group substitutes；
(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 miscellaneous containing one or more heteroatomic 3-14 members saturations, insatiable hunger and/or fragrance Ring, 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 substitutes；
B, E and H independently selected from:
(a) singly-bound,
(b) nitrogen, oxygen and sulphur are selected from containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles, hetero atom,
(c) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic,
Wherein (b) or (c) is optionally by one or more R5Group substitutes；
(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 by selected from following group replacement：- O- ,-S (O)p- ,-NR6- ,-(C=O)-,-C (=NR6)-,-S (O)pNR6- ,-NR6S(O)p- and-NR6S(O)pNR6-,
Ii) any one of (d) just mentioned above-(f) is optionally by one or more R5Group substitutes, and
Iii) any one of (d) just mentioned above-(f) is optionally by-(C1-8Alkyl)-R5Group substitutes；
- (CR (g)6R6)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 miscellaneous originals 3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of son, hetero atom are selected from nitrogen, oxygen and sulphur, (pp) 3-14 members saturation, insatiable hunger and/or virtue Fragrant carbocyclic ring, (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)-haloalkyl, (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 substitutes；
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)- (containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur), (q)-(C1-8Alkane Base)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), and (r)-haloalkyl, (s)-SR6, (t) is selected from containing one or more Heteroatomic -3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of nitrogen, oxygen and sulphur, and (u) -3-14 members saturation, insatiable hunger and/or fragrance Carbocyclic ring；Or two R5Group is combined together, and forms carbocyclic ring；
Wherein (m) to (r) and (t) to (u) is optionally by one or more R8Substitution；
R6It is selected from：(a) hydrogen, (b)-C1-8Alkyl, or two R6Group is combined together to form carbocyclic ring, (c)-haloalkyl, (d) containing one or more heteroatomic -3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur, and (e) -3- 14 yuan of saturations, 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)- (containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur), (q)-(C1-8Alkane Base)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), and (r)-haloalkyl, (s)-NR6R8, (t)-OR8, (u)-(CR6R6)tNR6R8, (v)-CR6R8R8, (w)-SR6, (x) containing it is one or more selected from nitrogen, oxygen and sulphur heteroatomic -3-14 members saturation, Insatiable hunger and/or aromatic heterocycle, (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(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)- (containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur), (q)-(C1-8Alkane Base)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), (r) contains one or more heteroatomic -3- for being selected from nitrogen, oxygen and sulphur 14 yuan of saturations, insatiable hunger and/or aromatic heterocycle, (s) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (t)-haloalkyl, (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(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)-C1-8 Alkynyl, (q) are selected from heteroatomic -3-14 members saturation, insatiable hunger and/or the aromatic heterocycles of nitrogen, oxygen and sulphur containing one or more, (r) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (s)-haloalkyl, (t)-(CR6R6)tOR6, (u)-O (CR6R6)tNR6R10, (v)-C (O) R6, (w)-SR6, (x)-C (O) OR10, (y)-S (O)pR6, (z)-(C1-8Alkyl)-(contain one or more Individual heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycle 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)-C1-8 Alkynyl, (q) are selected from heteroatomic -3-14 members saturation, insatiable hunger and/or the aromatic heterocycles of nitrogen, oxygen and sulphur containing one or more, (r) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (s)-haloalkyl, (t)-(CR6R6)tOR6, (u)-O (CR6R6)tNR6R6, (v)-C(O)R6, (w)-SR6, (x)-C (O) OR6, (y)-S (O)pR6, (z)-(C1-8Alkyl)-(containing it is one or more selected from nitrogen, Heteroatomic 3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of 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 (for example, group-D-E-F or group-G-H-J represents hydrogen) is not present in-D-E-F or-G-H-J one of both, But both-D-E-F and-G-H-J can not be not present simultaneously；
P is 0,1 or 2, and
T is 0,1,2 or 3,
Or its officinal salt, ester, dynamic isomer or pro-drug.
In addition, the invention provides the method for synthesis above-claimed cpd.After synthesis, can by the one of therapeutically effective amount or A variety of compounds are made into preparation with pharmaceutical acceptable carrier, as antimicrobial especially antiseptic, for giving human or animal. In certain embodiments, compound of the invention can be effectively used for treating, prevent microorganism infection or reducing its danger, or use Its dangerous medicine can be treated, prevents microorganism infection or reduce in preparing.Correspondingly, it is effective in order to be provided to human or animal The compound of amount, the compound or preparation can be given by following approach：Orally, parenteral, ear, eyes, nose or office Portion's approach.
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.
Embodiment
The invention provides the chemical families that may be used as antimicrobial, more specifically as antiseptic.
The present invention includes its officinal salt, ester, dynamic isomer, 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, how to prepare optically active form and be it is well known that For example, racemic form is split, or synthesized with the initiation material of optically active.Many geometry of alkene, C=N double bonds etc. Isomers is there may also be 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 isomer of the compounds of this invention, and can be with the form of mixtures of isomers Or individually isomeric form separates.All chiralitys, diastereomeric, racemic and the geometrical isomerism form of structure are object forms, Unless specifically indicate that specific spatial chemistry or isomeric form.For preparing all methods of the compounds of this invention and wherein preparing Intermediate be the present invention a part.It is additionally considered that all dynamic isomers of indicated or description compound are of the invention A part.In addition, present invention additionally comprises the metabolin of compound described herein.
Present invention additionally comprises all isotopes for the atom being present among the compounds of this invention.Isotope includes having phase Homoatomic ordinal number but different those atoms of mass number.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 there is the once above in any part or formula of compound, it is every Secondary definition when occurring with its it is any other occur when definition it is unrelated.Thus, if for example, showing group by one or more Individual R6Group substitutes, then R6At each occurrence independently selected from R6Definition.Equally, substituent and/or variable can combine, But condition is：This combination can produce stable compound in the range of the common fare of the atom indicated.
Display represents that the chemical constitution of the dotted line of chemical bond exists with showing the key option.For example, it is close to solid line singly-bound The dotted line drawn shows that the key can be singly-bound or double bond.
When the key table of connect substituent is shown as intersecting with the key of two atoms in connection ring, then this substituent can be with Any atomistic binding on ring.When list substituent without show this substituent and given chemical formula compound remaining Part bonding via atom in the case of, this substituent can be via any atomistic binding in this substituent.Take It can be combined for base and/or variable, but condition is：This combination can produce stable compound.
In the compounds of this invention have nitrogen-atoms in the case of, if appropriate, by using oxidant (for example, MCPBA and/or hydrogen peroxide) handle, these nitrogen-atoms can be changed into N- oxides.Thus, it is believed that shown and requirement Nitrogen-atoms includes shown nitrogen and its N- oxides (N → O) derivative (depending on the circumstances).
A method for developing improved antiproliferative and anti-infectious agent is to provide the conditioning agent of ribose body function and (such as suppressed Agent).
Ribosomes is ribonucleoprotein, and it is present in prokaryotes and eucaryote.Ribosomes is responsible for protein conjunction Into 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, i.e. peptide acyl-transfer enzyme reaction of protein synthesis, and including at least three Different tRNA binding sites (be referred to as aminoacyl, peptide acyl and exit site).The ammonia introduced is received at aminoacyl site or A positions Acyl-tRNA, its amino acid can be supplied to the peptide chain of growth by it.In addition, the A intervals at A positions are important.Peptidyl site Or peptide acyl-tRNA compounds are received in P positions, i.e. have the tRNA of its amino acid, it is the part for increasing peptide chain.In deacylation After tRNA provides its amino acid to the polypeptide chain increased, exit position or E- positions and receive deacylated tRNA.
1. definition
" isomerism " refers to there is identical molecular formula but in the bonding order or their atom sky of property or their atom Between compound different in terms of arrangement.Different isomers is referred to as " stereoisomer " in terms of their steric arrangement. Be not each other mirror image stereoisomer be referred to as " diastereoisomer ", be that the stereoisomer of non-overlapped mirror image is referred to as each other " enantiomer ", or sometimes referred to as optical isomer.The carbon atom of the substituent bonding different from four is referred to as " chiral centre ".
" chiral isomer " refers to the compound with least one chiral centre.It has two opposite-handed mappings 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 referred to as " racemic mixture ".Compound with more than one chiral centre is with 2n-1Individual 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 referred to as " non-enantiomer mixture ") form presence.When a chiral centre be present, stereoisomer can To be characterized by the absolute configuration of the chiral centre (R or S).Absolute configuration refers to the sky for the substituent being connected with chiral centre Between arrangement mode.The substituent being connected with the chiral centre in consideration is the Cahn-Ingold-Prelog sequence rule according to 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)。
It is due to that there is the diastereomer of interrupted rotation around double bond that " geometric isomer ", which refers to that it is present,.At these Represent 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 reversion (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 the rotation of macoradical around center key cause hinder rotation act on.It is this reversion isomers typically with Mixture form is present, however, the development due to recent chromatographic technique, it is already possible to two reversions of separation in the case of selected The mixture of isomers.
" dynamic isomer " 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 different dynamic isomers.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 compounds of the present invention can exist with tautomeric form, and these tautomeric forms are also included within the present invention In the range of.
Compound, salt and the pro-drug of the present invention may have some tautomeric forms, including its enol and imines Form, and ketone and enamine form and geometric isomer and mixture.All this tautomeric forms are included in the scope of the invention It is interior.In the solution, dynamic isomer exists in the form of the mixture of one group of dynamic isomer.It is generally a kind of in solid form Dynamic isomer is dominant.Even if a kind of dynamic isomer may only be described, but the present invention includes all of the compounds of this invention Dynamic isomer.
Dynamic isomer is one kind in two or more constitutional isomers, and they are evenly present, and easily 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 dynamic isomer can be reached.Tautomerism The definite ratio of body depends on some factors, including temperature, solvent and pH value.By tautomerization and the change that mutually converts The concept of isomers is referred to as tautomerism.
Among the various types of possible tautomerism, two kinds of patterns are generally can observe.Mutually made 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 reacts with a hydroxyl (- OH) in identical molecule, obtains the result of ring (ring-type) form.
Tautomerization can be catalyzed by following material: alkali: 1. deprotonations；2. formation delocalization anion (such as enolization Thing)；3. the protonation of the diverse location of anion；Acid: 1. protonations；2. form delocalization cation；3. close to cation not With the deprotonation of position.
Common tautomerism is to being: keto-enol, acid amides-nitrile, lactams-lactim, acid amides-imines in heterocycle Sour tautomerism (for example, in core base 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 individual embodiment:
。
Term " crystal polymorph " or " polymorph " or " crystal form " 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 generally 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 factorses can cause A kind of crystal habit is dominant.Can be by crystallizing the crystal polymorph come prepare compound at different conditions.
Terms used herein " substitution " refer on specified atom (be typically carbon, oxygen or nitrogen-atoms) any one or it is more Individual hydrogen is substituted by the group selected from specified group, and condition is：No more than the common fare of specified atom, and the substitution produces stabilization Compound.When substituent is ketone group (that is ,=O), then 2 on the atom hydrogen is substituted.Ring double bond used herein is two The double bond formed between individual adjacent cyclic atom (for example, C=C, C=N, N=N etc.).
Terms used herein " anomeric carbon " refers to the acetal carbon of glucosides.
Terms used herein " glucosides " is cyclic acetal.
Terms used herein " alkyl " includes having specific carbon number purpose side chain 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, the tert-butyl group, n-pentyl, sec-amyl, n-hexyl, n-heptyl and n-octyl.
" alkenyl " used herein includes the hydrocarbon chain of straight or branched configuration and one or more unsaturated carbon-carbon bonds, no Saturation carbon-carbon bond may reside in any point of safes 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 or branched configuration and one or more carbon-to-carbon triple bonds, carbon-to-carbon Three keys may reside in any point of safes 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, i.e. has two tie points, it is in the present invention An example be when D is selected from these chemical groups.The non-limitative example of this moieties (biradical) is- CH2CH2-, i.e. pass through each terminal carbon and the C of the remainder 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 " cycloalkyl " includes saturation cyclic group, such as cyclopropyl, cyclobutyl or cyclopenta.C3-8Ring Alkyl includes C3、C4、C5、C6、C7And C8Cycloalkyl.
" counter ion " used herein refer to the ions binding of opposite charges existing for it is positively charged or negatively charged Species.The non-limitative example of counter ion is the ion that balance is provided to the electric 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 refer to fluorine, chlorine, bromine and iodine substituent.
" haloalkyl " used herein includes branch with specific number carbon atom, being substituted 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 haloalkyl includes But it is not limited to：Trifluoromethyl, trichloromethyl, pentafluoroethyl group and five chloroethyls.
" alkoxy " used herein refer to it is being connected by oxygen bridge, have and specify number the abovementioned alkyl of carbon atom.C1-6 Alkoxy includes C1、C2、C3、C4、C5And C6Alkoxy.C1-6Alkoxy includes C1、C2、C3、C4、C5、C6、C7And C8Alkoxy.Alkane The example of epoxide includes but is not limited to：Methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, sec-butoxy, uncle Butoxy, n-pentyloxy, secondary amoxy, positive epoxide in heptan and n-octyloxy.
" alkylthio group " used herein refer to it is being connected by sulphur bridge, have and specify number the abovementioned alkyl of carbon atom.C1-6 Alkylthio group includes C1、C2、C3、C4、C5And C6Alkylthio group.C1-6Alkylthio group includes C1、C2、C3、C4、C5、C6、C7And C8Alkylthio group.
Unless otherwise noted, " carbocyclic ring " used herein or " carbocyclic ring " refer to any stabilization 3,4,5,6, 7th, 8,9,10,11 or 12 unit monocycles, bicyclic or three rings, any of which one can be saturation, unsaturation (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 within 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.Preferable bridge is one or two Individual carbon atom.It will be noted that bridge always makes monocyclic to be converted into three rings.When ring is bridged ring, the substituent of cited ring It may reside on bridge.Also include the ring (such as naphthyl and tetralyl) and loop coil of fusion.
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 three rings, it is saturation, unsaturation (including partially and fully unsaturated) or aromatic heterocycle, by carbon atom 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 in this bicyclic or three cyclic groups, is appointed independently selected from nitrogen, oxygen and sulphur, and including any bicyclic or three cyclic groups What heterocycle as defined above is condensed or is connected with second ring (for example, phenyl ring).Nitrogen and sulfur heteroatom can be optionally oxidized (that is, N → O and S (O)p, wherein p=1 or 2).When nitrogen-atoms is included in ring, whether it is connected according to it with the double bond in ring Connect, it can be N or be NH (that is, if necessary to three chemical valences for keeping nitrogen-atoms, then hydrogen being present).Nitrogen-atoms can To be substituted or unsubstituted (that is, N or NR, wherein R are the other substituents of H or defined).Heterocycle be able to can produce It is connected on any hetero atom or carbon atom of raw rock-steady structure with its side base.If obtained compound is stable chemical combination Thing, then heterocycle described herein can be substituted on carbon or nitrogen.Miscellaneous nuclear nitrogen can be optionally quaternized.Bridged ring also 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.Preferable 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, there may also be on bridge for the substituent of cited ring.Also include loop coil and fused rings.
Terms used herein " aromatic heterocycle " or " heteroaryl " refer to 5,6,7,8,9,10,11 or 12 stable unit monocycles Or Bicyclic ring, it is made up 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 It is aromatic rings (for example, 2,3- indoline) to only require a ring, but two rings can also all be aromatic rings (for example, quinoline). Second ring can also be fusion defined in heterocycle above or bridge joint ring.Nitrogen-atoms can be it is substituted or unsubstituted (i.e., N or NR, wherein R are another substituents of H or defined).Nitrogen and sulfur heteroatom can optionally be oxidized (that is, N → O and S (O)p, wherein p=1 or 2).In some 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), Azocine base, benzimidazolyl, benzofuranyl, benzimidazole thiophanate furyl, benzothienyl, benzoxazolyl, benzoxazole quinoline Base, benzothiazolyl, BTA base, benzo tetrazole radical, benzoisoxazole base, benzisothia oxazolyl, benzimidazoline base, benzene And dioxolyl (benzodioxoly), Ben Bing oxadiazolyl, carbazyl, 4aH- carbazyls, carboline base, benzo two Hydrogen pyranose, chromene base, scold Lin Ji, suberyl, decahydroquinolyl, dihydrobenzo bioxin base, 2H, 6H-1,5,2- dithiazine Base, dihydrofuran simultaneously [2,3-b] tetrahydrofuran, furyl, furazanyl, imidazolidinyl, imidazolidinyl imines, imidazolinyl, miaow Oxazolyl, imidazoline ketone group, 1H- indazolyls, indoles alkenyl (indolenyl), indolinyl, indenes piperazine base, indyl, 3H- Yin Diindyl base, isatin base（isatinoyl）, isobenzofuran-base, isochroman base, iso indazolyl, different dihydro nitrogen Indenyl, isoindolyl, isoquinolyl, isothiazolyl , isoxazolyls, methylenedioxyphenyl base, methylbenzotrazole base, methyl Furyl, methylimidazolyl, methyl thiazolium oxazolyl, morpholinyl, naphthyridines base, octahydro isoquinolyl, oxadiazolyl, 1,2,3- oxadiazole Base, 1,2,4- oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4- oxadiazolyl, oxazolidine base, oxazolidine ketone group, oxazolyl, hydroxyl Indyl, phenanthridinyl, ferrosin base, phenazinyl, phenothiazinyl, phenoxanthein base（phenoxathinyl）, phenoxazine groups, phthalazines Base, piperazinyl, piperazine ketone group (piperazinonyl), piperidyl, tetrahydro pyridyl (piperidenyl), piperidone base, 4- Piperidone base, piperonyl, pteridine radicals, purine radicals, pyranose, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, Bi Ding Bing oxazolyls, pyridine-imidazole base, pyridothiazole base, pyridine radicals, pyriconyl (pyridinonyl), pyridine radicals are phonetic Piperidinyl, pyrrolidone-base（pyrroldionyl）, pyrrolidinyl, pyrrolidone-base, pyrrolinyl, 2H- pyrrole radicals, pyrrole radicals, Quinazolyl, quinolyl, 4H- quinolizine bases, quinoxalinyl, quininuclidinyl, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydroquinoline Base, tetrazole radical, 6H-1,2,5- thiadiazine bases, 1,2,3- thiadiazolyl group, 1,2,4- thiadiazolyl group, 1,2,5- thiadiazolyl group, 1,3, 4- thiadiazolyl groups, thianthrene group, thiazolyl, thienyl, thiophene benzothiazolyl, thiophene fen and oxazolyl, Thienoimidazole base, thienyl (thiophenyl), thiomorpholine base dioxide (thiomorpholinyldioxidyl), triazine radical, triazolopyrimidinyl, 1, 2,3- triazolyls, 1,2,4- triazolyl, 1,2,5- triazolyl, 1,3,4- triazolyl andTon base.
Terms used herein " pharmaceutically acceptable " refers to：In reliable medical judgment scope, it is adapted to the tissue with patient to connect Touch but without excessive toxicity, excitant, allergy or other problems or complication those compounds, raw material, composition and/ Or formulation, it matches with rational benefit/hazard ratio.
" officinal salt " used herein refers to the derivative of disclosed compound, and wherein parent compound passes 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 be derived from those salt selected from following inorganic and organic acid：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, ethyl sulfonic acid, fumaric acid, Glucoheptonic acid, gluconic acid, GLU, glycol acid, glycollyl Arsanilic Acid (glycollyarsanilic), hexylresorcinol two Phenolic acid (hexylresorcinic), hydrabamic, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, carbonaphthoic acid, hydroxyl second Sulfonic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, Loprazolam, 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), butanedioic 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 alkalescence or acidic moiety synthesize it is of the invention can medicine Use salt.Generally, this salt can be prepared as follows：In water or organic solvent, or in both mixtures, these compounds The suitable alkali or acid reaction of free acid or alkali form and stoichiometric；Generally, it is preferred to non-aqueous media, for example, ether, acetic acid Ethyl ester, ethanol, 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)。
Because known precursors medicine can improve many desirable quality of medicine (for example, solubility, biological utilisation Rate, prepare, etc.), so, compound of the invention can be delivered with prodrug form.Thus, the present invention includes being advocated The pro-drug of compound, the method for delivering it and the composition containing it." pro-drug " includes any covalently bound load Body, when giving this pro-drug to mammalian subject, it discharges the active parent drug of the present invention in vivo.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.Hydroxyl, amino or the sulfydryl of pro-drug including the compounds of this invention 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 ether or salt derivative.
" stable compound " and " rock-steady structure " used herein refer to the compound fully consolidated, can stand from anti- Answer in mixture and separate to effective purity, and can be formulated as effective therapeutic agent.
Terms used herein " patient " refers to be performed 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 invaded The dangerous method of entering property method, or the method for preventing the infection caused by surgical procedure or invasive method.Can be with Think that this patient or subject need the prevention in peri-operation period.
Terms used herein " treatment " refers to the therapeutic intervention in order to cure or improve infection and provide.
Terms used herein " prevention " refers to that completely or almost completely terminating infection occurs, for example, working as patient or tested Person tends to infect or when among risk of infection.Prevention can also include suppressing infection, that is, the development to prevent infections.
Terms used herein " reduce dangerous " refers to reduce possibility or the probability that infection occurs, for example, as patient or Subject tends to infect or when among risk of infection.
The compound that " unsaturation " used herein refers to have at least one degree of unsaturation is (for example, at least one multiple Key), and including partially and fully unsaturated compound.
Terms used herein " effective dose " refers 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 dose, which refers to be present in give, receives patient or subject Composition, the compound amounts in preparation or medical apparatus, it is 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 dose of given the compounds of this invention, this effective dose be used to preventing by In the infection caused by surgical procedure or invasive medical procedures or reduce its danger.
Further understand, state " hydrogen bond receptor-hydrogen bond receptor-hydrogen-bond donor " and " hydrogen bond receptor-hydrogen bond receptor-hydrogen bond Acceptor " 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 It can include other atoms or atomic group between kind group.
In this specification, singulative also includes plural number, unless being clearly dictated otherwise in context.It is unless fixed in addition There are those skilled in the art generally to manage for justice, otherwise, all technologies and scientific term used herein The identical meanings of solution.In the case of contradiction, it is defined by this specification." mammal " used herein refers to people and inhuman trouble Person.
Terms used herein " therapeutically effective amount " refers to the compounds of this invention for being supplied to recipient or chemical combination of the present invention The composition quantity of thing, the quantity 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 synergy. 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, Chou and Talalay, Adv. Enzyme RegulVol. 22, the synergy described by pp. 27-55 (1984) Occur.Generally, under the suboptimum concentration of compound, it will acted synergistically most apparent from performance.Synergy can reduce thin Cellular toxicity, improve antiproliferative and/or anti-infection effect, or some other beneficial effect of combination (compared with one-component).
Terms used herein " the micro- spirals of RNA (microhelix) binding site " refers to shared by the micro- spirals of RNA of formula III According to large ribosomal subunit kernel function (ribofunctional) position.The micro- thread joint locator qualifications at least one of RNA Part E- sites are overlapping with E- positions.
Terms used herein " A positions " refers to just participate in its institute before peptide combines to form reaction in aminoacyl tRNA molecules The kernel function position occupied.
Terms used herein " E- positions " refers to that participating in peptide in deacylated tRNA combines to form after reaction occupied by it Kernel function position.
Terms used herein " P- positions " refers to when peptidyl tRNA participates in peptide bond composition reaction, by peptide acyl-tRNA institutes The kernel function position occupied.
Terms used herein " A- intervals " refers 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 A positions 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 formed.Forming the residue of this part can be, for example, (i) is based on such as rRNA Or the consecutive residue of the primary sequence of ribosomal protein, (ii) form the continuous portion of ribosomes or ribosomal subunit's three-dimensional structure The residue divided, or (c) its combination.When using and refer to herein the micro- spirals of RNA, term " part " or " part for three-dimensional structure " The part for referring to the micro- helix three-dimensional structures of RNA, including distribution of charges and hydrophilic/hydrophobic characteristic are can be regarded as, by formula III One or more parent nucleus residues at least three, more preferably at least three to ten atomic buildings.Form the original of this part Son can be, for example, the inaccessible atom of solvent that the micro- spiral parent nucleus of (i) RNA is embedded in, the solvent of the micro- spirals of (ii) RNA Accessible atom, or (iii) its combination.
All percentages used herein and ratio, unless otherwise stated, are by weight.
Through the specification, when composition to have including, or when being described comprising specific component, or when method to have Have including or when being described comprising specific method and step, the composition for referring to the present invention is also substantially made up of the component enumerated, or Formed by enumerating component, and the method for the present invention is also substantially made up of the processing step enumerated, or be made up of processing step.Enter One step, it should be appreciated that the order of step or the order for carrying out some operations are non-substantial, as long as the present invention is still to grasp Make.In addition, two or more steps or operation can be carried out simultaneously.
2. the compound of the present invention
On the one hand, the present invention relates to the compound with having structure:
WhereinSelected from following chemical group:
,,
, or,
Wherein U is selected from CR3R3, O, NR4Or S (O)n, C=O, C=NOR3, or, two R3It is combined together, forms carbonyl,
V is independently selected from-CR4a- or-N-；
WhereinRepresent 5 to 7 yuan of saturations, insatiable hunger and/or the aromatic carbocyclic or heterocyclic ring system of fusion；
W is O, NR1, NOR1Or S, or W=combination selected from the HO- and H- being both connected with identical carbon atoms, or both all (the C being connected with identical carbon atoms1-8Alkyl) O- and H- combination；
X---Y represents 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, work as X---Y When being 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,
R4aSelected from H and C1-8Alkyl,
N is 0,1 or 2,
Or-G-H-J is selected from:
,
Wherein RxSelected from CH2, NH, N (C1-8Alkyl), S or O；RyAnd RzC or CH, each independently by one or more F, CH3、CF3, OH and OCH3Substitution；Or Rx、RyAnd RzIt is each independently selected from CH2Or CRaRb, wherein RaAnd RbIt is combined together, shape Into C1-5Carbocyclic ring；
J is selected from NH2, NH (C1-8Alkyl), N (C1-8Alkyl)2, NHC (=O) CH3, NHC (=O) NH2, NHC (=NH) NH2, NHC (= NH)H；
Wherein n is 0,1 or 2；
Or-G-H-J is selected from:
Wherein RxSelected from CH2, NH, N (C1-8Alkyl), S or O；RzIt is C or CH, it is by one or more CH3Substitution, or RzIt is CRaRb, wherein RaAnd RbIt is combined together, forms C1-5Carbocyclic ring,
Wherein m is 1,2 or 3；
J is selected from NH2, NH (C1-8Alkyl), N (C1-8Alkyl)2, NHC (=O) CH3, NHC (=O) NH2, NHC (=NH) NH2, NHC (= NH)H；
C-B-A- ,-D-E-F and-G-H-J are chemical groups, 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 by selected from following group replacement：- O- ,-S (O)p- ,-NR6- ,-(C=O)-,-S (O)pNR6- ,-NR6S(O)p- and-NR6S(O)pNR6-,
Ii) any one of (b) just mentioned above-(d) is optionally by one or more R5Group substitutes, and
Iii) any one of (b) just mentioned above-(d) is optionally by-(C1-8Alkyl)-R5Group substitutes；
(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 miscellaneous containing one or more heteroatomic 3-14 members saturations, insatiable hunger and/or fragrance Ring, 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 substitutes；
B, E and H independently selected from:
(a) singly-bound,
(b) nitrogen, oxygen and sulphur are selected from containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles, hetero atom,
(c) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic,
Wherein (b) or (c) is optionally by one or more R5Group substitutes；
(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 by selected from following group replacement：- O- ,-S (O)p- ,-NR6- ,-(C=O)-,-C (=NR6)-,-S (O)pNR6- ,-NR6S(O)p- and-NR6S(O)pNR6-,
Ii) any one of (d) just mentioned above-(f) is optionally by one or more R5Group substitutes, and
Iii) any one of (d) just mentioned above-(f) is optionally by-(C1-8Alkyl)-R5Group substitutes；
- (CR (g)6R6)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 miscellaneous originals 3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of son, hetero atom are selected from nitrogen, oxygen and sulphur, (pp) 3-14 members saturation, insatiable hunger and/or virtue Fragrant carbocyclic ring, (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)-haloalkyl, (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 substitutes；
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)- (containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur), (q)-(C1-8Alkane Base)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), and (r)-haloalkyl, (s)-SR6, (t) is selected from containing one or more Heteroatomic -3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of nitrogen, oxygen and sulphur, and (u) -3-14 members saturation, insatiable hunger and/or fragrance Carbocyclic ring；Or two R5Group is combined together, and forms carbocyclic ring；
Wherein (m) to (r) and (t) to (u) is optionally by one or more R8Substitution；
R6It is selected from：(a) hydrogen, (b)-C1-8Alkyl, or two R6Group is combined together to form carbocyclic ring, (c)-haloalkyl, (d) containing one or more heteroatomic -3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur, and (e) -3- 14 yuan of saturations, 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)- (containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur), (q)-(C1-8Alkane Base)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), and (r)-haloalkyl, (s)-NR6R8, (t)-OR8, (u)-(CR6R6)tNR6R8, (v)-CR6R8R8, (w)-SR6, (x) containing it is one or more selected from nitrogen, oxygen and sulphur heteroatomic -3-14 members saturation, Insatiable hunger and/or aromatic heterocycle, (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(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)- (containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur), (q)-(C1-8Alkane Base)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), (r) contains one or more heteroatomic -3- for being selected from nitrogen, oxygen and sulphur 14 yuan of saturations, insatiable hunger and/or aromatic heterocycle, (s) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (t)-haloalkyl, (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(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)-C1-8 Alkynyl, (q) are selected from heteroatomic -3-14 members saturation, insatiable hunger and/or the aromatic heterocycles of nitrogen, oxygen and sulphur containing one or more, (r) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (s)-haloalkyl, (t)-(CR6R6)tOR6, (u)-O (CR6R6)tNR6R10, (v)-C (O) R6, (w)-SR6, (x)-C (O) OR10, (y)-S (O)pR6, (z)-(C1-8Alkyl)-(contain one or more Individual heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycle 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)-C1-8 Alkynyl, (q) are selected from heteroatomic -3-14 members saturation, insatiable hunger and/or the aromatic heterocycles of nitrogen, oxygen and sulphur containing one or more, (r) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (s)-haloalkyl, (t)-(CR6R6)tOR6, (u)-O (CR6R6)tNR6R6, (v)-C(O)R6, (w)-SR6, (x)-C (O) OR6, (y)-S (O)pR6, (z)-(C1-8Alkyl)-(containing it is one or more selected from nitrogen, Heteroatomic 3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of 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 can not be not present simultaneously；
P is 0,1 or 2, and
T is 0,1,2 or 3,
Or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or precursor medicine Thing, whereinFurther include hydrogen-bond donor part or other hydrogen bond receptor parts.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or precursor medicine Thing, whereinIt is the chemical part comprising 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, dynamic isomer or precursor medicine Thing, 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 does not refer to that hydrogen-bond donor or acceptor portion must be connected directly between one Rise, because there may be other atoms or atomic group between hydrogen-bond donor or acceptor portion.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or precursor medicine Thing, 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, dynamic isomer or precursor medicine Thing, 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, dynamic isomer or precursor medicine Thing, wherein hydrogen bond receptor are partly comprised within cyclic structure, wherein the cyclic structure is the polycyclic of single ring architecture or fusion Structure.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or precursor medicine Thing, 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, dynamic isomer or precursor medicine Thing, 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 does not refer to that hydrogen-bond donor or acceptor portion must be connected directly between one Rise, because there may be other atoms or atomic group between hydrogen bond receptor part.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or precursor medicine Thing, wherein within the scope of about the 5 of at least one other hydrogen bond receptor part in each hydrogen bond receptor part.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or precursor medicine Thing, 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, dynamic isomer or precursor medicine Thing, wherein at least two hydrogen bond receptor are partly comprised within cyclic structure, wherein the cyclic structure is single ring architecture or thick The multiring structure of conjunction.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or precursor medicine Thing, wherein the hydrogen bond receptor part is sub- independently selected from carbonyl, thiocarbonyl, imine group, alkyl-substituted imine group 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 or pharmaceutically acceptable salt thereof, ester, dynamic isomer or precursor medicine Thing, wherein the 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, dynamic isomer or precursor medicine Thing, wherein
Include having structure part
W is O, NR1, NOR1Or S, or W=combination selected from the HO- and H- being both connected with identical carbon atoms, or both all (the C being connected with identical carbon atoms1-8Alkyl) O- and H- combination；
X---Y represents 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, work as X---Y When being 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, dynamic isomer or precursor medicine Thing, wherein W are O, NR1, NOR1Or S；Wherein R1Selected from H and C1-6Alkyl.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or precursor medicine Thing, wherein
Include having structure part
Wherein Z is selected from O, NR4Or S (O)n；
R4Selected from H 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, dynamic isomer or precursor medicine Thing, wherein
Include 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, dynamic isomer or precursor medicine Thing, wherein R4It is H.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or precursor medicine Thing, wherein
Include cytimidine or isocytosine moieties or derivatives thereof.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or precursor medicine Thing, wherein
Include having structure part
,,
, or,
Wherein U is selected from CR3R3, O, NR4Or S (O)n, C=O, C=NOR3, or, two R3It is combined together, forms carbonyl,
V is independently selected from-CR4a- or-N-；
WhereinRepresent 5 to 7 yuan of saturations, insatiable hunger and/or the aromatic carbocyclic or heterocyclic ring system of fusion；
W is O, NR1, NOR1Or S, or W=combination selected from the HO- and H- being both connected with identical carbon atoms, or both all (the C being connected with identical carbon atoms1-8Alkyl) O- and H- combination；
X---Y represents 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, work as X---Y When being 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,
R4aSelected from H and C1-8Alkyl,
N is 0,1 or 2.
In some embodiments, the present invention relates to the compound of following formula:
(I),(II),
(III), or(IV),
Wherein U is selected from CR3R3, O, NR4Or S (O)n, C=O, C=NOR3, or, two R3It is combined together, forms carbonyl,
V is independently selected from-CR4a- or-N-；
WhereinRepresent 5 to 7 yuan of saturations, insatiable hunger and/or the aromatic carbocyclic or heterocyclic ring system of fusion；
W is O, NR1, NOR1Or S, or W=combination selected from the HO- and H- being both connected with identical carbon atoms, or both all (the C being connected with identical carbon atoms1-8Alkyl) O- and H- combination；
X---Y represents 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, work as X---Y When being 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,
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,
Or-G-H-J is selected from:
,
Wherein RxSelected from CH2, NH, N (C1-8Alkyl), S or O；RyAnd RzC or CH, each independently by one or more F, CH3、CF3, OH and OCH3Substitution；Or Rx、RyAnd RzIt is each independently selected from CH2Or CRaRb, wherein RaAnd RbIt is combined together, shape Into C1-5Carbocyclic ring；
J is selected from NH2, NH (C1-8Alkyl), N (C1-8Alkyl)2, NHC (=O) CH3, NHC (=O) NH2, NHC (=NH) NH2, NHC (= NH)H；
Wherein n is 0,1 or 2；
Or-G-H-J is selected from:
Wherein RxSelected from CH2, NH, N (C1-8Alkyl), S or O；RzIt is C or CH, it is by one or more CH3Substitution, or RzIt is CRaRb, wherein RaAnd RbIt is combined together, forms C1-5Carbocyclic ring,
Wherein m is 1,2 or 3；
J is selected from NH2, NH (C1-8Alkyl), N (C1-8Alkyl)2, NHC (=O) CH3, NHC (=O) NH2, NHC (=NH) NH2, NHC (= NH)H；
C-B-A- ,-D-E-F and-G-H-J are chemical groups, 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 by selected from following group replacement：- O- ,-S (O)p- ,-NR6- ,-(C=O)-,-S (O)pNR6- ,-NR6S(O)p- and-NR6S(O)pNR6-,
Ii) any one of (b) just mentioned above-(d) is optionally by one or more R5Group substitutes, and
Iii) any one of (b) just mentioned above-(d) is optionally by-(C1-8Alkyl)-R5Group substitutes；
(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 miscellaneous containing one or more heteroatomic 3-14 members saturations, insatiable hunger and/or fragrance Ring, 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 substitutes；
B, E and H independently selected from:
(a) singly-bound,
(b) nitrogen, oxygen and sulphur are selected from containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles, hetero atom,
(c) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic,
Wherein (b) or (c) is optionally by one or more R5Group substitutes；
(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 by selected from following group replacement：- O- ,-S (O)p- ,-NR6- ,-(C=O)-,-C (=NR6)-,-S (O)pNR6- ,-NR6S(O)p- and-NR6S(O)pNR6-,
Ii) any one of (d) just mentioned above-(f) is optionally by one or more R5Group substitutes, and
Iii) any one of (d) just mentioned above-(f) is optionally by-(C1-8Alkyl)-R5Group substitutes；
- (CR (g)6R6)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 miscellaneous originals 3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of son, hetero atom are selected from nitrogen, oxygen and sulphur, (pp) 3-14 members saturation, insatiable hunger and/or virtue Fragrant carbocyclic ring, (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)-haloalkyl, (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 substitutes；
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)- (containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur), (q)-(C1-8Alkane Base)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), and (r)-haloalkyl, (s)-SR6, (t) is selected from containing one or more Heteroatomic -3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of nitrogen, oxygen and sulphur, and (u) -3-14 members saturation, insatiable hunger and/or fragrance Carbocyclic ring；
Wherein (m) to (r) and (t) to (u) is optionally by one or more R8Substitution；
R6It is selected from：(a) hydrogen, (b)-C1-8Alkyl, or two R6Group is combined together to form carbocyclic ring, (c)-haloalkyl, (d) containing one or more heteroatomic -3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur, and (e) -3- 14 yuan of saturations, 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)- (containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur), (q)-(C1-8Alkane Base)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), and (r)-haloalkyl, (s)-NR6R8, (t)-OR8, (u)-(CR6R6)tNR6R8, (v)-CR6R8R8, (w)-SR6, (x) containing it is one or more selected from nitrogen, oxygen and sulphur heteroatomic -3-14 members saturation, Insatiable hunger and/or aromatic heterocycle, (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(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)- (containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur), (q)-(C1-8Alkane Base)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), (r) contains one or more heteroatomic -3- for being selected from nitrogen, oxygen and sulphur 14 yuan of saturations, insatiable hunger and/or aromatic heterocycle, (s) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (t)-haloalkyl, (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(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)-C1-8 Alkynyl, (q) are selected from heteroatomic -3-14 members saturation, insatiable hunger and/or the aromatic heterocycles of nitrogen, oxygen and sulphur containing one or more, (r) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (s)-haloalkyl, (t)-(CR6R6)tOR6, (u)-O (CR6R6)tNR6R10, (v)-C (O) R6, (w)-SR6, (x)-C (O) OR10, (y)-S (O)pR6, (z)-(C1-8Alkyl)-(contain one or more Individual heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycle 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)-C1-8 Alkynyl, (q) are selected from heteroatomic -3-14 members saturation, insatiable hunger and/or the aromatic heterocycles of nitrogen, oxygen and sulphur containing one or more, (r) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (s)-haloalkyl, (t)-(CR6R6)tOR6, (u)-O (CR6R6)tNR6R6, (v)-C(O)R6, (w)-SR6, (x)-C (O) OR6, (y)-S (O)pR6, (z)-(C1-8Alkyl)-(containing it is one or more selected from nitrogen, Heteroatomic 3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of 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 can not be not present simultaneously；
P is 0,1 or 2, and
T is 0,1,2 or 3,
Or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to according to Formulas I, II, III, IV, V, VI, VII or VIII compound, Wherein A is selected from
(a) nitrogen, oxygen and sulphur are selected from containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles, hetero atom, With
(b) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic,
(c) singly-bound,
Wherein (a) or (b) is optionally by one or more R5Group substitutes；
B is selected from：(a)-(C1-8Alkyl)-, (b)-(C2-8Alkenyl)-, (c)-(C2-8Alkynyl)-, (d) singly-bound, wherein
I) 0-4 carbon atom in any one of (a) just mentioned above-(c) is optionally by selected from following group replacement：- O- ,-S (O)p- ,-NR6- ,-(C=O)-,-C (=NR6)-,-S (O)pNR6- and-NR6S(O)pNR6-,
Ii) any one of (a) just mentioned above-(c) is optionally by one or more R5Group substitutes, and
Iii) any one of (a) just mentioned above-(c) is optionally by-(C1-8Alkyl)-R5Group substitutes, and
C is selected from：(a)NH2, (b)-NHC (=NH) NH2, and (c) hydrogen,
Or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to according to Formulas I, II, III, IV, V, VI, VII or VIII compound, Wherein A is selected from
(a) nitrogen, oxygen and sulphur are selected from containing one or more heteroatomic 4-7 members saturation, insatiable hunger and/or aromatic heterocycles, hetero atom, With
(b) 4-7 members saturation, insatiable hunger and/or aromatic carbocyclic,
(c) singly-bound,
Wherein (a) or (b) is optionally by one or more R5Group substitutes；
Or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to according to Formulas I, II, III, IV, V, VI, VII or VIII compound, Wherein A is selected from nitrogen heterocyclic heptyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, phenyl, pyridine radicals, cyclohexenyl group, hexamethylene two Alkenyl, dihydropyridine base, furyl, tetrahydrofuran base, tetrahydro pyridyl, azetidinyl, pyrrolidinyl, piperidyl and four Pyridinium hydroxide base (piperidenyl)；
Any one of the A wherein just mentioned above is optionally by one or more R5Group substitutes；
Or A is singly-bound；
B is selected from：(a)-(C1-8Alkyl)-, wherein
I) 0-4 carbon atom in (a) just mentioned above is optionally by selected from following group replacement：- O- ,-S (O)p- ,- NR6- ,-(C=O)-,-S (O)pNR6- and-NR6S(O)pNR6-,
Ii) (a) just mentioned above is optionally by one or more R5Group substitutes, and
Iii) (a) just mentioned above is optionally by-(C1-8Alkyl)-R5Group substitutes；Further,
Or B is singly-bound；
C is selected from：(a)NH2, (b)-NHC (=NH) NH2, and (c) hydrogen；
Or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to according to Formulas I, II, III, IV, V, VI, VII or VIII compound, G It is 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 by selected from following group replacement：- O- ,-S (O)p- ,-NR6- ,-(C=O)-,-C (=NR6)-,-S (O)pNR6- ,-NR6S(O)p- and-NR6S(O)pNR6-,
Ii) any one of (b) just mentioned above-(d) is optionally by one or more R5Group substitutes, and
Iii) any one of (b) just mentioned above-(d) is optionally by-(C1-8Alkyl)-R5Group substitutes；
(e) nitrogen, oxygen and sulphur are selected from containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles, hetero atom, With
(f) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic,
Wherein (e) or (f) is optionally by one or more R5Group substitutes；
Or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to according to Formulas I, II, III, IV, V, VI, VII or VIII compound, G It is 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 by selected from following group replacement：- O- ,-S (O)p- ,-NR6- ,-(C=O)-,-C (=NR6)-,-S (O)pNR6- ,-NR6S(O)p- and-NR6S(O)pNR6-,
Ii) any one of (b) just mentioned above-(d) is optionally by one or more R5Group substitutes, and
Iii) any one of (b) just mentioned above-(d) is optionally by-(C1-8Alkyl)-R5Group substitutes；
Wherein p is 0,1 or 2,
Or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to according to Formulas I, II, III, IV, V, VI, VII or VIII compound, WhereinIt is selected from:
,,, or,
Or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to according to Formulas I, II, III, IV, V, VI, VII or VIII compound, WhereinIt is selected fromOr its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to according to Formulas I, II, III, IV, V, VI, VII or VIII compound, Wherein-G-H-J is selected from
Or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to the compound of following formula:
(I),
Wherein C-B-A- ,-D-E-F ,-G-H-J, K, U, V, W, X, Y and Z are as defined in the formula (I) just mentioned above, or it can Pharmaceutical salts, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or precursor medicine Thing, whereinRepresent hexa-atomic saturation, insatiable hunger and/or the aromatic carbocyclic or heterocyclic ring system of fusion.
In some embodiments, the present invention relates to the compound of following formula:
Wherein C-B-A- ,-D-E-F ,-G-H-J, U, V, W, X, Y and Z as defined in formula (I),
Wherein Q1、Q2、Q3And Q4Independently selected from nitrogen-atoms, carbon atom or CH, wherein-D-E-F or-G-H-J, when present, It is connected with carbon phase, or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to the compound of following formula:
Wherein C-B-A- ,-G-H-J, U, V, W, X, Y and Z as defined in formula (I),
Wherein Q1a、Q2aAnd Q4aIndependently selected from nitrogen-atoms, carbon atom or CH, or its officinal salt, ester, dynamic isomer or preceding Body medicine.
In some embodiments, the present invention relates to the compound of following formula:
Wherein C-B-A- ,-D-E-F ,-G-H-J, U, V, W, X, Y and Z as defined in formula (II),
Or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or precursor medicine Thing, whereinRepresent hexa-atomic saturation, insatiable hunger and/or the aromatic carbocyclic or heterocyclic ring system of fusion.
In some embodiments, the present invention relates to the compound of following formula:
Wherein C-B-A- ,-D-E-F ,-G-H-J, U, V, W, X, Y and Z as defined in formula (II),
Wherein Q1、Q2、Q3And Q4Independently selected from nitrogen-atoms, carbon atom or CH, wherein-D-E-F or-G-H-J, when present, It is connected with carbon phase, or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to the compound of following formula:
Wherein C-B-A- ,-G-H-J, U, V, W, X, Y and Z are as defined in formula (II), wherein Q1、Q2And Q4It is former independently selected from nitrogen Son, carbon atom, or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to the compound of following formula:
Wherein C-B-A- ,-G-H-J, V, W, X and Y are as defined in formula (I), wherein T1It is CH or NH, condition is to work as T1It is NH When ,-D-E-F is not present；Or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to the compound of following formula:
(I) or(II),
Wherein C-B-A- ,-D-E-F ,-G-H-J, U, V, W, X, Y and Z is as defined in formula (I) or formula (II), or its is pharmaceutically acceptable Salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to the compound with formula (I) or (II), whereinRepresent fusion 6 yuan of aromatic carbocyclics or heterocyclic ring system；Or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to the compound of following formula:
(Ia) or(IIa),
Wherein C-B-A- ,-D-E-F ,-G-H-J, U, V, W, X, Y and Z is as defined in formula (I) or formula (II), or its is pharmaceutically acceptable Salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to the compound of following formula:
(Ia),
Wherein C-B-A- ,-D-E-F ,-G-H-J, U, V, W, X, Y and Z are as defined in formula (I), or its officinal salt, ester, change Isomers or pro-drug.
In some embodiments, the present invention relates to Formula V, VI, VII or VIII compound:
(V),(VI),
(VII), or(VIII)
Wherein C-B-A- ,-D-E-F and-G-H-J are as defined in formula (I), or its officinal salt, ester, dynamic isomer or precursor Medicine.
In some embodiments, the present invention relates to the compound of following formula:
(V),
Wherein C-B-A- ,-D-E-F and-G-H-J are as defined in formula (I), or its officinal salt, ester, dynamic isomer or precursor Medicine.
In some embodiments, the present invention relates to the compound of following formula:
,
Wherein D and E is singly-bound, and F is hydrogen；Wherein C-B-A- and-G-H-J are as defined in formula (I), or its officinal salt, ester, mutually Tautomeric or pro-drug.
In some embodiments, the present invention relates to the compound of following formula:
(Ib) or(Ic),
Wherein C-B-A- and-G-H-J are as defined in formula (I), or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to the compound of following formula:
(Ic),
Wherein C-B-A- and-G-H-J are as defined in formula (I), or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to the compound of following formula:
Or ,
Wherein A is selected from
(a) nitrogen, oxygen and sulphur are selected from containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles, hetero atom, With
(b) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic,
(c) singly-bound,
Wherein (a) or (b) is optionally by one or more R5Group substitutes；
B is selected from：(a)-(C1-8Alkyl)-, (b)-(C2-8Alkenyl)-, (c)-(C2-8Alkynyl)-, (d) singly-bound, wherein
I) 0-4 carbon atom in any one of (a) just mentioned above-(c) is optionally by selected from following group replacement：- O- ,-S (O)p- ,-NR6- ,-(C=O)-,-C (=NR6)-,-S (O)pNR6- and-NR6S(O)pNR6,
Ii) any one of (a) just mentioned above-(c) is optionally by one or more R5Group substitutes, and
Iii) any one of (a) just mentioned above-(c) is optionally by-(C1-8Alkyl)-R5Group substitutes, and
C is selected from：(a)NH2, (b)-NHC (=NH) NH2, and (c) hydrogen,
Or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to the compound of following formula:
Or ,
Wherein A is selected from nitrogen heterocyclic heptyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, phenyl, pyridine radicals, cyclohexenyl group, ring Hexadienyl, dihydropyridine base, furyl, tetrahydrofuran base, tetrahydro pyridyl, azetidinyl, pyrrolidinyl, piperidyl With tetrahydro pyridyl (piperidenyl)；
Any one of the A wherein just mentioned above is optionally by one or more R5Group substitutes；
Or A is singly-bound；
B is selected from：(a)-(C1-8Alkyl)-, wherein
I) 0-4 carbon atom in (a) just mentioned above is optionally by selected from following group replacement：- O- ,-S (O)p- ,- NR6- ,-(C=O)-,-S (O)pNR6- and-NR6S(O)pNR6-,
Ii) (a) just mentioned above is optionally by one or more R5Group substitutes, and
Iii) (a) just mentioned above is optionally by-(C1-8Alkyl)-R5Group substitutes；Further,
Or B is singly-bound；
C is selected from：(a)NH2, (b)-NHC (=NH) NH2, and (c) hydrogen；
Or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to the compound of following formula:
Or ,
Wherein C-B-A- is selected from:
Hydrogen,
Or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to the compound of following formula:
Or
Wherein G is 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 by selected from following group replacement：- O- ,-S (O)p- ,-NR6- ,-(C=O)-,-C (=NR6)-,-S (O)pNR6- ,-NR6S(O)p- and-NR6S(O)pNR6-,
Ii) any one of (b) just mentioned above-(d) is optionally by one or more R5Group substitutes, and
Iii) any one of (b) just mentioned above-(d) is optionally by-(C1-8Alkyl)-R5Group substitutes；
(e) nitrogen, oxygen and sulphur are selected from containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles, hetero atom, With
(f) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic,
Wherein (e) or (f) is optionally by one or more R5Group substitutes；
Or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to the compound of following formula:
Or
Wherein G is 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 by selected from following group replacement：- O- ,-S (O)p- ,-NR6- ,-(C=O)-,-C (=NR6)-,-S (O)pNR6- ,-NR6S(O)p- and-NR6S(O)pNR6-,
Ii) any one of (b) just mentioned above-(d) is optionally by one or more R5Group substitutes, and
Iii) any one of (b) just mentioned above-(d) is optionally by-(C1-8Alkyl)-R5Group substitutes；
Wherein p is 0,1 or 2,
Or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to the compound of following formula:
WhereinIt is selected from:
,,, or
Or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to the compound of following formula: Wherein-G-H-J is selected from:
Or its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to the compound of following formula:, whereinIt is selected from:
Or-G-H-J is selected from:
,
Wherein RxSelected from CH2, NH, N (C1-8Alkyl), S or O；RyAnd RzC or CH, each independently by one or more F, CH3、CF3, OH and OCH3Substitution；Or Rx、RyAnd RzIt is each independently selected from CH2Or CRaRb, wherein RaAnd RbIt is combined together, shape Into C1-5Carbocyclic ring；
J is selected from NH2, NH (C1-8Alkyl), N (C1-8Alkyl)2, NHC (=O) CH3, NHC (=O) NH2, NHC (=NH) NH2, NHC (= NH)H；
Wherein n is 0,1 or 2；
Or-G-H-J is selected from:
Wherein RxSelected from CH2, NH, N (C1-8Alkyl), S or O；RzIt is C or CH, it is by one or more CH3Substitution, or RzIt is CRaRb, wherein RaAnd RbIt is combined together, forms C1-5Carbocyclic ring,
Wherein m is 1,2 or 3；
J is selected from NH2, NH (C1-8Alkyl), N (C1-8Alkyl)2, NHC (=O) CH3, NHC (=O) NH2, NHC (=NH) NH2, NHC (= NH)H；
Or its officinal salt, ester, dynamic isomer 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)-C1-8 Alkyl, (n)-C1-8Alkenyl, (o)-C1-8Alkynyl, (p)-(C1-8Alkyl)-(contain one or more miscellaneous originals for being selected from nitrogen, oxygen and sulphur 3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of son), (q)-(C1-8Alkyl)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), (r)-haloalkyl, (s)-SR6, (t) is containing one or more selected from nitrogen, the heteroatomic -3-14 members saturation of oxygen and sulphur, insatiable hunger And/or aromatic heterocycle, and (u) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic；Or two R5Group is combined together, and is formed Carbocyclic ring；Or its officinal salt, ester, dynamic isomer 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)-haloalkyl, (d) containing it is one or more selected from nitrogen, oxygen and 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 carbocyclic；Or Its officinal salt, ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to according to Formulas I, II, III, IV, V, VI, VII or VIII compound or Its officinal salt, ester, dynamic isomer or pro-drug, wherein group-D-E-F represent hydrogen.
In some embodiments, the present invention relates to according to Formulas I, II, III, IV, V, VI, VII or VIII compound or Its officinal salt, ester, dynamic isomer or pro-drug, wherein in the presence of W, W is O, NR1, NOR1Or S.
In some embodiments, the present invention relates to according to Formulas I, II, III, IV, V, VI, VII or VIII compound or Its officinal salt, ester, dynamic isomer or pro-drug, wherein working as X--- In the presence of Y, it is double bond, and X is N, and Y is carbon original Son.
In some embodiments, the present invention relates to according to Formulas I, II, III, IV, V, VI, VII or VIII compound or Its officinal salt, ester, dynamic isomer or pro-drug, wherein working as R4aIn the presence of, it is H.
In some embodiments, the present invention relates to according to Formulas I, II, III, IV, V, VI, VII or VIII compound or Its officinal salt, ester, dynamic isomer or pro-drug, wherein in the presence of Z, it is NR4。
In some embodiments, the present invention relates to according to Formulas I, II, III, IV, V, VI, VII or VIII compound or Its officinal salt, ester, dynamic isomer or pro-drug, wherein R4It is H.
In some embodiments, the present invention relates to according to Formulas I, II, III, IV, V, VI, VII or VIII compound or Its officinal salt, ester, dynamic isomer or pro-drug, it is combined with ribosomes.
In some embodiments, the present invention relates to according to Formulas I, II, III, IV, V, VI, VII or VIII compound or Its officinal salt, ester, dynamic isomer or pro-drug, it is combined with ribosomes, and wherein ribosomes is bacterial ribosome.
In some embodiments, the present invention relates to the compound or pharmaceutically acceptable salt thereof according to any of table 1 compound, Ester, dynamic isomer or pro-drug.
In some embodiments, the present invention relates to include the compounds of this invention or its officinal salt, ester, dynamic isomer Or the pharmaceutical composition of pro-drug and pharmaceutical acceptable carrier.
In some embodiments, the present invention relates to treat, prevent the morbid state of human or animal or reduce its danger Method, this method include：Give the compounds of this invention for needing its human or animal's effective dose or its officinal salt, ester, change Isomers 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 to include： Give the compounds of this invention or its officinal salt, ester, dynamic isomer or pro-drug of human or animal's effective dose.
In some embodiments, the present invention relates to the compounds of this invention or its officinal salt, ester, dynamic isomer or preceding Purposes of the body medicine in medicine is prepared, the medicine are used for the microorganism infection for treating 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：Give the compounds of this invention or its officinal salt, ester, dynamic isomer of human or animal's effective dose Or pro-drug, or it is related to the compounds of this invention or its officinal salt, ester, dynamic isomer or pro-drug in medicine is prepared Purposes, the medicine be used for treat, prevent human or animal microorganism infection or reduce its danger,
Wherein microorganism infection is selected from:
Skin infection, Gram positive infections, Gram-negative infection, Nosocomial Pneumonia, community acquired pneumonia, after virus infection Pneumonia, Nosocomial Pneumonia/Ventilator Associated Pneumonia, respiratory tract infection, such as CRTI, acute pelvic infection, concurrently Skin and skin structure infection, Skin and soft tissue infection (SSTI), including not concurrent Skin and soft tissue infection (uSSTI) and concurrent Skin and soft tissue infection, abdominal infection, infect in concurrent abdomen, urinary tract infections, bacteremia, sepsis Disease, endocarditis, atrioventricular shunt infection, the sexy dye of contacts blood, meningitis, surgical prophylaxis, peritoneal infection, infection of bone, close Section infection, the S. aureus infection of methicillin-resistant, the enterococcus infection of anti-vancocin, anti-Linezolid (linezolid) organism infection, infection due to Bacillus anthracis, soil draw hot Francisella infection, Yersinia pestis sense Dye and pulmonary tuberculosis.
In some embodiments, the present invention relates to method or purposes, in this method or purposes, the compounds of this invention or Its officinal salt, ester, dynamic isomer or pro-drug be by ear, eye, nose, it is oral, parenteral, local or intravenously to Give.
In some embodiments, the present invention relates to treat, infect in the concurrent abdomen of prevention human or animal or reduce it Dangerous method, this method include：Give human or animal effective dose according to Formulas I, II, III, IV, V, VI, VII or VIII Compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or pro-drug, or be related to according to Formulas I, II, III, IV, V, VI, VII or Purposes of VIII compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or the pro-drug in medicine is prepared, the medicine are used for Treat, prevent infection in concurrent abdomen or reduce its danger,
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 skin of prevention human or animal and skin texture sense Contaminate or reduce its dangerous method, this method includes：Give human or animal's effective dose according to Formulas I, II, III, IV, V, VI, VII or VIII compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or pro-drug, or be related to according to Formulas I, II, III, Use of IV, V, VI, VII or VIII compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or the pro-drug in medicine is prepared On the way, the medicine is used to treating, prevent concurrent skin and skin structure infection or reducing its danger,
Wherein concurrent skin and skin structure infection are selected from due to diabetic keratopathy feel dye (not having osteomyelitis) caused by following： Staphylococcus aureus (Staphylococcus aureus) (methicillin-susceptible and resistance to the action of a drug isolate), Streptococcusagalactiae (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 sugared rufous monad (Porphyromonas asaccharolytica) or two tunnel bacteroids (Prevotella bivia)。
In some embodiments, the present invention relates to treatment, prevention human or animal community acquired pneumonia or reduce it Dangerous method, this method include：Give human or animal effective dose according to Formulas I, II, III, IV, V, VI, VII or VIII Compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or pro-drug, or be related to according to Formulas I, II, III, IV, V, VI, VII or Purposes of VIII compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or the pro-drug in medicine is prepared, the medicine are used for Treatment, prevention community acquired pneumonia reduce its danger,
Wherein community acquired pneumonia (including with the bacteremic situation of concurrency) is due to streptococcus pneumonia (Streptococcus pneumoniae) (penicillin sensitivity and resistance to the action of a drug isolate), haemophilus influenzae (Haemophilus influenzae) (including beta-lactam enzyme positive isolate), Moraxella catarrhalis (Moraxella catarrhalis) or atypical bacterium such as mycoplasm hyopneumoniae (Mycoplasma spp.) caused by.
In some embodiments, the present invention relates to treatment, prevention human or animal concurrent urinary tract infections or reduce it Dangerous method, this method include：Give human or animal effective dose according to Formulas I, II, III, IV, V, VI, VII or VIII Compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or pro-drug, or be related to according to Formulas I, II, III, IV, V, VI, VII or Purposes of VIII compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or the pro-drug in medicine is prepared, the medicine are used for It is dangerous to treat, prevent concurrent urinary tract infections or reduce it,
Wherein concurrent urinary tract infections be selected from due to Escherichia coli (Escherichia coli), concurrent bacteremia or Cray it is white Family name bacillus (Klebsiella pneumoniae) caused by pyelonephritis.
In some embodiments, the present invention relates to the acute pelvic for the treatment of, prevention human or animal to infect or reduce its danger The method of danger, this method include：Give human or animal's effective dose according to Formulas I, II, III, IV, V, VI, VII or VIII change Compound or its officinal salt, ester, dynamic isomer or pro-drug, or be related to according to Formulas I, II, III, IV, V, VI, VII or Purposes of VIII compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or the pro-drug in medicine is prepared, the medicine are used for Treatment, the infection of prevention acute pelvic reduce its danger,
Wherein acute pelvic infection (including postpartum Endomyometritis, septic abortion and postoperative gynecological infection) be due to Streptococcusagalactiae (Streptococcus agalactiae), Escherichia coli (Escherichia coli), bacteroides fragilis (Bacteroides fragilis), do not understand sugared rufous monad (Porphyromonas asaccharolytica), digestion Streptococcus (Peptostreptococcus spp.) or two tunnel bacteroids (Prevotella bivia) caused by.
In some embodiments, the present invention relates to treatment, Nosocomial Pneumonia/lung ventilator phase of prevention human or animal Closing property pneumonia reduces its dangerous method, and this method includes：Give human or animal's effective dose according to Formulas I, II, III, IV, V, VI, VII or VIII compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or pro-drug, or be related to according to Formulas I, II, III, IV, V, VI, VII or VIII compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or pro-drug are in medicine is prepared Purposes, the medicine be used for treat, prevent Nosocomial Pneumonia/Ventilator Associated Pneumonia or reduce its danger,
Wherein Nosocomial Pneumonia/Ventilator Associated Pneumonia be due to streptococcus pneumonia (Streptococcus pneumoniae) (penicillin sensitivity and resistance to the action of a drug isolate), Staphylococcus aureus (Staphylococcus aureus) (methicillin-susceptible and resistance to the action of a drug isolate), Klebsiella pneumoniae (Klebsiella pneumoniae), Pseudomonas aeruginosa (Pseudomonas aeruginosa), acinetobacter (Acinetobacter spp.), stenotrophomonas maltophilia (Stenotrophomonas maltophilia), haemophilus influenzae (Haemophilus influenzae) (including β-interior Acid amides enzyme positive isolate) or legionella pneumophilia (Legionella pneumophilia) caused by.
In some embodiments, the present invention relates to treatment, prevention humans and animals with aerobic and facultative Gram-positive The related microorganism infection of microorganism reduces its dangerous method, and this method includes：Give humans and animals effective dose according to Formulas I, II, III, IV, V, VI, VII or VIII compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or pro-drug, or relate to And according to Formulas I, II, III, IV, V, VI, VII or VIII compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or precursor medicine Purposes of the thing in medicine is prepared, the medicine is used to treating, it is related to aerobic and facultative gram positive microbes micro- to prevent Biological infection reduces its danger,
Wherein aerobic and facultative gram positive microbes are selected from:
Staphylococcus aureus (Staphylococcus aureus) (methicillin-susceptible and resistance to the action of a drug isolate), pneumonia chain Coccus (Streptococcus pneumoniae) (penicillin sensitivity and resistance to the action of a drug isolate), enterococcus (Enterococcus spp.) (vancomycin sensitive and resistance to the action of a drug isolate), Streptococcusagalactiae (Streptococcus agalactiae), micrococcus scarlatinae (Streptococcus pyogenes) or MRSE (Staphylococcus epidermidis) (methicillin-susceptible and resistance to the action of a drug isolate).
In some embodiments, the present invention relates to treatment, prevention humans and animals with aerobic and facultative Gram-negative The related microorganism infection of microorganism reduces its dangerous method, and this method includes：Give humans and animals effective dose according to Formulas I, II, III, IV, V, VI, VII or VIII compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or pro-drug, or relate to And according to Formulas I, II, III, IV, V, VI, VII or VIII compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or precursor medicine Purposes of the thing in medicine is prepared, the medicine is used to treating, it is related to aerobic and facultative Gram-negative microorgansims micro- to prevent Biological infection reduces its danger,
Wherein aerobic and facultative Gram-negative microorgansims are selected from:
Escherichia coli (Escherichia coli) (including isolate caused by ESBL and KPC), haemophilus influenzae (Haemophilus influenzae) (including beta-lactam enzyme positive isolate), Klebsiella pneumoniae (Klebsiella pneumoniae) (including isolate caused by ESBL and KPC), 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) (including isolate caused by ESBL and KPC), proteus vulgaris (Proteus vulgaris), providencia rettgeri (Providencia rettgeri) or providencia stuartii (Providencia stuartii)。
In some embodiments, the present invention relates to treatment, the micro- life related to anaerobe of prevention human or animal Thing infects or reduces its dangerous method, and this method includes：Give human or animal's effective dose according to Formulas I, II, III, IV, V, VI, VII or VIII compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or pro-drug, or be related to according to Formulas I, II, III, IV, V, VI, VII or VIII compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or pro-drug are in medicine is prepared Purposes, the medicine be used for treat, prevent the infection related to anaerobe or reduce its danger,
Wherein the anaerobe is selected from: 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 sugared 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 method or purposes, in this method or purposes, the compounds of this invention or Its officinal salt, ester, dynamic isomer or pro-drug be by ear, eye, nose, it is oral, parenteral, local or intravenously to Give.
In some embodiments, the present invention relates to synthesis the compounds of this invention or its officinal salt, ester, dynamic isomer 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, dynamic isomer Or the medical treatment device of pro-drug.
In some embodiments, the present invention relates to the medical treatment device containing the compounds of this invention, the wherein device is branch Frame.
The invention further relates to following technical scheme：
1. the compound with following formula:
(V),(VI),
(VII), or(VIII)
Or wherein-G-H-J is selected from
,
Wherein each H and J is selected independently,
Or-G-H-J is selected from:
,
Wherein RxSelected from CH2, NH, N (C1-8Alkyl), S or O；RyAnd RzC or CH, each independently by one or more F, CH3、CF3, OH and OCH3Substitution；Or Rx、RyAnd RzIt is each independently selected from CH2Or CRaRb, wherein RaAnd RbIt is combined together, shape Into C1-5Carbocyclic ring；
J is selected from NH2, NH (C1-8Alkyl), N (C1-8Alkyl)2, NHC (=O) CH3, NHC (=O) NH2, NHC (=NH) NH2, NHC (= NH)H；
Wherein n is 0,1 or 2；
Or-G-H-J is selected from:
Wherein RxSelected from CH2, NH, N (C1-8Alkyl), S or O；RzIt is C or CH, it is by one or more CH3Substitution, or RzIt is CRaRb, wherein RaAnd RbIt is combined together, forms C1-5Carbocyclic ring,
Wherein m is 1,2 or 3；
J is selected from NH2, NH (C1-8Alkyl), N (C1-8Alkyl)2, NHC (=O) CH3, NHC (=O) NH2, NHC (=NH) NH2, NHC (= NH)H；
C-B-A- ,-D-E-F and-G-H-J are chemical groups, 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 by selected from following group replacement：- O- ,-S (O)p- ,-NR6- ,-(C=O)-,-S (O)pNR6- ,-NR6S(O)p- and-NR6S(O)pNR6-,
Ii) any one of (b) just mentioned above-(d) is optionally by one or more R5Group substitutes, and
Iii) any one of (b) just mentioned above-(d) is optionally by-(C1-8Alkyl)-R5Group substitutes；
(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 miscellaneous containing one or more heteroatomic 3-14 members saturations, insatiable hunger and/or fragrance Ring, 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 substitutes；
B, E and H independently selected from:
(a) singly-bound,
(b) nitrogen, oxygen and sulphur are selected from containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles, hetero atom,
(c) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic,
Wherein (b) or (c) is optionally by one or more R5Group substitutes；
(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 by selected from following group replacement：- O- ,-S (O)p- ,-NR6- ,-(C=O)-,-C (=NR6)-,-S (O)pNR6- ,-NR6S(O)p- and-NR6S(O)pNR6-,
Ii) any one of (d) just mentioned above-(f) is optionally by one or more R5Group substitutes, and
Iii) any one of (d) just mentioned above-(f) is optionally by-(C1-8Alkyl)-R5Group substitutes；
- (CR (g)6R6)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 miscellaneous originals 3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of son, hetero atom are selected from nitrogen, oxygen and sulphur, (pp) 3-14 members saturation, insatiable hunger and/or virtue Fragrant carbocyclic ring, (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)-haloalkyl, (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 substitutes；
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)- (containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur), (q)-(C1-8Alkane Base)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), and (r)-haloalkyl, (s)-SR6, (t) is selected from containing one or more Heteroatomic -3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of nitrogen, oxygen and sulphur, and (u) -3-14 members saturation, insatiable hunger and/or fragrance Carbocyclic ring；Or two R5Group is combined together, and forms carbocyclic ring；
Wherein (m) to (r) and (t) to (u) is optionally by one or more R8Substitution；
R6It is selected from：(a) hydrogen, (b)-C1-8Alkyl, or two R6Group is combined together to form carbocyclic ring, (c)-haloalkyl, (d) containing one or more heteroatomic -3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur, and (e) -3- 14 yuan of saturations, 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)- (containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur), (q)-(C1-8Alkane Base)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), and (r)-haloalkyl, (s)-NR6R8, (t)-OR8, (u)-(CR6R6)tNR6R8, (v)-CR6R8R8, (w)-SR6, (x) containing it is one or more selected from nitrogen, oxygen and sulphur heteroatomic -3-14 members saturation, Insatiable hunger and/or aromatic heterocycle, (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(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)- (containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur), (q)-(C1-8Alkane Base)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), (r) contains one or more heteroatomic -3- for being selected from nitrogen, oxygen and sulphur 14 yuan of saturations, insatiable hunger and/or aromatic heterocycle, (s) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (t)-haloalkyl, (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(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)-C1-8 Alkynyl, (q) are selected from heteroatomic -3-14 members saturation, insatiable hunger and/or the aromatic heterocycles of nitrogen, oxygen and sulphur containing one or more, (r) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (s)-haloalkyl, (t)-(CR6R6)tOR6, (u)-O (CR6R6)tNR6R10, (v)-C (O) R6, (w)-SR6, (x)-C (O) OR10, (y)-S (O)pR6, (z)-(C1-8Alkyl)-(contain one or more Individual heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycle 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)-C1-8 Alkynyl, (q) are selected from heteroatomic -3-14 members saturation, insatiable hunger and/or the aromatic heterocycles of nitrogen, oxygen and sulphur containing one or more, (r) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (s)-haloalkyl, (t)-(CR6R6)tOR6, (u)-O (CR6R6)tNR6R6, (v)-C(O)R6, (w)-SR6, (x)-C (O) OR6, (y)-S (O)pR6, (z)-(C1-8Alkyl)-(containing it is one or more selected from nitrogen, Heteroatomic 3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of 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 can not be not present simultaneously；
P is 0,1 or 2, and
T is 0,1,2 or 3,
Or its officinal salt, ester, dynamic isomer or pro-drug.
According to the compound of project 1, there is following formula:
,
Or its officinal salt, ester, dynamic isomer or pro-drug.
According to the compound of project 2, there is following formula:
,
Wherein-D-E-F is hydrogen；Or its officinal salt, ester, dynamic isomer or pro-drug.
According to the compound of project 3, there is following formula:
Or,
Or its officinal salt, ester, dynamic isomer or pro-drug.
According to the compound of project 4, there is following formula:
,
Or its officinal salt, ester, dynamic isomer or pro-drug.
According to the compound of project 4, wherein A is selected from：
(a) nitrogen, oxygen and sulphur are selected from containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles, hetero atom,
(b) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, and
(c) singly-bound,
Wherein (a) or (b) is optionally by one or more R5Group substitutes；
B is selected from：(a)-(C1-8Alkyl)-, (b)-(C2-8Alkenyl)-, (c)-(C2-8Alkynyl)-and (d) singly-bound, wherein
I) 0-4 carbon atom in any one of (a) just mentioned above-(c) is optionally by selected from following group replacement：- O- ,-S (O)p- ,-NR6- ,-(C=O)-,-C (=NR6)-,-S (O)pNR6- and-NR6S(O)pNR6,
Ii) any one of (a) just mentioned above-(c) is optionally by one or more R5Group substitutes, and
Iii) any one of (a) just mentioned above-(c) is optionally by-(C1-8Alkyl)-R5Group substitutes, and
C is selected from：(a)NH2, (b)-NHC (=NH) NH2, and (c) hydrogen,
Or its officinal salt, ester, dynamic isomer or pro-drug.
According to the compound of project 6, wherein A is selected from：Nitrogen heterocyclic heptyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, Phenyl, pyridine radicals, cyclohexenyl group, cyclohexadienyl, dihydropyridine base, furyl, tetrahydrofuran base, tetrahydro pyridyl, azepine Cyclobutane base, pyrrolidinyl, piperidyl and tetrahydro pyridyl (piperidenyl)；
Any one of the A wherein just mentioned above is optionally by one or more R5Group substitutes；
Or A is singly-bound；
B is selected from：(a)-(C1-8Alkyl)-, wherein
I) 0-4 carbon atom in (a) just mentioned above is optionally by selected from following group replacement：- O- ,-S (O)p- ,- NR6- ,-(C=O)-,-S (O)pNR6- and-NR6S(O)pNR6-,
Ii) (a) just mentioned above is optionally by one or more R5Group substitutes, and
Iii) (a) just mentioned above is optionally by-(C1-8Alkyl)-R5Group substitutes；Further,
Or B is singly-bound；
C is selected from：(a)NH2, (b)-NHC (=NH) NH2, and (c) hydrogen；
Or its officinal salt, ester, dynamic isomer or pro-drug.
According to the compound of project 7, wherein C-B-A- is selected from：
Hydrogen,
Or its officinal salt, ester, dynamic isomer or pro-drug.
According to the compound of project 4, wherein G is 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 by selected from following group replacement：- O- ,-S (O)p- ,-NR6- ,-(C=O)-,-C (=NR6)-,-S (O)pNR6- ,-NR6S(O)p- and-NR6S(O)pNR6-,
Ii) any one of (b) just mentioned above-(d) is optionally by one or more R5Group substitutes, and
Iii) any one of (b) just mentioned above-(d) is optionally by-(C1-8Alkyl)-R5Group substitutes；
(e) nitrogen, oxygen and sulphur are selected from containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles, hetero atom, With
(f) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic,
Wherein (e) or (f) is optionally by one or more R5Group substitutes；
Or its officinal salt, ester, dynamic isomer or pro-drug.
According to the compound of project 6, wherein R6It 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)-(contain one or more heteroatomic 3-14 members saturation, unsaturations for being selected from nitrogen, oxygen and sulphur Or aromatic heterocycle), (q)-(C1-8Alkyl)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), and (r)-haloalkyl, (s)-SR6, (t) containing one or more heteroatomic -3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur, and (u) -3- 14 yuan of saturations, insatiable hunger and/or aromatic carbocyclic；Or two R5Group is combined together, and forms carbocyclic ring；Or its officinal salt, ester, Dynamic isomer or pro-drug.
According to the compound of project 6, wherein R6It is selected from：(a) hydrogen, (b)-C1-8Alkyl, or two R6Group is incorporated in one Rise and form carbocyclic ring, (c)-haloalkyl, (d) containing it is one or more selected from nitrogen, oxygen and sulphur heteroatomic -3-14 members saturation, Insatiable hunger and/or aromatic heterocycle, and (e) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic；Or its officinal salt, ester, dynamic isomer Or pro-drug.
According to the compound of project 9, wherein G is 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 by selected from following group replacement：- O- ,-S (O)p- ,-NR6- ,-(C=O)-,-C (=NR6)-,-S (O)pNR6- ,-NR6S(O)p- and-NR6S(O)pNR6-,
Ii) any one of (b) just mentioned above-(d) is optionally by one or more R5Group substitutes, and
Iii) any one of (b) just mentioned above-(d) is optionally by-(C1-8Alkyl)-R5Group substitutes；
Wherein p is 0,1 or 2,
Or its officinal salt, ester, dynamic isomer or pro-drug.
According to the compound of project 2, whereinIt is selected from:
, , or,
Or its officinal salt, ester, dynamic isomer or pro-drug.
According to the compound of project 13, whereinIt is selected from:
Or-G-H-J is selected from:
,
Wherein RxSelected from CH2, NH, N (C1-8Alkyl), S or O；RyAnd RzC or CH, each independently by one or more F, CH3、CF3, OH and OCH3Substitution；Or Rx、RyAnd RzIt is each independently selected from CH2Or CRaRb, wherein RaAnd RbIt is combined together, shape Into C1-5Carbocyclic ring；
J is selected from NH2, NH (C1-8Alkyl), N (C1-8Alkyl)2, NHC (=O) CH3, NHC (=O) NH2, NHC (=NH) NH2, NHC (= NH)H；
Wherein n is 0,1 or 2；
Or-G-H-J is selected from:
Wherein RxSelected from CH2, NH, N (C1-8Alkyl), S or O；RzIt is C or CH, it is by one or more CH3Substitution, or RzIt is CRaRb, wherein RaAnd RbIt is combined together, forms C1-5Carbocyclic ring,
Wherein m is 1,2 or 3；
J is selected from NH2, NH (C1-8Alkyl), N (C1-8Alkyl)2, NHC (=O) CH3, NHC (=O) NH2, NHC (=NH) NH2, NHC (= NH)H；
Or its officinal salt, ester, dynamic isomer or pro-drug.
According to the compound of any one of project 1 to 14, it is combined with ribosomes.
According to the compound of project 15, wherein ribosomes is bacterial ribosome.
According to any compound or its officinal salt, ester, dynamic isomer or pro-drug of compound in table 1.
Pharmaceutical composition, compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer comprising any one according to project 1-17 Or pro-drug and pharmaceutical acceptable carrier.
Treatment, the morbid state for preventing human or animal reduce its dangerous method, and this method includes：Giving needs its Compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or the precursor of any one according to project 1-17 of human or animal's effective dose Medicine.
The method for treating the microorganism infection of human or animal, this method include：Give human or animal's effective dose according to item Compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or the pro-drug of any one of mesh 1-17.
Made according to the compound or pharmaceutically acceptable salt thereof of any one of project 1-17, ester, dynamic isomer or pro-drug Purposes in standby medicine, the medicine, which is used to treat caused by the microorganism of human or animal, to be infected.
Treatment, the microorganism infection for preventing human or animal reduce its dangerous method, and this method includes：Give people or dynamic Compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or the pro-drug of any one according to project 1-17 of thing effective dose, its Middle microorganism infection is selected from:
Skin infection, Gram positive infections, Gram-negative infection, Nosocomial Pneumonia, community acquired pneumonia, after virus infection Pneumonia, Nosocomial Pneumonia/Ventilator Associated Pneumonia, respiratory tract infection, such as CRTI (chronic respiratory tract infection) is anxious Property pelvic infection, concurrent skin and skin structure infection, Skin and soft tissue infection (SSTI), including not concurrent skin and Soft tissue infection (uSSTI) and concurrent Skin and soft tissue infection, abdominal infection, concurrent abdomen is interior to be infected, urinary tract infections, bacterium Mass formed by blood stasis, septicemia, endocarditis, atrioventricular shunt infection, the sexy dye of contacts blood, meningitis, surgical prophylaxis, peritoneal infection, Infection of bone, the infection of joint, the S. aureus infection of methicillin-resistant, the enterococcus infection of anti-vancocin, how is anti-profit The organism infection of azoles amine (linezolid), infection due to Bacillus anthracis, soil draw hot Francisella infection, Shu Yiyeersenshi Bacterium infects and pulmonary tuberculosis.
According to the method or purposes of any one of project 19-22, wherein compound or pharmaceutically acceptable salt thereof, ester, tautomerism Body or pro-drug pass through ear, eye, nose, oral, parenteral, intravenous or administer locally to.
According to the conjunction of the compound or pharmaceutically acceptable salt thereof of any one of project 1-17, ester, dynamic isomer or pro-drug Into method.
Compound or pharmaceutically acceptable salt thereof, ester, dynamic isomer or pro-drug containing any one according to project 1-17 Medical treatment device.
According to the medical treatment device of project 25, the wherein device is support.
Compound with following formula:
(I),(II),
(III), or(IV),
Wherein U is selected from CR3R3, O, NR4Or S (O)n, C=O, C=NOR3, or, two R3It is combined together, forms carbonyl,
V is independently selected from-CR4a- or-N-；
WhereinRepresent 5 to 7 yuan of saturations, insatiable hunger and/or the aromatic carbocyclic or heterocyclic ring system of fusion；
W is O, NR1, NOR1Or S, or W=combination selected from the HO- and H- being both connected with identical carbon atoms, or both all (the C being connected with identical carbon atoms1-8Alkyl) O- and H- combination；
X---Y represents 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, work as 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,
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,
Or-G-H-J is selected from:
,
Wherein RxSelected from CH2, NH, N (C1-8Alkyl), S or O；RyAnd RzC or CH, each independently by one or more F, CH3、CF3, OH and OCH3Substitution；Or Rx、RyAnd RzIt is each independently selected from CH2Or CRaRb, wherein RaAnd RbIt is combined together, shape Into C1-5Carbocyclic ring；
J is selected from NH2, NH (C1-8Alkyl), N (C1-8Alkyl)2, NHC (=O) CH3, NHC (=O) NH2, NHC (=NH) NH2, NHC (= NH)H；
Wherein n is 0,1 or 2；
Or-G-H-J is selected from:
Wherein RxSelected from CH2, NH, N (C1-8Alkyl), S or O；RzIt is C or CH, it is by one or more CH3Substitution, or RzIt is CRaRb, wherein RaAnd RbIt is combined together, forms C1-5Carbocyclic ring,
Wherein m is 1,2 or 3；
J is selected from NH2, NH (C1-8Alkyl), N (C1-8Alkyl)2, NHC (=O) CH3, NHC (=O) NH2, NHC (=NH) NH2, NHC (= NH)H；
C-B-A- ,-D-E-F and-G-H-J are chemical groups, 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 by selected from following group replacement：- O- ,-S (O)p- ,-NR6- ,-(C=O)-,-S (O)pNR6- ,-NR6S(O)p- and-NR6S(O)pNR6-,
Ii) any one of (b) just mentioned above-(d) is optionally by one or more R5Group substitutes, and
Iii) any one of (b) just mentioned above-(d) is optionally by-(C1-8Alkyl)-R5Group substitutes；
(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 miscellaneous containing one or more heteroatomic 3-14 members saturations, insatiable hunger and/or fragrance Ring, 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 substitutes；
B, E and H independently selected from:
(a) singly-bound,
(b) nitrogen, oxygen and sulphur are selected from containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles, hetero atom,
(c) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic,
Wherein (b) or (c) is optionally by one or more R5Group substitutes；
(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 by selected from following group replacement：- O- ,-S (O)p- ,-NR6- ,-(C=O)-,-C (=NR6)-,-S (O)pNR6- ,-NR6S(O)p- and-NR6S(O)pNR6-,
Ii) any one of (d) just mentioned above-(f) is optionally by one or more R5Group substitutes, and
Iii) any one of (d) just mentioned above-(f) is optionally by-(C1-8Alkyl)-R5Group substitutes；
- (CR (g)6R6)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 miscellaneous originals 3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of son, hetero atom are selected from nitrogen, oxygen and sulphur, (pp) 3-14 members saturation, insatiable hunger and/or virtue Fragrant carbocyclic ring, (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)-haloalkyl, (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 substitutes；
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)- (containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur), (q)-(C1-8Alkane Base)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), and (r)-haloalkyl, (s)-SR6, (t) is selected from containing one or more Heteroatomic -3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of nitrogen, oxygen and sulphur, and (u) -3-14 members saturation, insatiable hunger and/or fragrance Carbocyclic ring；Or two R5Group is combined together, and forms carbocyclic ring；
Wherein (m) to (r) and (t) to (u) is optionally by one or more R8Substitution；
R6It is selected from：(a) hydrogen, (b)-C1-8Alkyl, or two R6Group is combined together to form carbocyclic ring, (c)-haloalkyl, (d) containing one or more heteroatomic -3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur, and (e) -3- 14 yuan of saturations, 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)- (containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur), (q)-(C1-8Alkane Base)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), and (r)-haloalkyl, (s)-NR6R8, (t)-OR8, (u)-(CR6R6)tNR6R8, (v)-CR6R8R8, (w)-SR6, (x) containing it is one or more selected from nitrogen, oxygen and sulphur heteroatomic -3-14 members saturation, Insatiable hunger and/or aromatic heterocycle, (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(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)- (containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles for being selected from nitrogen, oxygen and sulphur), (q)-(C1-8Alkane Base)-(3-14 members saturation, insatiable hunger and/or aromatic carbocyclic), (r) contains one or more heteroatomic -3- for being selected from nitrogen, oxygen and sulphur 14 yuan of saturations, insatiable hunger and/or aromatic heterocycle, (s) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (t)-haloalkyl, (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(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)-C1-8 Alkynyl, (q) are selected from heteroatomic -3-14 members saturation, insatiable hunger and/or the aromatic heterocycles of nitrogen, oxygen and sulphur containing one or more, (r) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (s)-haloalkyl, (t)-(CR6R6)tOR6, (u)-O (CR6R6)tNR6R10, (v)-C (O) R6, (w)-SR6, (x)-C (O) OR10, (y)-S (O)pR6, (z)-(C1-8Alkyl)-(contain one or more Individual heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycle 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)-C1-8 Alkynyl, (q) are selected from heteroatomic -3-14 members saturation, insatiable hunger and/or the aromatic heterocycles of nitrogen, oxygen and sulphur containing one or more, (r) -3-14 members saturation, insatiable hunger and/or aromatic carbocyclic, (s)-haloalkyl, (t)-(CR6R6)tOR6, (u)-O (CR6R6)tNR6R6, (v)-C(O)R6, (w)-SR6, (x)-C (O) OR6, (y)-S (O)pR6, (z)-(C1-8Alkyl)-(containing it is one or more selected from nitrogen, Heteroatomic 3-14 members saturation, insatiable hunger and/or the aromatic heterocycle of 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 can not be not present simultaneously；
P is 0,1 or 2, and
T is 0,1,2 or 3,
Or its officinal salt, ester, dynamic isomer or pro-drug.
3. the synthesis of the compounds of this invention
The invention provides the preparation method of the compounds of this invention.Following reaction scheme 1c-2c, which is briefly described, synthesizes this hair The exemplary approach of bright compound.More specifically chemistry is described in detail and is provided in embodiment.
Reaction scheme 1c- [6,6,6] cytimidine
Reaction scheme 2c- [6,6,6] iso-cytosine
4. the sign of the compounds of this invention
Designed, selected and/or optimized compound by the above method, once preparing, those skilled in the art can be used Known various experiments characterize, so that it is determined that whether the compound has bioactivity.For example, it can be characterized with routine test Molecule, experiment including but not limited to as described below, so that it is determined that they whether have estimated activity, binding 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 of molecule is described, for example, anticancer, antibacterium, antimycotic, anti parasitic or antivirotic.Equally, use is known in the art Technology, how can be interacted with test compound with ribosomes or ribosomal subunit, and/or, how effectively as egg The conditioning agent (for example, inhibitor) synthesized in vain.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) US 5,763,263.High throughput test can To use one or more different tests technologies, those technologies including but not limited to as described below.
(1) Surface binding
Various binding tests can be effectively used for the new molecule with binding activity of screening.A kind of method is total to including surface plasma Technology of shaking (SPR), it can be used for evaluating combination of the molecule for making one interested for ribosomes, ribosomal subunit or its fragment Performance.
SPR methods are by producing quantum-mechanical surface plasma come between the two or more macromoleculars of the real time measure Interaction.A kind of device (BIAcore Biosensor RTM, are obtained from Pharmacia Biosensor, Piscataway, N.J.) to golden film (in the form of disposable biological sensor " dummy slider " provide) and can be by between surge chamber that user is adjusted Interface provides heterogeneous light focused beam acts.Thick 100 nm " hydrogel " (is made up of, it provides covalent carboxymethylated glucan The fixed matrix for making one analyte interested) it is affixed in golden film.When the light and the free electron cloud phase interaction of golden film of focusing Used time, plasma resonance enhancing.Obtained reflected light exhausts spectrum in the wavelength for most preferably sending the resonance.Passing through will The polychromatic light of reflection is separated into its composition wavelength (by means of prism) and determines exhausted frequency, and BIAcore is formed Optical interface, it accurately reports the characteristic of formed surface plasma resonance.When according to being designed above, plasma (and the spectrum thus exhausted) is resonated to the mass-sensitive in evanescent field (it corresponds roughly to the thickness of hydrogel).If mutually One part of effect pair is fixed in hydrogel, and provides interaction participant (partner) by surge chamber, Then can be using the corresponding effect of quality accumulation and its spectrometric plasma resonance by exhausting in evanescent field as base The interaction that plinth comes between two parts of the real time measure.This system can the quickly and delicately intermolecular phase of the real time measure Interaction, it is not necessary to mark any one component.
(2) Fluorescence polarization
Fluorescence polarization (FP) is the measure skill that can be readily used for protein-protein, protein ligand or the interaction of RNA- parts Art, so as to obtain the IC of the association reaction between two molecules50Value and Kd.In this technology, interested one point is made one Son and fluorophore conjugated.This is typically the relatively small molecule (in this case, being compound interested) in the system.With hang down Straight polarised light excites the sample mixture containing ligand-probe conjugate and ribosomes, ribosomal subunit or its fragment.Light is Fluorescence probe group is absorbed, and is launched again after the short time.The degree of polarization of measure transmitting light.The polarization for launching light depends on one A little factors, but most significantly depending on the viscosity of solution and the apparent molecular weight of fluorogen.Under suitable control, launch light Degree of polarization change be solely dependent upon fluorogen apparent molecular weight change, its next depend on probe-ligand conjugate whether Free state is kept in solution or is combined with acceptor.Binding tests based on FP have many important benefits, including：Correct Homogeneous equilibrium under the conditions of determine IC50Value and Kd, analyze speed and suitable automation, and in cloudy suspension and color solution The ability of shielding.
(3) Albumen synthesizes
In addition to being characterized by above-mentioned biochemical test, it can also be lived with the function of ribosomes or ribosomal subunit Conditioning agent (for example, protein synthesis inhibitor) form of property characterizes compound interested.
Furthermore, it is possible to being carried out as follows more specific albumen synthesis suppresses experiment：Give whole organism, tissue, organ, Organelle, cell, cell or subcellular fraction extract or the ribose body preparation of purifying, and closed by determining such as its suppression albumen Into inhibition constant (IC50Value) observe its pharmacology and rejection.In order to study albumen synthesizing activity, can carry out3H Leucine or35The merging of S methionines or similar experiment.In the presence of the molecule for making one interested, the albumen in cell Synthesis quantity or speed change, if showing that the molecule is the speed or quantity of the conditioning agent albumen synthesis of albumen synthesis Reduce, it is protein synthesis inhibitor to show the molecule.
(4) Anti-microbial test and other evaluations
Furthermore, it is possible to the antiproliferative or anti-infection property energy of the compound are tested under cellular level.If for example, targeting organism Microorganism, then can be interested to test by cultivating the microorganism in the culture medium containing compound or no compound Compound activity.Growth inhibition can represent that the molecule can serve as protein synthesis inhibitor.More specifically, it is interested Compound bacteria resistance pathogen activity can by the compound suppress determined by human pathogen bacterial strain growth come Prove.For the purpose, strainses can be assembled（panel）, it is included various targeting pathogenic species, some of them are included Resistance Mechanism through sign.The use of this organism group can determine structure-activity relation, not only consider efficiency and spectrum System, 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 measure minimum inhibitory concentration (MICs), 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)。
Can be in the various experiments of mammal in vivo, 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 because of reduction of the bacterial load to fatal rate and It is different.For the terminal of the latter, PD is generally used50Value represents result, or with 50% animal of protection from dead drug dose come table Show.
In order to further evaluate class medicine (drug-like) performance of compound, can also use recombinant people enzyme system or More complicated system (for example, people's hepatomicrosome) determines the suppression of cytochrome P 450 enzymes and the second stage of metabolic enzyme activity.Further , compound can also be evaluated with the matrix forms of these metabolic enzymatic activitys.These activity can be effectively used for determining chemical combination Thing causes drug-drug interactions or forms metabolin (its reservation antimicrobial acivity or no useful antimicrobial work Property) 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 derived from the cell line of people's epithelium, uses it to measure ingestion of medicines and through Caco-2 cell monolayers (generally 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 individual layer can be determined, The medication amount of intestines individual layer can be passed through by assessing.It is required that suitable control, connected with gap to ensure the integrality of individual layer Compactness.Using this identical system, the outflow of P- glycoprotein mediation can be evaluated.P- glycoprotein is single positioned at polarization is formed The pump of the cell teleblem of layer.This pump can eliminate the activity or Passive intake across Caco-2 cell membranes, cause less medicine Thing passes through enteric epithelium layer.These results are generally used in combination with solubility test, and the two known factors can be moved in lactation Promote oral bioavailability rate in thing.Using conventional medicine dynamic experiment, oral bioavailability rate is determined in animal, finally Oral bioavailability rate is determined in people, thus determines absolute oral bioavailability rate.
Result of the test can be also used for establishing model, and this model can be with aid forecasting to the contributive thing of class pharmaceutical properties Reason-chemical parameters.When it is determined that during this model, experimental method can be simplified, while increase the dependence to model prediction.
5. preparation and administration
The compound of the present invention can be effectively used for preventing treat various people or other animals (including mammal and non-lactation are moved Thing) illness, including, for example, bacterium infection, fungal infection, virus infection, diarrhoea, parasitic disease and cancer.Once really Recognize, it is contemplated that bioactive molecule of the invention can be before the use with reference to entering in any suitable carrier.The dosage of bioactive molecule, administration The use of pattern and suitable carrier depends on intended recipient and targeting organism.Cured according to for animals and people of the compounds of this invention The preparation used is treated to typically comprise this compound and combined with pharmaceutical acceptable carrier.
In terms of with the compatibility of other components of preparation, carrier should be acceptable, and not have to its recipient Harm.In this respect, pharmaceutical acceptable carrier include matched with administering mode any and all solvent, decentralized medium, coating, resist 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 they are incompatible with reactive compound, otherwise, they can be used for group In compound.The reactive compound (confirm according to the present invention or design, and/or reactive compound known in the art) of auxiliary also may be used To combine in composition.Preparation can be provided suitably with dosage unit form, and can utilize pharmacy/microbiology neck It is prepared by domain well-known any method.Generally, some preparations are prepared as follows：Make compound and liquid-carrier or in small, broken bits consolidate Body carrier or both combines, then, if it is necessary, making formed product be target formulation.
The pharmaceutical composition of the present invention should be prepared, so that it is matched with desired for administration approach.The example of method of administration Attached bag includes oral, ear, eyes, nose or parenteral, for example, intravenous administration, intradermal administration, inhalation are transdermal to give Medicine (part), transmucosal administration and rectally.It can be wrapped for parenteral, intracutaneous or subcutaneous application solution or supensoid agent Include following component: sterile diluent, such as water for injection, saline solution, expressed oi, polyethylene glycol, glycerine, propane diols or The solvent of other synthesis；Antiseptic, such as phenmethylol 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 regulation The reagent of power, such as sodium chloride or glucose.Acid or alkali regulation pH value can be used, 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, the method in following is described：Remington'sPharmaceutical Sciences, (Gennaro, A., ed.), Mack Pub., (1990).The preparation of parenteral can also include the glycocholate for buccal administration, be used for The methoxysalicylate of rectally or the citric acid for vagina administration.Parenteral administration can be loaded by glass or modeling In bottle, disposable syringe or multidose phial made of material.Suppository for rectally can also be prepared as follows：Will Medicine 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.With It can include glycerine and other highly viscous compositions in the preparation of direct administration.Other potentially usefuls for these medicines Parenteral vehicles include ethylene-vinyl acetate copolymer particle, osmotic pumps, implantable infusion system and liposome.For The preparation of inhalation can include such as lactose (as excipient), or can be containing such as polyoxyethylene -9- lauryls The aqueous solution of ether, glycocholate and dexycholate, or the oil solution being administered in the form of nasal drop, or it is intranasal use it is solidifying Glue.Enema,retention can be also used for rectal delivery.
The invention formulation for being suitable for being administered orally can be following form: discrete unit, such as capsule, gelatin glue Capsule, pouch, tablet, lozenge or lozenge, each medicine containing predetermined quantity；Pulvis or particulate composition；Liquid, aqueous or Solution or supensoid agent in on-aqueous liquid；Or oil in water emulsion or water-in-oil emulsion.Can also be to inject（bolus）, paste Or paste form gives medicine.Tablet can be prepared by suppressing or moulding medicine together with one or more auxiliary agents.Compressed tablets It can prepare as follows：In suitable machinery, the medicine (such as powder or particle) of free-flowing form is extruded, optionally with gluing Mixture, lubricant, inert diluent, surfactant or dispersant.Molded tablet can be prepared as follows：In suitable mechanical In, the mixture of the powdered drug moistened with inert liquid diluent and suitable carrier 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.Using liquid-carrier prepare Orally administered composition (being used as mouthwash) in a liquid carrier It is oral to use including compound, rustle（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, lozenge 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 cataloid；Sweetener, such as sucrose or saccharin；Or flavor enhancement, such as peppermint（peppermint）, bigcatkin willow Sour methyl esters or orange flavor.
Being suitable for the pharmaceutical composition that injection uses includes aseptic aqueous solution (water miscible) or dispersion and sterile powder (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, it 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, ethanol, polyalcohol is (for example, glycerine, propane diols and the poly- second two of liquid Alcohol, etc.) and its suitable mixture.By using coating (such as lecithin), in the case of a dispersion, by keeping It is required that particle diameter, by using surfactant, suitable mobility can be kept.In many cases it is preferred in composition In include isotonic reagent, for example, sugared, polyalcohol, such as mannitol, D-sorbite, or sodium chloride.By including in the composition The reagent of delayed absorption, for example, aluminum monostearate and gelatin, can extend injectable composition and absorb.
Aseptic injectable solution agent can be prepared as follows：In a suitable solvent, by the reactive compound of requirement with it is upper The composition of a kind of component or component that face is enumerated combines, and then carries out filtration sterilization as needed.Generally, by that will activate Compound, which is attached in sterile excipient, prepares dispersion, and sterile excipient includes basic dispersion medium and above-named required Other components.In the case of the sterile powder for preparing aseptic injectable solution agent, preparation method include vacuum drying and It is lyophilized, obtain 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 medicine, and medicine can be crystallite shape Formula, for example, aqueous microcrystalline suspension form.Liposomal formulation or biodegradable polymer system also can be used to intra-articular Medicine is provided with eyes.
The preparation (including eye therapy) for being suitable for locally being administered includes liquid or semi-liquid preparations, for example, liniment, is washed Agent, gel, application（applicants）, oil-in-water or water-in-oil emulsion, such as cream, ointment or paste；Or solution Agent or supensoid agent, such as drops.Administering locally to the preparation of skin surface can prepare as follows：Medicine is acceptable with dermatology Carrier disperses together, such as lotion, cream, ointment or soap.Applied to position and suppress to depart from, it is particularly useful that The carrier of film or layer can be formed on 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 favourable, hydroxypropyl can be used Cellulose or fibrinogen/thrombin solution.Or tissue-coating solution can be used, for example, the preparation containing pectin.
For inhalation therapy, the powder inhalation that sprayer, atomizer or injector can be used to distribute is (self-propelled Preparation or spray agent).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 agent, there is target by selection The valve (that is, the spray with target grain size can be produced) of spray characteristics or the suspended powder shape that particle diameter is controlled by combining The active component of formula, effect can be obtained.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 area, for transmucosal administration, bag Include, for example, detersive and cholate.Transmucosal administration can be completed by using nose penetrating or suppository., will for cutaneous penetration Reactive compound is typically formulated as ointment commonly known in the art, ointment, gel or cream.
Reactive compound, such as controlled release system can be prepared with carrier that compound is quickly discharged from body can be prevented Agent, including implant and micro-encapsulated delivery system.Biodegradable, bio-compatible polymer, such as second can be used Alkene-vinyl acetate, polyanhydride, polyglycolic acid, collagen, poe and PLA.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 area 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 which the uniformity with dosage is easily administered, 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 being suitable to the reactive compound for producing objective response, and combined with required pharmaceutical carrier.Pass through activation The reactive compound field of the specific characteristic of compound and the concrete result for the treatment to be reached and this treatment individual of preparation is consolidated Some limitations (and directly depending on them) come determine the present invention dosage unit form standard.Furthermore, it is possible to by pushing away Note（bolus）Periodic injections be administered, or intravenous, flesh can be passed through with outside reservoir (for example, bag intravenously) Interior or Intraperitoneal medication is administered continuously.
If it is required that adhering on tissue surface, composition can include being dispersed in fibrinogen-thrombin composition Or the medicine in other bioadhesive polymers.It is then possible to compound is applied, spray or is applied on target tissue surface.Or can With compounding pharmaceutical, for ear, eyes, nose, parenteral or people or other mammals orally are given, for example, giving treatment has Effect amount, for example, suitable concn medicine can be provided, to target tissue so as to causing the quantity of target effect within a period of time.
If reactive compound is used as a part for implantation method, can be before tissue or organ is removed from donor The living tissue or organ to be transplanted provides the reactive compound.The compound can be supplied to donor host.Or or separately Other places, once organ or living tissue remove from donor, organ or living tissue can be placed on containing the reactive compound Preserve in solution., 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 medicine include a part tissue or Organ preserves (preservation) solution, it can be advantageous to uses any commercially available preservation solution.For example, this area is The useful solution known includes Collins solution, Wisconsin solution, Belzer solution, Eurocollins solution and lactic acid The Ringer's solution of change.
The compounds of this invention is used to medical treatment device, the device contacts with tissue, thus can by compound directly to Give to tissue site.The example of medical treatment device is support, and it contains or be coated with one or more compounds of the invention.
For example, reactive compound can be applied on the support of vascular lesions sites.Support 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 use The intermetallic composite coating support of stainless steel or other bio-compatibles, or
It can be made of biocompatible polymer.Reactive compound can be combined with rack surface, be embedded in institute on support In coated polymeric material, and discharge therefrom, or be coated or cover the carrier of support and wrapped up, and pass through its release. Support can be used for giving the single or multiple reactive compounds of tissue close to the support.
The reactive compound that method described herein confirms or designed can be given to individual, to treat illness (prevention Or treatment).It is combined with this treatment, it may be considered that pharmacogenomics is (that is, in individual genotype and individual to externalization The research of relation between compound or medicine response).By changing between the dosage of active pharmacological agent and blood concentration Ratio, the metabolism difference for the treatment of can cause serious toxicity or Endodontic failure.Thus, doctor or clinician can use Knowledge obtained in relevant pharmacogenomics research, it is determined whether give the dosage of medicine and the design drug therapy And/or therapeutic scheme.
, 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 kept in the animal treated The active component concentration (quantity) or blood level or tissue of antimicrobial validity are horizontal.Generally, the effective agent of active component Amount is 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 body weight/days. Quantity is administered possibly also on following variables：For example, the disease or the type and extent of indication treated, specific patient's General health, the Relative biological effect of the compound delivered, the preparation of medicine, excipient and class present in preparation Type, and method of administration.It should also be understood that horizontal in order to rapidly obtain target blood level or tissue, initial dosages can So that optimal dose can be less than more than above-mentioned higher level, or predose, and can be during treatment, according to specific feelings Condition gradually steps up daily dose.If desired, daily dose may be divided into multiple dosages, for example, twice daily extremely Four times.
In people and other mammals, find various morbid states or illness as caused by nonsense mutation or ambiguity mutation Or mediated by them.These mutation synthesized, folded by negatively affecting such as albumen, transported and/or function causing or Mediated disease state or illness.Think that disease or illness as caused by nonsense or ambiguity mutation account for the morbid state of obvious 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 regulatory 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 (ASM 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, which can be used for treating or preventing, feeds The morbid state for being caused or being mediated by this nonsense or ambiguity mutation of newborn animal, this treatment or prevention, which are given, needs its food in one's mouth The compound of the invention of newborn animal effective dose, so as to suppress the nonsense or the ambiguity mutation that are related to morbid state.
6. embodiment
Nuclear magnetic resonance (NMR) spectrum is obtained on Bruker Avance 300 or the spectrometers of Avance 500, or in some cases Use the spectrometers of GE-Nicolet 300.Popular response solvent is high performance liquid chromatography (HPLC) grade or American Chemical Society (ACS) grade, obtained with anhydrous form from manufacturer, unless otherwise mentioned." chromatogram " or " silica gel purification " refers to use silica gel The flash column chromatography of (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=ethanol；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 acid carbonate；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=the dichloro [(diphenylphosphines of 1,1'- bis- Base) ferrocene] palladium (II).
The illustrative compounds synthesized according to the present invention are listed in Table 1 below.Runic or empty key represent 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,.Should also Solution, in order to save space, the chemical constitution of some compounds is divided into two parts, and each free wavy line of two tie points is handed over The key of fork represents.See, e.g. compound 956, it is classified as two parts and draws:
It is but corresponding with following complete chemical constitution:
。
Compound of the 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 during display compound.
The compound of the present invention is shown in Table 1.If appropriate, there is provided LCMS (liquid chromatography mass) data.When not having When there are acquisition data, represented by " NA ".LCMS data are using conventional m/z, with [M+H]+Form provide, in another manner Except situation about showing.
Table 1
In further embodiment, compound of the invention does not include the compound with having structure:
。
Using synthesising chemical technology well known to those skilled in the art, compound of the invention can be prepared.
The synthesis of embodiment 1-592
Using synthesising chemical technology well known to those skilled in the art, including the reaction scheme listed herein, this hair can be prepared Bright compound.For illustrative purposes, the synthesis of compound 592 is described as follows.
4- benzyloxycarbonyl aminos-piperidines -1- carboxylates
At 23 DEG C, to the THF (80 mL) of 4- amino-piperadine -1- carboxylates (11.98 g, 58.4 mmol, 1 equivalent) In solution add saturated sodium bicarbonate solution (200 mL), then add benzyl chloroformate (9.19 mL, 64.2 mmol, 1.1 Equivalent).The reaction 55 min is stirred, is then distributed between ethyl acetate (200 mL) and water (100 mL).Separate organic layer, Washed with saturated brine solution (200 mL), dry (MgSO4), filter, concentration, obtain 20.4 g brown solids.The material is not Just it is used in next step with being further purified.
Piperidin-4-yl-carbamic acid benzyl ester
At 23 DEG C, to the dichloro of 4- benzyloxycarbonyl aminos-piperidines -1- carboxylates (20.4 g, the crude product of abovementioned steps) Trifluoroacetic acid (40 mL) is added in methane (100 mL) solution.After stirring 45 min, the reactant mixture is concentrated.By remnants Thing is dissolved in water (100 mL), is then added solid carbonic acid potassium, is alkalized to pH11.By obtained solution with dichloromethane (2 × 150 mL) extraction.Organic extract is very muddy；It is dried (Na2SO4), filter, concentration.Residue is dissolved/is suspended in In chloroform (70 mL), and by frit, remove the particulate observed.The solution is concentrated, obtains 15 g brown oils. The material does not have to purifying and just used in a subsequent step.
(the bromo- propyl group of 3-)-carbamate
At 23 DEG C, to the 3- bromopropyl amine hydrobromate (12.8 g, 58.4 mmol, 1 equivalent) in dichloromethane (200 mL) It is middle addition triethylamine (10.2 mmol, 73.6 mmol, 1.26 equivalents), then add two dimethyl dicarbonate butyl esters (12.8 g, 58.4 mmol, 1 equivalent).After stirring 1 hour, washed successively with water (200 mL) and then saturated brine solution (200 mL) The reactant mixture；Then (MgSO is dried4), filter, concentration, obtain the limpid oil of 13.9 g target products.The material is under One step is neutral to be used.
[1- (3- t-butoxycarbonyl aminos-propyl group)-piperidin-4-yl]-carbamic acid benzyl ester
At 23 DEG C, to the two of piperidin-4-yl-carbamic acid benzyl ester (15 g, 58.4 mmol, the crude product of Boc deprotection steps) In NMF (60 mL) solution add potassium carbonate (12.1 g, 87.6 mmol, 1.5 equivalents), KI (4.85 g, 29.2 mmol, 0.5 equivalent) and (the bromo- propyl group of 3-)-carbamate (13.9 g, 58.4 mmol, 1 equivalent).Will To mixture be heated to 60 DEG C (oil baths).After 60 DEG C of min of process 90, the reactant mixture is cooled to 23 DEG C, then Distributed between ethyl acetate and water (respective 100 mL).Organic layer is separated, is washed with saturated brine solution (150 mL), is dried (MgSO4), filter, concentration.Use the automatic chromatographic system purified products of Isco CombiFlash.By residue with dichloromethane (25 mL) solution form is loaded on 330 g silicagel columns, then with 2M ammonia-ethanol/methylene (0-12.5% 2M ammonia/methanol Linear gradient, 12 column volumes, the mL/min of flow velocity 100) elution, obtain 16.9 g (43.2 mmol, 74%, 3 step) title compound The limpid oil of thing.
[3- (4- amino-piperadine -1- bases)-propyl group]-carbamate
At 23 DEG C, to [1- (3- t-butoxycarbonyl aminos-propyl group)-piperidin-4-yl]-carbamic acid benzyl ester (16.9 g, 43.2 Mmol, 1 equivalent) ethanol (200 mL) solution in add palladium/carbon (2.25 g, 10 wt.%, moistening, Degussa types).Will Reaction vessel is placed in atmosphere of hydrogen (sacculus), and is stirred 14 hours.Now TLC analysis shows reaction is incomplete, passes through Celite pad filters the mixture, is washed with ethanol (100 mL).By obtained solution with new palladium catalyst (2.25 g) place Reason, is then placed in atmosphere of hydrogen (sacculus) at 50 DEG C.After 7 hours, TLC analyses show that initiation material consumes completely.Will The reactant mixture is cooled to 23 DEG C, is then filtered by diatomite, is washed with ethanol (200 mL).Filtrate is concentrated, is obtained 11.1 g (43.2 mmol, 100%) target compound.
[3- (4- urea groups-piperidin-1-yl)-propyl group]-carbamate
0 DEG C (ice-water bath), to [3- (4- amino-piperadine -1- bases)-propyl group]-carbamate (7.34 g, 28.6 Mmol, 1 equivalent) dichloromethane solution in add triethylamine (5.97 mL, 42.9 mmol, 1.5 equivalents), then add chloromethane Sour phenylester (3.97 mL, 31.4 mmol, 1.1 equivalents).The reactant mixture is stirred at 0 DEG C 2.5 hours, then in dichloromethane Distributed between alkane (200 mL) and saturated sodium bicarbonate aqueous solution (250 mL).Separate organic layer.By water layer dichloromethane (50 ML) extract again.The organic layer of merging is dried into (MgSO4), filter, concentration, it is solid to obtain 10.5 g phenyl carbamates white half Body.Crude residue is dissolved in methanol (60 mL), then handled with ammonium hydroxide aqueous solution (28% ammonia, 60 mL).At 23 DEG C After stirring 15 hours, the reactant mixture is concentrated.Residue is handled with ether (300 mL), is precipitated.It is quiet at 23 DEG C After putting 2 hours, filtered by mesoporous glass material, collect precipitation.The white solid of collection is dried in vacuo, obtains 6.23 g (20.8 mmol, 73%) target urea.
(the bromo- 2- nitro-phenoxies of 4-)-ethyl acetate
It is molten to the dimethylformamide (40 mL) of the bromo- 2- Nitro-phenols of 4- (3.28 g, 15.0 mmol, 1 equivalent) at 23 DEG C In liquid add potassium carbonate (4.14 g, 30 mmol, 2 equivalents), then add bromoacetate (1.84 mL, 16.6 mmol, 1.1 Equivalent).Obtained mixture is heated to 60 DEG C (oil baths), 90 min is kept, is subsequently cooled to 23 DEG C.By the reactant mixture In ethyl acetate: heptane (1:1) distributed between water (respective 100 mL).Organic layer is separated, it is (each with water, saturated brine solution From 100 mL) wash successively, then dry (MgSO4), filter, concentration, obtain 4.50 g (11.5 mmol, 77%) product yellow Oil.
[4- (3- fluoro-phenyls acetenyl) -2- nitro-phenoxies]-ethyl acetate
In microwave reaction container, to (the bromo- 2- nitro-phenoxies of 4-)-ethyl acetate (2.95 g, 9.70 mmol, 1 equivalent) Three are added with dimethylformamide (15 mL) solution of 1- acetenyl -3- fluorobenzene (1.34 mL, 11.6 mmol, 1.2 equivalents) Ethamine (4.05 mL, 29.1 mmol, 3 equivalents), cuprous iodide (55 mg, 0.29 mmol, 0.03 equivalent) and trans-dichloro are double (three-O- tolylphosphines) palladium (II) (152 mg, 0.19 mmol, 0.02 equivalent).The reaction is set to be in argon atmospher, Ran Hou 80 DEG C are heated in microwave reactor, keeps 30 min.Then by the reactant mixture in ethyl acetate: heptane (1:1) and Distributed between 1.0N aqueous hydrochloric acid solutions (respective 100 mL).Organic layer is separated, with saturated sodium bicarbonate aqueous solution, 1:1 saturated carbon Sour hydrogen sodium water solution: saturated aqueous ammonium chloride, saturated brine solution (respective 100 mL) wash successively, then dry (MgSO4), filter, concentration.Use the automatic chromatographic system purified products of Isco CombiFlash.By residue with dichloromethane (5 mL) solution form is loaded on 120 g silicagel columns, then with ethyl acetate/heptane (0-40% ethyl acetate linear gradients, 16 column volumes, the mL/min of flow velocity 85) elution, obtain 1.72 g (5.01 mmol, 52%) title compound brown oil.
6- [2- (3- fluoro-phenyls)-ethyl] -4H- benzos [1,4] oxazine -3- ketone
To [4- (3- fluoro-phenyls acetenyl) -2- nitro-phenoxies]-ethyl acetate (1.72 g, 5.01 mmol, 1 equivalent) Palladium/carbon (500 mg, 10 wt.%, moistening, Degussa types) is added in ethyl acetate (50 mL) solution.Reaction vessel is put Put in atmosphere of hydrogen (sacculus), and stirred 15 hours at 23 DEG C.Now, lcms analysis shows：The reaction contains target benzene The mixture of Bing oxazinones product (main) and not cyclized aniline (secondary).The mixture is filtered by Celite pad, uses second Acetoacetic ester (100 mL) washs.The solution is concentrated, is then re-dissolved in ethyl acetate (100 mL), is flowed back 2 hours.LCMS points Analysis shows, is cyclized: not cyclized ratio does not improve.Add p-methyl benzenesulfonic acid hydrate (111 mg), and the solution that will be obtained Further backflow 1 hour.The solution is cooled to 23 DEG C, then with water, 1.0N aqueous hydrochloric acid solutions, saturated brine solution (each 100 mL) wash successively, dry (MgSO4), filter, concentration.Use the automatic chromatographic system purifying productions of Isco CombiFlash Thing.Residue is loaded on 80 g silicagel columns with dichloromethane (5 mL) solution form, then with ethanol/methylene (0- 5% methanol linear gradient, 18 column volumes, the mL/min of flow velocity 60) elution, it is titled to obtain 1.15 g (4.24 mmol, 85%) Compound brown solid.
The chloro- 6- of 3- [2- (3- fluoro-phenyls)-ethyl]-benzo [1,4] oxazine -2- ylidenylmethyls }-dimethyl-amines
At 0 DEG C, chlorine is added into chloroform (10 mL) solution of dimethylformamide (0.82 mL, 10.6 mmol, 2.5 equivalents) Phosphorous oxide (V) (0.78 mL, 8.49 mmol, 2 equivalents).After 0 DEG C is stirred 10 min, reaction vessel is heated to 23 DEG C, 10 min are kept, are then cooled to 0 DEG C.Addition 6- [2- (3- fluoro-phenyls)-ethyl] -4H- benzos be [1,4] oxazine -3- ketone Chloroform (7 mL) solution.After 0 DEG C further 5 min of stirring, the reaction is heated to flowing back (oil bath), holding 4 hours, so After be cooled to 23 DEG C, and distributed between dichloromethane and water (respective 100 mL).Water layer is adjusted with 5N sodium hydrate aqueous solutions Section then separates organic layer to pH12.Organic layer is washed with salt solution (100 mL), and retained.By original water layer dichloro Methane (100 mL) extracts again.Two organic extracts are merged, dry (MgSO4), filter, concentration.Use Isco The automatic chromatographic system purified products of CombiFlash.Residue is loaded into 80 g silica gel with dichloromethane (5 mL) solution form On post, then eluted with ethyl acetate/heptane (0-40% ethyl acetate linear gradients, 16 column volumes, the mL/min of flow velocity 60), Obtain 985 mg (2.86 mmol, 67%) title compound orange/brown oil.
3- [4- (3- 2- dimethylamino methylenes -6- [2- (3- fluoro-phenyls)-ethyl] -2H- benzos [1,4] oxazine - 3- yls }-urea groups)-piperidin-1-yl]-propyl group }-carbamate
To the chloro- 6- of 3- [2- (3- fluoro-phenyls)-ethyl]-benzo [1,4] oxazine -2- ylidenylmethyls }-dimethyl-amines (500 Mg, 1.45 mmol, 1 equivalent) and [3- (4- urea groups-piperidin-1-yl)-propyl group]-carbamate (435 mg, 1.45 Mmol, add in 1 equivalent) dioxanes (15 mL) solution palladium (II) (3.2 mg, 0.0145 mmol, 0.01 equivalent), 4,5- double (diphenylphosphino) -9,9- dimethyl xanthene (xanthene, xantphos, 17 mg, 0.029 mmol, 0.02 Equivalent) and cesium carbonate (709 mg, 2.18 mmol, 1.5 equivalents).The reactant mixture is purged with argon gas, then sealing reaction is held Device (nut), and be put into 100 DEG C of oil baths.After 100 DEG C are kept for 14 hours, the reaction is cooled to 23 DEG C, then in second Distributed between acetoacetic ester and water (respective 100 mL).Organic layer is separated, is washed with saturated brine solution (100 mL), then dried (MgSO4), filter, concentration.Use the automatic chromatographic system purified products of Isco CombiFlash.By residue with dichloromethane (5 mL) solution form is loaded on 80 g silicagel columns, with 2M ammonia-ethanol/methylene (0-8% 2M ammonia/methanol linear gradient, 18 column volumes, the mL/min of flow velocity 60) elution, it is solid to obtain 313 mg (0.515 mmol, 36%) title compound as yellow/brown Body.
[3- (4- the azepines of 7- [2- (3- fluoro-phenyls)-ethyl] -2- oxo -2,9- dihydro -10- oxa-s -1,3,9- three - Anthracene -3- bases (triazaanthracen-3-yl) }-piperidin-1-yl)-propyl group]-carbamate
By { 3- [4- (3- { 2- dimethylamino methylenes -6- [2- (3- fluoro-phenyls)-ethyl] -2H- benzos [1,4] oxazine -3- Base }-urea groups)-piperidin-1-yl]-propyl group-carbamate (310 mg, 0.510 mmol, 1 equivalent) acetic acid (15 ML) solution is placed in microwave reaction container.The reaction is in argon atmospher, 100 DEG C be then heated in microwave reactor, Keep 90 min.Lcms analysis shows, obtains target product, but lose a part of Boc.The acetic acid solution is concentrated, then will Residue is dissolved in tetrahydrofuran (25 mL), and with potassium carbonate (600 mg, 4.34 mmol, 8.5 equivalents) and two dimethyl dicarbonates Butyl ester (190 mg, 0.872 mmol, 1.7 equivalents) processing.After 23 DEG C are stirred 30 min, by the reactant mixture in second Distributed between acetoacetic ester and water (respective 60 mL).Organic layer is separated, is washed with saturated brine solution (50 mL), then dried (MgSO4), filter, concentration.Residue is dissolved/it is suspended in 1:1 ethyl acetate: in heptane (10 mL, heat).After cooling, filtering Collect solid.By in solid absorption to silica gel (5 g), then purified using the automatic chromatographic systems of Isco CombiFlash.Make production Thing is by 40 g silicagel columns, with 2M ammonia-ethanol/methylene (0-8% 2M ammonia/methanol linear gradient, 24 column volumes, flow velocity 40 mL/min) elution, obtain 94 mg (0.167 mmol, 33%) title compound light yellow solid.
3- [1- (3- amino-propyls)-piperidin-4-yl] -7- [2- (3- fluoro-phenyls)-ethyl] -3H, 9H-10- oxa- -1, Tri- azepines of 3,9--anthracene -2- ketone
At 23 DEG C, to [3- (4- { 7- [2- (3- fluoro-phenyls)-ethyl] -2- oxo -2,9- dihydro -10- oxa-s -1,3, the nitrogen of 9- tri- Miscellaneous-anthracene -3- bases }-piperidin-1-yl)-propyl group] and-carbamate (94 mg, 0.167 mmol, 1 equivalent) dichloromethane Trifluoroacetic acid (4.0 mL) is added in alkane (10 mL) solution.30 min are stirred into the reaction, then concentrated.Residue is dissolved in In water (10 mL), then handled with 1.0N aqueous hydrochloric acid solutions (2.0 mL).Obtained solution is concentrated, by residue again then It is dissolved in water (10 mL), is handled with hydrochloric acid (2.0 mL), concentration.Residue is dissolved in water (10 mL), will then be obtained Solution freezes, and then freezes, obtains 88 mg (0.165 mmol, 99%) target product (dihydrochloride) yellow solid.LCMS (EI): 464.1(M + H)+。
Chloro- 2- dimethylaminos methylene -3,4- dihydros -2H- benzos [1,4] oxazine -6- carboxylic acid methyl esters (2) of 3-
4.05 mL DMF (52.5 mmol, 2.5 equivalents (eq)) are added to CHCl3It is in (100 mL), obtained solution is cold But to 0 DEG C, then handled with trichlorfon 98 (6.43g, 42 mmol, 2.0 equivalents).The reaction solution is heated to room temperature, stirred Mix 20 minutes, be then cooled to 0 DEG C again, at 0 DEG C, add 3- oxo -3,4- dihydro -2H- benzo [Isosorbide-5-Nitrae] oxazine -6- formic acid Methyl ester (1) (4.36g, 21 mmol, 1.0 equivalents), and obtained reactant mixture is heated to flowing back, kept for 6 hours.When When TLC and LCMS display reactions are completed, the reactant mixture is cooled to room temperature, and matched somebody with somebody with dichloromethane and moisture, by water layer Alkalized to pH12 with 5N NaOH, extracted with dichloromethane (mL of 3 x 100).The organic layer of merging is concentrated, it is pure with column chromatography Change (SiO2, 20-50% EtOAc/ heptane gradient elution), obtain chloro- 2- dimethylaminos methylene -3, the 4- dihydros of target 3- - 2H- benzos [Isosorbide-5-Nitrae] oxazine -6- carboxylic acid methyl esters (2) (4.13g, 5.9g, it is theoretical, 70%) yellow solid.
3- { 3- [1- (3- t-butoxycarbonyl aminos-propyl group)-piperidin-4-yl]-urea groups } -2- dimethylaminos methylene - 3,4- dihydro -2H- benzos [1,4] oxazine -6- carboxylic acid methyl esters (4) and 3- [1- (3- t-butoxycarbonyl aminos-propyl group)-piperidines - 4- yls] three azepines of -2- oxo -2,3,9,9a- tetrahydrochysene -1H-10- oxa- -1,3,9--anthracene -7- carboxylic acid methyl esters (5)
By chloro- 2- dimethylaminos methylene -3,4- dihydros -2H- benzos [1,4] oxazine -6- carboxylic acid methyl esters (2) of 3- (1.28g, 4.6 mmol, 1.0 equivalents) and [3- (4- urea groups-piperidin-1-yl)-propyl group]-carbamate (3) (1.37g, 4.6 mmol, 1.0 equivalent) dioxanes (20.0 mL) solution are with Pd (OAc)2(20.6 mg, 0.092mmol, 0.02 equivalent), xanthene (10.6mg, 0.18mmol, 0.04 equivalent) and Cs2CO3(2.25g, 6.9 mmol, 1.5 equivalents) place Reason, and obtained reactant mixture is heated to 90 DEG C, kept for 6 hours.When TLC and MS display reactions are completed, to the reaction Acetic acid (8ml) is directly added into mixture, is stirred 1 hour at 100 DEG C, without separating 3- { 3- [1- from the reactant mixture (3- t-butoxycarbonyl aminos-propyl group)-piperidin-4-yl]-urea groups } -2- dimethylamino methylene -3,4- dihydro -2H- benzos [1,4] oxazine -6- carboxylic acid methyl esters (4).The reaction solution is concentrated in vacuo, and residue is directly purified with column chromatography (SiO2, 0-5% MeOH/CH2Cl2Gradient elution), obtain target 3- [1- (3- t-butoxycarbonyl aminos-propyl group)-piperidines -4- Base] -2- oxos -2,3,9,9a- tetrahydrochysene -1H-10- oxa-s -1,3, tri- azepines of 9--anthracene -7- carboxylic acid methyl esters (5) (760 mg, 2295.4 mg, it is theoretical, 33%) brown oil material.For 4: C27H40N6O6, LCMS(EI)m/e 545(M++ H) for 5∶C25H33N5O6, LCMS(EI)m/e 500(M+ + H)。
3- [1- (3- t-butoxycarbonyl aminos-propyl group)-piperidin-4-yl] -2- oxo -2,9- dihydro -3H-10- oxa- -1, Tri- azepines of 3,9--anthracene -7- formic acid (6)
By the 1M LiOH aqueous solution (4.5 mL, 3 equivalents) and 3- [1- (3- t-butoxycarbonyl aminos-propyl group)-piperidin-4-yl] -2- Three azepines of oxo -2,3,9,9a- tetrahydrochysene -1H-10- oxa- -1,3,9--anthracene -7- carboxylic acid methyl esters (5;760 mg, 1.52 Mmol, 1.0 equivalents) it is added in THF (5 mL), 50 DEG C are heated to, stirring, is until LCMS is displayed without starting material left Only.The reaction solution is cooled to room temperature, extracted with EtOAc.Water layer is acidified to pH2, is settled out target product, filters, obtains To 3- [1- (3- t-butoxycarbonyl aminos-propyl group)-piperidin-4-yl] -2- oxo -2,9- dihydro -3H-10- oxa-s -1,3,9- three Azepine-anthracene -7- formic acid (412 mg, 738 mg, it is theoretical, 56%) light tan solid.For 6: C24H31N5O6, LCMS(EI)m/e 486(M+ + H)。
4- [3- ({ 3- [1- (3- t-butoxycarbonyl aminos-propyl group)-piperidin-4-yl] -2- oxo -2,9- dihydros -3H-10- Three azepines of oxa- -1,3,9--anthracene -7- carbonyls }-amino)-propyl group]-piperazine -1- carboxylates (7)
By 3- [1- (3- t-butoxycarbonyl aminos-propyl group)-piperidin-4-yl] -2- oxo -2,9- dihydro -3H-10- oxa- -1,3, Tri- azepines of 9--anthracene -7- formic acid (6) (150 mg, 0.31 mmol, 1 equivalent) and 4- (3- amino-propyls)-piperazine -1- formic acid uncles With HATU, (235 mg, 0.62 mmol, 2.0 work as DMF (5 mL) solution of butyl ester (150 mg, 0.62 mmol, 2.0 equivalents) Amount) and Hunig's alkali process.Obtained solution is stirred at room temperature 6 hours.When TLC and LCMS display reactions are completed, very Sky concentrates the reaction solution, and residue directly purified into (SiO with column chromatography2, 0-10% MeOH/CH2Cl2 gradient elutions), obtain To target 4- [3- ({ 3- [1- (3- t-butoxycarbonyl aminos-propyl group)-piperidin-4-yl] -2- oxo -2,9- dihydro -3H-10- oxygen Miscellaneous -1,3,9- tri- azepines-anthracene -7- carbonyls }-amino)-propyl group]-piperazine -1- carboxylates (106 mg, 220mg, it is theoretical, 48%), it is handled with 4M HCl/ dioxanes, obtains final products 3- [1- (3- amino-propyls)-piperidin-4-yl] -2- oxygen Generation three azepines of -2,9- dihydro -3H-10- oxa- -1,3,9--anthracene -7- formic acid (3- piperazines -1- bases-propyl group)-acid amides (8).For 7 ∶C36H54N8O7, LCMS(EI)m/e 711(M++ H) is for 8: C26H38N8O3, LCMS(EI)m/e 511(M+ + H).
Embodiment 2- 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, uses the micro- dilution test of standard, measure minimum inhibitory concentration (MICs).Data are provided, wherein "+" represents that the compound has 16 micrograms/ml or smaller MIC value, and "-" represents that the compound has more than 16 micrograms/ml's MIC value." N/A " refers to that data can not be obtained.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, are not intended to limit this The scope 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 Measure.In addition, the boundary value of "+", "-" and 16 micrograms/ml of " N/A " statement and selection is also illustrative, it is not intended to Limit the scope of the present invention.For example, "-" does not indicate that compound necessarily without activity or application, but it is directed to and specifies micro- life The MIC value of thing is more than 16 micrograms/ml.
Table 2
With reference to bibliography
For all purposes, by the complete disclosure of each patent document and scientific paper that are mentioned above in a manner of being cited It is incorporated herein in.
Equivalent
Without departing from the spirit or essential characteristics of the present invention, the present invention can be expressed in other specific forms.Cause This, it should it is all illustrative embodiment in every respect to think the embodiment above, rather than described herein of limitation Invention.Thus, the scope of the present invention is shown by appended claims, rather than is shown by description above, and in right It is required that equivalent implication and scope in all changes be included in wherein.

Claims (10)

1. the compound with following formula:
(V)
C-B-A- ,-D-E-F and-G-H-J are chemical groups, wherein
- D-E-F is hydrogen；
C-B-A- is selected from：
G is selected from:
(a) singly-bound, (b)-(C1-8Alkyl)-, (d)-(C2-8Alkynyl)-, wherein
I) 0-4 carbon atom in (b) just mentioned above is optionally by selected from following group replacement：- O- ,-NR6- and-(C= O)-,
Ii) any one of (b) or (d) just mentioned above is optionally by one or more R5Group substitutes, and
Iii) any one of (b) or (d) just mentioned above is optionally by-(C1-8Alkyl)-R5Group substitutes；
(e)-O-, (h)-C (O)-, (i)-C (O) O-, (l)-C (O) NR6-, (cc)-C (O) NR6(CR6R6)t-, (dd) contains one Or multiple heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles, hetero atom are selected from nitrogen and oxygen,
(ee) 3-14 members aromatic carbocyclic, and
(ff)-(CR6R6)t-,
Wherein (dd) or (ee) are optionally by one or more R5Group substitutes；
H is selected from:
(a) singly-bound,
(b) nitrogen and sulphur are selected from containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles, hetero atom,
(c) 3-14 members saturation, insatiable hunger and/or aromatic carbocyclic,
Wherein (b) or (c) is optionally by one or more R5Group substitutes；
(d)-(C1-8Alkyl)-, (e)-(C2-8Alkenyl)-, wherein
I) 0-4 carbon atom in (d) just mentioned above is optionally by selected from following group replacement：- O- ,-S (O)p- ,- NR6- ,-(C=O)-and-C (=NR6)-,
Ii) (d) just mentioned above is optionally by one or more R5Group substitutes, and
Iii) (d) just mentioned above is optionally by-(C1-8Alkyl)-R5Group substitutes；
- (CR (g)6R6)t-,
J is selected from:
(a) hydrogen, (c) F, (d) Cl, (e) Br, (g)-CF3, (h)-CN, (k)-NR6(CR6R6)tR8, (l)-OR8, (m)-S (O)p (CR6R6)tR8, (n)-C (O) (CR6R6)tR8, (q)-C (O) O (CR6R6)tR8, (s)-C (O) NR6(CR6R6)tR8, (dd)-NR6R8, (ee)-NR6(CR6R6)R8, (ff)-OH, (gg)-NR8R8, (hh)-OCH3, (ii)-S (O)pR8, (kk)-NR6C(NR6)NR6R8, (ll)C1-8Alkyl, (nn) C2-8Alkynyl, (oo) are miscellaneous containing one or more heteroatomic 3-14 members saturations, insatiable hunger and/or fragrance Ring, hetero atom are selected from nitrogen and oxygen, (pp) 3-14 members saturation or aromatic carbocyclic, (uu)-haloalkyl, and (yy)-NR6C(O) CR8R8R8；
Wherein (ll) to (mm) and (pp) is optionally by one or more R7Group substitutes；
R5It is selected from：(a) hydrogen, (b) F, (f)-CF3, (g)-CN, (j)-NR6R6, (k)-OR8, (m)-C1-8Alkyl, (p)-(C1-8Alkane Base)-(the 3-14 membered aromatic heterocycles containing one or more nitrogen), (q)-(C1-8Alkyl)-(3-14 members aromatic carbocyclic), (r)-halogen Substituted alkyl, (t) contain one or more heteroatomic -3-14 members saturations or aromatic heterocycle selected from nitrogen and oxygen, and (u) -3-14 First aromatic carbocyclic；
Wherein (m) and (p) to (r) is optionally by one or more R8Substitution；
R6It is selected from：(a) hydrogen, (b)-C1-8Alkyl, or two R6Group is combined together to form carbocyclic ring, (c)-haloalkyl, (d) Contain one or more heteroatomic -3-14 members saturations or aromatic heterocycle selected from nitrogen and oxygen, and (e) -3-14 member aromatic carbocyclics；
Wherein (b) to (e) is optionally by one to multiple R8Substitution；
R7It is selected from：(a) hydrogen, (b) F, (d) Br, (f)-CF3, (g)-CN, (j)-NR6R6, (k)-OR6, (l)-NR6(CNR6)NR6R6, (m)-C1-8Alkyl, (p)-(C1-8Alkyl)-(contain one or more heteroatomic 3-14 members saturations or fragrance selected from nitrogen and oxygen Heterocycle), (q)-(C1-8Alkyl)-(3-14 members aromatic carbocyclic), and (r)-haloalkyl, (s)-NR6R8, (t)-OR8, (u)- (CR6R6)tNR6R8, (v)-CR6R8R8, (x) contains one or more heteroatomic -3-14 members saturations or fragrance selected from nitrogen and oxygen Heterocycle, (y) -3-14 member aromatic carbocyclics, (z)-(CR6R6)tC(O)NR8R8, (aa)-S (O)pR8, (bb)-NR6C(O)NR6R6With (cc)-NR6C(O)R6；
Wherein (m) and (p) to (q) and (x) to (y) are optionally by one or more R9Substitution；
R8It is selected from：(a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g)-CN, (j)-NR6R9, (k)-OR9, (l)-NR6 (CNR6)NR6R6, (m)-C1-8Alkyl, (p)-(C1-8Alkyl)-(contain one or more heteroatomic 3-14 selected from nitrogen and oxygen First saturation or aromatic heterocycle), (q)-(C1-8Alkyl)-(3-14 members saturation or aromatic carbocyclic), (r) is selected from containing one or more Heteroatomic -3-14 members the saturation or aromatic heterocycle of nitrogen and oxygen, (s) -3-14 members saturation or aromatic carbocyclic, (t)-haloalkyl, (z)-NR6(CNR9)(NR6R6), (bb)-C (=NR9)NR6R6, and (ff)-(CR6R6)tNR6R9；
Wherein (m) and (p) to (s) are optionally by one to multiple R9Substitution；
R9It is selected from：(a) hydrogen, (b) F, (c) Cl, (d) Br, (f)-CF3, (j)-NR6R10, (k)-OR6, (l)-NR6(CNR6)NR6R6, (n)-C1-8Alkyl, (q) contain one or more heteroatomic -3-14 members saturations or aromatic heterocycle selected from nitrogen and oxygen, (r) -3- 14 yuan of aromatic carbocyclics, (s)-haloalkyl, (z)-(C1-8Alkyl)-(contain one or more heteroatomic 3- selected from nitrogen and oxygen 14 yuan of saturations or aromatic heterocycle), (aa)-(C1-8Alkyl)-(3-14 members aromatic carbocyclic), (cc)-C (=NR6)NR6R6(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, (j)-NR6R6, (l)-NR6(CNR6)NR6R6, (n)-C1-8Alkyl, (cc)-C (=NR6)NR6R6 (hh)-(CR6R6)tNR6R6；
Wherein-G-H-J is not hydrogen；
P is 0,1 or 2, and
T is 1,2 or 3,
Or its officinal salt or dynamic isomer.
2. according to the compound of claim 1, there is following formula:
Or,
Or its officinal salt or dynamic isomer.
3. according to the compound of claim 2, there is following formula:
,
Or its officinal salt or dynamic isomer.
4. according to the compound of claim 2, wherein G is selected from：
(a) singly-bound, (b)-(C1-8Alkyl)-, (d)-(C2-8Alkynyl)-, wherein
I) 0-4 carbon atom in (b) just mentioned above is optionally by selected from following group replacement：- O- ,-NR6- and-(C= O)-,
Ii) any one of (b) or (d) just mentioned above is optionally by one or more R5Group substitutes, and
Iii) any one of (b) or (d) just mentioned above is optionally by-(C1-8Alkyl)-R5Group substitutes；
(e) nitrogen and oxygen are selected from containing one or more heteroatomic 3-14 members saturation, insatiable hunger and/or aromatic heterocycles, hetero atom, and
(f) 3-14 members aromatic carbocyclic,
Wherein (e) or (f) is optionally by one or more R5Group substitutes；
Or its officinal salt or dynamic isomer.
5. according to the compound of claim 2, wherein R5It is selected from：(a) hydrogen, (b) F, (f)-CF3, (g)-CN, (j)-NH2, (k)- OR8, (m)-C1-8Alkyl, (p)-(C1-8Alkyl)-(the 3-14 membered aromatic heterocycles containing one or more nitrogen), (q)-(C1-8Alkane Base)-(3-14 members or aromatic carbocyclic), (r)-haloalkyl, (t) contains one or more heteroatomic -3- selected from nitrogen and oxygen 14 yuan of saturations or aromatic heterocycle, and (u) phenyl；Or its officinal salt or dynamic isomer.
6. according to the compound of claim 2, wherein R6It is selected from：(a) hydrogen, (b)-C1-8Alkyl, or two R6Group is incorporated in Carbocyclic ring is formed together, and (c)-haloalkyl, (d) is full containing one or more heteroatomic -3-14 members selected from nitrogen, oxygen and sulphur With, insatiable hunger and/or aromatic heterocycle, and (e) -3-14 members saturation or aromatic carbocyclic；Or its officinal salt or dynamic isomer.
7. according to the compound of claim 4, wherein G is selected from：
(a) singly-bound, (b)-(C1-8Alkyl)-, wherein
I) 0-4 carbon atom in (b) just mentioned above is optionally by selected from following group replacement：- O- ,-NR6- and-(C= O)-,
Ii) (b) just mentioned above is optionally by one or more R5Group substitutes, and
Iii) (b) just mentioned above is optionally by-(C1-8Alkyl)-R5Group substitutes；
Or its officinal salt or dynamic isomer.
8. according to the compound of claim 3, whereinIt is selected from:
Or its officinal salt or dynamic isomer.
9. according to the compound of claim 1, it is selected from
Or its officinal salt or dynamic isomer.
10. pharmaceutical composition, compound or pharmaceutically acceptable salt thereof or dynamic isomer comprising any one according to claim 1-9 And pharmaceutical acceptable carrier.
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Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ599289A (en) 2009-10-16 2014-11-28 Melinta Therapeutics Inc Antimicrobial compounds and methods of making and using the same
EP2488502A4 (en) 2009-10-16 2013-05-15 Rib X Pharmaceuticals Inc Antimicrobial compounds and methods of making and using the same
TW201125566A (en) * 2009-10-16 2011-08-01 Rib X Pharmaceuticals Inc Antimicrobial compounds and methods of making and using the same
BR112013026410A2 (en) * 2011-04-15 2017-06-27 Melinta Therapeutics Inc antimicrobial compounds and methods of preparation and use thereof
JP2016529325A (en) 2013-09-09 2016-09-23 メリンタ セラピューティクス，インコーポレイテッド Antimicrobial compounds and methods for their production and use
SG11201601654TA (en) 2013-09-09 2016-04-28 Melinta Therapeutics Inc Antimicrobial compunds and methods of making and using the same
SG11201707346RA (en) 2015-03-11 2017-10-30 Melinta Therapeutics Inc Antimicrobial compounds and methods of making and using the same

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1157611A (en) * 1994-04-28 1997-08-20 普罗克特和甘保尔公司 Novel quinolone 5-(N-heterosubstituted amino) antimicrobials
WO2002048138A1 (en) * 2000-12-14 2002-06-20 The Procter & Gamble Company Antimicrobial quinolones
WO2002097134A2 (en) * 2001-05-25 2002-12-05 Isis Pharmaceuticals, Inc. Modified peptide nucleic acid
CN1867570A (en) * 2003-08-12 2006-11-22 艾其林医药公司 Isothiazoloquinolones and related compounds as anti-infective agents
CN101263146A (en) * 2005-07-27 2008-09-10 艾其林医药公司 8-methoxy-9H-isothiazolo[5,4-B]quinoline-3,4-diones and related compounds as anti-infective agents

Family Cites Families (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3980781A (en) * 1966-03-31 1976-09-14 Imperial Chemical Industries Limited Fungicidal composition and method containing 2-amino-pyrimidines
US3673184A (en) * 1970-09-02 1972-06-27 Dainippon Pharmaceutical Co Certain 2-substituted-5,8-dihydro-5-oxopyrido{8 2,3-d{9 pyrimidine-6-carboxylic acid derivatives
EP0067610A1 (en) * 1981-06-16 1982-12-22 Beecham Group Plc Penicillins, a process for their preparation and compositions containing them
ZA835684B (en) * 1982-08-27 1985-03-27 Roussel Uclaf Imidazo(1,2-a)pyrimidines
IT1197876B (en) * 1986-10-15 1988-12-21 Pharmachim Engineering Srl PROCEDURE FOR THE PREPARATION OF 5,8-DIHYDRO-8-ETHYL-5-BONE-2- (1-PIPERAZINYL) PYRID (2,3-D) PYRIMIDIN-6-CARBOXYLIC
JP2549931B2 (en) * 1990-01-12 1996-10-30 株式会社大塚製薬工場 Pyrimidobenzimidazole derivative
JP2991382B2 (en) * 1990-07-18 1999-12-20 大日本製薬株式会社 Fused tricyclic compounds and salts thereof
US5208141A (en) * 1990-10-09 1993-05-04 Konica Corporation Silver halide color photographic light-sensitive material
JP2811230B2 (en) * 1990-10-17 1998-10-15 コニカ株式会社 New photographic coupler
US6451968B1 (en) * 1991-05-24 2002-09-17 Isis Pharmaceuticals, Inc. Peptide nucleic acids
US5434257A (en) * 1992-06-01 1995-07-18 Gilead Sciences, Inc. Binding compentent oligomers containing unsaturated 3',5' and 2',5' linkages
IT1263804B (en) * 1993-01-22 1996-09-03 Luso Farmaco Inst PYRIMIDINONIC DERIVATIVES MELT WITH NITROGEN HETEROCYCLES ACTIVATED IN II ANTAGONIST
ATE206406T1 (en) * 1993-05-12 2001-10-15 Du Pont FUNGICIDAL CONDENSED BIZYCLIC PYRIMIDINONES
US5502177A (en) * 1993-09-17 1996-03-26 Gilead Sciences, Inc. Pyrimidine derivatives for labeled binding partners
US5668127A (en) * 1995-06-26 1997-09-16 Pathogenesis Corporation Nitroimidazole antibacterial compounds and methods of use thereof
CA2309340C (en) * 1997-11-07 2006-02-21 Isis Pharmaceuticals Inc. Pyrimidine derivatives for labeled binding partners
DE19838998A1 (en) * 1998-08-27 2000-03-09 Bayer Ag New natural product derivatives
SE9903894D0 (en) * 1999-10-28 1999-10-28 New Pharma Research Ab Novel compounds
EP2251015B1 (en) * 2000-10-18 2013-02-20 Gilead Pharmasset LLC Modified nucleosides for the treatment of viral infections and abnormal cellular proliferation
DE10061542A1 (en) * 2000-12-11 2002-06-13 Bayer Ag New alkanoylamino-pyrimidine derivatives used as antibacterial agents, especially for prevention and control of Staphylococcal infections
DE10061538A1 (en) * 2000-12-11 2002-06-20 Bayer Ag New ureido-substituted dihydropyrimidinone derivatives, useful as broad-spectrum antibacterial agents with strong activity against Gram positive bacteria
CA2436665C (en) * 2001-01-29 2012-01-10 Bio-Rad Laboratories, Inc. Nucleic acid derivatives
TWI248936B (en) * 2001-03-21 2006-02-11 Merck Sharp & Dohme Imidazo-pyrimidine derivatives as ligands for GABA receptors
CA2452458A1 (en) * 2001-07-03 2003-01-16 Isis Pharmaceuticals, Inc. Nuclease resistant chimeric oligonucleotides
JP4306206B2 (en) * 2001-09-04 2009-07-29 住友化学株式会社 Imidazo [1,2-a] pyrimidine, its use and production intermediate
GB0205165D0 (en) * 2002-03-06 2002-04-17 Astrazeneca Ab Chemical compounds
WO2004080466A1 (en) * 2003-03-07 2004-09-23 Ribapharm Inc. Cytidine analogs and methods of use
WO2007101871A1 (en) * 2006-03-08 2007-09-13 Basf Se Substituted imidazolopyrimidines, method for the production thereof and use thereof for controlling parasitic fungi and agents containing the latter
US20100112561A1 (en) * 2006-08-25 2010-05-06 Stefan Lutz Fluorescent nucleoside analogues
EP1964841A1 (en) * 2007-02-28 2008-09-03 sanofi-aventis Imidazo[1,2-a]azine and their use as pharmaceuticals
KR20090098710A (en) * 2008-03-14 2009-09-17 주식회사 씨티아이바이오 Peptide nucleic acid derivatives with good cell penetration and affinity for nucleic acid
TW201125566A (en) * 2009-10-16 2011-08-01 Rib X Pharmaceuticals Inc Antimicrobial compounds and methods of making and using the same

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1157611A (en) * 1994-04-28 1997-08-20 普罗克特和甘保尔公司 Novel quinolone 5-(N-heterosubstituted amino) antimicrobials
WO2002048138A1 (en) * 2000-12-14 2002-06-20 The Procter & Gamble Company Antimicrobial quinolones
WO2002097134A2 (en) * 2001-05-25 2002-12-05 Isis Pharmaceuticals, Inc. Modified peptide nucleic acid
CN1867570A (en) * 2003-08-12 2006-11-22 艾其林医药公司 Isothiazoloquinolones and related compounds as anti-infective agents
CN101263146A (en) * 2005-07-27 2008-09-10 艾其林医药公司 8-methoxy-9H-isothiazolo[5,4-B]quinoline-3,4-diones and related compounds as anti-infective agents

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
FRANCOIS DEBAENE ET AL.: ""Expanding the scope of PNA-encoded libraries: divergent synthesis of libraries targeting cysteine, serine and metalloproteases as well as tyrosine phosphatases"", 《TETRAHEDRON》 *
JOSE-ANTONIO ORTEGA ET AL.: ""Binding Affinities of Oligonucleotides and PNAs Containing Phenoxazine and G-Clamp Cytosine Analogues Are Unusually Sequence-Dependent"", 《ORGANIC LETTERS》 *
KALLANTHOTTATHIL G. RAJEEV ET AL.: ""High-Affinity Peptide Nucleic Acid Oligomers Containing Tricyclic Cytosine Analogues"", 《ORGANIC LETTERS》 *
PETER STOSS ET AL.: ""Novel Pyrimidine and Pyrimido[1,2-α]pyrimidine Derivatives. By-products of a Guanidine Based Thymine Synthesis"", 《J. HETEROCYCLIC CHEM.》 *

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