CN101528228A

CN101528228A - Bicyclic heteroaryl inhibitors of PDE4

Info

Publication number: CN101528228A
Application number: CNA2007800330480A
Authority: CN
Inventors: S·P·戈瓦克; A·K·施奥; S·A·诺布勒; D·J·托马斯
Original assignee: Individual
Current assignee: Individual
Priority date: 2006-07-07
Filing date: 2007-07-06
Publication date: 2009-09-09
Also published as: UA98112C2; ZA200900879B

Abstract

The present invention relates to compounds and methods which may be useful as inhibitors of phosphodiesterase 4(PDE4) for the treatment or prevention of inflammatory diseases and other diseases involving elevated levels of cytokines and proinflammatory mediators.

Description

The bicyclic heteroaryl inhibitors of PDE4

The application requires the priority of U.S. Provisional Application of submitting on July 7th, 2,006 60/819,509 and the U.S. Provisional Application of submitting on January 26th, 2,007 60/886,825, and its disclosure is hereby incorporated by reference, as its full content is write this paper.

Disclosed hereinly be effectively and optionally new bicyclic heteroaryl compounds (having found that wherein some can be used as the inhibitor of phosphodiesterase 4 (PDE4)), comprise described compound compositions and they are used for the treatment of the application of disease as medicine.Inhibition PDE4 also is provided active method, and the method that is used for the treatment of the inflammatory diseases and the other diseases of cytokine levels that relates to rising and pro-inflammatory mediator level.

Chronic inflammatory disease is a kind of multifactorial disease complication, it is characterized by the activation of polytype inflammatory cell, the cell of described inflammatory cell such as lymph pedigree (comprising the T lymphocyte) and bone marrow pedigree (comprising granulocyte, macrophage and mononuclear cell).These activating cells produce pro-inflammatory mediator, comprise cytokine, as tumor necrosis factor (TNF) and interleukin-11 (IL-1).Therefore, suppress the activation of these cells or suppress the therapeutic treatment of other diseases that its reagent that produces proinflammatory cytokine can be used for inflammatory diseases and relate to the cytokine levels of rising.

Cyclic adenosine monophosphate (cAMP) is a mediated cell to the second message,second messenger of the biological response of born of the same parents' external stimulus on a large scale.When appropriate agonist combined with the specific cells surface receptor, adenyl cyclase was activated, so that adenosine triphosphate (ATP) is converted into cAMP.Theorize: the cAMP of agonist induction is mainly mediated by the effect of cAMP deopendent protein kinase in intracellular effect.Be transported to effect in extracellular or the cell by being stopped cAMP by cyclic nucleotide phosphodiesterase (PDE) enzymatic lysis by nucleotide, described cyclic nucleotide phosphodiesterase hydrolysis 3 '-phosphodiester bond is to form 5 '-adenylic acid (5 '-AMP).5 '-AMP is the metabolite of non-activity.

The PDE superfamily is subdivided into two big classes: I class and II class, it does not contain discernible sequence similarity.The I class comprises all known mammal PDE, and by 11 tame group compositions through identifying that are the product of independent gene.Some PDE is a high specific for the hydrolysis of AMP (PDE4, PDE7, PDE8), and some is high cGMP specific (PDE5, PDE6, PDE9), and some has blended specificity (PDE1, PDE2, PDE3, PDE10, PDE11).The mammal PDE of all signs is a dimerization, but does not understand the importance of dimeric structure to the function of every kind of PDE.

The PDE4 subfamily is by 4 member composition: PDE4A, PDE4B, PDE4C and PDE4D.These enzymes have the N-terminal adjustment structure territory of inferring the mediation dimerization, and described dimerization causes the PDE activity of optimum adjustment.In addition, regulate activity by the cAMP deopendent protein kinase phosphorylation site in this upstream regulation domain.The PDE4 enzyme has expresses widely and distributes.

In human marrow and lymph pedigree cell, the rising of cAMP level is relevant with the inhibition of cell activation.Therefore, the level that the PDE enzyme family is regulated cAMP in the cell in the born of the same parents.In these cells, PDE4 is a kind of main PDE isoform, and is the main contributor of cAMP degraded.Therefore, the inhibition of PDE function just can stop cAMP to transform to the metabolite 5 '-AMP of non-activity, thereby keeps higher cAMP level, and therefore suppresses cell activation.

Prove that the PDE4 inhibitor suppresses the generation of TNF α, and partly suppress monocytic IL-1 β release and (see people such as Semmler, Int.J.Immunopharmacol., 15, the 409-413 pages or leaves, (1993); People such as Molnar-Kimber, Mediators of Inflammation, 1, the 411-417 page or leaf, (1992)).Also prove, the PDE4 inhibitor suppress from human polymorphonuclear leukocyte produce superoxide radical (referring to people such as Verghese, J.Mol.Cell.Cardiol., 21 (supplementary issues 2), S61 (1989); People such as Nielson, J.Allergy Immunol., 86, the 801-808 pages or leaves, (1990)); Suppress people's basophiloid cell and discharge vasoactive amines and prostaglandins (referring to people such as Peachell, J.Immunol., 148, the 2503-2510 pages or leaves, (1992)); Suppress the respiratory burst (referring to people such as Dent, J.Pharmacol., 103, the 1339-1346 pages or leaves, (1991)) in the acidophil; And the activation (referring to people such as Robicsek, Biochem.Pharmacol., 42, the 869-877 pages or leaves, (1991)) that suppresses human T-lymphocyte.

The generation of the activation of inflammatory cell and excessive or unadjusted cytokine (as TNF α and IL-1 β) relates to following illness: allergia, autoimmune and inflammatory diseases and disease are as rheumatoid arthritis, osteoarthritis, gouty arthritis, spondylitis, thyroid-associated ophthalmopathy, behcet disease (Behcet ' sdisease), sepsis, septic shock, endotoxin shock, gram negative sepsis, gram positive sepsis, toxic shock syndrome, asthma, chronic bronchitis, the adult respiratory distress syndrome, chronic pulmonary inflammatory disease is (as chronic obstructive pulmonary disease, silicosis, pulmonary sarcoidosis), cardiac muscle, the reperfusion injury of brain and epiphysis, fibrosis, cystic fibrosis, keloid forms (keloidformation), cicatrization, atherosclerosis, transplant rejection disease (as graft versus host disease and allograft rejection (allograft rejection)), chronic glomerulonephritis, lupus, inflammatory bowel (as regional enteritis (Crohn ' s disease) and ulcerative colitis), hypertrophy lymphatic disease (as leukemia), ophthalmic diseases (xerophthalmia and the ophthalmalgia that cause as inflammation or operation) and inflammatory dermatosis are (as atopic dermatitis, psoriasis and urticaria).

With the cytokine levels that raises be other illness of feature cachexia of comprising brain injury, cardiomyopathy (as congestive heart failure), cachexia, infection or malignant tumor secondary that the moderate wound causes, acquired immune deficiency syndrome (AIDS) (AIDS) secondary cachexia, ARC (acquired immune deficiency syndrome (AIDS) dependency syndrome), infect that heating myalgia (fever myalgias), cerebral malaria, osteoporosis and the bone absorption disease, the keloid that cause form, scar tissue forms and heating.

In addition, some character of TNF α (as stimulating the collagen enzyme, stimulating that blood vessel takes place in the body, stimulate bone absorption and improve the adhesive capacity of tumor cell to endothelium) meet TNF effect in the growth of cancer and transfer are sent out in the host.TNF α has directly been related to growth and the transfer (referring to people such as Orosz, J.Exp.Med., 177, the 1391-1398 pages or leaves, (1993)) that promotes tumor cell recently.

Research worker is to using the PDE4 inhibitor to show suitable interest as antiinflammatory.Early stage evidence shows that PDE4 suppresses multiple inflammatory cell (as the T cell of mononuclear cell, macrophage, Th-1 pedigree, and granulocyte) is had useful effect.In these cells, the synthetic and/or release of many pro-inflammatory mediators (as cytokine), lipid medium, superoxides and alkamines (as histamine) is weakened by the effect of PDE4 inhibitor.Described PDE4 inhibitor also influences other cell functions, comprising: the granulocyte of T cell proliferation, the response chemical toxicity material integrity that (transmigration) is connected with endotheliocyte in the vascular system of dividing a word with a hyphen at the end of a line.

The design of many PDE4 inhibitor, synthetic and screening have been reported.Methylxanthine as caffeine and theophylline, be first batch of found PDE inhibitor, but these chemical compounds is nonselective with regard to suppressing which kind of PDE.Medicine rolipram (antidepressants) is one of specific PDE 4 inhibitor that are in the news in the first batch, the IC of the inhibition recombinant human PDE4 of its report ₅₀Be about 200nM.

Research worker continues searching and has more selectivity with regard to suppressing PDE4, have the IC lower than rolipram ₅₀And avoid the central nervous system that do not expect (CNS) side effect relevant such as the PDE4 inhibitor of retch, vomiting and sedation with the administration rolipram.In addition, some companies just carry out the clinical trial of other PDE4 inhibitor now.Yet,,, still do not solve as vomiting and central nervous system disorder about the problem of usefulness and adverse side effect.

Therefore, suppress PDE4 and reduce or eliminate the chemical compound of the adverse side effect of being correlated with previous PDE4 inhibitor can be useful in treating allergia and inflammatory diseases and the other diseases relevant with the excessive or unadjusted generation of cytokine (as TNF) for selectivity.In addition, optionally the PDE4 inhibitor can be used for treating and cAMP level that raises or the relevant disease of PDE4 function in the particular target tissue.

Found noval chemical compound and the pharmaceutical composition as antiinflammatory by inhibition PDE4, and method synthetic and the described chemical compound of use, comprise the method for coming inhibition PDE4 in the patient by the described chemical compound of administration.

Herein disclosed is a compounds, found that wherein some is effective in disease for the treatment of the PDE4 mediation and illness, this compounds defines by structural formula I:

Wherein:

A is the optional saturated or aliphatic unsaturated hydrocarbon that replaces or comprises heteroatomic hydrocarbon chain that it has 3-5 atom, forms five to heptatomic ring;

U and V are independently selected from O, N (R ⁷) and SO _q

R ¹And R ²Be independently selected from hydrogen ,-(CH ₂) _sG ¹G ²G ³, acyl group, acyl group alkyl, carboxyalkyl, cyano group alkyl, alkoxyl, alkoxyalkyl, amidoalkyl, amino, alkyl, alkyl alkoxy, aminoalkyl, thiazolinyl, alkynyl, carboxyl, carboxyalkyl, ether, assorted alkyl, haloalkyl, cycloalkyl, cycloalkyl-alkyl, Heterocyclylalkyl, Heterocyclylalkyl alkyl, aralkyl, aryl, guanidine, heteroaryl, heteroarylalkyl, hydrogen and hydroxyalkyl, wherein any one all can randomly be replaced;

S is 0-8;

G ¹Be selected from alkoxyl, amino, acylamino-, carbonyl, hydroxyl, ether, aminoacid and do not exist;

G ²Be selected from alkyl, alkoxyl, amino, aryl, halo, haloalkyl, Heterocyclylalkyl, heteroaryl, carboxyalkyl amino, guanidine, aminoacid and do not exist, wherein any one all can randomly be replaced;

G ³Be selected from alkyl, alkoxyl, amino, hydroxyl, ether, carboxyl, hydroxamic acid, aminoacid, phosphonate ester, phosphamide and do not exist, wherein any one all can randomly be replaced;

R ³And R ⁴Be selected from hydrogen, halogen, alkoxyl and low alkyl group independently of one another;

R ⁵Be selected from-(CR ⁸R ⁹) _mW (CR ¹⁰R ¹¹) _n-and-(CR ¹²R ¹³) _p-;

M, n and q are 0,1 or 2 independently of one another;

P is 1 or 2;

W is selected from O, N (R ⁷), C (O) N (R ⁷) and SO _q

R ⁶Be selected from carboxyl, alkyl carboxyl, acylamino-, aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, alkyl, assorted alkyl, acyl group and hydroxamic acid, wherein any one all can randomly be replaced;

R ⁷, R ⁸, R ⁹, R ¹⁰, R ¹¹, R ¹²And R ¹³Be selected from hydrogen, halogen, hydroxyl, low alkyl group, hydroxyalkyl, haloalkyl, alkoxyl, halogenated alkoxy, amino, aminoalkyl and aminoalkoxy independently of one another; And hydrogen and the optional low alkyl group that replaces.

Some chemical compound of the present invention has useful PDE4 to be suppressed or regulates actively, and can be used for treating or prevents PDE4 wherein to play the disease or the illness of active function.Therefore, aspect widely, certain embodiments of the present invention also provide the pharmaceutical composition that comprises one or more chemical compounds disclosed herein and pharmaceutically acceptable carrier, and preparation and use described chemical compound and method for compositions.Certain embodiments of the present invention provide the method that is used to suppress PDE4.Other embodiments of the present invention provide in the patient of the such treatment of needs the method for the disease of treatment PDE4 mediation, it comprise to described patient's drug treatment effective dose according to chemical compound of the present invention or compositions.Related embodiment discloses the purposes of some chemical compound disclosed herein as therapeutic agent, for example, and the purposes in the other diseases of treatment inflammatory diseases and cytokine levels that relates to rising and pro-inflammatory mediator level.The present invention also is intended to some chemical compound disclosed herein and is used to prepare the purposes that is used for treating by the medicine that suppresses disease that PDE4 improves or illness.

In further embodiment, chemical compound of the present invention has structural formula II

Wherein:

X ¹Be NR ¹⁴

X ²Be selected from C (O), (CR ¹⁵R ¹⁶) and do not exist;

X ³Be selected from C (O), N (R ¹⁷) and (CR ¹⁸R ¹⁹);

S is 0-8;

R ³And R ⁴Be independently selected from hydrogen, halogen, alkoxyl and low alkyl group;

M, n and q are 0,1 or 2 independently of one another;

P is 1 or 2;

W is selected from O, N (R ⁷), C (O) N (R ⁷) and SO _q

R ⁸, R ⁹, R ¹⁰, R ¹¹, R ¹²And R ¹³Be selected from hydrogen and the optional low alkyl group that replaces independently of one another;

R ¹⁴And R ¹⁷Be selected from hydrogen, halogen, hydroxyl, low alkyl group, hydroxyalkyl, haloalkyl, aminoalkyl and key independently of one another; And

R ¹⁵, R ¹⁶, R ¹⁸And R ¹⁹Be selected from hydrogen, halogen, low alkyl group, haloalkyl, alkoxyl, halogenated alkoxy, amino, aminoalkyl, aminoalkoxy and key independently of one another.

In further embodiment, chemical compound of the present invention has structural formula II I

Wherein:

X ¹Be NR ¹⁴

X ²Be selected from C (O) and do not exist;

X ³Be selected from C (O) and (CR ¹⁸R ¹⁹);

S is 1-8;

M, n and q are 0,1 or 2 independently of one another;

P is 1 or 2;

W is selected from O, N (R ⁷), C (O) N (R ⁷) and SO _q

R ⁷And R ¹⁴Be independently selected from hydrogen, halogen, hydroxyl, low alkyl group, hydroxyalkyl, haloalkyl and aminoalkyl; And

In certain embodiments, chemical compound of the present invention has structural formula IV

Wherein:

X ³Be (CR ¹⁸R ¹⁹);

S is 1-8;

R ⁵Be selected from-(CR ⁸R ⁹) _mW (CR ¹⁰R ¹¹) _n-and-(CR ¹²R ¹³) ^p-;

M, n and q are 0,1 or 2 independently of one another;

P is 1 or 2;

W is selected from O, N (R ⁷), C (O) N (R ⁷) and SO _q

R ¹⁸And R ¹⁹Be selected from hydrogen, halogen, low alkyl group, haloalkyl, alkoxyl, halogenated alkoxy, amino, aminoalkyl, aminoalkoxy and key independently of one another.

In further embodiment, chemical compound of the present invention has structural formula V

Wherein:

S is 1-8;

M, n and q are 0,1 or 2 independently of one another;

P is 1 or 2;

W is selected from O, N (R ⁷), C (O) N (R ⁷) and SO _q

R ¹⁹Be selected from hydrogen, halogen, low alkyl group and haloalkyl.

Further providing chemical compound in the embodiment, wherein R ⁷And R ¹⁴Be independently selected from hydrogen, halogen and the optional low alkyl group that replaces.

Further providing chemical compound in the embodiment, wherein R ⁶Be selected from aryl and heteroaryl, any one in described aryl and the heteroaryl all can randomly be replaced.

Further providing chemical compound in the embodiment, wherein R ¹⁹Be hydrogen.

Further providing chemical compound in the embodiment, wherein R ⁶Be selected from phenyl, pyridine, pyrimidine, pyridazine and pyrazine, wherein any one all can randomly be replaced.

Further providing chemical compound in the embodiment, wherein R ⁶Be selected from phenyl, pyridine and pyrimidine, wherein any one all can randomly be replaced.

Further providing chemical compound in the embodiment, wherein R ¹⁴Be hydrogen.

Further providing chemical compound in the embodiment, wherein:

R ⁵Be-(CR ⁸R ⁹) _mW (CR ¹⁰R ¹¹) _n-;

M and n all are 0;

W is N (R ⁷); And

R ⁷Be hydrogen.

Further providing chemical compound in the embodiment, wherein R ⁶Has following formula

Wherein

X ⁴Be CR ²⁰Or N;

X ⁵Be CR ²¹Or N;

X ⁶Be CR ²²Or N;

X ⁷Be CR ²³Or N;

X ⁸Be CR ²⁴Or N;

X wherein ⁴-X ⁸In to be no more than 2 can be N; And

R ²⁰, R ²¹, R ²², R ²³And R ²⁴Be independently selected from hydrogen, halogen, hydroxyl, low alkyl group, lower alkoxy, low-grade halogenated alkyl, elementary halogenated alkoxy, amino and carboxyl.

Further providing chemical compound in the embodiment, wherein R ⁶Have the following formula that is selected from:

Further providing chemical compound in the embodiment, wherein R ²It is low alkyl group.In embodiment further, R ²It is methyl.

Further providing chemical compound in the embodiment, wherein:

R ¹Be selected from-(CH ₂) _sG ¹G ²G ³, low alkyl group, cycloalkyl, cycloalkyl-alkyl and Heterocyclylalkyl, wherein any one all can randomly be replaced;

S is 1-6;

G ¹Be selected from amino, acylamino-and do not exist;

G ²Be selected from alkoxyl, aryl, halo, Heterocyclylalkyl and do not exist, wherein any one all can randomly be replaced; And

G ³Be selected from alkyl, carboxyl and do not exist, wherein any one all can randomly be replaced.

In further embodiment, chemical compound of the present invention has structural formula VI

Wherein:

S is 1-8;

G ³Be selected from alkyl, alkoxyl, amino, hydroxyl, ether, carboxyl, hydroxamic acid, aminoacid, phosphonate ester, phosphamide and do not exist, wherein any one all can randomly be replaced; And

R ²⁰And R ²⁴Be independently selected from hydrogen, halogen, hydroxyl, low alkyl group, lower alkoxy, low-grade halogenated alkyl, elementary halogenated alkoxy, amino and carboxyl.

In embodiment further, chemical compound of the present invention has structural formula VII

Wherein:

S is 1-8;

R ²⁰, R ²²And R ²⁴Be independently selected from hydrogen, halogen, hydroxyl, low alkyl group, lower alkoxy, low-grade halogenated alkyl, elementary halogenated alkoxy, amino and carboxyl.

Chemical compound of the present invention can have selectivity by multiple mode in PDE4 isoform PDE4A, PDE4B, PDE4C and PDE4D.For example, chemical compound described herein can surpass other two kinds of isoforms to the selectivity of PDE4B and PDE4D, can be the full inhibitor (pan-inhibitor) of all isoforms, perhaps can only have selectivity to a kind of isoform.In certain embodiments, The compounds of this invention can surpass other isoforms to the selectivity of PDE4B.

As described herein, the invention still further relates to the method that suppresses at least a PDE4 function, described method comprises the step with the chemical compound contact PDE4 of formula I.Can monitor combining of the expression of variation, PDE4 of the biochemistry output (output) that the activity of cell phenotype, cell proliferation, PDE4, active PDE4 produce or PDE4 and natural binding partners.Such method can be the pattern of disease treatment, bioassay, raji cell assay Raji, biochemical measurement etc.

As used herein, following term has specified implication.

When the scope that discloses value is also used " from n ₁To n ₂" (n wherein ₁And n ₂Be numeral) representation the time, except as otherwise noted, this representation is intended to comprise numeral itself and the scope between them.This scope can be integer or the successive range between end value, and comprises end value.For example, scope " from 2 to 6 carbon " is intended to comprise two, three, four, five and six carbon, because carbon is graduation of whole numbers of units.Contrast, for example, it is intended to comprise the extremely significant digits (for example, 1.255 μ M, 2.1 μ M, 2.9999-etc.) of any figure place of 1 μ M, 3 μ M and all numerals betwixt scope " from 1 to 3 μ M (micromole), ".

As used herein, term " about " is intended to limit the numerical value of its modification, shows that such value is the variable in the range of error.When special range of error is not described in detail in detail, during as given standard error of the mean in datagram or table, term " about " is interpreted as representing to comprise the scope of described value, and considers significant digits, can be by the included scope of the last round down of numeral (rounding up or down).

As used herein, term " acyl group " is independent or making up the carbonyl that middle finger is connected to thiazolinyl, alkyl, aryl, cycloalkyl, heteroaryl, Heterocyclylalkyl or any other group, and the atom that wherein is connected to described carbonyl is a carbon." acetyl group " (acyl group a kind of) refers to-C (O) CH ₃Group." alkyl-carbonyl " or " alkanoyl " refers to be connected to by carbonyl the alkyl of parent molecule group.Such examples of groups comprises methyl carbonyl and ethyl carbonyl.The example of acyl group comprises formoxyl, alkanoyl and aroyl.

As used herein, term " thiazolinyl " is independent or making up the straight or branched alkyl that middle finger has one or more pairs of keys and comprises 2 to 20 carbon atoms.In certain embodiments, described thiazolinyl can comprise 2 to 6 carbon atoms.Term " alkenylene " refers to be connected the carbon-carbon double bond system of two or more positions, as ethenylidene [(CH=CH-), (C::C-)].The example of suitable thiazolinyl comprises vinyl, acrylic, 2-methylpropenyl, 1,4-butadienyl etc.Except as otherwise noted, term " thiazolinyl " can comprise " alkenylene " group.

As used herein, term " alkoxyl " is separately or at combination middle finger alkyl ether groups, wherein the term alkyl such as hereinafter definition.The example of suitable alkyl ether groups comprises methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy etc.

As used herein, term " alkyl " is independent or making up the straight or branched alkyl that middle finger contains 1 to 20 carbon atom.In certain embodiments, described alkyl can comprise 1 to 10 carbon atom.In further embodiment, described alkyl can comprise 1 to 6 carbon atom.Alkyl can randomly be substituted as defined herein.The example of alkyl comprises methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, isopentyl, hexyl, octyl group, nonyl (noyl) etc.As used herein, term " alkylidene " is connected the saturated aliphatic groups derived from the straight or branched saturated hydrocarbons of two or more positions separately or at the combination middle finger, as methylene (CH ₂-).Except as otherwise noted, term " alkyl " can comprise " alkylidene " group.

As used herein, term " alkyl amino " is independent or making up middle finger is connected to the parent molecule group by amino alkyl.Suitable alkyl amino can be list or dialkyl groupization, forms such as for example N-methylamino, N-ethylamino, N, N-dimethylamino, N, the group of N-ethylmethylamino etc.

As used herein, term " alkylidene (alkylidene) " separately or the combination middle finger wherein a carbon atom of carbon-carbon double bond belong to the thiazolinyl of the group that thiazolinyl connects.

As used herein, term " alkylthio group " is separately or at combination middle finger alkyl thioether (R-S-) group, wherein the term alkyl as hereinbefore defined, and wherein said sulfur can be by single or dual oxidation.The example of suitable alkyl sulfide ether comprises methyl mercapto, ethylmercapto group, positive rosickyite base, iprotiazem base, positive butylthio, isobutyl sulfenyl, secondary butylthio, uncle's butylthio, mesyl, ethylsulfonyl etc.

As used herein, term " alkynyl " separately or be the straight or branched alkyl that contains one or more triple bonds and contain 2 to 20 carbon atoms in combination.In certain embodiments, described alkynyl comprises 2 to 6 carbon atoms.In further embodiment, described alkynyl comprises 2 to 4 carbon atoms.Term " alkynylene " refers to be connected the carbon carbon triple bond of two positions, as ethynylene (C:::C-,-C ≡ C-).The example of alkynyl comprises acetenyl, propinyl, hydroxypropyn base, butine-1-base, crotonylene-Ji, pentyne-1-base, 3-methyl butine-1-base, hexin-2-base etc.Except as otherwise noted, term " alkynyl " can comprise " alkynylene " group.

As used herein, term " acylamino-" and " carbamoyl " are connected to the amino as mentioned below of parent molecule group by carbonyl separately or at the combination middle finger, or vice versa.As used herein, term " C-acylamino-" separately or combination middle finger-C (=O)-N (R) ₂Group, wherein R as defined herein.As used herein, (=O) N (R ')-group, wherein R and R ' are as defined herein separately or at combination middle finger RC for term " N-acylamino-".As used herein, term " acyl amino " separately or comprise the acyl group that is connected to precursor group by amino in combination." acyl amino " examples of groups is acetylamino (CH ₃C (O) NH-).

As used herein, term " amino " separately or combination middle finger-N (R) (R ') or-N ⁺(R) (R ') (R "), wherein R, R ' and R " be independently selected from hydrogen, alkyl, acyl group, assorted alkyl, aryl, cycloalkyl, heteroaryl and Heterocyclylalkyl, wherein any one can randomly be replaced itself.

As used herein, term " aminoacid " is separately or in combination middle finger form-substituent group of NRCH (R ') C (O) OH, wherein R is generally hydrogen, but can with N cyclisation (as situation) at amino proline, and R ' is selected from hydrogen, alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, amino, acylamino-, cycloalkyl-alkyl, Heterocyclylalkyl alkyl, aryl alkyl, heteroaryl alkyl, aminoalkyl, amidoalkyl, hydroxyalkyl, mercaptan, alkylthio, alkylthio alkyl and alkylthio group, and wherein any one can randomly be replaced.Term " aminoacid " comprises all naturally occurring aminoacid and synthetic analog.

As used herein, term " aryl " contains the carbocyclic aromatic system of one, two or three ring separately or at the combination middle finger, and wherein such ring can link together or can be condensed by the side chain mode.Term " aryl " comprises the aromatic group as benzyl, phenyl, naphthyl, anthryl, phenanthryl, indanyl, indenyl, wheel thiazolinyl, Flos Chrysanthemi cyclic group, tetralyl and xenyl.

As used herein, term " aryl alkenyl " or " arylalkenyl " are independent or making up middle finger is connected to the parent molecule group by thiazolinyl aryl.

As used herein, term " alkoxy aryl " or " aralkoxy " are independent or making up middle finger is connected to the parent molecule group by alkoxyl aryl.

As used herein, term " aryl alkyl " or " aralkyl " are independent or making up middle finger is connected to the parent molecule group by alkyl aryl.

As used herein, term " aromatic yl polysulfide yl " or " sweet-smelling alkynyl " are independent or making up middle finger is connected to the parent molecule group by alkynyl aryl.

As used herein; term " aromatic yl silane terephthalamide yl " or " aralkanoyl " or " aroyl " separately or the acyl group of the alkanecarboxylic acid (alkanecarboxylic acid) that replaces derived from aryl at the combination middle finger, as benzoyl, naphthoyl, phenylacetyl group, 3-hydrocinnamoyl (hydrocinnamoyl), 4-benzene bytyry, (2-naphthyl) acetyl group, 4-chlorine hydrocinnamoyl etc.

As used herein, term aryloxy is independent or making up middle finger is connected to the parent molecule group by oxygen aryl.

As used herein, term " benzo (benzo and benz) " is independent or making up the divalent group C of middle finger derived from benzene ₆H ₄=.Example comprises benzothiophene and benzimidazole.

As used herein, (NHCOO-), it can be connected to the parent molecule group from nitrogen or sour end to term " carbamate ", and it can randomly be substituted as defined herein separately or at the carbamic ester of combination middle finger.

As used herein, term " O-carbamoyl " separately or at combination middle finger-OC (O) NRR ' group, wherein R and R ' are as defined herein.

As used herein, term " N-carbamoyl " separately or at combination middle finger ROC (O) NR '-group, wherein R and R ' are as defined herein.

As used herein, term " carbonyl " comprises formoxyl [C (O) H] when using separately, when using in combination is-C (O)-group.

As used herein, term " carboxyl " refers to-C (O) OH, O-carboxyl, C-carboxyl or corresponding " carboxylate radical " anion (as in carboxylate)." O-carboxyl " group refers to RC (O) O-group, and wherein R as defined herein." C-carboxyl " group refers to-C (O) OR group that wherein R as defined herein.

As used herein, term " cyano group " is independent or making up middle finger-CN.

As used herein, term " cycloalkyl ", or " carbocyclic ring " separately or monocycle, dicyclo or the tricyclic alkyl of or fractional saturation saturated at the combination middle finger alternatively, wherein each cyclic group contains 3 to 12 carboatomic ring members, and it can be randomly be randomly substituted fused benzo ring system as herein defined.In certain embodiments, described cycloalkyl can comprise 5 to 7 carbon atoms.The example of such cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, octahydro naphthyl, 2,3-dihydro-1H-indenyl, adamantyl etc.As used herein, " dicyclo " and " three rings " all is intended to comprise two kinds of condensed ring systems (as decahydronaphthalenes, octahydro-naphthalene) and multi-ring (multicenter) saturated or unsaturated type of part.Generally being illustrated as of the isomer of back one type: dicyclo [1,1,1] pentane, Camphora, diamantane (obsolete) and dicyclo [3,2,1] octane.

As used herein, term " ester " is independent or making up two carboxyls at the groups of carbon atom place connection of middle finger bridge joint.

As used herein, term " ether " separately or refer generally to the oxygen bases of two groups that connect at the carbon atom place of bridge joint in combination." ether " can also comprise polyethers, such as for example-RO (CH ₂) ₂O (CH ₂) ₂O (CH ₂) ₂OR ' ,-RO (CH ₂) ₂O (CH ₂) ₂OR ' ,-RO (CH ₂) ₂OR ' and-RO (CH ₂) ₂OH.

As used herein, term " halo " or " halogen " are independent or making up middle finger fluorine, chlorine, bromine or iodine.

As used herein, term " halogenated alkoxy " is independent or making up middle finger is connected to the parent molecule group by oxygen atom haloalkyl.

As used herein, term " haloalkyl " is had an above alkyl of defined implication by what halogen replaced separately or at wherein one or more hydrogen of combination middle finger.Specifically comprise single haloalkyl, dihalo alkyl and multi-haloalkyl.For example, single haloalkyl can have iodine, bromine, chlorine or a fluorine atom in group.Dihalo and multi-haloalkyl can have the combination of two or more identical halogen atoms or different halo group.The example of haloalkyl comprises methyl fluoride, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl group, seven fluoropropyls, difluoro chloromethyl, dichlorofluoromethyl, two fluoro ethyls, two fluoropropyls, Dichloroethyl and two chloropropyls." halo alkylidene " refers to the haloalkyl in the connection of two or more positions.Example comprises fluorine methylene (CFH-), difluoro methylene (CF ₂-), the chlorine methylene (CHCl-) etc.

As used herein, term " assorted alkyl " is saturated fully or contain 1 to 3 degree of unsaturation separately or at the combination middle finger, carbon atom and one to three stable straight or branched or cyclic hydrocarbon group that the hetero atom that is selected from O, N and S is formed by defined amount, or its combination, and wherein nitrogen and sulphur atom can be randomly oxidized, and nitrogen heteroatom can be randomly by quaternized.Hetero atom O, N and S can place any interior location of assorted alkyl.Go up to two hetero atoms and can link to each other, such as for example ,-CH ₂-NH-OCH ₃The assorted alkyl of term can comprise ether.

As used herein, term " heteroaryl " separately or combination 3 to 7 yuan of unsaturated assorted monocycles of middle finger or wherein at least one condensed ring be undersaturated fused polycycle, wherein at least one atom is selected from O, S and N.In certain embodiments, described heteroaryl can comprise 5 to 7 carbon atoms.This term also comprises the fused polycycle group, heterocyclic radical and aryl-condensed wherein, and wherein heteroaryl and other are heteroaryl-condensed, perhaps heteroaryl and Cycloalkylfused wherein.The example of heteroaryl comprises pyrrole radicals, pyrrolinyl, imidazole radicals, pyrazolyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, triazolyl, pyranose, furyl, thienyl oxazolyl isoxazolyl oxadiazole base, thiazolyl, thiadiazolyl group, isothiazolyl, indyl, isoindolyl, the indolizine base, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolyl, indazolyl, the benzotriazole base, the benzo dioxolyl, benzopyranyl benzoxazolyl Ben Bing oxadiazole base, benzothiazolyl, the diazosulfide base, benzofuranyl, benzothienyl, the chromone base, the coumarin base, benzopyranyl, tetrahydric quinoline group, the tetrazolo pyridazinyl, tetrahydro isoquinolyl, the thienopyridine base, the furo pyridine radicals, pyrrolopyridinyl etc.Exemplary tricyclic heterocyclic group comprises carbazyl, benzindole base (benzidolyl), phenanthroline base, dibenzofuran group, acridinyl, phenanthridinyl, xanthyl etc.

As used herein, term " Heterocyclylalkyl " and " heterocycle " interchangeably separately or in combination, all refer to contain at least one hetero atom as ring members saturated, part is undersaturated or complete undersaturated monocycle, dicyclo or tricyclic heterocyclic base, wherein each described hetero atom can be independently selected from nitrogen, oxygen and sulfur.In certain embodiments, described Heterocyclylalkyl can comprise 1 to 4 hetero atom as ring members.In further embodiment, described Heterocyclylalkyl can comprise 1 to 2 heteroatomic ring member.In certain embodiments, described Heterocyclylalkyl can comprise 3 to 8 ring memberses in each ring.In further embodiment, described Heterocyclylalkyl can comprise 3 to 7 ring memberses in each ring.In embodiment further, described Heterocyclylalkyl can comprise 5 to 6 ring memberses in each ring." Heterocyclylalkyl " and " heterocycle " is intended to comprise sugar, sulfone, sulfoxide, uncle's azo-cycle member's N-oxide and the carbocyclic ring condensed ring system fused benzo ring system that unifies; In addition, two terms also include the system that heterocycle is fused to aryl (as defined herein) or another heterocyclic radical.The example of Heterocyclylalkyl comprises '-aziridino, azetidine base, 1,3-benzo dioxolyl, dihydro-iso indolyl, dihydro-isoquinoline base, dihydro cinnolines base, dihydrobenzo bioxin base, dihydro [1,3] oxazoles also [4,5-b] pyridine radicals, benzothiazolyl, indolinyl, dihydropyridine base, 1,3-alkyl dioxin, 1,4-alkyl dioxin, 1,3-dioxolanyl, isoindoline base, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydro pyridyl, piperidyl, tetrahydro-1,4-thiazine base etc.Unless clearly forbid, described Heterocyclylalkyl can randomly be replaced.

As used herein, term " diazanyl " passes through singly linked two amino separately or at the combination middle finger, promptly-and N-N-.

As used herein, term " hydroxamic acid " separately or at combination middle finger-C (O) ON (R) O (R '), wherein R and R ' perhaps refer to corresponding " hydroxamic acid root " anion as defined herein, comprise any corresponding hydroxamate.

As used herein, term " hydroxyl " is independent or making up middle finger-OH.

As used herein, term " hydroxyalkyl " is independent or making up middle finger is connected to the parent molecule group by alkyl hydroxyl.

As used herein, term " imino group " is independent or making up middle finger=N-.

As used herein, term " imino group hydroxyl " separately or combination middle finger=N (OH) and=N-O-.

Term " isocyanate group " refers to-the NCO group.

Term " isothiocyanic acid base " refers to-the NCS group.

Phrase " straight chain of atom " refers to be independently selected from the long linear of the atom of carbon, nitrogen, oxygen and sulfur.

As used herein, term " rudimentary " contains 1 to 6 and comprise 6 carbon atoms separately or at the combination middle finger.

As used herein, term " sulfydryl " separately or at combination middle finger RS-group, wherein R as defined herein.

As used herein, term " nitro " is independent or making up middle finger-NO ₂

As used herein, term " oxygen base " or " oxa-" are independent or making up middle finger-O-.

As used herein, term " oxo " is independent or making up middle finger=O.

Term " perhalogeno alkoxyl " refers to the alkoxyl that all hydrogen atoms are all replaced by halogen atom.

As used herein, term " whole haloalkyl " is separately or at the combination middle finger alkyl that all replaced by halogen atom of all hydrogen atoms wherein.

As used herein, term " phosphamide " is independent or making up wherein one or more hydroxyls of middle finger by the bound phosphate groups of nitrogen, amino or acylamino-replacement [(OH) ₂P (O) O-].

As used herein; term " phosphonate ester " is independent or making up (OR) group of O-form of middle finger ROP (OR '); wherein R and R ' are selected from hydrogen, alkyl, acyl group, assorted alkyl, aryl, cycloalkyl, heteroaryl and Heterocyclylalkyl, and wherein any one can randomly be replaced itself." phosphonate ester " comprises that " phosphate ester [(OH) ₂P (O) O-] but with the relevant salifiable phosphate anion of shape.

As used herein, term " sulphonic acid ester (sulfonate) ", " sulfonic acid " and " (sulfonic) of sulfonic acid " are separately or at combination middle finger-SO ₃H group and the anion when sulfonic acid is used to form salt thereof.

As used herein, term " sulfane base " is independent or making up middle finger-S-.

As used herein, term " sulfinyl " separately or combination middle finger-S (O)-.

As used herein, term " sulfonyl " is independent or making up middle finger-S (O) ₂-.

Term " N-sulfonamido " refer to RS (=O) ₂NR '-group, wherein R and R ' are as defined herein.

Term " S-sulfonamido " refer to-S (=O) ₂NRR ' group, wherein R and R ' are as defined herein.

As used herein, term " thia " and " sulfenyl (thio) " separately or combination middle finger-S-group or wherein oxygen by the alternate ether of sulfur.The oxidized derivatives that comprises sulfenyl in the definition of thia and sulfenyl, i.e. sulfinyl and sulfonyl.

As used herein, term " mercaptan " is independent or making up middle finger-SH group.

As used herein, term " thiocarbonyl " comprises thioformyl-C (S) H when using separately, when being used in combination is-C (S)-group.

Term " N-thiocarbamoyl " refers to ROC (S) NR '-group, and wherein R and R ' are as defined herein.

Term " O-thiocarbamoyl " refers to-OC (S) NRR ' group, and wherein R and R ' are as defined herein.

Term " thiocyano " refers to-the CNS group.

Term " three halo methanesulfonamidos " refers to X ₃CS (O) ₂The NR-group, wherein X be halogen and R as defined herein.

Term " three halo mesyls " refers to X ₃CS (O) ₂-group, wherein X is a halogen.

Term " three halogenated methoxies " refers to X ₃The CO-group, wherein X is a halogen.

Silicone group as used herein, that term " trisubstituted silicyl " group independent or that listed under the substituted-amino definition by this paper in its three free valencys of combination middle finger replaces.Example comprises trimethyl silyl, uncle's fourth dimetylsilyl, triphenyl silicyl etc.

Any definition of this paper can be used to describe the composite construction group with any other combinations of definitions.By convention, the ending element of any such definition all is connected to precursor group.For example, compound group alkyl amido can be represented the alkyl that is connected to parent molecule by acylamino-, and the term alkoxyalkyl can be represented the alkoxyl that is connected to parent molecule by alkyl.

When group was defined as " not existing ", the meaning was not have described group.The group that appears at " not existing " between two other groups also can be understood as the fracture of side-chain radical.For example, if at-(CH ₂) _sG ¹G ²G ³In, element G ²Do not exist, then described group can be-(CH ₂) _sG ¹G ³

Term " randomly replaces " and refers to that previous group can be substituted or not be substituted.When being substituted; the substituent group of " optional replacement " group can include but not limited to, the independent or one or more substituent groups that are independently selected from following group or one group of specially appointed group in combination: low alkyl group; low-grade alkenyl; low-grade alkynyl; the rudimentary assorted alkyl of low-grade alkane acidyl; rudimentary Heterocyclylalkyl; low-grade halogenated alkyl; the lower halogenated thiazolinyl; the lower halogenated alkynyl; rudimentary whole haloalkyl; rudimentary perhalogeno alkoxyl; low-grade cycloalkyl; phenyl; aryl; aryloxy group; lower alkoxy; elementary halogenated alkoxy; oxo; low-grade acyloxy; carbonyl; carboxyl; lower alkylcarbonyl; low-carbon carboxylate; rudimentary amide groups (lowercarboxamido); cyano group; hydrogen; halogen; hydroxyl; amino; low-grade alkyl amino; arylamino; acylamino-; nitro; mercaptan; lower alkylthio; the lower halogenated alkylthio group; rudimentary perhalogeno alkylthio group; arylthio; sulphonic acid ester; sulfonic acid; three replace silicyl; N ₃, SH, SCH ₃, C (O) CH ₃, CO ₂CH ₃, CO ₂H, pyridine radicals, thiophene, furyl, rudimentary carbamate and rudimentary urea.Two substituent groups can be joined together to form condensed five, six or seven-element carbon ring or by zero heterocycle of forming to three hetero atoms, for example form methylene-dioxy or ethylenedioxy.The optional group that replaces can be unsubstituted (for example-CH ₂CH ₃), replace fully (for example-CF ₂CF ₃), mono-substituted (for example-CH ₂CH ₂F) or between replace fully and the replacement of any level between single the replacement (as-CH ₂CF ₃).If replacement is not limited when enumerating substituent group, then replacement and not replacement form include interior.When the qualification substituent group is " replacement ", then mean the replacement form especially.In addition, can be as required at special groups definition on the same group optional substituent group not; Under these kinds situation, described optional substituent group will be as defined usually directly phrase " randomly by ... replace " in.

Unless otherwise indicated, occur alone and do not have digital specified term R and term R ' to refer to be selected from the group of hydrogen, hydroxyl, halogen, alkyl, cycloalkyl, assorted alkyl, aryl, heteroaryl and Heterocyclylalkyl (wherein any one can randomly be replaced).As defined herein, such R and R ' group are interpreted as randomly being replaced.No matter whether the R group has specified numeral, each R group (comprises R, R ' and R ⁿ, wherein n=(1,2,3 ... n)), each substituent group and each term all be interpreted as being independent of selection every other in the group.If surpassing once appears in molecular formula or universal architecture in any variable, substituent group or term (for example: aryl, heterocycle, R etc.), then it is independent of its definition in other appearance in each definition that occurs.Those skilled in the art can further understand, and some group can be connected to parent molecule from any end that is write down maybe can occupy position the element chain.Therefore, only as an example, asymmetric group is as-C (O) N (R)-can be connected to precursor group on carbon or nitrogen.

In chemical compound of the present invention, there is asymmetric center.Specify by symbol " R " or " S " according to the substituent configuration around the chiral carbon atom at these centers.Be appreciated that to the present invention includes all stereochemistry heterogeneous forms, comprise diastereo-isomerism, enantiomerism and epimerism form, and d-isomer and l-isomer, and their mixture.The single stereoisomer of chemical compound can be from the commercially available synthetic preparation of raw material that contains chiral centre, or by preparation enantiomer mixture of products, separate then, as the mixture that changes into diastereomer then by separation or recrystallization, chromatographic technique, on chiral chromatographic column, directly separate enantiomer or other suitable methods known in the art and prepare.Specific stereochemical initial compounds is commercially availablely maybe can and split by technology known in the art preparation.In addition, can there be geometric isomer in chemical compound of the present invention.The present invention includes all cis (cis), trans (trans), (E) and homonymy (zusammen) (Z) isomer and their suitable mixture along (syns), anti-(anti), heteropleural (entgegen).In addition, chemical compound can exist by tautomer, comprises the ketoenol tautomerization body; The invention provides all tautomers.For example, following tautomer any two kinds of forms to having illustrated that this paper takes notice of:

In addition, chemical compound of the present invention can exist by the non-solvent form and with the solvation form of pharmacy acceptable solvent (as water, ethanol etc.).Usually, with regard to purpose of the present invention, think that the solvation form is equal to the non-solvent form.

Term " key " refers to covalently bound between two atoms or two groups (when the atom that connects by described key is considered to the part of big substructure).Except as otherwise noted, key can be singly-bound, two key and triple bond.Can there be or exist extra key in dotted line indication in the molecule diagram between two atoms in this position.

As used herein, term " disease " mean usually and term " disease " and " illness " (as in medical disorder) synonym, and can exchange with it, because it all reflects the abnormal conditions of a part of health or health, described abnormal conditions are damaged normal function, and manifest by distinguishing S﹠S usually.

Term " combined therapy " shows medicine two or more therapeutic agents, to treat therapeutic illness and the disease of describing in disclosure book.Such administration comprises these therapeutic agents of mode co-administered with the basic while, as single capsule with active component with fixed proportion, or with a plurality of, the isolating capsule of every kind of active component.In addition, such administration also comprises and uses every type therapeutic agent in a sequential manner.In both cases, therapeutic scheme can provide the useful influence of drug regimen in treatment illness as herein described and disease.

When " PDE4 inhibitor " used herein refers to that the PDE4 that summarizes hereinafter measures in measuring, the IC that shows at the PDE4 activity ₅₀Be no more than about 100 μ M and more generally be no more than the chemical compound of about 50 μ M." IC ₅₀" be the inhibitor concentration of the activity of enzyme (as PDE4) being reduced to half maximum level.Found that some representative compounds of the present invention shows the inhibitory action at PDE4.In certain embodiments, in the measurement that PDE4 as herein described measures, chemical compound can show the IC that is no more than about 10 μ M at PDE4 ₅₀In further embodiment, chemical compound can show the IC that is no more than about 5 μ M at PDE4 ₅₀In embodiment further, chemical compound can show the IC that is no more than about 1 μ M at PDE4 ₅₀In embodiment further, chemical compound can show the IC that is no more than about 200nM at PDE4 ₅₀

Term " treatment effectively " is intended to be defined for the amount of the active component for the treatment of disease or disease.This amount can realize alleviating or eliminating the target of described disease and disease.

As used herein, mention that patient's " treatment " is intended to comprise prevention.Term " patient " refers to comprise all human mammals.Patient's example comprises the mankind, cattle, Canis familiaris L., cat, goat, sheep, pig and rabbit.Preferably, described patient is human.

Term " prodrug " refers to the more activated chemical compound that becomes in vivo.Some The compounds of this invention also can be used as prodrug and exists, as Hydrolysis in Drug and Prodrug Metabolism:Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M.Wiley-VHCA, Zurich, Switzerland 2003) described in.The prodrug of chemical compound as herein described is the structural modification form of described chemical compound, and it experiences chemical change easily so that described chemical compound to be provided under physiological condition.In addition, prodrug can be converted into described chemical compound by chemistry or biochemical method in the environment that exsomatizes.For example, when placing transdermal patch bank (reservoir) with suitable enzyme or chemical reagent, prodrug can slowly be converted into chemical compound.Prodrug is normally useful, because in some cases, they are than described chemical compound or the easier administration of parent drug.For example, they can biological utilisation by oral administration, and parent drug then is not.Prodrug can also have the dissolubility above the improvement of parent drug in pharmaceutical composition.Known multiple prodrug derivant in this area, as depend on those of prodrug hydrolytic scission or oxidized activating.The limiting examples of prodrug is as ester (described " prodrug ") administration, but then is hydrolyzed to carboxylic acid by metabolism, i.e. its active entity.Other example comprises the peptide radical derivative of chemical compound.Term " treatment acceptable prodrugs " refers to be suitable for contacting patient tissue and do not produce undue toxicity, stimulation and anaphylaxis, with rational benefit/risk ratio quite and for effective prodrug of their desired use or amphion.

Chemical compound of the present invention can be used as the acceptable salt of treatment and exists.The present invention includes the salt form of the above-mentioned chemical compound of enumerating, comprise acid-addition salts.Suitable salt comprises and salt organic and that mineral acid forms.Such acid-addition salts generally can be that pharmacy is acceptable.Yet the salt of the acceptable salt of non-pharmacy can be used to prepare the chemical compound of discussing with purification.Also can form base addition salts, and be that pharmacy is acceptable.About the preparation of salt and the more complete discussion of selection, referring to PharmaceuticalSalts:Properties, Selection, and Use (Stahl, P.Heinrich.Wiley-VCHA, Zurich, Switzerland, 2002).

As used herein, the salt or the zwitterionic form of term " is treated acceptable salt " representative chemical compound of the present invention, it is oil-soluble or dispersible and treat acceptable (as defined herein) for water.Described salt can be in the last separation of chemical compound and purge process or the suitable chemical compound by making free alkali form and suitable acid reaction prepare individually.Representational acid-addition salts comprises acetate, adipate, alginate, the L-Ascorbate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, camphorate, camsilate, citrate, digluconate (digluconate), formates, fumarate, gentisate, glutarate, glycerophosphate, oxyacetate, Hemisulphate (hemisulfate), enanthate, caproate, hippurate, hydrochlorate, hydrobromate, hydriodate, 2-isethionate (isethionate), lactate, maleate, malonate, the DL-mandelate, sym-toluenesulfonic acid salt (mesitylenesulfonate), mesylate, inferior naphthalene sulfonate, nicotinate, the 2-naphthalene sulfonate, oxalates, pamoate, pectate (pectinate), persulfate, 3-phenylpropionic acid salt, phosphonate, picrate, Pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, the L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, Glu, bicarbonate, tosilate (p-toluene fulfonate) and undecylate.And the basic group in the The compounds of this invention can be quaternized by following group: methyl, ethyl, propyl group and butyl chloride, bromide and iodide; Dimethyl, diethyl, dibutyl and diamyl sulfate; Decyl, dodecyl, myristyl and steroid base chloride, bromide, iodide; And benzyl and phenethyl bromination thing.The example that can be used to form the acid of treatment acceptable addition salt comprises mineral acid example hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid, and organic acid such as oxalic acid, maleic acid, succinic acid and citric acid.Also can form salt by the coordination of chemical compound and alkali metal or alkaline earth ion.Therefore, present invention includes sodium salt, potassium salt, magnesium salt and the calcium salt etc. of chemical compound disclosed herein.

Base addition salts can be in the last separation of chemical compound and purge process prepares by making carboxyl and suitable alkali (as hydroxide, carbonate or the bicarbonate of metal cation) or reacting with ammonia or organic primary amine, secondary amine or tertiary amine.The cation for the treatment of acceptable salt comprises lithium, sodium, potassium, calcium, magnesium and aluminum, and nontoxic quaternary ammonium cation such as ammonium, tetramethylammonium, etamon, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethamine, tri-n-butylamine, pyridine, N, accelerine, N-methyl piperidine, N-methylmorpholine, hexanamine, procaine, dibenzylamine, N, N-dibenzyl phenethylamine, 1-ephenamine and N, N '-Dibenzylethylenediamine.Other representational organic amines that are used to form base addition salts comprise ethylenediamine, ethanolamine, diethanolamine, piperidines and piperazine.

Though chemical compound of the present invention may also may provide them as pharmaceutical preparation as the administration of original state chemicals.Therefore, provided herein is to comprise one or more some chemical compounds of the present invention, or the acceptable salt of its one or more pharmacy, ester, prodrug, amide or solvate, and the pharmaceutical preparation of their one or more pharmaceutically acceptable carriers and one or more other treatment compositions of choosing wantonly.Compatible with other compositions of described preparation and to the harmless meaning of its receiver on, described carrier must be " acceptable ".Appropriate formulation depends on the administration path of selection.Any technology of knowing, carrier and excipient all can be used as using that this area is suitable and understand; As in Remington ' sPharmaceutical Sciences.Pharmaceutical composition disclosed herein can be by any way production known in the art, as by conventional mixing, dissolving, granulation, manufacturing lozenge (dragee-making), porphyrize, emulsifying, encapsulated, embedding or compression (compression) process.

Described preparation comprises those that are suitable for oral, parenteral (comprising in subcutaneous, Intradermal, intramuscular, intravenous, intraarticular and the marrow), intraperitoneal, through mucous membrane, percutaneous, rectum and part (comprising skin, buccal, Sublingual and ophthalmic) administration, although only path for example can be dependent on, receiver's illness and disease.Described preparation can present with unit dosage form easily and can be by any known method preparation of pharmaceutical field.Usually, these methods comprise the associating step of carrier that makes chemical compound of the present invention or the acceptable salt of its pharmacy, ester, amide, prodrug or solvate (" active component ") and form one or more auxiliary agents.Usually, described preparation prepares by the following method: the solid carrier of active component and liquid-carrier or segmentation or both whiles evenly and are nearly associated, then, if desired, described product is made the preparation that needs.

The preparation of the present invention that is suitable for oral administration can be made discrete unit, as capsule, cachet or the tablet of the active component that contains scheduled volume separately; As powder or granule; As solution in liquid, aqueous or on-aqueous liquid or suspensoid; Or as oil-in-water liq Emulsion or water-in-oil type liquid emulsion.Described active component can also be made and inject agent (bolus), electuary (electuary) or paste.

The pharmaceutical preparation that can orally use comprises sucking fit formula (push-fit) capsule of tablet, gelatin preparation and by the soft capsule of the sealing of gelatin and plasticizer (as glycerol or sorbitol) preparation.Can randomly prepare tablet by compression or molding with one or more auxiliary agents.Compressed tablets can be by compression in suitable machine randomly with binding agent, inert diluent or lubricant, surfactant or dispersant, the active component of free-flowing form (as powder or granule) prepares.Molded tablet can prepare by the mixture of molding in suitable machine with the moistening powdered compounds of inert liquid diluent.Described tablet can randomly also can be prepared so that the wherein slow release or the controlled release of active component to be provided by coating or indentation (scored).The preparation of all oral administrations should be suitable for such administration on dosage.Described sucking fit formula capsule can comprise active component and filler (as lactose), binding agent (as starch) and/or lubricant (as Talcum or magnesium stearate), and and the mixture of optional stabilizing agent.In soft capsule, reactive compound can dissolve or be suspended in (as fatty oil, liquid paraffin or liquid polyethylene glycol) in the suitable liquid.In addition, can add stabilizing agent.Provide suitable coating to the ingot core.For this reason, can use concentrated sugar solution, it can randomly comprise arabic gum, Talcum, polyvinylpyrrolidone, carbopol gel, Polyethylene Glycol and/or titanium dioxide, lacquer solution and appropriate organic solvent or solvent mixture.Can in tablet or lozenge coating, add dyestuff or pigment to differentiate or to characterize the various combination of active compound doses.

Described chemical compound can be formulated into by injection (as by injecting fast or continuous infusion) and carry out parenteral.The preparation that is used to inject can be made unit dosage form with the antiseptic that adds, as in ampoule or in multi-dose container.Described compositions can adopt as suspensoid, solution or Emulsion form in oiliness or aqueous carrier (vehicle), and can comprise preparaton such as suspending agent, stabilizing agent and/or dispersant.Described preparation can be formed in unit dose or the multi-dose container, for example Mi Feng ampoule and bottle, and can store by powder type or lyophilization (lyophilizing) state, its needs directly add sterile liquid carrier before use, as saline or aseptic apirogen water.Promptly use injection solution and suspensoid aseptic powder, granule and the preparation tablets of kind from above.

The preparation that is used for parenteral comprises moisture and non-moisture (oiliness) aseptic injectable solution agent of reactive compound, and it can comprise antioxidant, buffer agent, antibacterial and give the blood isoosmotic solute of described preparation with the expection receiver; And moisture and non-moisture aseptic suspensoid, it can comprise suspending agent and thickening agent.Suitable lipophilic solvent or carrier comprise fatty oil (as Oleum sesami) or synthetic fatty acid ester (as ethyl oleate or triglyceride) or liposome.Moisture injection suspension can comprise the material that increases described suspensoid viscosity, as sodium carboxymethyl cellulose, sorbitol or glucosan.Randomly, described suspensoid also can comprise suitable stabilizers or increase the compound dissolution degree to allow the reagent of preparation highly concentrated solution.

Except that previous formulations, described chemical compound can also be formulated as depot formulations (depotpreparation).Such durative action preparation can be by implantation (as subcutaneous or intramuscular) or by the intramuscular injection administration.Therefore, for example, described chemical compound can be prepared with suitable polymeric material or hydrophobic material (for example as the Emulsion in the acceptable oil) or ion exchange resin, or can be formulated as the microsolubility derivant, as slightly soluble salt.

For buccal or sublingual administration, described compositions can be taked the form of tablet, lozenge, pastille or the gel prepared in a usual manner.Such compositions can be included in the active component in the flavoured base (flavoredbasis) (as sucrose and arabic gum or Tragacanth).

Described chemical compound also can be formulated into rectal compositions, such as, for example comprise the suppository or the retention enema of conventional suppository bases, described conventional suppository bases such as cocoa butter, Polyethylene Glycol or other glyceride.

Some chemical compound of the present invention can topical, promptly by non-whole body administration.This comprise chemical compound applications of the present invention to epidermis or oral cavity and such chemical compound instil to ear, eye and nose so that described chemical compound can obviously not enter blood flow.On the contrary, the whole body administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

The preparation that is suitable for topical comprises liquid or the semi-liquid preparations that is applicable to transdermal arrival inflammation site, as gel, liniment, lotion, ointment, ointment or paste, and the drop that is suitable for being administered to eye, ear or nose.The active component that is used for topical can account for described preparation, for example 0.001% to 10%w/w (by weight).In certain embodiments, active component can account for nearly 10%w/w.In other embodiments, it can account for and be less than 5%w/w.In certain embodiments, described active component can account for 2%w/w to 5%w/w.In other embodiments, its can account for described preparation 0.1% to 1%w/w.

The gel that is used for part or percutaneous dosing can comprise the mixture of volatile solvent, nonvolatile solvent and water usually.In certain embodiments, the volatile solvent component of buffer solvent system can comprise rudimentary (C1-C6) alkylol, low alkyl group two pure and mild lower glycol polymer.In further embodiment, described volatile solvent is an ethanol.Think that the volatile solvent component serves as penetration enhancer, and when it evaporates, also on skin, produce cooling effect.The part of the non-volatile solvents of described buffer solvent system is selected from rudimentary alkylene glycol and lower glycol polymer.In certain embodiments, use propylene glycol.Described non-volatile solvents slows down the evaporation of described volatile solvent and reduces the vapour pressure of described buffer solvent system.The amount of this non-volatile solvents component is the same with the amount of described volatile solvent, is determined by medical compounds that uses or medicine.When the non-volatile solvents in the described system very little the time, described medical compounds may be because the evaporation of volatile solvent and crystallization, then may be owing to medicine causes the bioavailability deficiency from the very few release of solvent mixture when excessive.The buffer components of described buffer solvent system can be selected from this area any buffer commonly used; In certain embodiments, make water.The common ratio of composition is about 20% non-volatile solvents, about 40% volatile solvent and about 40% water.In the described topical composition but add some optional ingredients.These include but not limited to chelating agen and gellant.Suitable gellant can include but not limited to, semisynthetic cellulose derivative (as hydroxypropyl emthylcellulose) and synthetic polymer, and cosmetics (cosmeticagents).

Lotion comprise those be suitable for administration to skin or the eye.Eye wass can comprise the aseptic aqueous solution that randomly contains antibacterial, and can be by preparing with the similar method of preparation drop.The washing liquid of application to skin or liniment also can comprise accelerates reagent (as ethanol or acetone) and/or humidizer (as glycerol) or oil (as Oleum Ricini or Oleum Arachidis hypogaeae semen) dry and cooling skin.

Ointment, ointment or paste are the semi-solid preparations of the active component of external.They can be by means of suitable machine, with separately or the solution of moisture or non-aqueous fluid or the active component segmentation in the suspension or powder type with oil or non-greasing base is mixed must.Described substrate can comprise hydrocarbon such as hard, soft or liquid paraffin, glycerol, Cera Flava, metallic soap; Mucilage; The oil of natural origin such as Semen Armeniacae Amarum, corn, Semen arachidis hypogaeae, Semen Ricini or Fructus Canarii albi; Lanoline or their derivant, or fatty acid (as stearic acid or oleic acid) and alcohol (as propylene glycol) or macrogel.Described preparation can mix any suitable surfactant such as anion, cation or nonionic surfactant, as sorbitan ester or its polyethylene oxide derivatives.Can also comprise suspending agent such as natural gum, cellulose derivative or inorganic material (as phyllosilicate Silicon stone (silicaceous silicas)), and other compositions (as lanoline).

Drop can comprise sterile aqueous or oily solution or suspension, and can be by preparing in the aqueous solution that active component is dissolved in suitable antibacterial and/or antifungal and/or any other suitable antiseptic (and in certain embodiments, comprising surfactant).Gained solution can be clarified by filtering then, is transferred to suitable containers, keeps sterilize half an hour down with described seal of vessel and by autoclaving or at 98-100 ℃ then.Alternatively, described solution can be transferred to container by filtration sterilization and by aseptic technique.Being fit to be included in the antibacterial in the drop and the example of antifungal is phenylmercuric nitrate or phenylmercuric acetate (0.002%), benzalkonium chloride (0.01%) and acetic acid chlorhexidine (0.01%).The suitable solvent of preparation oily solution comprises the pure and mild propylene glycol of glycerol, dilution.

The preparation that is used for mouth topical (as buccal or Sublingual) comprises the lozenge that is included in the active component in the flavoured base (as sucrose and arabic gum or Tragacanth), and the pastille that is included in the active component in the flavoured base (as gel and glycerol or sucrose and arabic gum).

For by inhalation, can be easily from insufflator, spraying compression wrap (nebulizerpressurized pack) or send spray other easily mode send chemical compound.Compression wrap can comprise suitable propellant, as dichlorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, carbon dioxide or other suitable gas.With regard to pressurized aerosol, dosage unit can be determined with the amount of sending metering by valve is provided.Alternatively,, can take the form of dry powder composite, the mixture of powders of for example described chemical compound and suitable powder substrate (as lactose or starch) according to chemical compound of the present invention for administration by sucking or being blown into.Described powder composition for example can be formed in, the unit dosage form in capsule, cartridge (cartridge), gelatina or the blister pack (blister pack), and described powder can carry out administration by means of inhaler or insufflator.

Preferred unit dose formulations is the preparation that comprises effective dose or its suitable part of active component as mentioned below.

Should be understood that except that the composition of above mentioning especially above-described preparation can comprise and relevant other conventional reagent of this area of preparation type of discussing that the preparation that for example is fit to oral administration can comprise correctives.

Can by oral or through injection with the dosed administration chemical compound of every day 0.1 to 500mg/kg.The dosage range that is used to be grown up normally every day 5mg to 2g.The tablet or other finished product forms that provide with discrete unit can be included in the amount of effective one or more chemical compounds under such dosage easily or as its many times, for example comprise the unit of 5mg to 500mg, usually about 10mg to 200mg.

Can with carrier material combination can be with the amount of the active component that generates the single dose form and different according to the AD HOC of subject host and administration.

Can be by the described chemical compound of various modes administration, for example oral, topical or by injection.Accurate amount to the chemical compound of patient's administration can be responsible for by the doctor in charge.The concrete dosage level of any particular patient can depend on multiple factor, comprise the activity, age, body weight, body constitution, sex, diet, administration time, administration path, discharge rate, drug regimen of the particular compound of use, the accurate disease of being treated, and the seriousness of indication of being treated or illness.Equally, the administration path can change according to illness and its seriousness.

In some cases, can be suitable with at least a chemical compound described herein (or the acceptable salt of its pharmacy, ester or prodrug) with another therapeutic agent combination medicine-feeding.Only as an example, be hypertension if accept one of side reaction that a kind of patient of this paper chemical compound occurs, can be suitable then with hypotensive agent and initial therapeutic agent combination medicine-feeding.Perhaps, only as example, can strengthen the therapeutic effect (that is: described accessory drugs self may have only minimum treatment benefit, but itself and another therapeutic agent combination can strengthen the total therapeutic effect to the patient) of one of chemical compound described herein by the administration accessory drugs.Perhaps, only as example, can and also have the benefit that another therapeutic agent for the treatment of benefit increases (it also comprises therapeutic scheme) patient experiences by a kind of chemical compound as herein described of administration.Only as example, in the treating diabetes that comprises one of administration chemical compound as herein described, can be by being provided for the treatment benefit that another therapeutic agents of diabetes obtains increasing to described patient simultaneously.Under any circumstance, no matter the disease of being treated, disease or illness are how, total the benefit that patient experiences arrives can be the simple adduction of two kinds of therapeutic agents, perhaps the patient can experience collaborative benefit.

Under any circumstance, multiple therapeutic agent (wherein at least a is chemical compound of the present invention) can be by any order administration or even administration simultaneously.If administration simultaneously, described multiple therapeutic agent can provide (only as example, as a pill or two independent pills) by single unified form or with multiple form.A kind of in the therapeutic agent can be by multiple dosed administration, and perhaps the two all can be by multiple dosed administration.If not the while administration, the timing between described a plurality of dosage can be a few minutes to around any persistent period in the scope.

Therefore, on the other hand, the method of the disease of treatment PDE4 mediation in the mankind that the invention provides in the such treatment of needs or the animal individual, described method comprises The compounds of this invention and at least a other reagent that are used for the treatment of described disease known in the art that effectively alleviate or stop the amount of the described disease in the individuality to described individual combination medicine-feeding.In a related aspect, the invention provides and comprise the therapeutic combination of other combination of agents that at least a chemical compound of the present invention and one or more are used for the treatment of the disease of PDE4 mediation.

Chemical compound of the present invention can be used for treating disease, disease and the illness of PDE4 mediation.In certain embodiments, described chemical compound can find the purposes in treating acute and chronic pain and inflammation.Chemical compound of the present invention can be used for treating patient's neuropathy, neuropathic pain or inflammatory pain such as reflex sympathetic dystrophy/causalgia (nerve injury), peripheral neuropathy (comprising diabetic neuropathy), intractable cancer pain, complicated regional pain syndrome and compressive neuropathy (carpal tunnel syndrome (carpel tunnel syndrome)).Described chemical compound also can be used for treating pain, postherpetic neuralgia (PHN) and relevant pain syndrome such as the ophthalmalgia that acute herpes zoster (herpeszoster) (herpes zoster (shingles)) is followed.Described chemical compound also can be used as the analgesic for the treatment of pain as the operation analgesic, perhaps as the antipyretic in the fever therapy.The pain indication includes but not limited to: the pain that pain, myalgia, mazalgia, the skin injury that various operating postoperative pains (comprising the postcardiac surgery pain), toothache/exodontia, cancer cause causes, low back pain, various etiologic etiological headache (comprising migraine) etc.Described chemical compound also can be used for treating pain relevant disease such as tactile allodynia and hyperpathia.Described pain can be somatogenic (nociceptive or neuropathic), acute and/or chronic.PDE4 inhibitor of the present invention also can be used for wherein the illness of administration NSAID, morphine or fentanyl opiate (fentanyl opiates) traditionally and/or other opium kind analgesicses.

In addition, The compounds of this invention can be used for treating or prevents the patient's of the opium kind analgesics that needs prolong opium toleration, and takes in the benzene phenodiazine

The patient's of class benzene phenodiazine

Toleration, and other addictive behavior are as nicotine addiction, alcoholism and eating disorders.In addition, Compounds and methods for of the present invention can be used for treatment or prophylactic agent withdrawal symptom, for example the withdrawal symptom of treatment or prevention opium, ethanol or cigarette addiction.

In addition, chemical compound of the present invention can be used for treating insulin resistant and other metabolic diseases common and the inflammation signal correction of amplifying, as atherosclerosis.

The present invention includes the Therapeutic Method that uses new selectivity PDE4 inhibitor for treating or prevention respiratory disorder or illness, it is included in the Therapeutic Method that medically is used to prevent and treat respiratory disorder or illness, described respiratory disorder or illness comprise: the asthma illness, comprise asthma that allergen brings out, exercise induced asthma, pollute the asthma of bringing out, asthma that cold is brought out and viral-induced asthma; The asthma relevant disease is as airway hyperreactivity and small airway disease; Chronic obstructive pulmonary disease comprises the chronic bronchitis of normal airflow (normal airflow), chronic bronchitis (chronic obstructive bronchitis), emphysema, asthmatic bronchitis and the bulla disease of airway obstruction; And other pneumonopathy that relate to inflammation, comprise bronchiolitis, bronchiectasis, cystic fibrosis, raise Columba livia person disease (pigeon fancier ' sdisease), farmer lung, adult respiratory distress syndrome, pneumonia, pneumonitis, mistake is inhaled or inhalation injury, pulmonary fat embolism, lung acidosis inflammation, acute lung edema, acute mountain sickness, acute pulmonary hypertension, neonatal persistent pulmonary hypertension, PAS, respiratory distress syndrome, acute pulmonary thromboembolism, the Heparin-Protamine reaction, sepsis, status asthmaticus, anoxia, dyspnea, hyperpnea, hyperinflation, hypoxemia and cough.In addition, chemical compound disclosed herein is used in treatment allergic conditions such as delayed hypersensitivity, contact dermatitis, allergic rhinitis and chronic sinusitis.

Treatable other diseases of The compounds of this invention or illness comprise inflammation and associated conditions.Chemical compound useful as anti-inflammatory agents of the present invention, it has significantly lower additional benefit of harmful side reaction.Described chemical compound can be used for the treatment of arthritis, include but not limited to rheumatoid arthritis, spondyloarthropathy, gouty arthritis, osteoarthritis, juvenile arthritis,juvenile chronic arthritis,juvenile rheumatoid arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, reactive arthritis (reiter syndrome) and suppurative arthritis, and autoimmune disease, comprise systemic lupus erythematosus (sle), the haemolysis syndrome, autoimmune hepatitis, the autoimmunity neuropathy, vitiligo (autoimmune thyroiditis), chronic lymphocytic thyroiditis, anemia, myositis (comprising polymyositis), alopecia, goodpasture syndrome (Goodpasture ' ssyndrome), hypophysitis (hypophytis) and pulmonary fibrosis.

Described chemical compound also can be used for the treatment of osteoporosis and other related bone diseases (bonedisorder).

These chemical compounds also can be used for the treatment of gastrointestinal tract disease, as reflux esophagitis, dysentery, inflammatory bowel, regional enteritis, gastritis, irritable bowel syndrome, Graves disease (hyperthyroidism), necrotizing enterocolitis and ulcerative colitis.Described chemical compound also can be used for the treatment of lung inflammation, as the lung inflammation relevant with viral infection and cystic fibrosis.

In addition, chemical compound of the present invention also can be used for the organ transplantation patient separately or with the combination of routine immunization adjusting medicine.The example of the illness that will be treated in described patient comprises graft versus host disease (being graft versus host disease), allograft rejection (for example acute allograft rejection and chronic allograft rejection), transplants reperfusion injury and early stage transplant rejection (as acute allograft rejection).

Further again, The compounds of this invention can be used for treating pruritus and vitiligo (vitaligo).

Chemical compound of the present invention also can be used for treating the tissue injury in the disease, and described disease is as angiopathy, migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin, scleroderma (sclerodoma), rheumatic fever, type i diabetes, neuromuscular junction disease (comprising myasthenia gravis), white matter disease (comprising multiple sclerosis), sarcoidosis, nephritis, nephrotic syndrome, langerhans cell histiocytosis, glomerulonephritis, reperfusion injury, pancreatitis, interstitial cystitis, behcet syndrome, polymyositis, gingivitis, periodontitis (periodontis), allergy, the swelling that the damage back occurs, ischemia (comprises myocardial ischemia, the ischemia of cardiovascular ischemia and asystole secondary), liver cirrhosis, septic shock, endotoxin shock, the negative sepsis of Pueraria lobota Lan Shi, toxic shock syndrome, apoplexy, ischemical reperfusion injury, multiple organs dysfunction, restenosis (comprise coronary artery bypass surgery after restenosis) etc.

Chemical compound of the present invention also can be used for treating neural some disease and disease.Wherein PDE4 suppress effectively central nervous system disorders comprise the cortex dementia comprise Alzheimer and mild cognitive impairment (MCI), in wind-induced central nervous system injury, ischemia comprise cerebral ischemia (focus ischemia, thrombotic apoplexy and global ischemia (for example Secondary cases asystole) and wound.Wherein PDE4 suppresses effective neurodegenerative disorders and comprise neural degeneration in the disease or neural downright bad, and described disease is anoxia, hypoglycemia, epilepsy and following situation for example: central nervous system (CNS) wound (as spinal cord and craniocerebral injury), hyperbaric oxygen faint from fear and poison, dull-witted (for example early the old dementia dementia relevant), cachexia, Xi Denghamu chorea, Huntingdon tarantism, parkinson disease, amyotrophic lateral sclerosis (ALS), korsakoff's neurosis and relate to the imbecility of cerebrovascular disease with acquired immune deficiency syndrome (AIDS).Wherein PDE4 suppresses to be proved to be effective more diseases and comprises central nervous system unify neuropathy (comprising, for example IgA neuropathy, film neuropathy and Te Fa neuropathy), chronic inflammatory demyelinating polyneuropathy, transverse myelitis, Gullain-Barre disease, encephalitis and the nervous system cancer of peripheral nervous system.Wherein PDE4 suppresses to find that effective CNS dysfunction comprises sleep disorder, schizophrenia, depression, depression or other symptoms relevant with premenstrual syndrome (PMS), and anxiety.

In addition, The compounds of this invention also can be used for suppressing the PDE4 activity to alleviate systemic disorders, and described systemic disorders comprises by the inductive whole body hypotension relevant with septic and/or toxic hemorrhagic shock of plurality of reagents; Comprise as with the treatment of cytokine such as TNF, IL-1 and IL-2; And comprise as transplantation treatment immunosuppressant a middle or short term accessory drugs.

The prevention or the treatment that can comprise cancer by other diseases or the illness of compounds for treating of the present invention, the cancer of described cancer such as colorectal carcinoma and mammary gland, lung, prostate, bladder, cervix uteri and skin.The neoplasia that chemical compound of the present invention can be used for the treatment of and prevent includes but not limited to the brain cancer, osteocarcinoma, leukemia, lymphoma, the deutero-neoplasia of epithelial cell (epithelial cancer) (as basal cell carcinoma), adenocarcinoma, human primary gastrointestinal cancers such as lip cancer, oral cancer, the esophageal carcinoma, carcinoma of small intestine and gastric cancer, colon cancer, hepatocarcinoma, bladder cancer, cancer of pancreas, ovarian cancer, cervical cancer, pulmonary carcinoma, breast carcinoma and skin carcinoma (as pinacocyte and basal cell carcinoma), carcinoma of prostate, renal cell carcinoma and other known epithelial cancers of whole machine body that influences.Described neoplasia can be selected from human primary gastrointestinal cancers, hepatocarcinoma, bladder cancer, cancer of pancreas, ovarian cancer, carcinoma of prostate, cervical cancer, pulmonary carcinoma, breast carcinoma and skin carcinoma (as pinacocyte and basal cell carcinoma).Compounds and methods for of the present invention also can be used for the treatment of the fibrosis of following radiotherapy to occur.Compounds and methods for of the present invention can be used for the treatment of the individuality with adenomatous polyp, comprises the individuality that those have familial adenomatous polyposis (FAP).In addition, Compounds and methods for of the present invention can be used for preventing polyp to form the patient with FAP risk.

Chemical compound of the present invention can be used for the treatment of oculopathy, as xerophthalmia, glaucoma, cornea rebirth blood vesselization, optic neuritis, sjogren syndrome (Sjogren ' s syndrome), ganglia retinae degeneration, eye ischemia, retinitis, retinopathy, uveitis, eye photophobia (ocular photophobia) and treatment and relevant inflammation and the pain of ocular tissue's acute injury.Especially, described chemical compound can be used for the treatment of glaucoma retinopathy and/or diabetic retinopathy.Described chemical compound also can be used for the treatment of the post-operation inflammatory or the pain of ophthalmologic operation (as cataract operation and refractive surgery).

In addition, chemical compound of the present invention can be used for treating menstrual cramps, dysmenorrhea, premature labor, endometriosis, tendinitis, bursitis, skin related disorders (as psoriasis, eczema, burn, sunburn, dermatitis), pancreatitis, hepatitis, lichen planus, scleritis, scleroderma, dermatomyositis etc.Can use other illness of chemical compound of the present invention to comprise diabetes (I type or II type), atherosclerosis, congestive heart failure, myocarditis, atherosclerosis, cerebral ischemia, blood vessel generation, pulmonary hypertension and aortic aneurysm.

Chemical compound of the present invention also can be used for co-therapy partially or completely, replaces other conventional anti-inflammatory therapies, as with steroid, NSAID, COX-2 selective depressant, 5-lipoxidase inhibitor, LTB ₄Antagonist and LTA ₄Hydrolase inhibitor is used for co-therapy.When with antibacterial or antiviral agent combined therapy, chemical compound of the present invention also can be used to prevent tissue injury.

Except being used for the human treatment, chemical compound of the present invention and preparation also can be used for the veterinary treatment of house pet, external animal (exotic animal) and domestic animal (comprising mammal, rodent etc.).Preferred animal comprises horse, Canis familiaris L. and cat.

The general synthetic method of preparation chemical compound

Following route can be used for implementing the present invention.

Route 1

Route 2

Route 3

Work as R ¹⁰¹When comprising ester:

Work as R ¹⁰¹When comprising bromide:

Further specify the present invention by following embodiment.

Embodiment 1

8-(cyclopentyloxy)-4-(3,5-dichloropyridine-4-base is amino)-7-methoxy quinoline-2 (1H)-ketone

Step 1

Under 0 ℃, to 3-hydroxyl-4-methoxyl methyl benzoate (3.64g, 20mmol), 4-butyl ammonium hydrogen sulfate (340mg, 1.0mmol), isopropyl nitrate (5.0mL, dripped through 2 minutes 50mmol) and in the solution of dichloromethane (40mL) sulphuric acid (3.0mL, 56mmol).Reactant is warming up to room temperature, kept 45 minutes, use frozen water (100mL) cessation reaction then.Extract this mixture with dichloromethane (250mL * 2).With extract drying, the filtration, concentrated that merges, and passed through silica gel chromatography (4: 1 → 3: 7; Hexane: ethyl acetate) purification, to obtain 3-hydroxyl-4-methoxyl group-2-nitrobenzoic acid methyl ester: MS (ESI): 228.4.

Step 2

With 3-hydroxyl-4-methoxyl group-2-nitrobenzoic acid methyl ester (1.14g, 5.0mmol), the bromine Pentamethylene. (0.7mL, 6.5mmol), potassium carbonate (2.0g, 14mmol) and the mixture of anhydrous acetonitrile (15mL) at N ₂The following backflow.After 19 hours, allow reactant be cooled to room temperature, to concentrate, and passed through silica gel chromatography (4: 1 → 3: 2; Hexane: ethyl acetate) purification, to obtain 3-(cyclopentyloxy)-4-methoxyl group-2-nitrobenzoic acid methyl ester: MS (ESI): 296.5.

Step 3

With 3-(cyclopentyloxy)-4-methoxyl group-2-nitrobenzoic acid methyl ester (750mg, 2.54mmol), the mixture of 10%Pd/C (50% water, 500mg, 0.23mmol Pd) and methanol (10mL) vigorous stirring in nitrogen atmosphere at room temperature.After 21 hours, mixture is passed through diatomite filtration, concentrates, to obtain 2-amino-3-(cyclopentyloxy)-4-methoxyl methyl benzoate: MS (ESI): 266.5.

Step 4

With 2-amino-3-(cyclopentyloxy)-4-methoxyl methyl benzoate (5.54g, 20.9mmol), acetic anhydride (21.0mL, 222mmol) He the solution of diox (35mL) at N ₂40 ℃ of heating 17 hours, allow it be cooled to room temperature then down.Add entry (10mL), stir concentration response thing after 15 minutes, to obtain 2-acetylaminohydroxyphenylarsonic acid 3-(cyclopentyloxy)-4-methoxyl methyl benzoate: MS (ESI): 307.9.

Step 5

At-78 ℃ in N ₂Down by syringe pump (1mL/min) to KHMDS (150mL, 0.5MPhMe, 75mmol) add in the solution 2-acetylaminohydroxyphenylarsonic acid 3-(cyclopentyloxy)-4-methoxyl methyl benzoate (6.42g, 20.9mmol) and the solution of anhydrous THF (60mL).Along with the controlled-temperature bath consumption of spending the night, reactant slowly rises to room temperature.After 17 hours, in reactant impouring ice/water (250mL), stirred layering then 10 minutes.Water layer with concentrated hydrochloric acid (7mL) acidify, and filters to obtain 8-(cyclopentyloxy)-4-hydroxyl-7-methoxy quinoline-2 (1H)-ketone: MS (ESI): 276.0 with ether (150mL) washing.

Step 6

With 8-(cyclopentyloxy)-4-hydroxyl-7-methoxy quinoline-2 (1H)-ketone (350mg, 1.3mmol), ammonium acetate (4.0g, 52mmol) and the mixture of anhydrous meta-xylene (10mL) at N ₂150 ℃ of heating 48 hours, allow it be cooled to room temperature then down.Mixture is concentrated into drying, and water (25mL) dilution was stirred 2 minutes, and supersound process 1 minute stirred 5 minutes then.Filter free-pouring solid, water (25mL) washing is drained to obtain 4-amino-8-(cyclopentyloxy)-7-methoxy quinoline-2 (1H)-ketone: MS (ESI) with pump: 274.9 then.

Step 7

(340mg is 1.24mmol) at room temperature, N with 4-amino-8-(cyclopentyloxy)-7-methoxy quinoline-2 (1H)-ketone ₂Under divide in 5 minutes, be added to for 3 times sodium hydride (110mg, 60%, 2.75mmol) and in the mixture of DMSO (4mL).After 5 minutes, add 3,4, and the 5-trichloropyridine (271mg, 1.49mmol).After 19 hours, add more sodium hydride (100mg, 60%, 2.5mmol), add then more 3,4, the 5-trichloropyridine (250mg, 1.37mmol).After 4 hours, reactant is inclined to 1M KH ₂PO ₄(75mL) and stirred 5 minutes.Cross filter solid, water (25mL) washing, and passed through reversed-phase HPLC (3: 7 → 1: 0; Acetonitrile: purification water).In some cases, need to pass through silica gel chromatography (1: 0 → 9: 1; Dichloromethane: methanol) carry out other purification, to obtain 8-(cyclopentyloxy)-4-(3,5-dichloropyridine-4-base is amino)-7-methoxy quinoline-2 (1H)-ketone: ¹H NMR (400MHz, DMSO-d ₆): δ 9.39 (s, 1H), 8.86 (s, 1H), 8.76 (s, 2H), 7.87 (d, 1H), 7.06 (d, 1H), 4.97 (m, 1H), 4.78 (s, 1H), 3.90 (s, 3H), 1.83-1.48 (m, 8H); MS (ESI): 419.7.

Embodiment 2

8-(cyclopentyloxy)-4-(3,5-dichloropyridine-4-base oxygen base)-7-methoxy quinoline-2 (1H)-ketone

By embodiment 1, the purification of step 7 separates title compound. ¹H NMR(400MHz，DMSO-d ₆)：δ10.28(s，1H)、8.84(s，2H)、7.71(d，1H)、7.11(d，1H)、5.35(s，1H)、4.97(m，1H)、3.91(s，3H)、1.86-1.43(m，8H)；MS(ESI)：420.7。

Embodiment 3

8-(cyclo propyl methoxy)-4-(3,5-dichloropyridine-4-base is amino)-7-methoxy quinoline-2 (1H)-ketone

(embodiment 1, and step 1) and (bromomethyl) cyclopropane prepare title compound by steps outlined among the embodiment 1 by 3-hydroxyl-4-methoxyl group-2-nitrobenzoic acid methyl ester. ¹H NMR(400MHz，DMSO-d ₆)：δ9.91(s，1H)、8.83(s，1H)、8.76(s，2H)、7.87(d，1H)、7.03(d，1H)、4.78(s，1H)、3.89(s，3H)、3.84(d，2H)、1.27(m，1H)、0.45(m，2H)、0.25(m，2H)；MS(ESI)：405.8。

Embodiment 4

8-(cyclopentyloxy)-4-(3,5-dichloropyridine-4-base is amino)-7-methoxyl group-1-methylquinoline-2 (1H)-ketone

Step 1

(embodiment 1 for 1.6g, 5.2mmol, and the solution of step 4) and anhydrous THF (30mL) is in 5 minutes, at 0 ℃ and N with 2-acetylaminohydroxyphenylarsonic acid 3-(cyclopentyloxy)-4-methoxyl methyl benzoate ₂Under add to sodium hydride (230mg be 5.75mmol) and in the mixture of anhydrous THF (10mL).Allow reactant be warming up to room temperature and after 20 minutes, be cooled to 0 ℃ again.In 3 minutes, add iodomethane (1.06g, 0.0075mol) and the solution of anhydrous THF (10mL).Allow anti-product be warming up to room temperature, concentrate after 30 minutes.Residue dilutes with ethyl acetate (40mL), and washs with saline (10mL * 2).Dry organic layer filters and concentrates, to obtain 3-(cyclopentyloxy)-4-methoxyl group-2-(N-methyl acetylamino) essence of Niobe: MS (ESI): 322.1.

Step 2

Prepare title compound by 3-(cyclopentyloxy)-4-methoxyl group-2-(N-methyl acetylamino) essence of Niobe according to steps outlined among the embodiment 1. ¹H NMR(400MHz，DMSO-d ₆)：δ8.75(s，1H)、8.74(s，2H)、7.92(d，1H)、7.13(d，1H)、4.92(s，1H)、4.53(m，1H)、3.90(s，3H)、3.59(s，3H)、1.80-1.48(m，8H)；MS(ESI)：433.9。

Embodiment 5

8-(cyclopentyloxy)-4-(3,5-lutidines-4-base is amino)-7-methoxy quinoline-2 (1H)-ketone

By 4-bromo-3, (embodiment 1, and step 6) prepares title compound according to steps outlined among the embodiment 8 for 5-lutidines and 4-amino-8-(cyclopentyloxy)-7-methoxy quinoline-2 (1H)-ketone. ¹H NMR(400MHz，DMSO-d ₆)：δ9.08(s，1H)、8.44(s，1H)、8.40(s，2H)、7.88(d，1H)、7.03(d，1H)、4.96(m，1H)、4.51(s，1H)、3.90(s，3H)、2.13(s，6H)、1.80-1.54(m，8H)；MS(ESI)：380.2。

Embodiment 6

1,3-two bromo-8-(cyclopentyloxy)-4-(3,5-dichloropyridine-4-base is amino)-7-methoxy quinoline-2 (1H)-ketone

Under 0 ℃, to 4-(3,5-dichloropyridine-4-base is amino)-8-(cyclopentyloxy)-7-methoxy quinoline-2 (1H)-ketone (0.100g, 0.240mmol, embodiment 1) and the solution of dry DMF (2mL) in add N-bromo-succinimide (0.118g, 0.61mmol).0 ℃ after following 2 hours, mixture is inclined to water, and filtering-depositing is to obtain 1,3-two bromo-8-(cyclopentyloxy)-4-(3,5-dichloropyridine-4-base is amino)-7-methoxy quinoline-2 (1H)-ketone: ¹H NMR (400MHz, DMSO-d ₆): δ 10.5 (s, 1H), 8.59 (s, 2H), 6.76 (d, 1H), 6.61 (d, 1H), 4.87 (m, 1H), 3.80 (s, 3H), 1.82-1.51 (m, 8H); MS (ESI): 575.8.

Embodiment 7

3-bromo-8-(cyclopentyloxy)-4-(3,5-dichloropyridine-4-base is amino)-7-methoxy quinoline-2 (1H)-ketone

Under 0 ℃, to 4-(3,5-dichloropyridine-4-base is amino)-8-(cyclopentyloxy)-7-methoxy quinoline-2 (1H)-ketone (0.246g, 0.585mmol, embodiment 1) and the solution of dry DMF (3mL) in add N-bromo-succinimide (0.104g, 0.585mmol).0 ℃ after following 4 hours, described mixture is inclined to water, and filtering-depositing.Solution to filter cake and methanol (5mL) adds saturated sodium thiosulfate solution (1mL).After LCMS confirmed to consume the dibromo intermediate, the dilute with water mixture also extracted with EtOAc.Dry organic extract liquid, filtration also concentrate, to obtain 3-bromo-8-(cyclopentyloxy)-4-(3,5-dichloropyridine-4-base is amino)-7-methoxy quinoline-2 (1H)-ketone: ¹H NMR (400MHz, DMSO-d ₆): δ 10.56 (s, 1H), 8.88 (br s, 1H), 8.42 (s, 2H), 7.62 (d, 1H), 7.04 (d, 1H), 4.98 (m, 1H), 3.89 (s, 3H), 1.84-1.51 (m, 8H); MS (ESI): 497.8.

Embodiment 8

8-(cyclo propyl methoxy)-4-(3,5-lutidines-4-base is amino)-7-methoxy quinoline-2 (1H)-ketone

At N ₂Down, to 4-amino-8-(cyclo propyl methoxy)-7-methoxy quinoline-2 (1H)-ketone (1.94g, 7.45mmol, the intermediate of embodiment 3), Pd ₂(dba) ₃(0.28g, 0.31mmol), 2,2-dicyclohexyl phosphorus tri isopropyl biphenyl (0.59g, 1.24mmol), sodium tert-butoxide (1.20g, 12.4mmol) and the mixture of degassed toluene (20mL) in add 4-bromo-3, the 5-lutidines (1.16g, 6.21mmol) and the solution of degassed toluene (5mL).110 ℃ of heating 2 hours, allow it be cooled to room temperature in described mixture, ultrasonic until solid dispersion, use EtOAc (500mL) to filter then by kieselguhr (Celite).Concentrated filtrate is by silica gel chromatography (0 → 8%MeOH/CH ₂Cl ₂) purification, then by reversed-phase HPLC (25 → 100%MeCN/H ₂O) repurity, to obtain 8-(cyclo propyl methoxy)-4-(3,5-lutidines-4-base is amino)-7-methoxy quinoline-2 (1H)-ketone: ¹H NMR (400MHz, DMSO-d ₆): δ 9.64 (s, 1H), 8.43 (s, 1H), 8.42 (s, 2H), 7.89 (d, 1H), 7.03 (d, 1H), 4.54 (s, 1H), 3.91 (s, 3H), 3.85 (d, 2H), 2.15 (s, 6H), 1.28 (m, 1H), 0.47 (m, 2H), 0.28 (m, 2H); MS (ESI): 365.8.

Embodiment 9

8-(cyclopentyloxy)-4-(3,5-dichloropyridine-4-base is amino)-1-(2-ethoxy)-7-methoxy quinoline-2 (1H)-ketone

Step 1

By 2-acetylaminohydroxyphenylarsonic acid 3-(cyclopentyloxy)-4-methoxyl methyl benzoate (embodiment 1, step 4) according among the embodiment 4 general introduction program (except: solvent is DMF; Temperature is 33 ℃; Time is to spend the night) preparation 3-(cyclopentyloxy)-4-methoxyl group-2-(N-(2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl) acetylamino) essence of Niobe.MS(ESI)：458.2(M+Na)。

Step 2

The program of being described according to embodiment 1 by 3-(cyclopentyloxy)-4-methoxyl group-2-(N-(2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl) acetylamino) essence of Niobe prepares 8-(cyclopentyloxy)-4-(3,5-dichloropyridine-4-base is amino)-7-methoxyl group-1-(2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl) quinoline-2 (1H)-ketone.MS(ESI)：570(M+Na)。

Step 3

To 8-(cyclopentyloxy)-4-(3,5-dichloropyridine-4-base is amino)-7-methoxyl group-1-(2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl) quinoline-2 (1H)-ketone (2.4g, 4.4mmol) and the solution of methanol (100mL) in add p-methyl benzenesulfonic acid (172mg, 1.0mmol).After stirring was spent the night, the concentration response thing with dichloromethane (100mL) dilution, was used saturated NaHCO then ₃(20mL) washing, water (20mL) washing again.Dry organic layer, filtration, concentrate, and in dichloromethane/petroleum ether (1: 2) recrystallization to obtain 8-(cyclopentyloxy)-4-(3,5-dichloropyridine-4-base amino)-1-(2-ethoxy)-7-methoxy quinoline-2 (1H)-ketone: ¹H NMR (400MHz, DMSO-d ₆): δ 8.74 (s, 2H), 8.73 (s, 1H), 7.91 (d, 1H), 7.11 (d, 1H), 4.92 (s, 1H), 4.65 (t, 2H), 4.59 (m, 1H), 4.50 (t, 1H), 3.90 (s, 3H), 3.32 (m 2H), 1.80-1.48 (m, 8H); MS (ESI): 463.9.

Embodiment 10

8-(cyclopentyloxy)-4-(3,5-dichloropyridine-4-base is amino)-1-(2-(dimethylamino) ethyl)-7-methoxy quinoline-2 (1H)-ketone

Step 1

Under 0 ℃, to 8-(cyclopentyloxy)-4-(3,5-dichloropyridine-4-base is amino)-1-(2-ethoxy)-7-methoxy quinoline-2 (1H)-ketone (embodiment 9 for 500mg, 1.08mmol) and CH ₂Cl ₂Add in the solution (30mL) Dai Si-Martin's oxidant (Dess-Martin periodinane) (933mg, 2.2mmol).After 30 minutes, allow mixture be warmed to room temperature.When raw material exhausts, with dichloromethane (25mL) diluting reaction thing, with NaOH aqueous solution (20mL * 2) washing, water (20mL) washing then.Dry organic layer, filtration, concentrated, and passed through silica gel chromatography (1: 2 → 1: 1; Ethyl acetate: purification petroleum ether), to obtain 2-(8-(cyclopentyloxy)-4-(3,5-dichloropyridine-4-base is amino)-7-methoxyl group-2-Oxoquinoline-1 (2H)-yl) acetaldehyde: MS (ESI): 462.2.

Step 2

To Dimethylammonium chloride (144mg, 1.74mmol), triethylamine (176mg, 1.74mmol) and the solution of dehydrated alcohol (20mL) in order add isopropyl titanate (IV) (496mg, 1.74mmol) and 2-(8-(cyclopentyloxy)-4-(3,5-dichloropyridine-4-base is amino)-7-methoxyl group-2-Oxoquinoline-1 (2H)-yl) acetaldehyde (400mg, 0.87mmol).After stirring is spent the night, and the adding sodium borohydride (50mg, 1.3mmol).After 3 hours, reactant is inclined to ammonia (30mL), filter, use washed with dichloromethane then.Filtrate extracts with dichloromethane (50mL * 3).The dry extract that merges, filtration, concentrated, and by the reversed-phase HPLC purification, to obtain 8-(cyclopentyloxy)-4-(3,5-dichloropyridine-4-base is amino)-1-(2-(dimethylamino) ethyl)-7-methoxy quinoline-2 (1H)-ketone: ¹H NMR (400MHz, DMSO-d ₆): δ 8.75 (s, 1H), 8.73 (s, 2H), 7.91 (d, 1H), 7.12 (d, 1H), 4.94 (s, 1H), 4.71 (t, 2H), 4.58 (m, 1H), 3.90 (s, 3H), 2.22 (m, 2H), 2.04 (s, 6H), 1.80-1.50 (m, 8H); MS (ESI): 491.0.

Embodiment 11

6-(4-(3,5-dichloropyridine-4-base is amino)-7-methoxyl group-2-oxo-1,2-dihydroquinoline-8-base oxygen base) caproic acid

Step 1

In the solution of 8-(cyclo propyl methoxy)-4-(3,5-dichloropyridine-4-base is amino)-7-methoxy quinoline-2 (1H)-ketone (embodiment 3 for 1.2g, 2.90mmol) and methanol (8ml), add concentrated hydrochloric acid (15mL).Reactant mixture was concentrated 50 ℃ of heating in 4 hours then.Use saturated NaHCO ₃Neutralization residue, filtration (with ethanol and ether washing) and dry: 352 to obtain 4-(3,5-dichloropyridine-4-base is amino)-8-hydroxyl-7-methoxy quinoline-2 (1H)-ketone: MS (ESI).

Step 2

At room temperature and N ₂Down, to 4-(3,5-dichloropyridine-4-base is amino)-8-hydroxyl-7-methoxy quinoline-2 (1H)-ketone (380mg, 1.08mmol) and add in the solution of DMSO (20mL) sodium hydride (54mg, 1.35mmol).After 1 hour, (770mg 3.45mmol), heats mixture 5 hours at 30 ℃ to add 6-bromocaproic acid ethyl ester.By dripping the number cessation reaction of dripping, incline to 0.5M KH ₂PO ₄In, and extract with EtOAc (100mL * 3).The extract elder generation water reuse salt water washing that merges, drying, filtration, concentrate and by silica gel chromatography (ethyl acetate: purification petroleum ether), (4-(3 to obtain 6-, 5-dichloropyridine-4-base is amino)-7-methoxyl group-2-oxo-1,2-dihydroquinoline-8-base oxygen base) ethyl hexanoate: MS (ESI): 494.0.

Step 3

(4-(3 to 6-, 5-dichloropyridine-4-base is amino)-7-methoxyl group-2-oxo-1,2-dihydroquinoline-8-base oxygen base) ethyl hexanoate (100mg, 0.20mmol), add Lithium hydrate (2.0mL in the solution of MeOH (2mL) and THF (8mL), 1M, 2.0mmol).Mixture was stirred 24 hours, use 1N HCl (30mL) cessation reaction, and extract with EtOAc (40mL * 2).Dry organic extract liquid, filtration also concentrate, to obtain 6-(4-(3,5-dichloropyridine-4-base is amino)-7-methoxyl group-2-oxo-1,2-dihydroquinoline-8-base oxygen base) caproic acid: ¹H NMR (400MHz, DMSO-d ₆): δ 10.10 (s, 1H), 8.88 (s, 1H), 8.77 (s, 2H), 7.89 (d, 1H), 7.06 (d, 1H), 4.80 (s, 1H), 3.95 (t, 2H), 3.90 (s, 3H), 2.22 (t, 2H), 1.76 (m, 2H), 1.55 (m, 2H), 1.39 (m, 2H); MS (ESI): 465.8.

Embodiment 12

4-(3,5-lutidines-4-base is amino)-8-isobutoxy-7-methoxy quinoline-2 (1H)-ketone

(embodiment 1, and step 1) and 1-bromo-2-methylpropane prepare title compound according to steps outlined in embodiment 1 and 8 by 3-hydroxyl-4-methoxyl group-2-nitrobenzoic acid methyl ester. ¹H NMR(400MHz，DMSO-d ₆)：δ9.39(s，1H)、8.42(s，1H)、8.39(s，2H)、7.89(d，1H)、7.03(d，1H)、4.51(s，1H)、3.89(s，3H)、3.74(d，2H)、2.13(s，6H)、2.13(m，1H)、0.97(d，6H)；MS(ESI)：368.2。

Embodiment 13

4-(3,5-dichloropyridine-4-base is amino)-8-(4-(dimethylamino) butoxy)-7-methoxy quinoline-2 (1H)-ketone

Step 1

By 4-(3,5-dichloropyridine-4-base is amino)-the 8-hydroxyl-(embodiment 11 for 7-methoxy quinoline-2 (1H)-ketone, step 1) and 1, the 4-dibromobutane, according to embodiment 11, steps outlined prepares 8-(4-bromine butoxy)-4-(3,5-dichloropyridine-4-base is amino)-7-methoxy quinoline-2 (1H)-ketone in the step 2.MS(ESI)：485.8。

Step 2

To 8-(4-bromine butoxy)-4-(3,5-dichloropyridine-4-base is amino)-7-methoxy quinoline-2 (1H)-ketone (146mg, 0.3mmol) and add in the solution of DMSO (3mL) dimethylamine solution (1.5mL, 2MTHF, 3mmol).2.5 after hour, reactant is inclined to 10%K ₂CO ₃Extract (30mL) and with dichloromethane (40mL * 2).The dry extract that merges, filtration, concentrated, and passed through silica gel chromatography (1: 0 → 4: 1; Dichloromethane: the NH of methanol w/1% concentration ₄OH solution) purification passed through reversed-phase HPLC (1: 9 → 1: 1 then; Acetonitrile: purification water), to obtain 4-(3,5-dichloropyridine-4-base is amino)-8-(4-(dimethylamino) butoxy)-7-methoxy quinoline-2 (1H)-ketone: ¹HNMR (400MHz, DMSO-d ₆): δ 10.29 (s, 1H), 8.81 (s, 1H), 8.75 (s, 2H), 7.87 (d, 1H), 7.04 (d, 1H), 4.77 (s, 1H), 3.99 (t, 2H), 3.90 (s, 3H), 2.27 (t, 2H), 2.13 (s, 6H), 1.73 (m, 2H), 1.54 (m, 2H); MS (ESI): 451.0.

Embodiment 14

4-(3,5-dichloropyridine-4-base is amino)-8-(5-(dimethylamino) amoxy)-7-methoxy quinoline-2 (1H)-ketone

(3,5-dichloropyridine-4-base is amino)-(embodiment 11, and step 1) and pentamethylene bromide prepare title compound according to steps outlined among the embodiment 13 for 8-hydroxyl-7-methoxy quinoline-2 (1H)-ketone by 4-. ¹H NMR(400MHz，DMSO-d ₆)：δ9.91(s，1H)、8.83(s，1H)、8.75(s，2H)、7.87(d，1H)、7.04(d，1H)、4.77(s，1H)、3.96(t，2H)、3.90(s，3H)、2.19(t，2H)、2.10(s，6H)、1.76(m，2H)、1.48-1.32(m，4H)MS(ESI)：465.0。

Following chemical compound can use method for preparing usually.What expect is that these chemical compounds that make can have similar activity to the chemical compound that makes in the above-described embodiments.

This paper uses the molecule input line of simplification to enter system (Simplified Molecular Input LineEntry System), or SMILES represents following chemical compound.SMILES is that the modern chemistry that embeds (built into) all main commercialization chemical constitution mapping software bags is represented system, by DavidWeininger and Daylight Chemical Information Systems, and the Inc. exploitation.The explanation of SMILES text-string does not need software, and relevant explanation of how SMILES being translated into structure can be at Weininger, D., and J.Chem.Inf.Comput.Sci.1988,28, find among the 31-36.All SMILES character strings used herein all use Accelrys ' s Pipeline Pilot 6.0 to produce.Many IUPAC titles used herein use CambridgeSoft ' s ChemDraw 10.0 to produce.

O＝C1C＝C(NC2＝C(C)C＝NC＝C2C)C3＝C(N1)C(OCCCCN(C)C)＝C(OC)C＝C3

O＝C1C＝C(NC2＝C(C)C＝NC＝C2C)C3＝C(N1)C(OCCCCCN(C)C)＝C(OC)C＝C3

O＝C1C＝C(NC2＝C(C)C＝NC＝C2C)C3＝C(N1)C(OCCCCC(O)＝O)＝C(OC)C＝C3

O＝C1C＝C(NC2＝C(C)C＝NC＝C2C)C3＝C(N1)C(OCCCCN4CCN(C)CC4)＝C(OC)C＝C3

O＝C1C＝C(NC2＝C(C)C＝NC＝C2C)C3＝C(N1)C(OCCCCN4CCOCC4)＝C(OC)C＝C3

O＝C1C＝C(NC2＝C(C)C＝NC＝C2C)C3＝C(N1)C(OCCCCCC(O)＝O)＝C(OC)C＝C3

O＝C1C＝C(NC2＝C(C)C＝NC＝C2C)C3＝C(N1)C(OCC(N)＝O)＝C(OC)C＝C3

O＝C1C＝C(NC2＝C(C)C＝NC＝C2C)C3＝C(N1)C(OCCCCC(N)＝O)＝C(OC)C＝C3

O＝C1C＝C(NC2＝C(C)C＝NC＝C2C)C3＝C(N 1)C(OCCCCCCC(O)＝O)＝C(OC)C＝C3

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN)Nc3c(C)cncc3C

CNCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3C

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN)Nc3c(C)cncc3C

Cc1cncc(C)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N)c(OCF)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N)Nc3c(C)cncc3C

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN)Nc3c(C)cncc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N)Nc3c(C)cncc3F

Cc1cncc(F)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N)c(OCF)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N)Nc3c(C)cncc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN)Nc3c(F)cncc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N)Nc3c(F)cncc3F

NC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N)Nc3c(F)cncc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN)Nc3c(C)cccc3C

Cc1cccc(C)c1NC2＝CC(＝O)Nc3c(OCCCCN)c(OCF)ccc23

CNCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3C

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN)Nc3c(C)cccc3C

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N)Nc3c(C)cccc3C

Cc1cccc(C)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N)c(OCF)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N)Nc3c(C)cccc3C

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN)Nc3c(C)cccc3F

CNCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN)Nc3c(C)cccc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N)Nc3c(C)cccc3F

Cc1cccc(F)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N)c(OCF)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N)Nc3c(C)cccc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N)Nc3c(C)cccc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N)Nc3c(C)cc(F)cc3C

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N)Nc3c(C)cc(F)cc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN)Nc3c(C)cc(O)cc3C

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N)Nc3c(C)cc(O)cc3C

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N)Nc3c(C)cc(O)cc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN)Nc3c(F)cccc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N)Nc3c(F)cccc3F

NC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N)Nc3c(F)cccc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N)Nc3c(F)cc(F)cc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N)Nc3c(F)cc(O)cc3F

CN(C)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3C

CCCN(C)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3C

Cc1cccc(C)c1NC2＝CC(＝O)Nc3c(OCCCCn4cccn4)c(OC(F)(F)F)ccc23

COCCOCCOCCOCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3C

Cc1cccc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCN)c(OC(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCn3ccnc3)Nc4c(C)cccc4C

Cc1cccc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCCNC(＝N)N)c(OC(F)(F)F)ccc23

Cc1cccc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCCN4CCCCC4)c(OC(F)F)ccc23

Cc1cccc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCCn4ccnn4)c(OCF)ccc23

CC(C)[C@H](NC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3C)C(＝O)O

Cc1cccc(C)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N[C@@H](Cc4ccccc4)C(＝O)O)c(OC(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N[C@@H](CCSC)C(＝O)O)Nc3c(C)cccc3C

Cc1cccc(C)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N[C@@H](CCCNC(＝N)N)C(＝O)O)c(OC(F)(F)F)ccc23

Cc1cccc(C)c1NC2＝CC(＝O)Nc3c(OCCCC(＝O)NCC(＝O)O)c(OC(F)(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H](CCCCN)C(＝O)O)Nc3c(C)cccc3C

Cc1cccc(C)c1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)N[C@@H](CCCCN)C(＝O)O)c(OCF)ccc23

Cc1cccc(C)c1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)N[C@@H](Cc4cnc[nH]4)C(＝O)O)c(OC(F)F)ccc23

CN1CCN(CC1)C(＝O)CCCCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(C)cccc4C

Cc1cccc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N[C@@H](Cc4ccc(O)cc4)C(＝O)O)c(OCF)ccc23

Cc1cccc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N[C@@H](Cc4ccc(O)cc4)C(＝O)O)c(OC(F)F)ccc23

CCNCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3F

CCN(C)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3F

COCCN(C)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCNC(＝N)N)Nc3c(C)cccc3F

Cc1cccc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCn4cnnc4)c(OC(F)F)ccc23

Cc1cccc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCOc4ccncc4)c(OCF)ccc23

CCNCCCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3F

Cc1cccc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCCN4CCCC(F)C4)c(OCF)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCOc3cccnc3)Nc4c(C)cccc4F

Cc1cccc(F)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N)c(OC(F)(F)F)ccc23

CN(C)CCOC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc 12)Nc3c(C)cccc3F

Cc1cccc(F)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N[C@@H](CO)C(＝O)O)c(OC(F)F)ccc23

Cc1cccc(F)c1NC2＝CC(＝O)Nc3c(OCCCC(＝O)N[C@@H](Cc4c[nH]c5ccccc45)C(＝O)O)c(OCF)ccc23

Cc1cccc(F)c1NC2＝CC(＝O)Nc3c(OCCCC(＝O)N[C@@H](Cc4c[nH]c5ccccc45)C(＝O)O)c(OC(F)F)ccc23

Cc1cccc(F)c1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)OCC[N+](C)(C)C)c(OC(F)(F)F)ccc23

CC(C)[C@H](NC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3F)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N[C@@H](CCCCN)C(＝O)O)Nc3c(C)cccc3F

Cc1cccc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N)c(OCF)ccc23

CN1CCN(CC1)C(＝O)CCCCCOc2c(OC(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(C)cccc4F

CC[C@H](C)[C@H](NC(＝O)CCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3F)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN3CCOCC3)Nc4c(C)cccc4Cl

Cc1cccc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCN4CCC(F)CC4)c(OC(F)F)ccc23

Cc1cccc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCOc4ccccn4)c(OC(F)(F)F)ccc23

Cc1cccc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCNC(＝N)N)c(OCF)ccc23

CCCCCN(C)CCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3Cl

Cc1cccc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCOc4cccnc4)c(OC(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCN)Nc3c(C)cccc3Cl

Cc1cccc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCCN4CCOCC4)c(OC(F)(F)F)ccc23

COCCOCCOCCCCCCOc1c2NC(＝O)C＝C(Nc3c(C)cccc3Cl)c2ccc1OC(F)F

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N[C@@H](C(C)C)C(＝O)O)Nc3c(C)cccc3Cl

CC(C)C[C@H](NC(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3Cl)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H](Cc3c[nH]c4ccccc34)C(＝O)O)Nc5c(C)cccc5Cl

Cc1cccc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCC(＝O)N[C@@H](CCCNC(＝N)N)C(＝O)O)c(OCF)ccc23

CC(C)[C@H](NC(＝O)CCCCOc 1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3Cl)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N[C@@H](CCCNC(＝N)N)C(＝O)O)Nc3c(C)cccc3Cl

CC(C)C[C@H](NC(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3Cl)C(＝O)O

Cc1cccc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCN)c(OC(F)F)ccc23

COCCN(C)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN3CCC(F)C3)Nc4c(C)cccc4Br

Cc1cccc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCN4CCCC(F)C4)c(OC(F)F)ccc23

Cc1cccc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCn4cccc4)c(OC(F)(F)F)ccc23

CCCNCCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCn3cnnn3)Nc4c(C)cccc4Br

COCCOCCOCCCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N[C@@H](CO)C(＝O)O)Nc3c(C)cccc3Br

Cc1cccc(Br)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N[C@@H](CCCCN)C(＝O)O)c(OC(F)F)ccc23

Cc1cccc(Br)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N[C@@H](CCC(＝O)O)C(＝O)O)c(OCF)ccc23

CN(C)CCN(C)C(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3Br

CN1CCN(CC1)C(＝O)CCCOc2c(OC(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(C)cccc4Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H](CO)C(＝O)O)Nc3c(C)cccc3Br

CN(C)CCCN(C)C(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3Br

CN(CCC[N+](C)(C)C)C(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3Br

CN(CCC[N+](C)(C)C)C(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cccc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](Cc3ccc(O)cc3)C(＝O)O)Nc4c(C)cccc4Br

CCCN(C)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(F)cc3C

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN3CCCCC3)Nc4c(C)cc(F)cc4C

Cc1cc(F)cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCN4CCCC4)c(OCF)ccc23

CCCCCN(C)CCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(F)cc3C

Cc1cc(F)cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCn4nccn4)c(OC(F)F)ccc23

Cc1cc(F)cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCOc4ccncc4)c(OC(F)(F)F)ccc23

Cc1cc(F)cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCCn4ccnc4)c(OC(F)F)ccc23

Cc1cc(F)cc(C)c1NC2＝CC(＝O)Nc3c(OCC(＝O)OCC[N+](C)(C)C)c(OCF)ccc23

CN(C)CCCN(C)C(＝O)CCCOc1c(OCF)ccc2C(＝CC(＝O)Nc 12)Nc3c(C)cc(F)cc3C

Cc1cc(F)cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)OCC[N+](C)(C)C)c(OC(F)(F)F)ccc23

Cc1cc(F)cc(C)c 1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)N4CCC[C@H]4C(＝O)O)c(OCF)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N(C)CCN(C)C)Nc3c(C)cc(F)cc3C

Cc1cc(F)cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N4CCC[C@H]4C(＝O)O)c(OC(F)(F)F)ccc23

Cc1cc(F)cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N[C@@H](Cc4ccccc4)C(＝O)O)c(OCF)ccc23

Cc1cc(F)cc(F)c1NC2＝CC(＝O)Nc3c(OCCCCn4cnnn4)c(OC(F)F)ccc23

Cc1cc(F)cc(F)c1NC2＝CC(＝O)Nc3c(OCCCCOc4ccncc4)c(OC(F)(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCO[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)Nc4c(C)cc(F)cc4F

CCCCN(C)CCCCCOc 1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(F)cc3F

Cc1cc(F)cc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCOc4ccncc4)c(OCF)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCN)Nc3c(C)cc(F)cc3F

COCCN(C)CCCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(F)cc3F

Cc1cc(F)cc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCCN4CCCCC4)c(OCF)ccc23

Cc1cc(F)cc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCCn4nccn4)c(OC(F)F)ccc23

CC(C)C[C@H](NC(＝O)COc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(F)cc3F)C(＝O)O

CC(C)[C@H](NC(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(F)cc3F)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H](CCCCN)C(＝O)O)Nc3c(C)cc(F)cc3F

CN(C)CCN(C)C(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(F)cc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N3CCNCC3)Nc4c(C)cc(F)cc4F

Cc1cc(F)cc(F)c1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)N[C@@H](Cc4ccc(O)cc4)C(＝O)O)c(OCF)ccc23

Cc1cc(F)cc(F)c1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)N[C@@H](CCC(＝O)N)C(＝O)O)c(OC(F)(F)F)ccc23

CC(C)[C@H](NC(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc 12)Nc3c(C)cc(F)cc3F)C(＝O)O

Cc1cc(F)cc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N[C@@H](Cc4ccccc4)C(＝O)O)c(OCF)ccc23

CCCCN(C)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(F)cc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCn3ccnc3)Nc4c(C)cc(F)cc4Cl

Cc1cc(F)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCOc4cccnc4)c(OC(F)(F)F)ccc23

COCCN(C)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(F)cc3Cl

Cc1cc(F)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCn4ncnn4)c(OC(F)(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCOc3cccnc3)Nc4c(C)cc(F)cc4Cl

Cc1cc(F)cc(Cl)c 1NC2＝CC(＝O)Nc3c(OCCCCCOc4ccncc4)c(OC(F)F)ccc23

CCCCN(C)CCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(F)cc3Cl

Cc1cc(F)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCCN4CCC(F)C4)c(OCF)ccc23

Cc1cc(F)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCCn4cccc4)c(OC(F)F)ccc23

Cc1cc(F)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCC(＝O)NCC(＝O)O)c(OC(F)(F)F)ccc23

Cc1cc(F)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N[C@@H](CO)C(＝O)O)c(OCF)ccc23

CN(CCC[N+](C)(C)C)C(＝O)CCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(F)cc3Cl

COc1ccc2C(＝CC(＝O)Nc2c 1OCCCC(＝O)N[C@@H](CCCCN)C(＝O)O)Nc3c(C)cc(F)cc3Cl

Cc1cc(F)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCC(＝O)N[C@@H](CCCCN)C(＝O)O)c(OC(F)F)ccc23

Cc1cc(F)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)N[C@@H](CO)C(＝O)O)c(OCF)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N[C@@H]([C@@H](C)O)C(＝O)O)Nc3c(C)cc(F)cc3Cl

Cc1cc(F)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)N[C@@H](CCCCN)C(＝O)O)c(OC(F)(F)F)ccc23

Cc1cc(F)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)N[C@@H](CCCNC(＝N)N)C(＝O)O)c(OC(F)F)ccc23

Cc1cc(F)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)OCC[N+](C)(C)C)c(OCF)ccc23Cc1cc(F)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N[C@@H](CO)C(＝O)O)c(OC(F)(F)F)ccc23

COCCN(C)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(F)cc3Br

Cc1cc(F)cc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCn4ccnn4)c(OC(F)F)ccc23

CCCCCN(C)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(F)cc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN3CCC(F)CC3)Nc4c(C)cc(F)cc4Br

COCCOCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(F)cc3Br

Cc1cc(F)cc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCCN4CCCC(F)(F)C4)c(OC(F)(F)F)ccc23

Cc1cc(F)cc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCCn4ccnc4)c(OC(F)F)ccc23

Cc1cc(F)cc(Br)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N[C@@H](CCC(＝O)O)C(＝O)O)c(OC(F)(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H](CCC(＝O)N)C(＝O)O)Nc3c(C)cc(F)cc3Br

Cc1cc(F)cc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)OCC[N+](C)(C)C)c(OCF)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N[C@@H](CCCCN)C(＝O)O)Nc3c(C)cc(F)cc3Br

Cc1cc(F)cc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)N[C@@H](CCCCN)C(＝O)O)c(OC(F)F)ccc23

Cc1cc(F)cc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)N[C@@H](CCCCN)C(＝O)O)c(OC(F)(F)F)ccc23

Cc1cc(F)cc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)OCC[N+](C)(C)C)c(OCF)ccc23

Cc1cc(F)cc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N[C@@H](CO)C(＝O)O)c(OC(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](CCCNC(＝N)N)C(＝O)O)Nc3c(C)cc(F)cc3Br

CCCNCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(O)cc3C

Cc1cc(O)cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCN4CCC(F)(F)C4)c(OCF)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCn3cnnc3)Nc4c(C)cc(O)cc4C

CCCNCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(O)cc3C

Cc1cc(O)cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCn4cncn4)c(OC(F)(F)F)ccc23

Cc1cc(O)cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCn4cnnn4)c(OC(F)F)ccc23

Cc1cc(O)cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCOc4ccncc4)c(OCF)ccc23

COCCN(C)CCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(O)cc3C

Cc1cc(O)cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCCN4CCOCC4)c(OC(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCN3CCCCC3)Nc4c(C)cc(O)cc4C

Cc1cc(O)cc(C)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N[C@@H](CC(＝O)O)C(＝O)O)c(OCF)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N[C@@H](CC(＝O)N)C(＝O)O)Nc3c(C)cc(O)cc3C

CN(C)CCCN(C)C(＝O)CCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(O)cc3C

CN(CCC[N+](C)(C)C)C(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(O)cc3C

C[C@H](NC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(O)cc3C)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](Cc3ccccc3)C(＝O)O)Nc4c(C)cc(O)cc4C

Cc1cc(O)cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N[C@@H](CO)C(＝O)O)c(OC(F)(F)F)ccc23

Cc1cc(O)cc(F)c1NC2＝CC(＝O)Nc3c(OCCCCn4cccn4)c(OCF)ccc23

COCCOCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(O)cc3F

CCCN(C)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(O)cc3F

Cc1cc(O)cc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCn4cccn4)c(OC(F)F)ccc23

Cc1cc(O)cc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCn4ncnn4)c(OC(F)(F)F)ccc23

CNCCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(O)cc3F

COCCOCCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(O)cc3F

Cc1cc(O)cc(F)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N)c(OC(F)(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N[C@@H](CC(C)C)C(＝O)O)Nc3c(C)cc(O)cc3F

Cc1cc(O)cc(F)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N[C@@H](CO)C(＝O)O)c(OCF)ccc23

Cc1cc(O)cc(F)c1NC2＝CC(＝O)Nc3c(OCCCC(＝O)N4CCNCC4)c(OC(F)F)ccc23

CN1CCN(CC1)C(＝O)CCCOc2c(OCF)ccc3C(＝CC(＝O)Nc23)Nc4c(C)cc(O)cc4F

Cc1cc(O)cc(F)c1NC2＝CC(＝O)Nc3c(OCCCC(＝O)N[C@@H](CCCNC(＝N)N)C(＝O)O)c(OC(F)(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N3CCNCC3)Nc4c(C)cc(O)cc4F

CC(C)[C@H](NC(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(O)cc3F)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)NCC[N+](C)(C)C)Nc3c(C)cc(O)cc3F

Cc1cc(O)cc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N[C@@H](Cc4ccc(O)cc4)C(＝O)O)c(OC(F)F)ccc23

CCN(CC)CCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(O)cc3Cl

Cc1cc(O)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCN4CCCCC4)c(OC(F)(F)F)ccc23

Cc1cc(O)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCN4CCC(F)C4)c(OC(F)F)ccc23

CCNCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(O)cc3Cl

CCCN(C)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(O)cc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCn3cnnc3)Nc4c(C)cc(O)cc4Cl

Cc1cc(O)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCOCCOCCOCCO)c(OC(F)(F)F)ccc23

CCN(CC)CCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(O)cc3Cl

Cc1cc(O)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCCn4ccnc4)c(OCF)ccc23

Cc1cc(O)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCC(＝O)OCC[N+](C)(C)C)c(OC(F)F)ccc23

Cc1cc(O)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N4CCC[C@H]4C(＝O)O)c(OCF)ccc23

C[C@H](NC(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc 12)Nc3c(C)cc(O)cc3Cl)C(＝O)O

C[C@@H](O)[C@H](NC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc 12)Nc3c(C)cc(O)cc3Cl)C(＝O)O

CN(CCC[N+](C)(C)C)C(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(O)cc3Cl

Cc1cc(O)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N4CCNCC4)c(OC(F)F)ccc23

Cc1cc(O)cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N[C@@H](CO)C(＝O)O)c(OC(F)(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](CC(＝O)N)C(＝O)O)Nc3c(C)cc(O)cc3Cl

Cc1cc(O)cc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCn4nccn4)c(OC(F)(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCOCCOCCOCCO)Nc3c(C)cc(O)cc3Br

Cc1cc(O)cc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCn4cnnc4)c(OC(F)F)ccc23

Cc1cc(O)cc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCOc4ccccn4)c(OC(F)(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCOc3ccncc3)Nc4c(C)cc(O)cc4Br

CCN(C)CCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(O)cc3Br

Cc1cc(O)cc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCCn4ncnn4)c(OCF)ccc23

Cc1cc(O)cc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCCOCCOCCOCCO)c(OC(F)(F)F)ccc23

CC[C@H](C)[C@H](NC(＝O)COc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(O)cc3Br)C(＝O)O

Cc1cc(O)cc(Br)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N[C@@H](Cc4ccc(O)cc4)C(＝O)O)c(OCF)ccc23

Cc1cc(O)cc(Br)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N[C@@H](CCCNC(＝N)N)C(＝O)O)c(OC(F)(F)F)ccc23

Cc1cc(O)cc(Br)c 1NC2＝CC(＝O)Nc3c(OCCCC(＝O)N4CCC[C@H]4C(＝O)O)c(OC(F)F)ccc23

CN(C)CCN(C)C(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(O)cc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N[C@@H](CC(＝O)O)C(＝O)O)Nc3c(C)cc(O)cc3Br

Cc1cc(O)cc(Br)c 1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N[C@@H](CCCNC(＝N)N)C(＝O)O)c(OCF)ccc23

Cc1cc(cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCn4cncn4)c(OC(F)F)ccc23)C(＝O)O

Cc1cc(cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCn4cnnc4)c(OC(F)(F)F)ccc23)C(＝O)O

Cc1cc(cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCOCCO)c(OCF)ccc23)C(＝O)O

COCCOCCOCCOCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(cc3C)C(＝O)O

Cc1cc(cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCn4cccn4)c(OC(F)F)ccc23)C(＝O)O

Cc1cc(cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCn4ncnn4)c(OCF)ccc23)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCOc3ccncc3)Nc4c(C)cc(cc4C)C(＝O)O

Cc1cc(cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCCN4CCOCC4)c(OC(F)F)ccc23)C(＝O)O

Cc1cc(cc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCCOCCO)c(OC(F)(F)F)ccc23)C(＝O)O

CN(C)CCNC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(cc3C)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N(C)CCCN(C)C)Nc3c(C)cc(cc3C)C(＝O)O

Cc1cc(cc(C)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N4CCNCC4)c(OC(F)F)ccc23)C(＝O)O

Cc1cc(cc(C)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N[C@@H](CO)C(＝O)O)c(OC(F)(F)F)ccc23)C(＝O)O

Cc1cc(cc(C)c1NC2＝CC(＝O)Nc3c(OCCCC(＝O)N[C@@H](CCCNC(＝N)N)C(＝O)O)c(OC(F)F)ccc23)C(＝O)O

C[C@@H](O)[C@H](NC(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(cc3C)C(＝O)O)C(＝O)O

CN(C)CCOC(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(cc3C)C(＝O)O

CN(C)CCNC(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(cc3C)C(＝O)O

Cc1cc(cc(F)c1NC2＝CC(＝O)Nc3c(OCCCCN4CCCC(F)(F)C4)c(OCF)ccc23)C(＝O)O

Cc1cc(cc(F)c1NC2＝CC(＝O)Nc3c(OCCCCOc4ccccn4)c(OC(F)F)ccc23)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCOc3cccnc3)Nc4c(C)cc(cc4F)C(＝O)O

Cc1cc(cc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCOc4ccncc4)c(OC(F)F)ccc23)C(＝O)O

CCCNCCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(cc3F)C(＝O)O

Cc1cc(cc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCCn4cnnc4)c(OC(F)(F)F)ccc23)C(＝O)O

Cc1cc(cc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCCOc4ccccn4)c(OCF)ccc23)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCOc3ccncc3)Nc4c(C)cc(cc4F)C(＝O)O

Cc1cc(cc(F)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N)c(OC(F)F)ccc23)C(＝O)O

Cc1cc(cc(F)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N[C@@H](Cc4ccc(O)cc4)C(＝O)O)c(OCF)ccc23)C(＝O)O

CN(CC[N+](C)(C)C)C(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(cc3F)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N[C@@H](CC(C)C)C(＝O)O)Nc3c(C)cc(cc3F)C(＝O)O

Cc1cc(cc(F)c1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)N4CCC[C@H]4C(＝O)O)c(OC(F)(F)F)ccc23)C(＝O)O

CN(CC[N+](C)(C)C)C(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(cc3F)C(＝O)O

CN(CC[N+](C)(C)C)C(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(cc3F)C(＝O)O

CC[C@H](C)[C@H](NC(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(cc3F)C(＝O)O)C(＝O)O

CCCN(C)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(cc3Cl)C(＝O)O

CCCCCN(C)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(cc3Cl)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN3CCCC3)Nc4c(C)cc(cc4Cl)C(＝O)O

Cc1cc(cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCn4cnnc4)c(OCF)ccc23)C(＝O)O

Cc1cc(cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCn4cccc4)c(OCF)ccc23)C(＝O)O

Cc1cc(cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCn4cncn4)c(OC(F)(F)F)ccc23)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCn3cnnn3)Nc4c(C)cc(cc4Cl)C(＝O)O

CN(C)CCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(cc3Cl)C(＝O)O

CCN(C)CCCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(cc3Cl)C(＝O)O

COCCOCCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(cc3Cl)C(＝O)O

Cc1cc(cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCCOCCOCCOCCO)c(OC(F)F)ccc23)C(＝O)O

CN(CC[N+](C)(C)C)C(＝O)COc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(cc3Cl)C(＝O)O

Cc1cc(cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCC(＝O)N4CCNCC4)c(OC(F)F)ccc23)C(＝O)O

Cc1cc(cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)NCC(＝O)O)c(OC(F)F)ccc23)C(＝O)O

Cc1cc(cc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)N[C@@H](Cc4ccccc4)C(＝O)O)c(OCF)ccc23)C(＝O)O

CSCC[C@H](NC(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(cc3Cl)C(＝O)O)C(＝O)O

CN1CCN(CC1)C(＝O)CCCCCOc2c(OCF)ccc3C(＝CC(＝O)Nc23)Nc4c(C)cc(cc4Cl)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](CO)C(＝O)O)Nc3c(C)cc(cc3Cl)C(＝O)O

CN(C)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(cc3Br)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN3CCOCC3)Nc4c(C)cc(cc4Br)C(＝O)O

Cc1cc(cc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCOCCOCCO)c(OCF)ccc23)C(＝O)O

Cc1cc(cc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCCN)c(OC(F)F)ccc23)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCN3CCCC3)Nc4c(C)cc(cc4Br)C(＝O)O

Cc1cc(cc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCCn4cnnn4)c(OC(F)(F)F)ccc23)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N[C@@H](Cc3c[nH]c4ccccc34)C(＝O)O)Nc5c(C)cc(cc5Br)C(＝O)O

Cc1cc(cc(Br)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N[C@@H](Cc4c[nH]c5ccccc45)C(＝O)O)c(OCF)ccc23)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c 1OCCCCC(＝O)N3CCN(C)CC3)Nc4c(C)cc(cc4Br)C(＝O)O

Cc1cc(cc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N)c(OC(F)F)ccc23)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)NCC(＝O)O)Nc3c(C)cc(cc3Br)C(＝O)O

C[C@H](NC(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cc(cc3Br)C(＝O)O)C(＝O)O

Cc1cc(cc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N[C@@H](CO)C(＝O)O)c(OC(F)(F)F)ccc23)C(＝O)O

CCN(CC)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3F

NC(＝N)NCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCOCCOCCOCCO)Nc3c(F)cccc3F

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN3CCOCC3)Nc4c(F)cccc4F

FC(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCCn3ccnn3)Nc4c(F)cccc4F

COCCOCCOCCCCCOc1c2NC(＝O)C＝C(Nc3c(F)cccc3F)c2ccc1OC(F)(F)F

FC(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCn3ccnc3)Nc4c(F)cccc4F

COCCOCCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3F

NCCCC[C@H](NC(＝O)COc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3F)C(＝O)O

NC(＝N)NCCC[C@H](NC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3F)C(＝O)O

NC(＝O)CC[C@H](NC(＝O)COc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3F)C(＝O)O

NC(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N3CCNCC3)Nc4c(F)cccc4F

NC(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3F

C[N+](C)(C)CCNC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3F

C[N+](C)(C)CCNC(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N(C)CC[N+](C)(C)C)Nc3c(F)cccc3F

NCCCC[C@H](NC(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3F)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](Cc3cnc[nH]3)C(＝O)O)Nc4c(F)cccc4F

NCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc 12)Nc3c(F)cccc3Cl

Fc1cccc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCn4nccn4)c(OC(F)(F)F)ccc23

COCCOCCOCCOCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN(C)C)Nc3c(F)cccc3Cl

Fc1cccc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCN4CCCC(F)(F)C4)c(OC(F)(F)F)ccc23

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCOc3ccccn3)Nc4c(F)cccc4Cl

OCCOCCOCCCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3Cl

CN(CCC[N+](C)(C)C)C(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3Cl

CN1CCN(CC1)C(＝O)COc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(F)cccc4Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N[C@@H](CCCCN)C(＝O)O)Nc3c(F)cccc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H](C)C(＝O)O)Nc3c(F)cccc3Cl

OC(＝O)[C@H](Cc1ccc(O)cc1)NC(＝O)CCCOc2c(OCF)ccc3C(＝CC(＝O)Nc23)Nc4c(F)cccc4Cl

C[C@@H](O)[C@H](NC(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3Cl)C(＝O)O

CN(CC[N+](C)(C)C)C(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3Cl

OC(＝O)CNC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3Cl

C[C@@H](O)[C@H](NC(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3Cl)C(＝O)O

OC(＝O)[C@H](Cc1cnc[nH]1)NC(＝O)CCCCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(F)cccc4Cl

NC(＝O)C[C@H](NC(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3Cl)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCOc3cccnc3)Nc4c(F)cccc4Br

FC(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN3CCC(F)CC3)Nc4c(F)cccc4Br

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCOc3ccccn3)Nc4c(F)cccc4Br

CNCCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3Br

COCCN(C)CCCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3Br

FCOc1ccc2C(＝CC(＝O)Nc2c 1OCCCCCCN3CCC(F)(F)C3)Nc4c(F)cccc4Br

NC(＝O)COc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3Br

CC[C@H](C)[C@H](NC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3Br)C(＝O)O

NC(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3Br

CN(C)CCNC(＝O)CCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3Br

OC(＝O)[C@H](Cc1ccccc1)NC(＝O)CCCCOc2c(OCF)ccc3C(＝CC(＝O)Nc23)Nc4c(F)cccc4Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N[C@@H](CO)C(＝O)O)Nc3c(F)cccc3Br

CN(C)CCNC(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cccc3Br

OC(＝O)[C@H](Cc1c[nH]c2ccccc12)NC(＝O)CCCCCOc3c(OCF)ccc4C(＝CC(＝O)Nc34)Nc5c(F)cccc5Br

CCCN(C)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3F

Fc1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCn4ccnc4)c(OC(F)(F)F)ccc23)c(F)c1

CCCNCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3F

NC(＝N)NCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3F

NC(＝N)NCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3F

CCCNCCCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3F

FC(F)Oc1ccc2C(＝CC(＝O)Nc2c 1OCCCCCCN3CCCC(F)C3)Nc4c(F)cc(F)cc4F

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCn3ccnc3)Nc4c(F)cc(F)cc4F

CN(C)CCOC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)NCC[N+](C)(C)C)Nc3c(F)cc(F)cc3F

CN(C)CCCN(C)C(＝O)COc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3F

CN(C)CCNC(＝O)CCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H](CC(C)C)C(＝O)O)Nc3c(F)cc(F)cc3F

C[N+](C)(C)CCOC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N[C@@H](Cc3ccc(O)cc3)C(＝O)O)Nc4c(F)cc(F)cc4F

NC(＝O)C[C@H](NC(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3F)C(＝O)O

C[N+](C)(C)CCOC(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3F

OC(＝O)[C@H](Cc1c[nH]c2ccccc12)NC(＝O)CCCCCOc3c(OC(F)F)ccc4C(＝CC(＝O)Nc34)Nc5c(F)cc(F)cc5F

NC(＝N)NCCC[C@H](NC(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3F)C(＝O)O

CCCN(C)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3Cl

FC(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCN3CCCCC3)Nc4c(F)cc(F)cc4Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN3CCCC(F)C3)Nc4c(F)cc(F)cc4Cl

CCN(C)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN3CCC(F)(F)CC3)Nc4c(F)cc(F)cc4Cl

COCCOCCOCCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3Cl

Fc1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCCCN4CCCCC4)c(OC(F)(F)F)ccc23)c(Cl)c1

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCN3CCCC3)Nc4c(F)cc(F)cc4Cl

NC(＝O)COc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N(C)CCN(C)C)Nc3c(F)cc(F)cc3Cl

CN(C)CCN(C)C(＝O)COc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3Cl

C[N+](C)(C)CCNC(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3Cl

NC(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N(C)CCC[N+](C)(C)C)Nc3c(F)cc(F)cc3Cl

C[C@H](NC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3Cl)C(＝O)O

CN(C)CCOC(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3Cl

CN(CCC[N+](C)(C)C)C(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3Cl

OC(＝O)[C@H](Cc1c[nH]c2ccccc12)NC(＝O)CCCCCOc3c(OC(F)(F)F)ccc4C(＝CC(＝O)Nc34)Nc5c(F)cc(F)cc5Cl

FC(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCN3CCCC3)Nc4c(F)cc(F)cc4Br

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCOc3ccccn3)Nc4c(F)cc(F)cc4Br

CCNCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3Br

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCOc3cccnc3)Nc4c(F)cc(F)cc4Br

OC[C@H]1O[C@@H](OCCCCCCOc2c(OC(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(F)cc(F)cc4Br)[C@H](O)[C@@H](O)[C@@H]1O

COCCOCCOCCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3Br

OCCOCCOCCOCCCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N[C@@H]([C@@H](C)O)C(＝O)O)Nc3c(F)cc(F)cc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H](CCSC)C(＝O)O)Nc3c(F)cc(F)cc3Br

NC(＝N)NCCC[C@H](NC(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3Br)C(＝O)O

CN(C)CCNC(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3Br

CN(CCC[N+](C)(C)C)C(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3Br

CN(C)CCCN(C)C(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(F)cc3Br

OC(＝O)[C@H](Cc1c[nH]c2ccccc12)NC(＝O)CCCCCOc3c(OCF)ccc4C(＝CC(＝O)Nc34)Nc5c(F)cc(F)cc5Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](CCCCN)C(＝O)O)Nc3c(F)cc(F)cc3Br

Oc1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCN4CCCC(F)(F)C4)c(OC(F)(F)F)ccc23)c(F)c1COc1ccc2C(＝CC(＝O)Nc2c1OCCCCOCCO)Nc3c(F)cc(O)cc3F

COCCOCCOCCOCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3F

CN(C)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)N12)Nc3c(F)cc(O)cc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN3CCCC(F)C3)Nc4c(F)cc(O)cc4F

Oc1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCCN4CCCC(F)C4)c(OC(F)(F)F)ccc23)c(F)c1

Oc1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCCn4ccnc4)c(OC(F)F)ccc23)c(F)c1

Oc1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCCCN4CCC(F)(F)CC4)c(OC(F)F)ccc23)c(F)c1

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCOc3ccccn3)Nc4c(F)cc(O)cc4F

C[N+](C)(C)CCOC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N[C@@H](Cc3ccccc3)C(＝O)O)Nc4c(F)cc(O)cc4F

C[N+](C)(C)CCNC(＝O)CCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3F

C[N+](C)(C)CCNC(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3F

CN(CC[N+](C)(C)C)C(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)OCCN(C)C)Nc3c(F)cc(O)cc3F

C[N+](C)(C)CCNC(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3F

CN(C)CCOC(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](CC(＝O)N)C(＝O)O)Nc3c(F)cc(O)cc3F

NC(＝O)CC[C@H](NC(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3F)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN)Nc3c(F)cc(O)cc3Cl

Oc1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCn4cccc4)c(OC(F)(F)F)ccc23)c(Cl)c1

Oc1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCCn4cnnc4)c(OC(F)F)ccc23)c(Cl)c1

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCOc3cccnc3)Nc4c(F)cc(O)cc4Cl

OCCOCCOCCOCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3Cl

CCCCCN(C)CCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3Cl

Oc1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCCCn4ncnn4)c(OC(F)(F)F)ccc23)c(Cl)c1

CN(C)CCOC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3Cl

NC(＝N)NCCC[C@H](NC(＝O)COc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3Cl)C(＝O)O

CSCC[C@H](NC(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3Cl)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H](CO)C(＝O)O)Nc3c(F)cc(O)cc3Cl

OC(＝O)[C@H](Cc1cnc[nH]1)NC(＝O)CCCOc2c(OCF)ccc3C(＝CC(＝O)Nc23)Nc4c(F)cc(O)cc4Cl

CN(C)CCCN(C)C(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N[C@@H](Cc3c[nH]c4ccccc34)C(＝O)O)Nc5c(F)cc(O)cc5Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](CCSC)C(＝O)O)Nc3c(F)cc(O)cc3Cl

C[C@@H](O)[C@H](NC(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3Cl)C(＝O)O

NC(＝N)NCCC[C@H](NC(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3Cl)C(＝O)O

CCNCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3Br

NC(＝N)NCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3Br

Oc1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCn4cnnn4)c(OCF)ccc23)c(Br)c1

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCn3nccn3)Nc4c(F)cc(O)cc4Br

OCCOCCOCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCN3CCC(F)C3)Nc4c(F)cc(O)cc4Br

C[N+](C)(C)CCOC(＝O)COc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3Br

OC(＝O)[C@H](Cc1ccccc1)NC(＝O)COc2c(OCF)ccc3C(＝CC(＝O)Nc23)Nc4c(F)cc(O)cc4Br

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N[C@@H](Cc3ccc(O)cc3)C(＝O)O)Nc4c(F)cc(O)cc4Br

OC(＝O)CC[C@H](NC(＝O)COc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3Br)C(＝O)O

NCCCC[C@H](NC(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3Br)C(＝O)O

OC(＝O)CC[C@H](NC(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3Br)C(＝O)O

CN(CC[N+](C)(C)C)C(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N[C@@H](CCCNC(＝N)N)C(＝O)O)Nc3c(F)cc(O)cc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N)Nc3c(F)cc(O)cc3Br

Oc1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N4CCNCC4)c(OCF)ccc23)c(Br)c1

CN1CCN(CC1)C(＝O)CCCCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(F)cc(O)cc4Br

CSCC[C@H](NC(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(O)cc3Br)C(＝O)O

CCCCN(C)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3F)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCOCCOCCO)Nc3c(F)cc(cc3F)C(＝O)O

COCCOCCOCCOCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc 12)Nc3c(F)cc(cc3F)C(＝O)O

OC(＝O)c1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCCn4ccnc4)c(OC(F)F)ccc23)c(F)c1

OC(＝O)c1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCCn4cnnc4)c(OCF)ccc23)c(F)c1

COCCOCCOCCOCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3F)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCN3CCOCC3)Nc4c(F)cc(cc4F)C(＝O)O

OC(＝O)c1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCCCN4CCOCC4)c(OC(F)F)ccc23)c(F)c1

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)NCC[N+](C)(C)C)Nc3c(F)cc(cc3F)C(＝O)O

CN(C)CCN(C)C(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3F)C(＝O)O

CN(CCC[N+](C)(C)C)C(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3F)C(＝O)O

OC(＝O)c1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCC(＝O)N4CCNCC4)c(OC(F)F)ccc23)c(F)c1

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H](CO)C(＝O)O)Nc3c(F)cc(cc3F)C(＝O)O

OC(＝O)[C@@H]1CCCN1C(＝O)CCCCOc2c(OC(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(F)cc(cc4F)C(＝O)O

C[C@@H](O)[C@H](HC(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3F)C(＝O)O)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](CC(C)C)C(＝O)O)Nc3c(F)cc(cc3F)C(＝O)O

CSCC[C@H](NC(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3F)C(＝O)O)C(＝O)O

CSCC[C@H](NC(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3F)C(＝O)O)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCn3nccn3)Nc4c(F)cc(cc4Cl)C(＝O)O

OCCOCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc 12)Nc3c(F)cc(cc3Cl)C(＝O)O

OC(＝O)c1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCCN4CCC(F)(F)CC4)c(OC(F)(F)F)ccc23)c(Cl)c1

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCn3cccn3)Nc4c(F)cc(cc4Cl)C(＝O)O

OC(＝O)c1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCCOc4ccncc4)c(OCF)ccc23)c(Cl)c1

OC(＝O)c1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCCCN4CCCC(F)(F)C4)c(OC(F)(F)F)ccc23)c(Cl)c1

OC(＝O)c1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCCCn4ncnn4)c(OC(F)F)ccc23)c(Cl)c1

COCCOCCOCCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3Cl)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N3CCNCC3)Nc4c(F)cc(cc4Cl)C(＝O)O

CSCC[C@H](NC(＝O)COc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3Cl)C(＝O)O)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)NCC(＝O)O)Nc3c(F)cc(cc3Cl)C(＝O)O

C[C@@H](O)[C@H](NC(＝O)CCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3Cl)C(＝O)O)C(＝O)O

NC(＝N)NCCC[C@H](NC(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3Cl)C(＝O)O)C(＝O)O

OC(＝O)[C@H](Cc1cnc[nH]1)NC(＝O)CCCOc2c(OC(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(F)cc(cc4Cl)C(＝O)O

C[N+](C)(C)CCNC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3Cl)C(＝O)O

CN(C)CCCN(C)C(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc 12)Nc3c(F)cc(cc3Cl)C(＝O)O

CCCN(C)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3Br)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN3CCOCC3)Nc4c(F)cc(cc4Br)C(＝O)O

OC(＝O)c1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCn4cccc4)c(OC(F)F)ccc23)c(Br)c1

CCN(CC)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc 12)Nc3c(F)cc(cc3Br)C(＝O)O

OC(＝O)c1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCCn4ccnn4)c(OC(F)F)ccc23)c(Br)c1

OC(＝O)c1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCCn4cncn4)c(OC(F)(F)F)ccc23)c(Br)c1

OC(＝O)c1cc(F)c(NC2＝CC(＝O)Nc3c(OCCCCCCn4ccnn4)c(OC(F)(F)F)ccc23)c(Br)c1

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCOCCOCCO)Nc3c(F)cc(cc3Br)C(＝O)O

CC(C)C[C@H](NC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3Br)C(＝O)O)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N[C@@H](Cc3ccc(O)cc3)C(＝O)O)Nc4c(F)cc(cc4Br)C(＝O)O

NC(＝O)C[C@H](NC(＝O)COc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3Br)C(＝O)O)C(＝O)O

CC(C)[C@H](NC(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3Br)C(＝O)O)C(＝O)O

NCCCC[C@H](NC(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3Br)C(＝O)O)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H](CC(＝O)N)C(＝O)O)Nc3c(F)cc(cc3Br)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N3CCNCC3)Nc4c(F)cc(cc4Br)C(＝O)O

CC(C)C[C@H](NC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3Br)C(＝O)O)C(＝O)O

CC[C@H](C)[C@H](NC(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3B r)C(＝O)O)C(＝O)O

CN(C)CCOC(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3Br)C(＝O)O

C[C@@H](O)[C@H](NC(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cc(cc3Br)C(＝O)O)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](CC(＝O)N)C(＝O)O)Nc3c(F)cc(cc3Br)C(＝O)O

CCCNCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Cl

CCCNCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Cl

CCCNCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Cl

OCCOCCOCCOCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCNC(＝N)N)Nc3c(Cl)cccc3Cl

FC(F)(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN3CCOCC3)Nc4c(Cl)cccc4Cl

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCn3cccc3)Nc4c(Cl)cccc4Cl

CCCCN(C)CCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Cl

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCOc3cccnc3)Nc4c(Cl)cccc4Cl

CN(C)CCOC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N(C)CCCN(C)C)Nc3c(Cl)cccc3Cl

OC(＝O)[C@H](Cc1ccccc1)NC(＝O)COc2c(OC(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Cl)cccc4Cl

NC(＝O)CC[C@H](NC(＝O)COc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Cl)C(＝O)O

C[C@@H](O)[C@H](NC(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Cl)C(＝O)O

C[C@H](NC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Cl)C(＝O)O

CC[C@H](C)[C@H](NC(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Cl)C(＝O)O

OC(＝O)[C@H](Cc1ccc(O)cc1)NC(＝O)CCCCCOc2c(OCF)ccc3C(＝CC(＝O)Nc23)Nc4c(Cl)cccc4Cl

NCCCC[C@H](NC(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Cl)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](CCC(＝O)O)C(＝O)O)Nc3c(Cl)cccc3Cl

NC(＝N)NCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Br

FC1CCCN(CCCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Cl)cccc4Br)Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCn3ccnc3)Nc4c(Cl)cccc4Br

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN3CCC(F)CC3)Nc4c(Cl)cccc4Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCn3cnnn3)Nc4c(Cl)cccc4Br

FC(F)(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCCn3cnnn3)Nc4c(Cl)cccc4Br

CNCCCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Br

CCCCN(C)CCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Br

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCn3cnnc3)Nc4c(Cl)cccc4Br

COCCOCCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Br

C[N+](C)(C)CCNC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)NCC(＝O)O)Nc3c(Cl)cccc3Br

NC(＝O)CC[C@H](NC(＝O)COc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Br)C(＝O)O

CN(C)CCNC(＝O)CCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Br

CC(C)C[C@H](NC(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Br)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N[C@@H](C)C(＝O)O)Nc3c(Cl)cccc3Br

C[C@H](NC(＝O)CCCCOc 1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Br)C(＝O)O

OC(＝O)C[C@H](NC(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Br)C(＝O)O

CN(CC[N+](C)(C)C)C(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cccc3Br

COCCOCCOCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(F)cc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCOCCOCCOCCO)Nc3c(Cl)cc(F)cc3Cl

Fc1cc(Cl)c(NC2＝CC(＝O)Nc3c(OCCCCCN4CCC(F)(F)C4)c(OC(F)(F)F)ccc23)c(Cl)c1

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCn3cccn3)Nc4c(Cl)cc(F)cc4Cl

OCCOCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(F)cc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCNC(＝N)N)Nc3c(Cl)cc(F)cc3Cl

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCn3nccn3)Nc4c(Cl)cc(F)cc4Cl

Fc1cc(Cl)c(NC2＝CC(＝O)Nc3c(OCCCCCCn4ncnn4)c(OC(F)(F)F)ccc23)c(Cl)c1

CN(C)CCOC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(F)cc3Cl

OC(＝O)CNC(＝O)COc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(F)cc3Cl

OC(＝O)[C@H](Cc1ccccc1)NC(＝O)COc2c(OC(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Cl)cc(F)cc4Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N3CCNCC3)Nc4c(Cl)cc(F)cc4Cl

OC(＝O)[C@@H]1CCCN1C(＝O)CCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Cl)cc(F)cc4Cl

OC[C@H](NC(＝O)CCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(F)cc3Cl)C(＝O)O

Fc1cc(Cl)c(NC2＝CC(＝O)Nc3c(OCCCCC(＝O)N4CCNCC4)c(OC(F)(F)F)ccc23)c(Cl)c1

NC(＝O)C[C@H](NC(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(F)cc3Cl)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N3CCC[C@H]3C(＝O)O)Nc4c(Cl)cc(F)cc4Cl

OC(＝O)[C@H](Cc1ccccc 1)NC(＝O)CCCCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Cl)cc(F)cc4Cl

OC(＝O)[C@H](Cc1c[nH]c2ccccc12)NC(＝O)CCCCCOc3c(OC(F)F)ccc4C(＝CC(＝O)Nc34)Nc5c(Cl)cc(F)cc5Cl

CCCN(C)CCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(F)cc3Br

COCCOCCOCCOCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(F)cc3Br

CCNCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(F)cc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN3CCCC(F)C3)Nc4c(Cl)cc(F)cc4Br

CCN(CC)CCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(F)cc3Br

FC1CCN(CCCCCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Cl)cc(F)cc4Br)CC1

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCOc3ccncc3)Nc4c(Cl)cc(F)cc4Br

FCOc1ccc2C(＝CC(＝O)Nc2c 1OCC(＝O)N3CCNCC3)Nc4c(Cl)cc(F)cc4Br

NCCCC[C@H](NC(＝O)COc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(F)cc3Br)C(＝O)O

CN(C)CCOC(＝O)CCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(F)cc3Br

CSCC[C@H](NC(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(F)cc3Br)C(＝O)O

C[N+](C)(C)CCNC(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(F)cc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N(C)CCCN(C)C)Nc3c(Cl)cc(F)cc3Br

CN(C)CCCN(C)C(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(F)cc3Br

NC(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(F)cc3Br

NC(＝N)NCCC[C@H](NC(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(F)cc3Br)C(＝O)O

Oc1cc(Cl)c(NC2＝CC(＝O)Nc3c(OCCCCn4nccn4)c(OCF)ccc23)c(Cl)c1

OCCOCCOCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(O)cc3Cl

NCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(O)cc3Cl

CCN(CC)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(O)cc3Cl

CN(C)CCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(O)cc3Cl

CCCNCCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(O)cc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCN3CCC(F)CC3)Nc4c(Cl)cc(O)cc4Cl

Oc1cc(Cl)c(NC2＝CC(＝O)Nc3c(OCCCCCCOc4cccnc4)c(OC(F)(F)F)ccc23)c(Cl)c1

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)OCCN(C)C)Nc3c(Cl)cc(O)cc3Cl

OC(＝O)CNC(＝O)COc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc 12)Nc3c(Cl)cc(O)cc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)NCC(＝O)O)Nc3c(Cl)cc(O)cc3Cl

CSCC[C@H](NC(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(O)cc3Cl)C(＝O)O

NCCCC[C@H](NC(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(O)cc3Cl)C(＝O)O

OC(＝O)[C@H](Cc1cnc[nH]1)NC(＝O)CCCOc2c(OCF)ccc3C(＝CC(＝O)Nc23)Nc4c(Cl)cc(O)cc4Cl

NC(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(O)cc3Cl

OC(＝O)CNC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(O)cc3Cl

C[N+](C)(C)CCNC(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(O)cc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)NCC(＝O)O)Nc3c(Cl)cc(O)cc3Cl

OC(＝O)[C@H](Cc1ccccc1)NC(＝O)CCCCCOc2c(OC(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Cl)cc(O)cc4Cl

CCN(CC)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(O)cc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN3CCC(F)(F)C3)Nc4c(Cl)cc(O)cc4Br

Oc1cc(Cl)c(NC2＝CC(＝O)Nc3c(OCCCCOc4cccnc4)c(OC(F)F)ccc23)c(Br)c1

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN)Nc3c(Cl)cc(O)cc3Br

Oc1cc(Cl)c(NC2＝CC(＝O)Nc3c(OCCCCCN4CCCC(F)C4)c(OC(F)F)ccc23)c(Br)c1

COCCOCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(O)cc3Br

CCCCN(C)CCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(O)cc3Br

Oc1cc(Cl)c(NC2＝CC(＝O)Nc3c(OCCCCCCOc4ccccn4)c(OCF)ccc23)c(Br)c1

Oc1cc(Cl)c(NC2＝CC(＝O)Nc3c(OCC(＝O)N4CCNCC4)c(OC(F)(F)F)ccc23)c(Br)c1

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N[C@@H](CCSC)C(＝O)O)Nc3c(Cl)cc(O)cc3Br

NC(＝O)CC[C@H](NC(＝O)COc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(O)cc3Br)C(＝O)O

CN1CCN(CC1)C(＝O)CCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Cl)cc(O)cc4Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H](C)C(＝O)O)Nc3c(Cl)cc(O)cc3Br

CN(C)CCCN(C)C(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(O)cc3Br

OC(＝O)CNC(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(O)cc3Br

COc1ccc2C(＝CC(＝O)Nc2c 1OCCCCC(＝O)N[C@@H](CCC(＝O)O)C(＝O)O)Nc3c(Cl)cc(O)cc3Br

CN(C)CCN(C)C(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(O)cc3Br

CN(CCC[N+](C)(C)C)C(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(O)cc3Br

OC(＝O)[C@H](Cc1ccccc1)NC(＝O)CCCCCOc2c(OC(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Cl)cc(O)cc4Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN(C)C)Nc3c(Cl)cc(cc3Cl)C(＝O)O

OC(＝O)c1cc(Cl)c(NC2＝CC(＝O)Nc3c(OCCCCOc4cccnc4)c(OC(F)(F)F)ccc23)c(Cl)c1

COCCOCCOCCOCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(cc3Cl)C(＝O)O

NC(＝N)NCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(cc3Cl)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN3CCCC(F)C3)Nc4c(Cl)cc(cc4Cl)C(＝O)O

OC(＝O)c1cc(Cl)c(NC2＝CC(＝O)Nc3c(OCCCCCN4CCC(F)(F)C4)c(OC(F)F)ccc23)c(Cl)c1

CNCCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(cc3Cl)C(＝O)O

CCN(C)CCCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(cc3Cl)C(＝O)O

COCCOCCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(cc3Cl)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N3CCC[C@H]3C(＝O)O)Nc4c(Cl)cc(cc4Cl)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)NCC(＝O)O)Nc3c(Cl)cc(cc3Cl)C(＝O)O

OC(＝O)[C@H](Cc1ccccc1)NC(＝O)CCCOc2c(OCF)ccc3C(＝CC(＝O)Nc23)Nc4c(Cl)cc(cc4Cl)C(＝O)O

CN(C)CCCN(C)C(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(cc3Cl)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N[C@@H](CC(C)C)C(＝O)O)Nc3c(Cl)cc(cc3Cl)C(＝O)O

C[C@H](NC(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(cc3Cl)C(＝O)O)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCNC(＝N)N)Nc3c(Cl)cc(cc3Br)C(＝O)O

OC(＝O)c1cc(Cl)c(NC2＝CC(＝O)Nc3c(OCCCCN4CCC(F)(F)C4)c(OC(F)F)ccc23)c(Br)c1

CN(C)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(cc3Br)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN3CCOCC3)Nc4c(Cl)cc(cc4Br)C(＝O)O

OC(＝O)c1cc(Cl)c(NC2＝CC(＝O)Nc3c(OCCCCCCn4ncnn4)c(OCF)ccc23)c(Br)c1

COCCOCCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc 12)Nc3c(Cl)cc(cc3Br)C(＝O)O

NC(＝O)COc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(cc3Br)C(＝O)O

CN(CCC[N+](C)(C)C)C(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(cc3Br)C(＝O)O

CN1CCN(CC1)C(＝O)COc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Cl)cc(cc4Br)C(＝O)O

C[N+](C)(C)CCNC(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(cc3Br)C(＝O)O

CN(C)CCCN(C)C(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cc(cc3Br)C(＝O)O

OC(＝O)[C@@H]1CCCN1C(＝O)CCCCCOc2c(OCF)ccc3C(＝CC(＝O)Nc23)Nc4c(Cl)cc(cc4Br)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](CCCNC(＝N)N)C(＝O)O)Nc3c(Cl)cc(cc3Br)C(＝O)O

CCCN(C)CCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cccc3Br

FC(F)(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCn3cncn3)Nc4c(Br)cccc4Br

COCCOCCOCCOCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cccc3Br

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN3CCOCC3)Nc4c(Br)cccc4Br

COCCOCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cccc3Br

CCN(CC)CCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cccc3Br

FC(F)(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCN3CCOCC3)Nc4c(Br)cccc4Br

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCn3cccn3)Nc4c(Br)cccc4Br

CN1CCN(CC1)C(＝O)COc2c(OC(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Br)cccc4Br

C[C@H](NC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cccc3Br)C(＝O)O

C[N+](C)(C)CCNC(＝O)CCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cccc3Br

C[C@H](NC(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cccc3Br)C(＝O)O

OC(＝O)[C@H](Cc1c[nH]c2ccccc12)NC(＝O)CCCOc3c(OC(F)(F)F)ccc4C(＝CC(＝O)Nc34)Nc5c(Br)cccc5Br

C[N+](C)(C)CCNC(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cccc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N[C@@H](CC(C)C)C(＝O)O)Nc3c(Br)cccc3Br

CN(C)CCN(C)C(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cccc3Br

CN(CC[N+](C)(C)C)C(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cccc3Br

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N3CCNCC3)Nc4c(Br)cccc4Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](CC(＝O)N)C(＝O)O)Nc3c(Br)cccc3Br

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCN3CCCC(F)(F)C3)Nc4c(Br)cc(F)cc4Br

FC(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCN3CCC(F)(F)CC3)Nc4c(Br)cc(F)cc4Br

COCCN(C)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(F)cc3Br

COc1ccc2C(＝CC(＝O)Nc2c 1OCCCCCN3CCOCC3)Nc4c(Br)cc(F)cc4Br

Fc1cc(Br)c(NC2＝CC(＝O)Nc3c(OCCCCCn4cccc4)c(OC(F)(F)F)ccc23)c(Br)c1

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCn3cnnn3)Nc4c(Br)cc(F)cc4Br

CNCCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(F)cc3Br

FC(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCn3ccnn3)Nc4c(Br)cc(F)cc4Br

NCCCC[C@H](NC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(F)cc3Br)C(＝O)O

OC(＝O)[C@H](Cc1cnc[nH]1)NC(＝O)COc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Br)cc(F)cc4Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)NCCN(C)C)Nc3c(Br)cc(F)cc3Br

CN(CC[N+](C)(C)C)C(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(F)cc3Br

OC(＝O)[C@H](Cc1ccccc1)NC(＝O)CCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Br)cc(F)cc4Br

NC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(F)cc3Br

CN(C)CCNC(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(F)cc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N3CCN(C)CC3)Nc4c(Br)cc(F)cc4Br

OC(＝O)CNC(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(F)cc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N3CCNCC3)Nc4c(Br)cc(F)cc4Br

C[C@@H](O)[C@H](NC(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(F)cc3Br)C(＝O)O

OC(＝O)[C@H](Cc1cnc[nH]1)NC(＝O)CCCCCOc2c(OCF)ccc3C(＝CC(＝O)Nc23)Nc4c(Br)cc(F)cc4Br

CCNCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(O)cc3Br

Oc1cc(Br)c(NC2＝CC(＝O)Nc3c(OCCCCN4CCCC4)c(OC(F)(F)F)ccc23)c(Br)c1

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN3CCC(F)CC3)Nc4c(Br)cc(O)cc4Br

CCCNCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(O)cc3Br

Oc1cc(Br)c(NC2＝CC(＝O)Nc3c(OCCCCCN4CCCC4)c(OC(F)(F)F)ccc23)c(Br)c1

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN3CCC(F)(F)C3)Nc4c(Br)cc(O)cc4Br

Oc1cc(Br)c(NC2＝CC(＝O)Nc3c(OCCCCCOc4ccccn4)c(OCF)ccc23)c(Br)c1

CN(C)CCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(O)cc3Br

Oc1cc(Br)c(NC2＝CC(＝O)Nc3c(OCCCCCCN4CCOCC4)c(OCF)ccc23)c(Br)c1

Oc1cc(Br)c(NC2＝CC(＝O)Nc3c(OCCCCCCn4cccc4)c(OC(F)(F)F)ccc23)c(Br)c1

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N(C)CCCN(C)C)Nc3c(Br)cc(O)cc3Br

CN1CCN(CC1)C(＝O)COc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Br)cc(O)cc4Br

NCCCC[C@H](NC(＝O)COc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(O)cc3Br)C(＝O)O

OC(＝O)[C@H](Cc1cnc[nH]1)NC(＝O)COc2c(OCF)ccc3C(＝CC(＝O)Nc23)Nc4c(Br)cc(O)cc4Br

OC(＝O)CNC(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(O)cc3Br

CSCC[C@H](NC(＝O)CCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(O)cc3Br)C(＝O)O

NC(＝N)NCCC[C@H](NC(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc 12)Nc3c(Br)cc(O)cc3Br)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H](CC(＝O)N)C(＝O)O)Nc3c(Br)cc(O)cc3Br

CN(C)CCNC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc 12)Nc3c(Br)cc(O)cc3Br

C[C@@H](O)[C@H](NC(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(O)cc3Br)C(＝O)O

OC(＝O)[C@H](Cc1cnc[nH]1)NC(＝O)CCCCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Br)cc(O)cc4Br

CNCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(cc3Br)C(＝O)O

CCN(C)CCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(cc3Br)C(＝O)O

OC(＝O)c1cc(Br)c(NC2＝CC(＝O)Nc3c(OCCCCN4CCC(F)C4)c(OC(F)(F)F)ccc23)c(Br)c1

OC(＝O)c1cc(Br)c(NC2＝CC(＝O)Nc3c(OCCCCCN4CCCC(F)(F)C4)c(OCF)ccc23)c(Br)c1

OC(＝O)c1cc(Br)c(NC2＝CC(＝O)Nc3c(OCCCCCn4cnnn4)c(OC(F)F)ccc23)c(Br)c1COCCOCCOCCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(cc3Br)C(＝O)O

CNCCCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(cc3Br)C(＝O)O

COCCN(C)CCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(cc3Br)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCN3CCCC(F)(F)C3)Nc4c(Br)cc(cc4Br)C(＝O)O

OCCOCCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(cc3Br)C(＝O)O

CN(C)CCNC(＝O)CCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(cc3Br)C(＝O)O

OC(＝O)c1cc(Br)c(NC2＝CC(＝O)Nc3c(OCCCC(＝O)N4CCNCC4)c(OC(F)F)ccc23)c(Br)c1

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H](CO)C(＝O)O)Nc3c(Br)cc(cc3Br)C(＝O)O

CN(C)CCNC(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(cc3Br)C(＝O)O

CN(CC[N+](C)(C)C)C(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(cc3Br)C(＝O)O

C[C@H](NC(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cc(cc3Br)C(＝O)O)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](CCCCN)C(＝O)O)Nc3c(Br)cc(cc3Br)C(＝O)O

CCN(CC)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc 12)Nc3c(C)cncc3C

CCCCN(C)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3C

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN3CCCC(F)(F)C3)Nc4c(C)cncc4C

Cc1cncc(C)c1NC2＝CC(＝O)Nc3c(OCCCCn4nccn4)c(OC(F)F)ccc23

Cc1cncc(C)c1NC2＝CC(＝O)Nc3c(OCCCCn4cncn4)c(OC(F)(F)F)ccc23

CNCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3C

COCCN(C)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3C

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN3CCC(F)CC3)Nc4c(C)cncc4C

Cc1cncc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCn4nccn4)c(OC(F)(F)F)ccc23

Cc1cncc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCOc4cccnc4)c(OC(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCN(C)C)Nc3c(C)cncc3C

CCNCCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3C

CCN(C)CCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3C

CCCCN(C)CCCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3C

C[C@H](NC(＝O)COc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3C)C(＝O)O

Cc1cncc(C)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N4CCC[C@H]4C(＝O)O)c(OC(F)(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N[C@@H](Cc3ccccc3)C(＝O)O)Nc4c(C)cncc4C

C[C@@H](O)[C@H](NC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3C)C(＝O)O

Cc1cncc(C)c1NC2＝CC(＝O)Nc3c(OCCCC(＝O)OCC[N+](C)(C)C)c(OC(F)F)ccc23

CN(CC[N+](C)(C)C)C(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3C

CN(C)CCCN(C)C(＝O)CCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3C

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N3CCN(C)CC3)Nc4c(C)cncc4C

Cc1cncc(C)c1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)N)c(OC(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N3CCNCC3)Nc4c(C)cncc4C

Cc1cncc(C)c1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)N[C@@H](CO)C(＝O)O)c(OCF)ccc23

C[C@@H](O)[C@H](NC(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3C)C(＝O)O

Cc1cncc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N4CCNCC4)c(OCF)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)NCC(＝O)O)Nc3c(C)cncc3C

Cc1cncc(C)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N4CCC[C@H]4C(＝O)O)c(OC(F)F)ccc23

CSCC[C@H](NC(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3C)C(＝O)O

Cc1cncc(F)c1NC2＝CC(＝O)Nc3c(OCCCCN4CCCCC4)c(OC(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN3CCC(F)(F)CC3)Nc4c(C)cncc4F

COCCOCCOCCOCCCCOc1c2NC(＝O)C＝C(Nc3c(C)cncc3F)c2ccc1OCF

COCCOCCOCCOCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3F

CN(C)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3F

Cc1cncc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCN4CCC(F)(F)CC4)c(OCF)ccc23

Cc1cncc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCn4cccn4)c(OC(F)(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCOCCO)Nc3c(C)cncc3F

CNCCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3F

CCN(CC)CCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3F

Cc1cncc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCCN4CCCCC4)c(OC(F)(F)F)ccc23

COCCOCCOCCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3F

Cc1cncc(F)c1NC2＝CC(＝O)Nc3c(OCC(＝O)OCC[N+](C)(C)C)c(OCF)ccc23

CN1CCN(CC1)C(＝O)COc2c(OC(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(C)cncc4F

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N[C@@H](C(C)C)C(＝O)O)Nc3c(C)cncc3F

Cc1cncc(F)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N[C@@H](Cc4c[nH]c5ccccc45)C(＝O)O)c(OC(F)(F)F)ccc23

Cc1cncc(F)c1NC2＝CC(＝O)Nc3c(OCCCC(＝O)NCC[N+](C)(C)C)c(OC(F)F)ccc23

CN1CCN(CC1)C(＝O)CCCOc2c(OCF)ccc3C(＝CC(＝O)Nc23)Nc4c(C)cncc4F

CN1CCN(CC1)C(＝O)CCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(C)cncc4F

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H](C)C(＝O)O)Nc3c(C)cncc3F

CN(C)CCN(C)C(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc 12)Nc3c(C)cncc3F

CN(CC[N+](C)(C)C)C(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3F

CN1CCN(CC1)C(＝O)CCCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(C)cncc4F

CSCC[C@H](NC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3F)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N[C@@H](CCC(＝O)N)C(＝O)O)Nc3c(C)cncc3F

CN(C)CCN(C)C(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3F

Cc1cncc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N[C@@H](CO)C(＝O)O)c(OCF)ccc23

Cc1cncc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N[C@@H](CO)C(＝O)O)c(OC(F)(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](CCCCN)C(＝O)O)Nc3c(C)cncc3F

Cc1cncc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCN4CCOCC4)c(OC(F)(F)F)ccc23

Cc1cncc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCN4CCC(F)CC4)c(OC(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCN3CCC(F)(F)C3)Nc4c(C)cncc4Cl

Cc1cncc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCOc4cccnc4)c(OCF)ccc23

CCN(CC)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Cl

Cc1cncc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCn4ccnc4)c(OC(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCn3ccnn3)Nc4c(C)cncc4Cl

Cc1cncc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCOc4ccncc4)c(OCF)ccc23

CNCCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Cl

Cc1cncc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCCN4CCCC(F)(F)C4)c(OC(F)(F)F)ccc23

Cc1cncc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCCOc4ccncc4)c(OC(F)F)ccc23

Cc1cncc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCCOCCO)c(OCF)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)OCCN(C)C)Nc3c(C)cncc3Cl

Cc1cncc(Cl)c1NC2＝CC(＝O)Nc3c(OCC(＝O)OCC[N+](C)(C)C)c(OC(F)F)ccc23

Cc1cncc(Cl)c1NC2＝CC(＝O)Nc3c(OCC(＝O)OCC[N+](C)(C)C)c(OC(F)(F)F)ccc23

C[C@@H](O)[C@H](NC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Cl)C(＝O)O

CN(C)CCCN(C)C(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Cl

CN(CCC[N+](C)(C)C)C(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H](C(C)C)C(＝O)O)Nc3c(C)cncc3Cl

Cc1cncc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCC(＝O)N[C@@H](CCC(＝O)N)C(＝O)O)c(OCF)ccc23

CN(C)CCNC(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)NCC[N+](C)(C)C)Nc3c(C)cncc3Cl

Cc1cncc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)N[C@@H](CCCNC(＝N)N)C(＝O)O)c(OCF)ccc23

Cc1cncc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCC(＝O)N[C@@H](CC(＝O)O)C(＝O)O)c(OC(F)F)ccc23

CN(C)CCOC(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Cl

Cc1cncc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)NCC(＝O)O)c(OCF)ccc23

C[C@H](NC(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Cl)C(＝O)O

Cc1cncc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N[C@@H](Cc4c[nH]c5ccccc45)C(＝O)O)c(OCF)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](Cc3cnc[nH]3)C(＝O)O)Nc4c(C)cncc4Cl

Cc1cncc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N[C@@H](Cc4cnc[nH]4)C(＝O)O)c(OC(F)F)ccc23

Cc1cncc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCN4CCCC(F)C4)c(OC(F)(F)F)ccc23

Cc1cncc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCN4CCCC(F)(F)C4)c(OC(F)F)ccc23

Cc1cncc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCN4CCC(F)(F)C4)c(OCF)ccc23

Cc1cncc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCOc4ccncc4)c(OCF)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCOCCO)Nc3c(C)cncc3Br

CN(C)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Br

CCN(CC)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Br

CCCCCN(C)CCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Br

Cc1cncc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCN4CCOCC4)c(OC(F)(F)F)ccc23

COCCOCCOCCOCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Br

Cc1cncc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCCN4CCC(F)CC4)c(OCF)ccc23

Cc1cncc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCCN4CCCC(F)(F)C4)c(OC(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCn3ccnn3)Nc4c(C)cncc4Br

Cc1cncc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCCOc4ccncc4)c(OC(F)F)ccc23

COCCOCCOCCCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Br

CN(C)CCOC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N(C)CC[N+](C)(C)C)Nc3c(C)cncc3Br

Cc1cncc(Br)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N[C@@H](Cc4c[nH]c5ccccc45)C(＝O)O)c(OC(F)(F)F)ccc23

Cc1cncc(Br)c1NC2＝CC(＝O)Nc3c(OCC(＝O)N[C@@H](CC(＝O)O)C(＝O)O)c(OC(F)F)ccc23

CC[C@H](C)[C@H](NC(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Br)C(＝O)O

CC[C@H](C)[C@H](NC(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Br)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N3CCC[C@H]3C(＝O)O)Nc4c(C)cncc4BrCc1cncc(Br)c1NC2＝CC(＝O)Nc3c(OCCCC(＝O)N[C@@H](CCCNC(＝N)N)C(＝O)O)c(OCF)ccc23

CC(C)[C@H](HC(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Br)C(＝O)O

C[C@@H](O)[C@H](HC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc 12)Nc3c(C)cncc3Br)C(＝O)O

C[C@@H](O)[C@H](NC(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Br)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N[C@@H](Cc3cnc[nH]3)C(＝O)O)Nc4c(C)cncc4Br

CN(C)CCNC(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Br

CN(CCC[N+](C)(C)C)C(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(C)cncc3Br

Cc1cncc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCC(＝O)N4CCNCC4)c(OCF)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N3CCC[C@H]3C(＝O)O)Nc4c(C)cncc4Br

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCN3CCCCC3)Nc4c(F)cncc4F

FC(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCN3CCCC(F)C3)Nc4c(F)cncc4F

FC1CCN(CCCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(F)cncc4F)Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCn3nccn3)Nc4c(F)cncc4F

CCCNCCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3F

CCN(C)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3F

COCCN(C)CCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3F

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCn3cnnc3)Nc4c(F)cncc4F

COCCN(C)CCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3F

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCN3CCC(F)CC3)Nc4c(F)cncc4F

Fc1cncc(F)c1NC2＝CC(＝O)Nc3c(OCCCCCCn4ncnn4)c(OC(F)(F)F)ccc23

FC(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCOc3ccccn3)Nc4c(F)cncc4F

COCCOCCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3F

C[N+](C)(C)CCNC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N(C)CCC[N+](C)(C)C)Nc3c(F)cncc3F

CC(C)C[C@H](NC(＝O)COc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3F)C(＝O)O

OC(＝O)[C@H](Cc1c[nH]c2ccccc12)NC(＝O)COc3c(OCF)ccc4C(＝CC(＝O)Nc34)Nc5c(F)cncc5F

OC(＝O)[C@H](Cc1cnc[nH]1)NC(＝O)COc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(F)cncc4F

NC(＝O)CC[C@H](NC(＝O)COc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3F)C(＝O)O

CC(C)[C@H](NC(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3F)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c 1OCCCC(＝O)N3CCC[C@H]3C(＝O)O)Nc4c(F)cncc4F

OC(＝O)[C@H](Cc1c[nH]c2ccccc12)NC(＝O)CCCOc3c(OCF)ccc4C(＝CC(＝O)Nc34)Nc5c(F)cncc5F

OC(＝O)[C@H](Cc1cnc[nH]1)NC(＝O)CCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(F)cncc4F

NC(＝O)CC[C@H](NC(＝O)CCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3F)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)NCCN(C)C)Nc3c(F)cncc3F

CC[C@H](C)[C@H](NC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3F)C(＝O)O

CSCC[C@H](NC(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc 12)Nc3c(F)cncc3F)C(＝O)O

CSCC[C@H](NC(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3F)C(＝O)O

NC(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3F

CN(C)CCN(C)C(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3F

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N(C)CCCN(C)C)Nc3c(F)cncc3F

NCCCC[C@H](NC(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3F)C(＝O)O

CCCCN(C)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Cl

CCCCCN(C)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Cl

FC(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCn3cnnn3)Nc4c(F)cncc4Cl

COCCOCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Cl

OCCOCCOCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN(C)C)Nc3c(F)cncc3Cl

CN(C)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Cl

CCN(C)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Cl

CCN(C)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Cl

NC(＝N)NCCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCn3cccc3)Nc4c(F)cncc4Cl

Fc1cncc(Cl)c1NC2＝CC(＝O)Nc3c(OCCCCCCOc4cccnc4)c(OC(F)(F)F)ccc23

COCCOCCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Cl

C[C@H](NC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Cl)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N[C@@H](CC(C)C)C(＝O)O)Nc3c(F)cncc3Cl

NCCCC[C@H](NC(＝O)COc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Cl)C(＝O)O

NC(＝N)NCCC[C@H](NC(＝O)COc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Cl)C(＝O)O

NC(＝N)NCCC[C@H](NC(＝O)COc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Cl)C(＝O)O

CN(C)CCN(C)C(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H](C)C(＝O)O)Nc3c(F)cncc3Cl

OC(＝O)[C@@H]1CCCN1C(＝O)CCCOc2c(OCF)ccc3C(＝CC(＝O)Nc23)Nc4c(F)cncc4Cl

NC(＝O)C[C@H](NC(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Cl)C(＝O)O

OC(＝O)[C@@H]1CCCN1C(＝O)CCCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(F)cncc4Cl

OC(＝O)[C@H](Cc1ccccc1)NC(＝O)CCCCOc2c(OC(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(F)cncc4Cl

OC(＝O)[C@H](Cc1cnc[nH]1)NC(＝O)CCCCOc2c(OCF)ccc3C(＝CC(＝O)Nc23)Nc4c(F)cncc4Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N[C@@H](CC(＝O)N)C(＝O)O)Nc3c(F)cncc3Cl

NC(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](CC(C)C)C(＝O)O)Nc3c(F)cncc3Cl

OC(＝O)[C@H](Cc1c[nH]c2ccccc12)NC(＝O)CCCCCOc3c(OC(F)(F)F)ccc4C(＝CC(＝O)Nc34)Nc5c(F)cncc5Cl

OC(＝O)C[C@H](NC(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Cl)C(＝O)O

Fc1cncc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCN4CCCCC4)c(OC(F)(F)F)ccc23

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCn3nccn3)Nc4c(F)cncc4Br

COCCOCCOCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Br

OCCOCCOCCOCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN(C)C)Nc3c(F)cncc3Br

Fc1cncc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCN4CCCC4)c(OC(F)(F)F)ccc23

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN3CCC(F)(F)C3)Nc4c(F)cncc4Br

FC(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCCOc3ccncc3)Nc4c(F)cncc4Br

OCCOCCOCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Br

NCCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCNC(＝N)N)Nc3c(F)cncc3Br

Fc1cncc(Br)c1NC2＝CC(＝O)Nc3c(OCCCCCCN4CCCCC4)c(OC(F)(F)F)ccc23

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCOc3ccncc3)Nc4c(F)cncc4Br

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)NCC[N+](C)(C)C)Nc3c(F)cncc3Br

CC(C)C[C@H](NC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Br)C(＝O)O

CC[C@H](C)[C@H](NC(＝O)COc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Br)C(＝O)O

OC(＝O)[C@H](Cc1ccccc1)NC(＝O)COc2c(OC(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(F)cncc4Br

NCCCC[C@H](NC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Br)C(＝O)O

CN(CC[N+](C)(C)C)C(＝O)CCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Br

CC(C)[C@H](NC(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Br)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H](CCCNC(＝N)N)C(＝O)O)Nc3c(F)cncc3Br

NC(＝O)C[C@H](NC(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Br)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N(C)CCC[N+](C)(C)C)Nc3c(F)cncc3Br

C[C@H](NC(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Br)C(＝O)O

C[C@H](NC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Br)C(＝O)O

CC(C)C[C@H](NC(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Br)C(＝O)O

C[N+](C)(C)CCOC(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Br

CN(C)CCNC(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)NCC[N+](C)(C)C)Nc3c(F)cncc3Br

C[N+](C)(C)CCNC(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(F)cncc3Br

CN(C)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCOCCO)Nc3c(Cl)cncc3Cl

OCCOCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Cl

OCCOCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN)Nc3c(Cl)cncc3Cl

FC(F)(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN3CCCC(F)(F)C3)Nc4c(Cl)cncc4Cl

FC(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCCN3CCC(F)C3)Nc4c(Cl)cncc4Cl

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCn3nccn3)Nc4c(Cl)cncc4Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCn3cnnc3)Nc4c(Cl)cncc4Cl

FC1CCN(CCCCCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Cl)cncc4Cl)CC1

FC(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCN3CCC(F)(F)CC3)Nc4c(Cl)cncc4Cl

OCCOCCOCCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCOCCOCCOCCO)Nc3c(Cl)cncc3Cl

CN(C)CCOC(＝O)COc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Cl

C[N+](C)(C)CCNC(＝O)COc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Cl

FCOc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N3CCNCC3)Nc4c(Cl)cncc4Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N[C@@H](Cc3c[nH]c4ccccc34)C(＝O)O)Nc5c(Cl)cncc5Cl

OC(＝O)[C@H](Cc1c[nH]c2ccccc12)NC(＝O)COc3c(OC(F)F)ccc4C(＝CC(＝O)Nc34)Nc5c(Cl)cncc5Cl

OC(＝O)[C@H](Cc1c[nH]c2ccccc12)NC(＝O)CCCOc3c(OCF)ccc4C(＝CC(＝O)Nc34)Nc5c(Cl)cncc5Cl

OC[C@H](NC(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Cl)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H]([C@@H](C)O)C(＝O)O)Nc3c(Cl)cncc3Cl

OC(＝O)C[C@H](NC(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Cl)C(＝O)O

OC(＝O)CNC(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Cl

NCCCC[C@H](NC(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Cl)C(＝O)O

OC(＝O)CC[C@H](NC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Cl)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N[C@@H](CCC(＝O)N)C(＝O)O)Nc3c(Cl)cncc3Cl

NC(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)OCCN(C)C)Nc3c(Cl)cncc3Cl

C[C@@H](O)[C@H](NC(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Cl)C(＝O)O

NC(＝O)C[C@H](NC(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Cl)C(＝O)O

CCCCN(C)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Br

FC1CCN(CCCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Cl)cncc4Br)Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCn3cccc3)Nc4c(Cl)cncc4Br

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCn3ccnc3)Nc4c(Cl)cncc4Br

FC1CCN(CCCCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Cl)cncc4Br)Cl

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCn3cnnc3)Nc4c(Cl)cncc4Br

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCn3ncnn3)Nc4c(Cl)cncc4Br

COCCOCCOCCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Br

NCCCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Br

COCCN(C)CCCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Br

FC(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCN 3CCCCC3)Nc4c(Cl)cncc4Br

COCCOCCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Br

NC(＝O)COc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)OCC[N+](C)(C)C)Nc3c(Cl)cncc3Br

CC(C)[C@H](NC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Br)C(＝O)O

OC(＝O)[C@H](Cc1ccc(O)cc1)NC(＝O)COc2c(OC(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Cl)cncc4Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)N[C@@H](C)C(＝O)O)Nc3c(Cl)cncc3Br

OC(＝O)[C@H](Cc1ccc(O)cc1)NC(＝O)CCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Cl)cncc4Br

OC(＝O)C[C@H](NC(＝O)CCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Br)C(＝O)O

OC(＝O)CC[C@H](NC(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Br)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)OCC[N+](C)(C)C)Nc3c(Cl)cncc3Br

CN(C)CCCN(C)C(＝O)CCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Br

CSCC[C@H](NC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Br)C(＝O)O

OC[C@H](NC(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Br)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](Cc3ccc(O)cc3)C(＝O)O)Nc4c(Cl)cncc4Br

CSCC[C@H](NC(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Br)C(＝O)O

OC(＝O)C[C@H](NC(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Br)C(＝O)O

NC(＝O)CC[C@H](NC(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Cl)cncc3Br)C(＝O)O

NC(＝N)NCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cncc3Br

FC(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCN3CCC(F)CC3)Nc4c(Br)cncc4Br

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCn3ccnn3)Nc4c(Br)cncc4Br

COCCOCCOCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cncc3Br

CCCNCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cncc3Br

CCCCN(C)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cncc3Br

FC1CCN(CCCCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Br)cncc4Br)Cl

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCn3ccnn3)Nc4c(Br)cncc4Br

CCCCN(C)CCCCCCOc1c(OC)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cncc3Br

FC(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCN3CCCCC3)Nc4c(B r)cncc4Br

FC(F)(F)Oc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCn3cccc3)Nc4c(Br)cncc4Br

FCOc1ccc2C(＝CC(＝O)Nc2c1OCCCCCCn3ncnn3)Nc4c(Br)cncc4Br

OC(＝O)CNC(＝O)COc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cncc3Br

COc1ccc2C(＝CC(＝O)Nc2c1OCC(＝O)N[C@@H](C)C(＝O)O)Nc3c(Br)cncc3Br

OC(＝O)[C@H](Cc1ccccc1)NC(＝O)COc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Br)cncc4Br

OC(＝O)[C@H](Cc1ccc(O)cc1)NC(＝O)COc2c(OC(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Br)cncc4Br

COc1ccc2C(＝CC(＝O)Nc2c1OCCCC(＝O)NCCN(C)C)Nc3c(Br)cncc3Br

CN(C)CCCN(C)C(＝O)CCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cncc3Br

OC(＝O)[C@H](Cc1ccc(O)cc1)NC(＝O)CCCOc2c(OC(F)(F)F)ccc3C(＝CC(＝O)Nc23)Nc4c(Br)cncc4Br

OC[C@H](NC(＝O)CCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cncc3Br)C(＝O)O

OC[C@H](NC(＝O)CCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cncc3Br)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCC(＝O)N(C)CC[N+](C)(C)C)Nc3c(Br)cncc3Br

CC(C)C[C@H](NC(＝O)CCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cncc3Br)C(＝O)O

OC(＝O)[C@@H]1CCCN1C(＝O)CCCCOc2c(OCF)ccc3C(＝CC(＝O)Nc23)Nc4c(Br)cncc4Br

C[C@@H](O)[C@H](NC(＝O)CCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cncc3Br)C(＝O)O

CN(C)CCN(C)C(＝O)CCCCCOc1c(OCF)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cncc3Br

C[C@H](NC(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc 12)Nc3c(Br)cncc3Br)C(＝O)O

CC(C)[C@H](NC(＝O)CCCCCOc1c(OC(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cncc3Br)C(＝O)O

COc1ccc2C(＝CC(＝O)Nc2c1OCCCCCC(＝O)N[C@@H](Cc3ccccc3)C(＝O)O)Nc4c(Br)cncc4Br

NC(＝O)CC[C@H](NC(＝O)CCCCCOc1c(OC(F)(F)F)ccc2C(＝CC(＝O)Nc12)Nc3c(Br)cncc3Br)C(＝O)O

The chemical compound of embodiment 1-14 describes in following mensuration as the activity of PDE4 inhibitor.Expect that above-mentioned other chemical compounds of listing (do not prepare as yet and/or test) also have activity in this measures.

New PDE/AK biological activity determination scheme

Phosphodiesterase is by being hydrolyzed to cAMP the activity that adenylic acid (AMP) is regulated second message,second messenger's cyclic adenosine monophosphate (cAMP).We have developed the activity that new coupling PDE/AK bioluminescence high throughput assay method is measured phosphodiesterase.In PDE/AK measured, the phosphate transferase activity by adenylate kinase (being also referred to as ADK or myokinase) was converted into adenosine diphosphate (ADP) with the AMP that di-phosphate ester enzyme hydrolysis cAMP produces.Adenylate kinase meeting 1 mole of AMP of catalysis and 1 mole of ATP change into 2 moles of ADP.Therefore, AMP can cause the minimizing of ATP subsequently to the conversion of ADP.Use luciferase in reaction, the minimizing of ATP concentration can be used as light output and monitors, and luciferase needs ATP to produce light.PDE/AK measures and uses luciferase, and the ATP that its catalysis exists from reactant mixture produces light.The AMP level that exists in the amount of the light of emission and the reaction is inversely proportional to.The chemical compound of test is with the phosphodiesterase incubation, and phosphodiesterase inhibitor can reduce the speed of cAMP hydrolysis and reduce the generation subsequently of AMP.Therefore, phosphodiesterase inhibitor can reduce ATP to the conversion of ADP and produce maximum luminous.

Can be according to functional usefulness (functional potency) SCREENED COMPOUND in the external biological chemical assay, this functional usefulness is that chemical compound suppresses the active ability of phosphodiesterase (PDE).Utilize new coupling PDE/AK to measure and measure the inhibition activity of chemical compound the PDE isoform.The catalyst structure domain of PDE4B is fused to aminoterminal six-histidine affinity tag and purification.PDE4B enzyme and chemical compound incubation 10 minutes.In this PDE enzymatic mixture, add ring AMP substrate, ATP and adenylate kinase then, and incubation 45 minutes at room temperature.Add commercial ATP detection assay (Perkin Elmer ' seasyLite ATP detectable) then to measure the relative amount of the ATP that exists in the reaction.Behind the incubation 10 minutes, use Perkin Elmer Viewlux or Molecular Devices Acquest or the quantitative luminous signal of Analyst.Use roflumilast and rolipram as positive control in the mensuration.

Available any cAMP dependency phosphodiesterase carries out PDE/AK to be measured, and can be 96, carry out on 384-or 1536 orifice plates.Different with other phosphodiesterase activities mensuration, PDE/AK measures substrate, pearl or the antibody that does not need radioactive substrates, modification, and they all have harm separately.Particularly, the special experimental design of needs of the radioactive substrates during phosphodiesterase activity is measured is used for operation and Waste disposal, and has reduced flux.The substrate of modifying has increased change and the bonded additional complexity of phosphodiesterase catalytic site.Fluorescence is modified substrate may cause the fluorescence illusion, its meeting interference measurement result's interpretation.The pearl of use and cAMP or AMP selective binding may cause the additional complexity in the reagent operation.The antibody of use and cAMP or AMP selective binding is very expensive, and has relatively little signal to noise ratio.Therefore, for known method, new PDE/AK of the present invention measures and has represented simple, cost-effective possibility.

In addition, the mechanism of PDE/AK mensuration makes it have advantage than other phosphodiesterase activities mensuration.CAMP concentration and bioluminescence are output in the conventional determining (as CambrexBiosciences ' s PDELight) of inverse ratio therein, the di-phosphate ester enzyme catalysis hydrolysis of cAMP to AMP, AMP is subsequently converted to ATP, and ATP is consumed by luciferase, causes the bioluminescence output that increases.Phosphodiesterase inhibitor stops cAMP to export to the hydrolysis of AMP and the bioluminescence that causes subsequently reducing.Yet, in conventional determining, can will show that luciferase suppresses active chemical compound and counts the false positive that PDE suppresses.On the contrary, new PDE/AK does not measure can count the false positive that PDE suppresses to the luciferase inhibitor, because the active inhibition of PDE can cause noctilcent increase.But, the chemical compound that can suppress PDE and luciferase simultaneously can cause false negative.In new PDE/AK measures, suppress the chemical compound of adenylate kinase and can be counted false positive.The data of using and compare them of these two types of mensuration can produce abundant more and reliable more data set.

Therefore, this paper is contained and is used to detect the method that suppresses with quantitative PDE, and it uses and the link coupled adenylate kinase of ATP-consumption mensuration thing.

In certain embodiments, said method comprising the steps of:

1. at first with PDE or its isolating isoform and chemical compound incubation to be tested;

2. add ATP, cAMP and AK substrate;

3. the described PDE of incubation for the second time;

4. with instrument (means) coupling of reading ATP-consumption; And

5. reading.

In further embodiment, described first time, incubation was between about 5 to about 15 minutes; In embodiment further, described first time, incubation was about 10 minutes.

In further embodiment, described second time, incubation was above about 30 minutes; In embodiment further, described adequate time length is between about 30 minutes to about one hour; In embodiment further, adequate time length is about 45 minutes.

In further embodiment, the described instrument of reading is a luciferase assay.In embodiment further, described luciferase assay is that Perkin Elmer easyLite measures.

In further embodiment, described reading carries out on the machine that detects luminous signal.In embodiment further, described machine is selected from Perkin Elmer Viewlux, MolecularDevices Acquest and Molecular Devices Analyst.

The results are shown in the following table 1.

Table 1. biological activity

Embodiment number	IC ₅₀+ indication≤1 μ M-indication＞1 μ M
Embodiment number	IC ₅₀+ indication≤1 μ M-indication＞1 μ M	1	+
2	+	1	+
2	+	3	+
4	+	3	+
4	+	5	+
6	+	5	+
6	+	7	+
8	+	7	+
8	+	9	+
10	+	9	+
10	+	11	+
12	+	11	+
12	+	13	+
14	+	13	+

Measure in the body

The inductive xerophthalmia of lachrymal gland inflammation in the rabbit

The more detailed description of algoscopy used herein can be at Naglehout, people such as TJ, 2005, " Preservation of Tear Film Integrity and Inhibition of Corneal Injury byDexamethasone in a Rabbit Model of Lacrimal Gland Inflammation-InducedDry Eye ", J.Ocular Pharm.Ther., 21:2.139-148 in find, its disclosure is hereby incorporated by reference, and writes this paper in full as it.

The initiation of xerophthalmia and processing

(n=4/group) is divided into processed group at random with rabbit, and brings into use maxidex carrier or testing drug to carry out local BID administration the previous day in the initiation xerophthalmia.Every rabbit both sides lachrymal gland is accepted saline or ConA (300 μ g/30 μ l) injection, and carries out local BID ocular administration in whole research continuously.

Corneal dyeing

In lachrymal gland injection the last 1-2 hour, by will clear-headed rabbit placing environmental cabinet (environmentalchamber) (10-15% humidity/72) beginning drying.After being exposed to this dry environment in continuous 72 hours, with Animal Anesthesia, palpebra inferior and mentioning in the stitching is to form cornea/conjunctiva calices (cup).In this calices, add methylene blue dye (1mL, 1%, soluble in water), continue 3 minutes, then by using 200mL

Superfluous dyestuff is removed in cleaning.Then with the eye dyeing of same operation with offside.Behind the staining procedure, immediately rabbit is sentenced euthanasia and excision eye.Use the trepan isolated cornea, the 9.5-mm hole of cornea is placed in 2mL acetone/saturated sodium sulfate (7: 3, volume ratio).Under 660nm, measure the absorbance of the dyestuff that extracts.

Breakup time of tear film

Quantitative TBUT in the independent group of processed animal.The 5 μ L fluorescein sodium and the eyelid of manually blinking are usually measured TBUT to distribute fluorescence in the tear film by instiling to calices (cul de sac).Under slit lamp, observe, make eye keep opening and write down one or more by this black speck or striped appears at time in the precorneal tear film.ConA injected back 3 days, and rabbit is sentenced euthanasia.

The data that are reported as NT refer to the embodiment that do not test as yet.

Table 2. activity in vivo

By above description, those skilled in the art can easily determine substitutive characteristics of the present invention, and can be under the situation that does not deviate from its spirit and scope, and the present invention is carried out multiple variation and modifies to adapt to multiple application and situation.

Claims

1. the method that suppresses PDE4, described method comprise PDE4 contacted with compound or its salt, ester or the prodrug of structural formula IV,

Wherein:

X ³Be (CR ¹⁸R ¹⁹);

R ¹And R ²Be independently selected from-(CH ₂) _sG ¹G ²G ³, acyl group, acyl group alkyl, carboxyalkyl, cyano group alkyl, alkoxyl, alkoxyalkyl, amidoalkyl, amino, alkyl, alkyl alkoxy, aminoalkyl, thiazolinyl, alkynyl, carboxyl, carboxyalkyl, ether, assorted alkyl, haloalkyl, cycloalkyl, cycloalkyl-alkyl, Heterocyclylalkyl, Heterocyclylalkyl alkyl, aralkyl, aryl, guanidine, heteroaryl, heteroarylalkyl, hydrogen and hydroxyalkyl, wherein any one all can randomly be replaced;

S is 1-8;

W is selected from O, N (R ⁷), C (O) N (R ⁷) and SO _q

M, n and q are 0,1 or 2 independently;

P is 1 or 2;

R ⁷, R ⁸, R ⁹, R ¹⁰, R ¹¹, R ¹²And R ¹³Be selected from hydrogen and the optional low alkyl group that replaces independently of one another;

R ¹⁴Be selected from hydrogen, halogen, hydroxyl, low alkyl group, hydroxyalkyl, aminoalkyl and haloalkyl; And

2. the method for the disease of treatment PDE4 mediation, described method comprise to its compound or its salt, ester or the prodrug of formula IV of patient's drug treatment effective dose of needs,

Wherein:

X ³Be (CR ¹⁸R ¹⁹);

S is 1-8;

W is selected from O, N (R ⁷), C (O) N (R ⁷) and SO _q

M, n and q are 0,1 or 2 independently;

P is 1 or 2;

3. method as claimed in claim 2, the disease of wherein said PDE4 mediation is an oculopathy.

4. method as claimed in claim 3, wherein said oculopathy be selected from xerophthalmia, glaucoma, cornea rebirth blood vesselization, optic neuritis, sjogren syndrome, ganglia retinae degeneration, eye ischemia, retinitis, retinopathy, uveitis, eye photophobia with relevant inflammation and the pain of ocular tissue's acute injury.

5. method as claimed in claim 2, wherein said PDE4 is the PDE4B hypotype.

6. treat the method for the disease of PDE4 mediation, described method comprises administration:

A. treat compound or its salt, ester or the prodrug of the structural formula IV of effective dose,

Wherein:

X ³Be (CR ¹⁸R ¹⁹);

S is 1-8;

W is selected from O, N (R ⁷), C (O) N (R ⁷) and SO _q

M, n and q are 0,1 or 2 independently;

P is 1 or 2;

R ¹⁸And R ¹⁹Be selected from hydrogen, halogen, low alkyl group, haloalkyl, alkoxyl, halogenated alkoxy, amino, aminoalkyl, aminoalkoxy and key independently of one another; With

B. another therapeutic agent.

7. the chemical compound of structural formula V, or its salt, ester or prodrug,

Wherein:

R ¹And R ²Be independently selected from-(CH ₂) _sG ¹G ²G ³, acyl group, acyl group alkyl, carboxyalkyl, cyano group alkyl, alkoxyl, alkoxyalkyl, amidoalkyl, amino, alkyl, alkyl alkoxy, aminoalkyl, thiazolinyl, alkynyl, carboxyl, carboxyalkyl, ether, assorted alkyl, haloalkyl, cycloalkyl, cycloalkyl-alkyl, Heterocyclylalkyl, Heterocyclylalkyl alkyl, aralkyl, aryl, guanidine, heteroaryl, heteroarylalkyl and hydroxyalkyl, wherein any one all can randomly be replaced;

S is 1-8;

W is selected from O, N (R ⁷), C (O) N (R ⁷) and SO _q

M, n and q are 0,1 or 2 independently;

P is 1 or 2;

R ⁷And R ¹⁴Be independently selected from hydrogen, halogen, hydroxyl, low alkyl group, hydroxyalkyl, haloalkyl and aminoalkyl;

R ⁸, R ⁹, R ¹⁰, R ¹¹, R ¹²And R ¹³Be independently selected from hydrogen and the optional low alkyl group that replaces;

And R ¹⁹Be selected from hydrogen, halogen, low alkyl group and haloalkyl.

8. chemical compound as claimed in claim 7, wherein R ⁷And R ¹⁴Be independently selected from hydrogen, halogen and the optional low alkyl group that replaces.

9. chemical compound as claimed in claim 8, wherein R ⁶Be selected from aryl and heteroaryl, described aryl and heteroaryl all can randomly be replaced.

10. chemical compound as claimed in claim 9, wherein R ¹⁹Be hydrogen.

11. chemical compound as claimed in claim 10, wherein R ⁶Be selected from phenyl, pyridine, pyrimidine, pyridazine and pyrazine, wherein any one all can randomly be replaced.

12. chemical compound as claimed in claim 11, wherein R ¹⁴Be hydrogen.

13. chemical compound as claimed in claim 12, wherein:

R ⁵Be-(CR ⁸R ⁹) _mW (CR ¹⁰R ¹¹) _n-;

M and n are 0;

W is N (R ⁷); And

R ⁷Be hydrogen.

14. chemical compound as claimed in claim 13, wherein R ²It is low alkyl group.

15. chemical compound as claimed in claim 14, wherein:

S is 1-6;

G ¹Be selected from amino, acylamino-and do not exist;

16. chemical compound as claimed in claim 15, wherein R ²It is methyl.

17. chemical compound as claimed in claim 16, wherein R ⁶Have and be selected from

With

Formula; And

18. the chemical compound of structural formula VI, or its salt, ester or prodrug,

Wherein:

S is 1-8;

19. chemical compound as claimed in claim 18, wherein R ²⁰And R ²⁴Be independently selected from hydrogen, halogen and low alkyl group.

20. chemical compound as claimed in claim 19, wherein R ²It is low alkyl group.

21. chemical compound as claimed in claim 20, wherein:

S is 1-6;

G ¹Be selected from amino, acylamino-and do not exist;

22. chemical compound as claimed in claim 21, wherein R ²It is methyl.

23. the chemical compound of structural formula VII, or its salt, ester or prodrug,

Wherein:

S is 1-8;

24. chemical compound as claimed in claim 23, wherein R ²⁰, R ²²And R ²⁴Be independently selected from hydrogen, halogen and low alkyl group.

25. chemical compound as claimed in claim 24, wherein R ²It is low alkyl group.

26. chemical compound as claimed in claim 25, wherein:

S is 1-6;

G ¹Be selected from amino, acylamino-and do not exist;

27. chemical compound as claimed in claim 26, wherein R ²It is methyl.

28. chemical compound, it is selected from embodiment 1 to 14.

29. chemical compound as claimed in claim 7 or compositions, it is as medicine.

30. chemical compound as claimed in claim 7, it is used for preparing and is used to prevent or treat by the disease that inhibition improved of PDE4 or the medicine of illness.

31. chemical compound as claimed in claim 30, wherein said PDE4 are the PDE4B hypotypes.

32. pharmaceutical composition, it comprises chemical compound as claimed in claim 7 and pharmaceutically acceptable carrier.