Antimicrobial compounds and methods of making and using the same.

(54) Title: ANTIMICROBIAL COMPOUNDS AND METHODS TO MANUFACTURE AND USE THEM. (54) Title: ANTIMICROBIAL COMPOUNDS AND METHODS OF MAKING AND USING THE SAME.

(57) Summary

The present invention is generally related to the field of antimicrobial compounds and to the methods of manufacture and use thereof. These compounds are used to treat, prevent, and reduce the risk of microbial infections in humans and animals.

(57) Abstract

The present invention relates generally to the field oí antimicrobial compounds and to methods oí making and using them. These compounds are uselul for treating, preventing, and reducing the risk oí microbial infections in humans and animais.

ANTIMICROBIAL COMPOUNDS AND METHODS FOR MANUFACTURING AND

USE THE SAME

RELATED REQUESTS

This application claims priority to US Provisional Patent Application No. 61 / 252,478 filed on October 16, 2009; US Provisional Patent Application No. 61 / 314,287 filed on March 16, 2010; and US Provisional Patent Application No. 61 / 358,201 filed on June 24, 2010. The contents of the aforementioned applications are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates generally to the field of antimicrobial compounds and the methods of manufacture and use thereof. These compounds are useful for treating, preventing, and reducing the risk of microbial infections in humans and animals.

BACKGROUND

Since the discovery of penicillin in 1920 and streptomycin in 1940, many new compounds have been discovered or specifically designed for use as antibiotic agents. It was once thought that infectious diseases could be completely controlled or eradicated with the use of such therapeutic agents. However, such views have been challenged by cell strains or microorganisms resistant to currently effective therapeutic agents continue to evolve. Almost every antibiotic agent developed for clinical use has ultimately had problems with the emergence of resistant bacteria. For example, resistant strains of Gram-positive bacteria, such as methicillin-resistant staphylococci, penicillin-resistant streptococci, and vancomycin-resistant enterococci have been developed. Resistant bacteria can cause serious and even fatal results for infected patients. See, eg, Lowry, FD Antimicrobial Resistance: Example of Staphylococcus aureus, J. Clin. Invest., Vol. 111, no. 9, pp. 1265-1273 (2003); and Gold, HS and Moellering, RC, Jr., Antimicrobial Drug Resistance, N. Engl. J. Meó., Vol. 335, pp. 1445-53 (1996).

The discovery and development of new antibacterial agents have been an important focus for many pharmaceutical companies for decades. However, in more recent years there has been an exodus of pharmaceutical companies from this area of ​​drug research and development. As a consequence of this exodus, there have been very few new antibiotics entering the market. This lack of new antibiotics is especially worrisome, especially at a time when bacterial resistance to current treatments is increasing both in hospitals and in the community.

In the search for new antibiotic agents, researchers have attempted to combine or link various portions of the antibiotic molecules to create multifunctional or hybrid compounds. Other researchers have attempted to prepare derivatives of the known classes of antibiotics, for example, telithromycin, which is sold under the trade name Ketek®, is a derivative of erythromycin. However, these approaches have had limited success.

One approach to developing new antimicrobial compounds is to design modulators, eg, inhibitors, of bacterial ribosome function. By modulating or inhibiting the function of bacterial ribosomes, such antimicrobial compounds could interfere with essential processes, such as RNA interpretation and protein synthesis, thereby providing an antimicrobial effect. In fact, some antibiotic compounds such as erythromycin, clindamycin, and linezolid are known to bind to the ribosome.

The present invention uses a structure

<td>based on the</td><td colspan="2">design approach</td><td>of</td><td>drugs</td><td>for him</td>

<td>discovery</td><td>and</td><td>developing</td><td>of</td><td>new</td><td>agents</td>

<td>antimicrobials.</td><td>East</td><td colspan="2">approach begins</td><td colspan="2">with the x-rays of</td>

<td>high resolution</td><td>by</td><td>crystals of</td><td colspan="2">ribosome for</td><td>to design</td>

new classes of antimicrobial compounds that have specific chemical structures, ribosome binding characteristics, and antimicrobial activity. This drug discovery structure-based approach is described in the following publication: Franceschi, F. and Duffy, EM, Ribosome-Based Structure-Based Drug Design, Biochemical Pharmacology, vol. 71, pp. 1016-1025 (2006).

Based on this structure based on the approach of drug design, the present invention describes new chemical classes of antimicrobial compounds useful for the treatment of bacterial infections in humans and animals. Without being limited by theories, these compounds are believed to inhibit bacterial ribosome function by binding to ribosomes. By taking advantage of these ribosome binding sites, the antimicrobial compounds of the present invention can provide better activity, especially against resistant strains of bacteria, than current antibiotic compounds.

The present invention uses a structure based on the drug design approach for the discovery and development of new antimicrobial agents. This approach begins with high-resolution X-rays by ribosome crystals to design new classes of antimicrobial compounds that have specific chemical structures, ribosome binding characteristics, and desired antimicrobial activity. This structure-based drug discovery approach is described in the following publication: Franceschi, F., and Duffy, EM, Ribosome-Based Structure-Based Drug Design, Biochemical Pharmacology, vol. 71, pp.

1016-1025 (2006).

The present invention therefore fulfills an ongoing important need to provide new antimicrobial agents, in particular for antimicrobial agents, that has activity against resistant bacterial pathogens.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates generally to the field of antimicrobial compounds and methods of manufacture and use. These compounds are useful for treating, preventing, and reducing the risk of microbial infections in humans and animals. The present invention also provides pharmaceutically acceptable salts, esters, oxides, and prodrugs of these compounds.

The present invention provides compounds having the structure:

CB — A

<img file="MX2012004342A_D0001.tif" />

(where is a selected chemical fraction of:

<img file="MX2012004342A_D0002.tif" />

<img file="MX2012004342A_D0003.tif" />

where V is independently selected from -CR^4th-oN,

W is O, NR¹, ÑOR¹, or S, alternatively W - is selected from the combination of HO-yH both attached to the same carbon atom or the combination of (Ci-₈ alkyl) O- and Hambas linked to the same carbon atom;

X - - - Y represents a single bond or a double bond such that when X - - - Y is a single bond, X is selected from O, NR², And so)_n and Y is CR³, and when X - - - Y is a double bond, X is N and Y is a carbon atom,

Z is selected from the group consisting of O, NR⁴, S (O)_n, NR⁴CO, CONR⁴, or NR⁴CONR⁴,

<td>R¹</td><td>I know</td><td>Choose</td><td>of</td><td>H</td><td>And ci-₈</td><td>I rent,</td>

<td>R²</td><td>I know</td><td>Choose</td><td>of</td><td>H</td><td>and Ci-8</td><td>I rent,</td>

<td>R³</td><td>I know</td><td>Choose</td><td>of</td><td>H</td><td>and Ci-8</td><td>I rent,</td>

<td>R⁴</td><td>I know</td><td>Choose</td><td>of</td><td>H</td><td>and Ci-8</td><td>I rent,</td>

<td>R^4th</td><td>I know</td><td>Choose</td><td>of</td><td>H</td><td>and Ci-8</td><td>I rent</td>

n is 0, 1, or 2, alternatively -GHJ is selected from

<img file="MX2012004342A_D0004.tif" />

where each H and J are independently selected,

CBA -, - DEF, and GHJ are chemical fractions, where,

A, D and G are independently selected from the group consisting of:

(a) a single bond, (b) - (Cx-₈ alkyl) (c)

- (C₂-8 alkenyl) -, (d) - (C₂-₈ alkynyl) -, where

i) 0-4 carbon atoms in any of (b) (d) immediately above are optionally substituted by a fraction selected from the group consisting of -O -, - S (O)_p, -NR⁶-, - (C = O) -, S (O) pNR⁶-, - NR⁶S (O) p, y-NR⁶S (O) _PNR6, ii) any one of (b) - (d) immediately above is optionally substituted with one or more R groups⁵, and iii) any of (b) - (d) immediately above is optionally substituted with groups - (Cx-₈ alkyl) -R⁵;

(e) -0-, (f) -NR⁶-, (g) -S (0)_D-, (h) -C (0) -, (i) -C (0) 0-, (j) -OC (O) -, k) -OC (O) O-, (1) -C (O ) NR⁶-, (m) -NR⁶CO-, (n) NR⁶C (O) NR⁶-, (o) -C (= NR⁶) -, (p) -C (= NR⁶) O-, (q) -0C (= NR⁶) -, (r) -C (= NR⁶) NR⁶-, (S) -NR⁶C (= NR⁶) -, (t) -C (= S) ~, (u)

C (= S) NR⁶-, (v) -NR⁶C (= S) -, (w) -C (O) S-, (x) -SC (O) -, (y) OC (= S) -, (z) -C (= S) O-, (aa) -NR⁶ (CNR⁶) NR⁶-, (bb) -CR⁶R⁶C (O) -, (cc) —C (0) NR⁶ (CR⁶R⁶) _t-, (dd) a 3-14 saturated, unsaturated, or aromatic heterocycle member containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (ee) a 3-14 saturated, unsaturated, or aromatic carbocycle member , and (ff) - (CR⁶R⁶) _t-, where (dd) or (ee) is optionally substituted with one or more R groups⁵;

B, E and H are independently selected from the group consisting of:

(a) a single bond, (b) a 3-14 saturated, unsaturated, or aromatic heterocycle member containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (c) a 3-14 saturated member, unsaturated or aromatic carbocycle, where (b) or (c) is optionally substituted with one or more R groups⁵;

(d) - (Ci-8 alkyl) -, (e) - (C₂-₈ alkenyl) -, (f) - (C₂₈alkynyl) -, where

i) 0-4 carbon atoms in any of (d) - (f) immediately above is optionally substituted by a fraction selected from the group consisting of -O-, -S (O)_P-, -NR⁶-, - (C = O) -, C (= NR⁶) -, -S (O) PNR⁶-, -NR⁶S (O) p-, and -NR⁶S (O) _PNR⁶-, ii) any of (d) - (f) immediately above is optionally substituted with one or more R groups⁵, and iii) any of (d) - (f) immediately above is optionally substituted with (Ci-8 alkyl) -R groups⁵;

and (g) - (CR⁶R⁶) _t-,

C, F and J are independently selected from the group consisting of:

(a) hydrogen, (c) F, (d) Cl, (e) Br, (f) I, (g) CF₃, (h) -CN, (i) -N₃(j) -NO₂, (k) -NR⁶ (CR⁶R⁶) _tR⁸, (1) -OR⁸, (m) -S (O) p (CR⁶R⁵) tR⁸, (n) -C (O) (CR⁶R⁶) _tR⁸, (o) -OC (O) (CR⁶R⁶) tR⁸, (p) -SC (O) (CR⁶R⁶) tR⁸, (q) C (O) O (CR⁶R⁶) tR⁸, (r) -NR⁶C (O) (CR⁶R⁶) tR⁸, (s) C (O) NR⁶ (CR⁶R⁶) tR⁸, (t) -C (= NR⁶) (CR⁶R⁶) tR⁸, (u) C (= NNR⁶R⁶) (CR⁶R⁶) tR⁸, (v) -C (= NNR⁶C (O) R⁶) (CR⁶R⁶) tR⁸, (w) —C (= NOR⁸) (CR⁶R⁶) tR⁸, (x) -NR⁶C (O) O (CR⁶R⁶) tR⁸, (and) OC (O) NR⁶ (CR⁶R⁶) tR⁸, (z) -NR⁶C (O) NR⁶ (CR⁶R⁶) tR⁸, (aa) NR⁶S (O) p (CR⁶R⁶) tR⁸, (bb) -S (O) pNR⁶ (CR⁶R⁶) tR⁸, (cc) NR⁶S (O) pNR⁶ (CR⁶R⁶) tR⁸, (dd) -NR⁶R⁸, (ee) -NR⁶ (CR⁶R⁶) R⁸, (ff) -OH, (gg) -NR⁸R⁸, (hh) -OCH3, (ii) -S (O) pR⁸, (jj) -NC (O) R⁸, (kk) -NR⁶C (NR⁶) NR⁶R⁸, (11) a ^ _θ alkyl group, (mm) a C2-g alkenyl group, (nn) a C₂.₈ alkynyl group, (oo) a 3-14 saturated, unsaturated member or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (pp) a 3-14 member saturated, unsaturated or aromatic carbocycle, (qq) (CR⁶R⁶) tNR⁶ (CR⁶R⁶) tR⁸, (rr)

N [(CR⁶R⁵) tR⁸] [C = O (CR⁶R⁶) tR⁸], (ss) (CR⁶R⁶) tN [(CR⁵R⁶) cR⁸] [(CR⁶R⁶)_tR®], (tt) (CR⁶R⁶) tNR⁶ (C = O) (CR⁶R⁶) tR⁸, (uu) -haloalquil, (w) C (O) (CR⁶) [(CR⁶R⁶) tR⁸] R⁸, (w) - (CR⁶R⁶) tC (O) NR⁸R⁸, (xx) - (CR⁶R⁶) tC (0) 0 (CR⁵R⁵) tR⁸, (yy) -NR⁶C (0) CR⁸R⁸R⁸, (zz) -N [(CR⁶R⁶) tR⁸] C (0) R⁸, and (aaa) -S (O) PNR⁸R⁸; where (II) to (pp) is optionally substituted with one or more R groups⁷;

R⁵ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) -CF₃, (g) -CN, (h) -N₃(i) -N0₂, (j) -NR⁶R⁶, (k) -OR⁸, (1) -NR⁶ (CNR⁶) NR⁶R⁶, (m) -Ci-8 alkyl, (n) -Ci-₈ alkenyl, (o) -Ci_₈ alkynyl, (p) - (Ci_₈ alkynyl) - (3-14 saturated, unsaturated member, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (q) - (Ci-₈alkyl) - (3-14 saturated, unsaturated or aromatic carbocycle member), (r) -haloalkyl, (s) -SR⁶, (t) -3-14 saturated, unsaturated, or aromatic member containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (u) -3-14 saturated, unsaturated, or aromatic carbocycle member; alternatively two R groups⁵ come together to form a carbocycle;

where (m) a (r) and (t) a (u) is optionally substituted with one or more R⁸;

R⁶ is selected from (a) hydrogen, (b) -Cx-g alkyl, or alternatively two R groups⁶ taken together to form a carbocycle, (c) -haloalkyl, (d) -3-14 saturated, unsaturated member or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and (e ) -3-14 saturated, unsaturated or aromatic carbocycle member;

where (b) to (e) is optionally substituted with one or more R⁸;

R⁷ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) -CF₃, (g) -CN, (h) -N₃(i) -N0₂, (j) -NR⁶R⁶, (k) -OR⁶, (1) -NR⁶ (CNR⁶) NR⁶R⁶, (m) -Ci-₈ alkyl, (n) -Ci_₈ alkenyl, (o) -Ci_₈ alkynyl, (p) - (Ci_₈ alkyl) - (3-14 saturated, unsaturated member, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (q) - (Cl8 alkyl) - (3-14 saturated member , unsaturated or aromatic carbocycle), (r) -haloalkyl, (s) -NR⁶R⁸, (t)

OR⁸, (u) - (CR⁶R⁶)_tNR⁶R⁸, (v) -CR⁶R⁸R⁸, (w) -SR⁶, (x) -3-14 saturated, unsaturated, or aromatic heterocycle member containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (y) -3-14 saturated, unsaturated, or aromatic carbocyblic member, (z) (CR⁶R⁶) tC (O) NR⁸R⁸, (aa) -S (O) PR⁸, (bb) -NR⁶C (O) NR⁶R⁶, (cc) NR⁶C (O) R⁶, and (dd) -C (= NR⁶) NR⁶R⁶;

<td>where (m) a</td><td>(q)</td><td>y (x)</td><td>to</td><td>(and they are</td>

<td>optionally replaced with</td><td>one</td><td>or more R⁹;</td><td></td><td></td>

<td>R⁸ is selected from</td><td>(to)</td><td>hydrogen,</td><td>(b)</td><td>F, (c) Cl,</td>

<td>(d) Br, (e) I, (f) -CF₃, (g) -</td><td>CN,</td><td>(h) -N₃(i) -</td><td>-not₂,</td><td>(j) -NR⁶R⁹,</td>

<td>(k) -OR⁹, (1) -NR⁶ (CNR⁶) NR⁶R⁶,</td><td>(m)</td><td colspan="2">-Ci_₈ I rent,</td><td>(n) -Ci-₈</td>

alkenyl, (o) -Ci_₈ alkynyl, (p) - (Ci-₈ alkyl) - (3-14 saturated, unsaturated member, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (q) - (Ci-₈ alkyl) - (3-14 saturated, unsaturated, or aromatic carbocycle member), (r) -3-14 saturated, unsaturated, or aromatic member containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, ( s) -3-14 saturated, unsaturated or aromatic carbocycle member, (t) -haloalkyl, (u) -C (0) (CR⁶R⁶) _tR⁹, (v) -SR⁶, (w)

0C (0) (CR⁶R⁶)_tR⁹, (x) -NR⁶C (O) NR⁶R⁹, (and) -NR⁶C (0) R⁹, (z)

NR⁶ (CNR⁹) (NR⁶R⁶), (aa) -ONR⁶(CNR⁶) NR⁶R⁶, (bb) -C (= NR⁹) NR⁶R⁶, (cc) -S (O) PR⁹, (dd) - (CR⁶R⁶) tC (O) NR^SR⁹, (ee) - (CR⁶R⁶) t0R⁹, and (ff) - (CR⁶R⁶) tNR⁶R⁹ ;

wherein (m) to (s) is optionally substituted with one or more R9;

R⁹ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) -CF₃, (g) -CN, (h) -N₃(i) -NO₂, (j) 14

NR⁶R¹⁰, (k) -OR⁶, (1) -NR⁶(CNR⁶) NR⁶R⁶, (m) -C (O) (CR⁶R⁶)_tNR⁶R⁶, (n) -Ci-8 alkyl, (o) -Ci_₈ alkenyl, (p) -Ci_₈ alkynyl, (q) -3-14 saturated, unsaturated or aromatic member containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (r) -3-14 saturated, unsaturated or aromatic carbocycle member, (t) - (CR⁶R⁶) tOR⁶, (u) -O (CR⁶R⁶) tNR⁶R¹⁰, (v) -C (O) R⁶, (w) -SR⁶, (x) -C (O) OR¹⁰, (And so)_PR⁶, (z) - (Ci-s alkyl) - (3-14 saturated, unsaturated member, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (aa) ~ (Ci -₈alkyl) - (3-14 saturated, unsaturated, or aromatic carbocycle member), (bb) -0 (CR⁶R⁶) t0R⁶, (cc) -C (= NR⁶) NR⁵R⁶, (dd) ONR⁶R⁶, (ee) -NR⁶C (O) nr⁶r⁶, (ff) -0 (CR⁶R⁶) tOR⁶, (gg) NR⁶C (O) R⁶, and (hh) - (CR⁶R⁶) _tNR⁶R¹⁰;

wherein (n) through (r) and (z) through (aa) is optionally substituted with one or more R¹⁰;

R¹⁰ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) -CF₃, (g) -CN, (h) -N₃(i) -N0₂, (j) -NR⁶R⁶, (k) -OR⁶, (1) -NR⁶(CNR⁶) NR⁶R⁶, (m) -C (0) (CR⁶R⁶) _tNR⁶R⁶, (n) -Ci_ ₈ alkyl, (o) -Ci_₈ alkenyl, (p) -Ci_₈ alkynyl, (q) -314 saturated, unsaturated or aromatic member containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (r) -3-14 saturated, unsaturated or aromatic carbocycle member, (s ) 15 haloalkyl, (t) - (CR⁶R⁶) tOR⁶, (u) -O (CR⁶R⁶) tNR⁶R⁶, (v) C (O) R⁶, (w) -SR⁶, (x) -C (O) OR⁶, (y) -S (O) PR⁶, (z) - (Ci_8 alkyl) - (3-14 saturated, unsaturated member, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (aa) - (Ci-8 alkyl) - (3-14 saturated, unsaturated or aromatic carbocycle member), (bb) -O (CR⁶R⁶) _tOR⁶, (cc) c (= nr⁶ ) nr⁶r⁶ , (dd) -onr⁶r⁶, (ee) -nr⁶c (o) nr⁶r⁶ , (ff)

O (CR⁶R⁶) tOR⁶, (gg) -NR⁶C (O) R⁶, and (hh) - (CR⁶R⁶) tNR⁶R⁶;

optionally, where either the -DEF group or the -GHJ group is absent, (eg, the -DEF group or -GHJ group represents hydrogen), but both -DEF and -GHJ are not absent simultaneously;

p is 0, 1 or 2, and t is 0, 1, 2, or 3, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

Furthermore, the invention provides methods for synthesizing the above compounds. Upon synthesis, a therapeutically effective amount of one or more of the compounds can be formulated with a pharmaceutically acceptable carrier for administration to a human or animal for use as antimicrobial agents, in particular as antibacterial agents. In certain embodiments, the compounds of the present invention are useful for treating, preventing, or reducing the risk of microbial infections or for the manufacture of a medicament for treating, preventing, or reducing the risk of microbial infections. Accordingly, the compounds or formulations can be administered, for example, orally, parenterally, otically, ophthalmically, nasally, or topically, to provide an effective amount of the compound to human or animal.

The foregoing and other aspects and embodiments of the invention may be more fully understood by reference to the following detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a family of compounds that can be used as antimicrobial agents, more particularly as antibacterial agents.

The present invention includes the pharmaceutically acceptable salts, esters, tautomers, N-oxides, and prodrugs of the compounds described herein.

The compounds described here can have asymmetric centers. The compounds of the present invention that contain an asymmetrically substituted atom can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis of optically active starting materials. Many geometric isomers of olefins, C = N double bonds, and the like can also be present in the compounds described herein, and all of these stable isomers are contemplated by the present invention. The cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separate isomeric forms. All chiral, diastereomeric, racemic, and geometric isomeric forms of a structure are intended, unless a specific stereochemical or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and the intermediates performed therein are considered part of the present invention. All tautomers of the compounds shown or described are also considered part of the present invention. Furthermore, the invention also includes the metabolites of the compounds described herein.

The present invention is intended to include all isotopes of atoms that occur in

<td>present</td><td>compounds. Isotopes</td><td>are</td><td>the atoms</td><td>than</td>

<td colspan="2">have the same atomic number but</td><td colspan="2">different number</td><td>of</td>

<td>mass. TO</td><td>general example mode and</td><td>without</td><td>limitation,</td><td>the</td>

<td>isotopes</td><td colspan="2">hydrogen include tritium</td><td>and deuterium.</td><td>The</td>

<td>isotopes</td><td>Of car are the C-13 and C-14. When any variable</td><td>(by</td><td>example R⁶)</td><td>I know</td>

produces more than once in any constituent or formula for a compound, its definition in each case is independent of its definition in each different occurrence. Thus, for example, if a group is shown to be substituted with one or more R fractions⁶, then R⁶ at each occurrence is selected regardless of the definition of R⁶. Also, combinations of. substituents and / or variables are permissible, but only if such combinations result in stable compounds within normal valence of a designated atom.

A chemical structure showing a dotted line representation for a chemical bond indicates that the bond is optionally present. For example, a dotted line drawn next to a solid single bond indicates that the bond can be a single bond or a double bond.

When a bond for a substituent is shown to pass through a bond connecting two atoms in a ring, then that substituent can be attached to any atom in the ring. When a substituent is listed without indicating the atom through which said substituent is attached to the rest of the compound of a given formula, then said substituent may be attached through any atom in said substituent. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

In cases where there are nitrogen atoms in the compounds of the present invention, these, if any, can be converted to // -oxides by treatment with an oxidizing agent (eg MCPBA and / or hydrogen peroxides) . Therefore, the shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its derived W-oxide (N-&gt; 0) derivative, as appropriate.

One approach to the development of better anti-proliferative and anti-infective agents is to provide modulators (eg, inhibitors) of ribosome function.

Ribosomes are ribonucleoproteins, which are present in both prokaryotes and eukaryotes. Ribosomes are the cellular organelles responsible for protein synthesis. In gene expression, ribosomes translate the genetic information encoded in a messenger RNA into protein (Garrett et al (2000) The Ribosome: Structure, Function, Antibiotics, and Cell Interactions, American Society for Microbiology, Washington, DC).

Ribosomes consist of two non-equivalent ribonucleoprotein subunits. The large subunit (also known as the large ribosomal subunit) is approximately twice the size of the small subunit (also known as the small ribosomal subunit). The small ribosomal subunit binds messenger RNA (mRNA) and mediates interactions between mRNA and transfers the RNA anticodons (tRNA) on which the fidelity of interpretation depends. The large ribosomal subunit catalyzes the formation of the peptide bond, that is, the peptidyl transferase reaction of protein synthesis, and includes at least three different tRNA binding sites known as aminoacyl, peptidyl, and exit sites. The aminoacyl site or an A site accommodates the aminoacyl-TARN entrant which is to contribute its amino acid to the growing peptide chain. Also, space A of Site A is important. The peptidyl site or P Site accommodates the peptidyl-tRNA complex, that is, the tRNA with its amino acid that is part of the growing peptide chain. The exit or Site E accommodates the deacylated tRNA after it has donated its amino acid to the growing polypeptide chain.

one. Definitions that are not are called

Isomerism means compounds that have identical molecular formulas but differ in the nature or sequence of attachment of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called stereoisomers. Stereoisomers that are not mirror images of each other are called diastereoisomers, and superimposable stereoisomers are enantiomeric mirror images, or sometimes optical isomers. A carbon atom attached to four non-identical substituents is called a guiral center.

Chiral isomer means a compound with at least one chiral center. It has two enantiomeric forms of opposite chirality and can exist as a single enantiomer or as a mixture of enantiomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a racemic mixture. A compound that has more than one chiral center has enantiomeric pairs 2^n_1, where n is the number of chiral centers. Compounds with more than one chiral center can exist as a single diastereomer or as a mixture of diastereomers, termed a diastereomeric mixture. When a chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Substituents attached to the chiral center under consideration are classified according to the Cahn, Ingold and Prelog Sequence Rule. (Cahn et al, Angew Chem. Inter Edition 1966, 5, 385; errata 511; Cahn et al., Angew Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41,

116) .

Geometric isomers refers to diastereomers that owe their existence to hindered rotation around double bonds. These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same side or opposite the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

Furthermore, the structures and other compounds described in this application include all atrophic isomers thereof. Atrophic Isomers are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. The

Atrophic isomers owe their existence to a restricted rotation caused by impeding the rotation of large groups around a central bond. Such atrophic isomers typically exist as a mixture, however, as a result of recent advances in chromatographic techniques, it has been possible to separate mixtures of two atrophic isomers in selected cases.

Tautomers refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium. It is to be understood that the compounds of the present invention can be represented as different tautomers. It should also be understood that when the compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the nomenclature of the compounds does not exclude any tautomeric form.

Some compounds of the present invention may exist in a tautomeric form which are also intended to be within the scope of the present invention.

The compounds, salts and prodrugs of the present invention can exist in various tautomeric forms, including the enolic and imine forms and the keto and enamine forms and geometric isomers and mixtures thereof. All tautomeric forms are included within the scope of the present invention. Tautomers exist as mixtures of a tautomer established in solution. In solid form, usually one tautomer predominates. Although a tautomer can be described, the present invention includes all tautomers of the present compounds.

A tautomer is one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. This reaction results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. In solutions where tautomerization is possible, a chemical balance of the tautomers can be achieved. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonly observed. In keto-enolic tautomerism a simultaneous change of electrons and a hydrogen atom occurs. Ring chain tautomerism is present by glucose. It arises as a result of the aldehyde group (-CHO) in a sugar chain molecule that reacts with one of the hydroxy groups (-0H) in the same molecule to give it a cyclic (ring-shaped) shape.

The tautomerizations are catalyzed by: Base: 1. deprotonation; 2. formation of a delocalized anion (eg, an enolate); 3. protonation at a different position of the anion; Acid: 1. protonation; 2. formation of a delocalized cation; 3. deprotonation in a different position adjacent to the cation.

Common tautomeric pairs are: ketone enol, amide-nitrile, lactam-lactim, amide tautomerism of imidic acid in heterocyclic rings (eg, in guanine nucleobases, thymine, and cystosine), amine-enamine, and enamine. The following is an example for illustrative purposes and the present invention is not limited to this example:

<img file="MX2012004342A_D0005.tif" />

N '

H

<img file="MX2012004342A_D0006.tif" />

Λα

The terms crystal polymorphs or polymorphs or crystalline forms means crystal structures in which a compound (or salt or solvate thereof) can crystallize in different crystalline packaging regimes, all of which have the same elemental composition. Different crystal shapes generally have different diffraction X-ray patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can cause a crystal shape to dominate. The crystal polymorphs of the compounds can be prepared by crystallization under different conditions.

The term substituted, as used herein, means that one or more hydrogens on the designated atom, generally one of car, oxygen, or nitrogen atom, is replaced with a selection from the indicated group, provided that the normal valence of the atom designated is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e. = O), then 2 hydrogens on the atom are substituted, double-ring s, as used herein, are double bonds that form between two adjacent ring atoms (for example , C = C, C = N, N = N, etc.)

As used herein, the term "anomeric car" means the car acetal of a glycoside.

As used herein, the term "glycoside" is a cyclic acetal.

As used herein, alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example Ci-₆ alkyl is intended to include Ci, C alkyl groups₂, C₃, C₄, C5 and C₆. Some examples of alkyl include, but are not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, nheptyl, and n-octyl.

As used herein, alkenyl is intended to include hydrocarbon chains of one or the other linear or branched configuration and one or more unsaturated car-car bonds that can occur at any stable point along the chain, such as ethenyl and propenyl . For example alkenyl C₂.₆ is intended to include alkenyl groups C₂, C₃, C₄, C₅, C₆.

As used herein, alkynyl is intended to include hydrocarbon chains of one or the other linear or branched configuration and one or more car-car triple bonds that can occur at any stable point along the chain, such as ethynyl and propynyl. For example, alkynyl C₂-₆ is intended to include alkynyl C groups₂, C₃, C₄, C5, C₆.

In addition, alkyl, alkenyl, and alkynyl are intended to include fractions that are diradical, that is, having two attachment points, an example of which in the present invention is when D is selected from these chemical groups. A non-limiting example of said alkyl fraction which is an es-CH dirradical₂CH₂-, i.e. an alkyl group C₂ which is covalently attached through each terminal carbon atom to the rest of the molecule.

Alkyl diradicals are also known as alkylene radicals. Alkenyl diradicals are also known as alkenylene radicals. Alkynyl diradicals are also known as alkynylenyl radicals.

As used herein, cycloalkyl is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. Cycloalkyl C₃-₈ is intended to include cycloalkyl groups C₃, C₄, C₅, C₆, C₇, C₈.

As used in the present counterion it is used to mean a positively or negatively charged species present in conjunction with an ion of opposite charge. A non-limiting example of a counter ion is an ion or ions present to counteract the charge (s) on an organic compound. Non-limiting examples of counter ions include chloride, bromide, hydroxide, acetate, sulfate, and ammonium.

As used herein, halo or halogen refers to fluorine, chlorine, bromine, iodine, and the substituents.

As used herein, haloalkyl is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (eg -C_vF_w where v = la3yw = la (2v +1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, pentafluoroethyl, trichloromethyl, and pentachloroethyl.

As used herein, "alkoxy" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Alkoxy Ci-6, is intended to include Ci, C₂, C₃, C₄, C₅, C₆ and alkoxy groups. Ci-6 alkoxy, is intended to include Ci, C alkoxy groups₂, C₃, C₄, C₅, c₆, C₇, C₈. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, s-pentoxy, n-heptoxy, and noctoxy .

As used herein, "alkylthio" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through a sulfur bridge. Alkylthio Ci-₆, is intended to include alkylthio C groups₁₍ C₂, C₃, C₄, C₅, C₆. Alkylthio

Cl-6, is intended to include Ci, C alkylthio groups₂, C₃, C4 / C5, C6, C7, Cs

As used herein, carbocycle or carbocyclic ring is intended to mean, unless otherwise specified, any stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclic or tricyclic ring, any of which can be saturated, unsaturated (including partially and completely unsaturated), or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctanyl, cyclooctadienyl, [4.3.0] bicyclononane, [4.4.0] bicyclodecane, [2.2.2] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl. As shown above, bridged rings are also included in the definition of carbocycle (eg, [2.2.2] bicyclooctane). A bridged ring occurs when one or more carbon atoms join two non-adjacent carbon atoms. The preferred bridges are one or two carbon atoms. It is observed that a bridge always converts a monocyclic ring to a tricyclic ring. When a ring is bridged, the described substituents for the ring may also be present on the bridge. Eespiro and condensed rings (eg, naphthyl and tetrahydronaphthyl) are also included.

As used herein, the term heterocycle means, unless otherwise indicated, a monocyclic, bicyclic, or tricyclic ring consisting of 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 stable that is saturated, unsaturated (including partially and completely unsaturated), or aromatic, and is made up of carbon atoms and one or more ring heteroatoms, for example heteroatoms 1 or 1-2 or 1-3 or 1 -4 or 1-5 or 1-6, independently selected from nitrogen, oxygen and sulfur, and including any bicyclic or tricyclic groups which in any of the above defined heterocyclic rings are fused or attached to a second ring (eg, a benzene ring). Nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., N-O and S (O)_p, where p = 1 or 2). When a nitrogen atom is included in the ring, it is either N or NH, depending on whether or not it is connected to a double bond in the ring (that is, a hydrogen is present, if it is necessary to maintain the trivalence of the atom nitrogen). The nitrogen atom can be substituted or unsubstituted (ie, N or NR where R is H or another substituent, as defined). The heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein can be substituted on the car or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle can optionally be quaternized. Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more atoms (i.e., C, O, N, or S) join two non-adjacent carbon or nitrogen atoms. Preferred bridges include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a car-nitrogen group. When a ring is bridged, the substituents recited for the ring may also be present on the bridge. Spiro and fused rings are also included.

As used herein, the term "aromatic heterocycle or heteroaryl" is intended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic or bicyclic aromatic ring consisting of carbon atoms and one or more heteroatoms, eg, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur. In the case of bicyclic heterocyclic aromatic rings, only one of the two rings needs to be aromatic (for example,

2,3-dihydroindole), although both can be (for example, quinoline). The second ring can also be fused or bridged as defined above for heterocycles. The nitrogen atom can be substituted or unsubstituted (ie, N or NR where R is H or another substituent, as defined). The nitrogen and sulfur heteroatoms can be optionally oxidized (ie, N- »O and S (O)_p, where p = 1 or 2). In certain compounds, the total number of atoms and O in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl, azabicyclooctanonyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranol, benzothiofenyl, benzothiazolol, benzoxazolyl, benzoisotiazolyl, benzoisotiazolyl, benzoisotiazolyl, benzoisothiazoyl 4aH-carbazola, carbolinyl, cycloheptyl, chromanyl, chromenyl, cinolinyl, decahydroquinolinyl, dihydrobenzodioxynyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-h] tetrahydrofuran, furanyl, furazanil, imidazolidinyl, imidazolidinylimine, imidazolinyl, imidazolonyl, lff-indazolyl, indolenyl, indolizinyl, indolyl, iso-indolyl, imidazolyl, indolinyl, isatinoyl, indolinyl, isatinoyl, isolininoyl, isininoyl, isininoyl, isininoyl, isatinoyl, isininoyl, isininoyl, isininoyl, isininoyl, isininoyl, isininoyl, isininoyl, isininoyl, isininoyl, isininoyl, isininoyl, isininoyl, isininoyl, isininoyl, isininoyl phenanthridine, phenoxatinyl, piperazinyl, piperazinyl,

4-piperidinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, methylbenzotriazolol, methylfuran, methylimidazole, methylthiazolyl, morpholinyl, naphthyridinyl, octahydroisoquinoline, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl 5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolidinonyl, oxaz olyl, oxindolyl, phenanthroline, phenazinyl, phenothiazine, phenoxazinyl, phthalazinyl, piperidinyl, piperidinyl, piperonyl, pteridinyl, purterininyl pyrazidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyridinonyl, pyridyl, pyrimidinyl, pyrroldionyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, 15-quinine tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1, 2,5-thiadiazinyl, 1,2,3-thiadiazolyl,

1,2,4 thiadiazolyl, 1,2,5 thiadiazolyl, 1,3,4 thiadiazolyl, 20 thiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, thiomorpholinyl dioxidyl, triazinyl, triazolopyrimidinyl,

1,2,3 triazolyl, 1,2,4 triazolyl, 1,2,5 triazolyl, 1,3,4 triazolyl, and xanthenyl.

As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of medical common sense, suitable for use in contact with human tissue and animals without excessive toxicity, irritation, allergic response, or other problem or complication, with a reasonable benefit / risk ratio.

As used herein, pharmaceutically acceptable salts refer to derivatives of the disclosed compounds in which the original compound is modified by the manufacture of acid or basic salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, organic acid minerals or salts of basic residues such as amines, alkaline or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional nontoxic salts or quaternary ammonium salts of the original compound formed, eg, non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from selected inorganic and organic acids of 2-acetoxybenzoic, 2-hydroxyethanesulfonic sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic , ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycol, sanilic, hexylresorcinic, hydrobaxnic, hydrobromic, hydrochloric, hydroiodide, hydroxylealeic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl-sulfonic, maleic, malic, mandelic, methane sulfonic, napsilic, nitric, oxalic, pantothenic, pamoic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfuric, tannic, tartaric, and toluene sulfonic.

The pharmaceutically acceptable salts of the present invention can be synthesized from the original compound containing a basic or acidic fraction by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; in general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.

The lists of suitable salts are found in Sciences

Remington Pharmaceuticals, 18th ed., Mack Publishing Company, Easton, PA, EU, p. 1445 (1990).

As prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (eg, solubility, bioavailability, manufacturing, etc.), the compounds of the present invention can be provided as a prodrug. Thus, the present invention is intended to cover prodrugs of the currently claimed compounds, the methods of delivery thereof and the compositions containing the same. The Prodrugs are intended to include any covalently linked carriers that release an active precursor drug of the present invention in vivo when such a prodrug is administered to a mammalian subject. The prodrugs of the present invention are prepared by modifying the functional groups present in the compound in such a way that the modifications adhere, either in routine manipulation or in vivo, to the original compound. Prodrugs include compounds of the present invention in a hydroxy, amino, or sulfhydryl group that is attached to any group that, when the prodrug of the present invention is administered to a mammalian subject, is cleaved to form a free hydroxy, free amino, or group of free sulfhydryl, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and derivatives of alcohol benzoate and amine functional groups in the compounds of the present invention

<td></td><td>How</td><td>I know</td><td>used in the</td><td>Present,</td><td>compound</td>

<td>stable</td><td>and</td><td colspan="2">stable structure</td><td>aims to</td><td>indicate a</td>

<td>compound</td><td>than</td><td>is it</td><td>enough</td><td colspan="2">robust to survive</td>

isolation to a useful degree of purity from a reaction mixture, and formulation in an effective therapeutic agent.

As used herein, the term patient, as used herein, means that the human or animal subject (in the case of an animal, more typically a mammal) undergoes an invasive or surgical medical procedure. Such a patient or subject could be considered in need of the methods of reducing the risk or prevention of infection due to a surgical procedure or an invasive medical procedure. Such a patient or subject may also be considered in need of peri-operative prophylaxis.

As used herein, the term "treating" means that it provides a therapeutic intervention to cure or alleviate an infection.

As used herein, the term prevention, as used herein, means that it completely or almost completely prevents an infection from occurring, for example when the patient or subject is predisposed to infection or at risk of get an infection. Prevention can also include inhibition, that is, stopping the development, of an infection.

As used herein, the term risk reduction of, as used in the

<td>present means</td><td>reduce</td><td>the</td><td>probability</td><td>or</td><td>the</td>

<td>probability of a</td><td>infection</td><td>than</td><td>occurs, for</td><td colspan="2">example</td>

<td>when the patient infection or at risk</td><td>or subject to contract</td><td>this a</td><td>predisposed infection.</td><td>to</td><td>a</td>

As used herein, "unsaturated" refers to compounds that have at least one degree of unsaturation (eg, at least one multiple bond) and include compounds that are partially and completely unsaturated.

As used herein, the term "effective amount" refers to an amount of a compound, or a combination of compounds, of the present invention effective when administered alone or in combination as an antimicrobial agent. For example, an effective amount refers to an amount of the compound present in a composition, formulation, or medical device given to a recipient or subject patient sufficient to elicit biological activity, eg, anti-infective activity, such as , antimicrobial activity, antibacterial activity, antifungal activity, anti-viral activity, or antiparasitic activity.

The term "prophylactically effective amount" means an effective amount of a compound or compounds of the present invention that is administered to prevent or reduce the risk of infection due to a surgical procedure or an invasive medical procedure.

It should further be understood that the representations of Hydrogen Link Acceptor - Hydrogen Link Acceptor - Hydrogen Link Donor and Hydrogen Link Acceptor - Hydrogen Link Acceptor Hydrogen Link Acceptor indicate the relative orientation of the acceptors and donor of hydrogen bonds and are not intended to limit that these groups are directly connected to each other as it is contemplated that additional atoms or groups of atoms may be included among such groups.

In the description, singular forms also include the plural, unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as that commonly understood by a person skilled in the art to which this invention belongs. In case of conflict, this description will be regulated.

As used herein, mammal refers to human and non-human patients.

As used herein, the term "therapeutically effective amount" refers to a compound, or a combination of compounds, of the present invention present in or on a receptor in an amount sufficient to elicit biological activity, eg, anti activity -microbial, anti-fungal activity, anti-viral activity, anti-parasitic activity, anti-diarrhea activity, and / or anti-proliferative activity. The compound combination is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Regul enzyme. vol. 22, pp. 27-55 (1984), occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of less cytotoxicity, increased anti-proliferative and / or anti-infective effect, or some other beneficial effect of the combination, compared to the individual components.

As used herein, the term "RNA micro-helix binding site" refers to the ribofunctional locus of the large ribosomal subunit occupied by the RNA micro-helix of Formula III. The RNA micro helix binding site defines at least a part or overlaps with the E site.

As used herein, the term site A refers to the ribofunctional locus occupied by an aminoacyl-TARN molecule immediately prior to its participation in the peptide bond formation reaction.

As used herein, the term "E site" refers to the ribofunctional locus occupied by a deacylated tRNA molecule after its involvement in the peptide-binding formation reaction.

As used herein, the term P Site refers to the ribofunctional locus occupied by a peptidyl-tRNA at the time it participates in the peptide bond formation reaction.

As used herein, the term "space A" refers to the portion of Site A within the peptidyl transferase center in which the amino acid portion of aminoacylated t-RNA bonds, or alternatively, the portion of Site A in which the linezolid oxazolidinone ring binds.

As used herein and in reference to a ribosome or ribosomal subunit, the terms a portion of or a portion of the three-dimensional structure of is meant a portion of the three-dimensional structure of a ribosome or ribosomal subunit, including the distribution of filler and hydrophilicity / hydrophobicity characteristics, consisting of at least three, more preferably at least three to ten, and most preferably at least ten amino acid residues or nucleotide residues of the ribosome or ribosomal subunit. The residues that form said portion can be, for example, (i) contiguous residues based on, for example, a primary sequence of ribosomal RNA or ribosomal protein, (ii) residues that form a contiguous portion of the three-dimensional structure of the subunit ribosomal ribosome or, (c) a combination of both. As used herein and in reference to the RNA helix, the

<td>terms a</td><td>portion</td><td>of or a</td><td>portion</td><td colspan="2">of the structure</td>

<td>three-dimensional</td><td>of himself</td><td>understands a</td><td>portion</td><td colspan="2">of the structure</td>

<td>three-dimensional</td><td>of</td><td>micro helix</td><td>RNA,</td><td>including</td><td>the</td>

<td>distribution</td><td>of</td><td>load and</td><td colspan="2">characteristics</td><td>of</td>

hydrophilicity / hydrophobicity, consisting of at least three, more preferably at least three to ten atoms of one or more basic residues of formula III. The atoms that form a part can be, for example, (i) inaccessible solvent atoms buried within the nucleus of the RNA micro-helix, (ii) the accessible solvent atoms of the RNA micro-helix, or (iii) a combination thereof.

All percentages and ratios used herein, unless otherwise noted, are by weight.

Throughout the description, when the compositions are described as having, including, or comprising the specific components, or where the processes are described as having, including, or comprising the specific steps of the process, it is contemplated that the compositions of the The present invention also consists essentially of, or consists of, the aforementioned components, and that the processes of the present invention also consist essentially of, or consist of, the processing steps described. Furthermore, it should be understood that the order of the steps or order to perform certain actions is irrelevant as long as the invention continues to be operable.

Furthermore, two or more steps or actions can be carried out simultaneously.

2. Compounds of the invention

The present invention provides compounds having the structure:

D-E-F

-L

R

AND

G — H — J

<img file="MX2012004342A_D0007.tif" />

where V is independently selected from-CR^4th-oN-,

W is O, NR¹, ÑOR¹, or S, alternatively W = is selected from the combination of HO-and H both attached to the same carbon atom or the combination of (Ci-s alkyl) -O and H-both attached to the same carbon atom;

X --- Y represents a single bond or a double bond such that when X --- Y is a single bond, X is selected from O, NR², And so)_n and Y is CR³, and when X --- Y is a double bond, X is N and Y is a carbon atom,

Z is selected from the group consisting of 0, NR⁴,

<td colspan="7">0 NH,</td>

<td>R¹</td><td>I know</td><td>Choose</td><td>of</td><td>H</td><td>And ci-₈</td><td>I rent,</td>

<td>R²</td><td>I know</td><td>Choose</td><td>of</td><td>H</td><td>and Ci-8</td><td>I rent,</td>

<td>R³</td><td>I know</td><td>Choose</td><td>of</td><td>H</td><td>and Ci-8</td><td>I rent,</td>

<td>R⁴</td><td>I know</td><td>Choose</td><td>of</td><td>H</td><td>and Ci-8</td><td>I rent,</td>

<td>_R4th</td><td>I know</td><td>Choose</td><td>of</td><td>H</td><td colspan="2">and Ci-8 alkyl,</td>

n is 0, 1, or 2, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or pro-drug thereof, wherein - further comprises a hydrogen bond donor fraction or an additional hydrogen bond acceptor fraction.

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or pro-drug thereof, where - it is a chemical moiety comprising at least two hydrogen bond accepting moieties and at least one hydrogen bond donor fraction.

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or pro-drug thereof, wherein the hydrogen bond acceptor fractions and the hydrogen bond donor fractions in the orientation of Hydrogen Link Acceptor - Hydrogen Link Acceptor - Hydrogen Link Donor.

As used above the term in the orientation of does not mean that the hydrogen bond donor or acceptor moieties are necessarily directly connected to each other since there may be other intermediate atoms or groups of atoms between the hydrogen bond donor or acceptor moieties.

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or pro-drug thereof, in which the hydrogen bond accepting moieties are within 5A of each other and the moiety hydrogen lace donor is within 5 Á of a hydrogen bond accepting fraction.

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or pro-drug thereof, in which the hydrogen bond accepting moieties are within 3A of each other and the moiety hydrogen lace donor is within 3 Á of a hydrogen bond accepting fraction.

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or pro-drug thereof, wherein the hydrogen bond accepting moieties are comprised within a ring structure, wherein said ring structure is a single ring structure or a multiple fused ring structure.

where

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or pro-drug thereof, in is a chemical fraction comprising at least three hydrogen acceptor fractions.

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or pro-drug thereof, wherein the hydrogen bond accepting moieties are in the orientation of

Hydrogen Bond Acceptor - Hydrogen Bond Acceptor - Hydrogen Bond Acceptor.

As used above the expression in the orientation of does not mean that the donor of hydrogen bonds or acceptor fractions are necessarily directly connected to each other since there may be other intermediate atoms or groups of atoms between the hydrogen bond acceptor fractions. .

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or pro-drug thereof, wherein each hydrogen bond acceptor moiety is within about 5A of at least one acceptor moiety of hydrogen another bond.

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or pro-drug thereof, wherein each hydrogen bond acceptor moiety is within about 3A of at least one acceptor moiety of hydrogen another bond.

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or pro-drug thereof, wherein at least two of the hydrogen bond accepting moieties are comprised within a ring structure. , wherein said ring structure is a single ring structure or a cast multiple ring structure.

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or pro-drug thereof, wherein said hydrogen acceptor fractions are independently selected from the group consisting of a carbonyl group, a thiocarbonyl group, one imine group, one imine substituted alkyl group, one sulfoxide group, one sulfone group, one oxime group, one oxime substituted alkyl group, one hydrazone group, a monoalkyl or dialkyl substituted hydrazone group, an oxygen ether (-O-) group, a sulfur, also known as a thioether (-S-) group, a hydroxy group, an alkoxy group, an amino group, a monoalkyl or dialkyl substituted amino group, and a nitro group.

In some embodiments, the present invention is directed to a compound of a pharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof, wherein the donor hydrogen bond moiety is selected from which said hydrogen bond donor moiety is selected. select from the group consisting of a hydroxy group, a thiol group, an amino group, and a monosubstituted amino group.

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or one of its prodrugs, where ~ R comprises the structural fraction.

UWv xAAAA?

<img file="MX2012004342A_D0008.tif" />

where W is O, NR¹, ÑOR¹, or S, alternatively W = is selected from the combination of HO-yH both attached to the same carbon atom or the combination of (Ci-s alkyl) O- and H- both attached to the same carbon atom;

X --- Y represents a single bond or a double bond such that when X --- Y is a single bond, X is selected from O, NR², And so)_n and Y is CR³, and when X --- y is a double bond, X is N and Y is a carbon atom,

Z is selected from the group consisting of O, NR⁴, BEAR)_n, NR⁴CO, CONR⁴, or NR⁴CONR⁴,

<td>R¹</td><td>I know</td><td>Choose</td><td>of</td><td>H</td><td>and rent</td><td>Cl-8,</td>

<td>R²</td><td>I know</td><td>Choose</td><td>of</td><td>H</td><td>and rent</td><td>Cl-8,</td>

<td>R³</td><td>I know</td><td>Choose</td><td>of</td><td>H</td><td>and rent</td><td>Cl-8 /</td>

<td>R⁴</td><td>I know</td><td>Choose</td><td>of</td><td>H</td><td>and rent</td><td>Cl-8 /</td>

<td>R^4th</td><td>I know</td><td>Choose</td><td>of</td><td>H</td><td>and rent</td><td>Cl-8 /</td>

and n is 0, 1, or 2.

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or pro-drug thereof, wherein W is O, NR¹, ÑOR¹, or S; where R⁴ is selected from H and alkyl Ci_₆.

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or prodrug thereof, wherein it comprises the structural fraction.

sAA / \ i JUVVb

<img file="MX2012004342A_D0009.tif" />

where Z is selected from the group consisting of 0, NR⁴, or S (0) „; R⁴ is selected from hydrogen and Ci-βalkyl, and

n is 0, 1, and 2.

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or one of its prodrugs, wherein

ΊΓ comprises the structural fraction.

<img file="MX2012004342A_D0010.tif" />

R⁴ where R⁴ is selected from H and alkyl Ci-₅.

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or pro-drug thereof, wherein

R⁴ it's H.

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or one of its prodrugs, wherein it comprises a fraction of cytosine or isocytosine or derivative thereof.

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or one of its prodrugs, wherein ~ R

<img file="MX2012004342A_D0011.tif" />

<img file="MX2012004342A_D0012.tif" />

where V is independently selected from-CR^4th-oN-,

W is O, NR¹, ÑOR¹, or S, alternatively W = is selected from the combination of HO-yH both attached to the same carbon atom or the combination of (Ci_₈ alkyl) O- and Hambas linked to the same carbon atom;

X --- Y represents a single bond or a double bond such that when X --- Y is a single bond, X is selected from O, NR², And so)_n and Y is CR³, and when X --- y is a double bond, X is N and Y is a carbon atom, Z is selected from the group consisting of 0, NR⁴, S (O)_n, or NR⁴CO, CONR⁴, or NR⁴CONR⁴,

R¹ is selected from H and Ci-₈I rent,

R² is selected from H and Ci-₈I rent,

R³ is selected from H and Ci-₈I rent,

R⁴ is selected from H and Ci-₈alkyl, &gt;&gt; 4a is selected from H and Ci-₈alkyl, n is 0, 1, or 2.

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or prodrug thereof, wherein - comprises the structural fraction.

7 ^ N ^^V^ N

<img file="MX2012004342A_D0013.tif" />

<img file="MX2012004342A_D0014.tif" />

where V is independently selected from-CR^4th-oN-, where Z is selected from the group consisting of O, NR⁴, S (O)_n, OR NR⁴CO, CONR⁴, OR NR⁴CONR⁴ ;

R⁴ is selected from H and Ci-e alkyl,

R^4th is selected from H and Ci-g alkyl, related acceptable, where LíL n is 0, 1, or 2,

In some embodiments, the present invention is comprised of a compound or a pharmaceutically ester, tautomer, or prodrug salt thereof, comprising the structural moiety.

Α-χκ

0^&lt;ÍÍÍ^^xN^&lt;^^X'nY

R⁴

I.

Α ^_νΎ οΑ_ΝΑ_Νγ

I.

<img file="MX2012004342A_D0015.tif" />

Ο 'νΥ

I

Where V is independently selected from -CR^4th-oN-,

Where R4 is selected from H or Ci-₈ I rent,

R4 is selected from H or Ci-₈ I rent.

In some embodiments, the present invention relates to a pharmaceutically acceptable compound or salt, ester, tautomer, or pro-drug thereof, where R⁴ it's H.

In some embodiments, the present invention relates to a compound having the formula:

<img file="MX2012004342A_D0016.tif" />

<img file="MX2012004342A_D0017.tif" />

where V is independently selected from-CR^4th-oN-,

W is 0, NR¹, ÑOR¹, or S, alternatively W = is selected from the combination of HO-yH both attached to the same carbon atom or the combination of (Ci-₈ alkyl) O- and Hambas linked to the same carbon atom;

X --- Y represents a single bond or a double bond such that when X --- Y is a single bond, X is selected from 0, NR², and S (0)_n and Y is CR³, and when X --- y is a double bond, X is N and Y is a carbon atom,

Z is selected from the group consisting of O, NR⁴, S (O)_n, or

<td>nr⁴co, conr⁴,</td><td>OR</td><td>nr⁴conr⁴ ,</td><td></td><td></td><td></td><td></td>

<td>R¹</td><td>I know</td><td>Choose</td><td>of</td><td>H</td><td>and</td><td>Ci-₈I rent,</td>

<td>R²</td><td>I know</td><td>Choose</td><td>of</td><td>H</td><td>and</td><td>Ci-₈I rent,</td>

<td>R³</td><td>I know</td><td>Choose</td><td>of</td><td>H</td><td>and</td><td>Ci-₈I rent,</td>

R⁴ is selected from H and Ci-8alkyl, R^4th is selected from H and Ci-8alkyl, n is 0, 1, or 2.

alternatively-GHJ is selected from

HH where H and J are each independently selected,

CBA -, - DEF, and GHJ are chemical fractions, in which

A, D and G are independently selected from the group consisting of:

(a) a simple bond, (b) - (Ci-₈ alkyl) -, (c)

- (C₂-8 alkenyl) -, (d) - (C₂.₈ alkynyl) -, where

i) 0-4 carbon atoms in any of (b) - (d) immediately above are optionally substituted by a fraction selected from the group consisting of -0-, S (O)_P, -NR⁶-, - (C = 0) -, S (O) PNR⁶-, -NR⁶S (O) P-, y-NR⁶S (0) _PNR⁶-, ii) any of (b) - (d) immediately above is optionally substituted with one or more R groups⁵, and iii) any of (b) - (d) immediately above is optionally substituted with (Ci-8 alkyl) -R groups⁵;

(e) -O-, (f) -NR⁶-, (g) -S (0)_p-, (h) -C (O) -, (i) C (O) O-, (j) -OC (O) -, k) -OC (O) O-, (1) -C (O) NR⁶-, (m) -NR⁶CO-, (n) -NR⁶C (O) NR⁶-, (o) -C (= NR⁶) -, (p)

-C (= NR⁶) O-, (q) -OC (= NR⁶) -, (r) -C (= NR⁶) NR⁶-, (s) NR⁶C (= NR⁶) -, (t) -C (= S) -, (u) -C (= S) NR⁶, (v) NR⁶C (= S) -, (w) -C (O) S-, (x) -SC (O) -, (y) -OC (= S), (z) -C (= S) O-, (aa) -NR⁶ (CNR⁶) NR⁶-, (bb)

CR⁶R⁶C (O) -, (cc) -C (O) NR⁶ (CR⁶R⁶) _t-, (dd) a saturated, unsaturated or aromatic heterocycle member 3-14 containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (ee) a saturated, unsaturated or aromatic carbocycle member 314, and (ff) - (CR⁶R⁶)_t-, where (dd) or (ee) is optionally substituted with one or more R groups⁵;

B, E and H are independently selected from the group consisting of:

(a) a single bond, (b) a 3-14 saturated, unsaturated member, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (c) a 3-14 saturated member , unsaturated or aromatic carbocycle, where (b) or (c) is optionally substituted with one more R groups⁵;

(d) - (Ci-8 alkyl) -, (e) - (C₂-e alkenyl) -, (f) (C₂-8 alkynyl) -, where

i) The 0-4 carbon atoms in any of (d) - (f) immediately above are optionally replaced by a selected fraction of the group consisting of -O-, -S (O)_P-, -NR⁶-, - (C = O), -C (= NR⁶) -, -S (O) pNR⁶-, -NR⁶S (O) p-, and -NR⁶S (O) _PNR⁶, ii) any of (d) - (f) immediately above is optionally substituted with one or more R groups⁵, and iii) any of (d) - (f) immediately above is optionally substituted with - (Ci-g alkyl) - R groups⁵;

and (g) - (CR⁶R⁶)_t-,

C, F, and J are independently selected from the group consisting of:

(a) hydrogen, (c) F, (d) Cl, (e) Br, (f) I, (g) -CF₃, (h) -CN, (i) -N₃(j) -NO₂, (k) -NR⁶ (CR⁶R⁶) _tR⁸, (1) -OR⁸, (m) -S (O) _p (CR⁵R⁶) tR⁸, (n) -C (O) (CR⁶R⁶) tR⁸, (o) OC (O) (CR⁶R⁶) tR⁸, (p) -SC (O) (CR⁶R⁶) cR⁸, (q) -C (O) O (CR⁶R⁶) _tR⁸, (r) -NR⁶C (O) (CR⁶R⁶) tR⁸, (s) -C (O) NR⁶ (CR⁶R⁶) tR⁸, (t)

C (= NR⁶) (CR⁶R⁶) tR⁸, (u) -C (= NNR⁶R⁶) (CR⁶R⁶) tR⁸, (v) C (= NNR⁶C (O) R⁵) (CR⁶R⁶) tR⁸, (w) -C (= NOR⁸) (CR⁶R⁶) tR⁸, (x) NR⁶C (O) O (CR⁶R⁶) tR⁸, (y) -OC (O) NR⁶ (CR⁶R⁶) tR⁸, (z) NR⁶C (O) NR⁶ (CR⁶R⁶) tR⁸, (aa) -NR⁶S (O) p (CR⁶R⁶) tR⁸, (bb) S (O) pNR⁶ (CR⁶R⁶) tR⁸, (cc) -NR⁶S (O) pNR⁶ (CR⁶R⁶) _tR⁸, (dd) -NR⁶R⁸, (ee) -NR⁶(CR⁶R⁶) R⁸, (ff) -OH, (gg) -NR⁸R⁸, (hh) -OCH₃, (ii) -S (O)_pR⁸, (jj) -NC (O) R⁸, (kk) -NR⁶C (NR⁶) NR⁶R⁸, (11) a C ^ alkyl group, (mm) a C group₂__to alkenyl, (nn) a group C₂_₈alkynyl, (oo) a 3-14 saturated, unsaturated, or aromatic heterocycle member containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur (pp) a 3-14 saturated, unsaturated, or aromatic carbocycle member , (qq) - (CR⁶R⁶) tNR⁶ (CR⁶R⁶) tR⁸, (rr)

N [(CR⁶R⁶) tR⁸] [C = O (CR⁶R⁶) tR⁸], (ss) (CR⁶R⁶) tN [(CR⁶R⁶) CR⁸] [(CR⁶R⁶) tR⁸] &lt;(tt) (CR⁶R⁶) tNR⁶ (C = O) (CR⁶R⁶) tR⁸, (uu) -haloalkyl, (w) C (O) (CR⁶) [(CR⁶R⁵) tR⁸] R⁸, (w) - (CR⁶R⁶) tC (O) NR⁸R⁸, (xx) (CR⁶R⁶) tC (O) O (CR⁶R⁶) tR⁸, (yy) -NR⁶C (O) CR⁸R⁸R⁸, (zz)

N [(CR⁶R⁶) cR⁸] C (O) R⁸, and (aaa) -S (O) PNR⁸R⁸;

where (11) through (pp) is optionally substituted with one or more R groups⁷;

R⁵ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) -CF3, (g) -CN, (h) -N3 (i) -NO2 , (j) -NR⁶R⁶, (k) -OR⁸, (1) -NR⁶ (CNR⁶) NR⁶R⁶, (m) -Ci-8 alkyl, (n) -Ci-₈alkenyl, (o) -Ci_₈ alkynyl, (p) - (Ci_₈ alkyl) - (member 3-14 saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur) (q) - (Ci-₈ alkyl) (3-14 member saturated, unsaturated or aromatic carbocycle), (r) -haloalkyl, (s) -SR⁶, (t) -3-14 saturated, unsaturated, or aromatic heterocycle member containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (u) 3-14 saturated, unsaturated, or aromatic carbocycle member; alternatively two R groups⁵ are taken together to form a carbocycle where (m) through (r) and (t) through (u) is optionally substituted with one or more R⁸;

R⁶ is selected from (a) hydrogen, (b) -Cl-8 alkyl or alternatively two R6 groups are taken to form a carbocycle, (c) -haloalkyl, (d) -3-14 saturated, unsaturated or aromatic heterocycle member that it contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur and (e) saturated, unsaturated, or aromatic carbocycle member-3-14;

where (b) through (e) is optionally substituted with one or more R⁸;

R⁷ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) -CF₃, (g) -CN, (h) -N₃(i) -NO₂, (j) -NR⁶R⁶, (k) -OR⁶, (1) -NR⁶ (CNR⁶) NR⁶R⁶, (m) -Ci_₈ alkyl, (n) -Ci_₈ alkenyl, (o) -Ci-₈ alkynyl, (p) - (Ci_₈ alkyl) - (3-14 saturated, unsaturated member, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (q) - (C! -₈alkyl) - (3-14 saturated, unsaturated or aromatic carbocycle member), (r) -haloalkyl, (s) -NR^andR⁸, (t) -OR⁸, (u) (CR⁶R⁶)_tNR⁶R⁸, (v) -CR⁶R⁸R⁸, (w) -SR⁶, (x) -3-14 saturated, unsaturated member, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (y) -3-14 saturated, unsaturated, or carbocycle member aromatic, (z) CR⁶R⁶) tC (0) NR⁸R⁸, (aa) -S (O) PR⁸, (bb) -NR⁶C (O) NR⁶R⁶, (cc) NR⁶C (O) R⁶, and (dd) —C (= NR⁶) NR^SR⁶ ;

where (m) through (q) and (x) through (y) are optionally substituted with one or more R⁹;

R⁸ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) -CF₃, (g) -CN, (h) -N₃(i) -N0₂, (j) -NR⁶R⁹, (k) -OR⁹, (1) -NR⁶(CNR⁶) NR⁶R⁶, (m) -Cx-s alkyl, (n) -Ci-₈ alkenyl, (o) -Ci_₈ alkynyl, (p) - (Ci_₈ alkyl) 64 (3-14 saturated, unsaturated member, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (q) - (Ci-8 alkyl) - (3- 14 saturated, unsaturated member, or aromatic carbocycle), (r) -3-14 saturated, unsaturated member, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (s) - 3-14 saturated, unsaturated or aromatic carbocycle member, (t) -haloalkyl, (u) -

<td>C (O) (CR⁶R⁶)_tR⁹,</td><td>(v) -SR⁶,</td><td>(w)</td><td>-OC (O) (CR⁶R⁶)_tR⁹,</td><td>(x)</td>

<td>NR⁶C (O) NR⁶R⁹,</td><td>(y) -NR⁶C (0) R⁹,</td><td>(z)</td><td>-NR⁶(CNR⁹) (NR⁶R⁶) ,</td><td>(aa) -</td>

<td>ONR⁶(CNR⁶) NR⁶R⁶</td><td>, (bb) -C (= NR⁹</td><td>) NR⁶R⁶</td><td>, (CC) -S (O)_PR⁹,</td><td>(dd) -</td>

(CR⁶R⁶) tC (0) NR⁶R⁹, (ee) - (CR⁶R⁶) t0R⁹, and (ff) - (CR⁶R⁶) _tNR⁶R⁹;

where (m) through (s) is optionally substituted with one or more R⁹;

R⁹ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) -CF₃, (g) -CN, (h) -N₃(i) -NO₂, (j) -NR⁶R⁹, (k) -OR⁹, (1) -NR⁵(CNR⁶) NR⁶R⁶, (m) C (0) (CR⁶R⁶) _tNR⁶R⁶, (n) -Ci-8 alkyl, (o) -Ci_₈ alkenyl, (p) -Ci_₈ alkynyl, (q) -3-14 saturated, unsaturated member, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (r) -3-14 saturated, unsaturated member , or aromatic carbocycle), (s) -haloalkyl, (t) - - (CR⁶R⁶) _t0R⁶, (or)

O (CR⁶R⁶) _tNR⁶R¹⁰, (v) -C (O) R⁶, (w) -SR⁶, (x) -C (O) OR¹⁰, (and) 65

SW)_PR⁶, (z) - (Ci-8 alkyl) - (3-14 saturated, unsaturated member or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (aa) - (Ci_₈ alkyl) - (3-14 saturated, unsaturated or aromatic carbocycle member), (bb) -O (CR⁶R⁶) tOR⁶, (cc) -C (= NR⁶) NR⁶R⁶, (dd) -ONR⁶R⁶, (ee)

NR⁶C (O) NR⁶R⁶, (ff) -O (CR⁶R⁶) tOR⁶, (gg) -NR⁶C (O) R⁶, and (hh) (CR⁶R⁶) tNR⁶R¹⁰;

where (n) through (r) and (z) through (aa) is optionally substituted with one or more R¹⁰;

R¹⁰ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) -CF₃, (g) -CN, (h) -N₃(i) -NO₂, (j) -NR⁶R⁶, (к) -OR⁶, (1) -NR⁶(CNR⁶) NR⁶R⁶, (m) -C (0) (CR⁶R⁶) _tNR⁶R⁶, (n) -Ci_ e alkyl, (o) -Ci-₈ alkenyl, (p) -Ci-₈ alkynyl, (q) -314 saturated, unsaturated member or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (r) -3-14 saturated, unsaturated or aromatic carbocycle member, (s) haloalkyl, (t) - (CR⁶R⁶) t0R⁶, (u) -0 (CR⁶R⁶) tNR⁶R⁶, (v) C (O) R⁶, (w) -SR⁶, (x) -C (O) OR⁶, (y) -S (O) PR⁶, (z) - (Ci_8 alkyl) - (3-14 saturated, unsaturated member, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (аа) - (Ci-8 alkyl) - (3-14 saturated, unsaturated or aromatic carbocycle member), (bb) -0 (CR⁶R⁶) _tOR⁶, (cc)

C (= NR⁶) NR⁶R⁶, (dd) -ONR⁶R⁶, (ee) -nr⁶c (O) nr⁶r⁶, (ff) O (CR⁶R⁶) cOR⁶, (gg) -NR⁶C (O) R⁶, and (hh) - (CR⁵R⁶) tNR⁶R⁶;

optionally, where either the -DEF group or the -GHJ group is absent (eg, the -DEF group or the -GHJ group represents hydrogen), but both -D-

<td>EF and GHJ</td><td>not</td><td colspan="2">is it so</td><td>simultaneously absent;</td>

<td>P</td><td>is</td><td> 0,</td><td> 1,</td><td>or 2, and</td>

<td>t</td><td>is</td><td> 0,</td><td> 1,</td><td>2 or 3,</td>

<td>OR</td><td colspan="2">a</td><td>Salt</td><td>pharmaceutically acceptable ester</td>

tautometer or prodrug thereof.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, V, la, lia, Illa, iva or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, where

A is selected from:

(a) a 3-14 saturated, unsaturated, or aromatic member containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (b) a 3-14 saturated, unsaturated, or aromatic carbocycle member, and ( c) a single bond, wherein (a) or (b) is optionally substituted with one or more R groups⁵;

In some modes of embodiment, the present invention relates to a compound according to formula i, II,

III, IV, V, la, lia, Illa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein B is selected from (a) - (Ci-₈ alkyl) -, (b) - (C₂-8 alkenyl) -, and (d) - (C₂.₈ alkynyl), or (d) a single bond, where

i) 0-4 carbon atoms in any of (a) - (C)

<td>immediately</td><td>by</td>

<td>replaced by</td><td>a</td>

<td>group formed</td><td>by</td>

<td>C (= NR⁶ ) -, - S (0) pNR</td><td>⁶-, and</td>

<td>ii) any</td><td>of</td>

<td>optionally is</td><td>substitu:</td>

above optionally selected fraction of -0 -, - S (O) p -, - NR⁶-, - (C = O) -, - NR⁶S (O) pNR⁶, (a) - (c) immediately by Ltuido with one or more groups

R⁵, and / or iii) any of (a) - (c) immediately above is optionally substituted with groups - (Ci-₈alkyl) -R⁵ groups.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa, or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof , where C is selected from (a) NH₂, (b) -NHC (= NH) NH₂ and (c) hydrogen.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, where A is selected from:

(a) a 4-7 saturated, unsaturated, or aromatic heterocycle member containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (b) a 4-7 saturated, unsaturated, or aromatic carbocycle member, and (c) a single bond, wherein (a) or (b) is optionally substituted with one or more R groups.⁵.

or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein A is selected from azepanyl, cyclobutyl, cyclohexyl, cyclohexenyl, furanyl, cycloheptyl, phenyl, cyclohexadienyl, tetrahydrofuranyl, pyrrolidinyl, cyclopentyl, pyridinyl, dihydropyridyl, tetrahydropyridyl, azetidinyl, piperidinyl, and piperidenyl;

wherein any of A immediately above is optionally substituted with one or more R groups⁵.

Alternatively, the present invention relates to a compound according to formula I, II, III, IV, V, la, lia, lila, iva or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, where A is a single bond.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, where B is selected from - (Ci- ₈ alkyl) -, where

i) 0-4 carbon atoms is optionally substituted by a fraction selected from -0-, S (O)_P, -NR⁶-, - (C = O) -, -S (0) PNR⁶-, or - (NR⁶S0) PNR6-, ii) (a) B is optionally substituted with one or more R5 groups, and / or iii) (a) B is optionally substituted with groups - (Ci-₈ alkyl) -R⁵ .

Alternatively, the present invention relates to a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa, or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, in which B is a single link.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa, or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof , where C is -NHC (= NH) NH₂ .

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa, or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof , in G is selected from (a) a 3-14 saturated, unsaturated, or aromatic heterocycle member containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (b) a 3-14 saturated, non-saturated member saturated or aromatic carbocycle, or (c) a single link;

wherein (a) or (b) is optionally substituted with one or more R groups⁵.

In some modes of embodiment, the present invention relates to a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa, or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein G is selected from (a) a 3-14 saturated, unsaturated, or aromatic heterocycle member containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (b) a 3-14 member saturated, unsaturated or aromatic carbocycle, or (c) a single link;

wherein (a) or (b) is optionally substituted with one or more R groups⁵.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa, or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof , where G is selected from azepanyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl, cyclohexadienyl, dihydropyridyl, furanyl, tetrahydrofuranyl, tetrahydropyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperidenyl, or a simple link.

In some embodiments, the present invention relates to a compound having the formula.

<img file="MX2012004342A_D0018.tif" />

wherein CBA -, - DEF, -GHJ, V, W, X, Y and Z are defined above, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

With reference to some embodiments, the present invention is composed having the formula:

B— A,

G -H — J \ NX (II), where CBA -, - DEF, -GHJ, V, W, X, Y and Z are defined as in formula (II), or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof.

In some embodiments, the present invention relates to a compound having the formula:

<img file="MX2012004342A_D0019.tif" />

wherein CBA -, - DEF, and GHJ, V, W, X, Y, and Z are defined as in formula (III) above, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound having the formula:

c— ^B“ ^TO\ / X

Ή

I&gt; θ ^—η — j \ λτ χ ^L (iv), where CBA -, - DEF, and GHJ, V, W, X, Y, and Z are defined as in formula (IV) above, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof .

In some embodiments, the present invention relates to a compound having the formula:

C- B— A ·

V.

V \ TX z (V), where CBA -, - DEF, and GHJ, V, W, X, Y, and Z are defined as in formula (V), or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound having the formula la, lia, Illa,

IVa, or Va:

<img file="MX2012004342A_D0020.tif" />

or

C-B-A.

..G-H-J (Va), or a pharmaceutically acceptable salt, ester, tautornero, or prodrug thereof, where the variables are as defined in formulas I, II, III, IV and V.

In some embodiments, the present invention relates to a compound having the formula:

<img file="MX2012004342A_D0021.tif" />

as in acceptable, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound having the formula:

<img file="MX2012004342A_D0022.tif" />

wherein CBA -, - DEF, and GHJ- are defined as in formula (II), or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound having the following formula:

<img file="MX2012004342A_D0023.tif" />

wherein CBA -, - DEF, and GHJ- are defined as in formula (III) above, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound having the formula:

<img file="MX2012004342A_D0024.tif" />

(IVa), wherein CBA -, - DEF, and GHJ-are defined as in formula (IV) above, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound having the formula:

C — B — A ^,_nx ^

Ú3 — H — J (Va), where CBA -, - DEF, and GHJ-are defined as in formula (V), or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV or V having formula (la), wherein Z is -NR⁴CONR⁴-, CBA-, DEF, and GHJ are defined as in formula (I), or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound having the formula:

C-B-A. ^ D— '^EF 'VV O (Ib), wherein CBA -, - DEF, and GHJ- are defined as in formula (I), or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound having the

C-B-A. vO formula: Η H where

A is selected from (a) heterocycle a 3-14 saturated, unsaturated, or aromatic member containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (b) a 3-14 saturated, unsaturated member or aromatic carbocycle, and (C) a single bond, wherein (a) or (b) is optionally substituted with one or more R groups⁵;

B is selected from (a) - (Ci-₈ alkyl) -, (b) (C₂-₈ alkenyl) -, (c) - (C₂-₈ alkynyl) -, and (d) a single bond wherein,

i) 0-4 carbon atoms in any of (a) (C) immediately above are optionally substituted by a residue selected from the group consisting of -0 -, - S (O)_p-, - NR⁶-, - (C = O) -, - C (= NR⁶) -, -S (O) pNR⁶-, and -NR⁶S (O) pNR⁶, ii) any one of (a) - (c) immediately above is optionally substituted with one or more R groups⁵, and / or iii) any of (a) - (c) immediately above is optionally substituted with groups - (Ci-C₈alkyl) -R⁵, and

C is selected from (a) NH₂, (b) -NHC (= NH) NH₂ and (c) hydrogen;

or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound having the formula:

C — B — A

<img file="MX2012004342A_D0025.tif" />

where

A is selected from azepanyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridinyl, cyclohexenyl, cyclohexadienyl, dihydropyridyl, furanyl, tetrahydrofuranyl, tetrahydropyridyl, azetidinyl, pyrrolidinyl, piperidinyl, and piperidenyl;

wherein any of A immediately above is optionally substituted with one or more R groups⁵;

alternatively, A is a single bond;

B is selected from (a) - (Ci-₈ alkyl) where

i) 0-4 carbon atoms in (a) immediately above is optionally substituted by a residue selected from the group consisting of -O -, - S (O)_p-, - NR⁶-, - (C = O) -, -S (O) PNR6-, yNR⁶S (O) PNR⁶-, ii) (a) immediately above is optionally substituted with one or more R groups⁵, and / or iii) (a) immediately above is optionally substituted with groups - (Ci- alkyl₈) -R⁵; alternatively, B is a single bond;

C is selected from (a) NH₂, (b) -NHC (= NH) NH₂ and (c) hydrogen;

or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound having the formula:

wherein CBA-is selected from the group consisting of: hydrogen,

<img file="MX2012004342A_D0026.tif" />

or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound having the formula:

<img file="MX2012004342A_D0027.tif" />

Ν '

H (a) a 3-14 saturated, unsaturated, or aromatic heterocycle member containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (b) a 3-14 saturated, unsaturated, or aromatic carbocycle member, or (c) a single link;

wherein (a) or (b) is optionally substituted with one or more R groups⁵, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa, Va or containing R⁵, where R⁵ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) -CF₃, (g) -CN, (h) -N₃ (i) -NO₂, (j) -NH₂, (k) - 0R₆, (L) -NHC (= NH)

NH₂, (m) -Cl-8-alkyl, (n) -Ci-₈ alkenyl, (0) -Ci-g alkynyl, (р) - (Ci- alkyl₈) - (3-14 saturated, unsaturated member, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (q) - (C! _₈ alkyl) - (3-14 saturated, unsaturated, or aromatic carbocycle member), (r) -haloalkyl, (s) alkylthio, (t) -3-14 saturated, unsaturated member, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (u) -3-14 saturated, unsaturated, or aromatic carbocycle member; alternatively two R groups⁵ they are taken together to form a carbocycle, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, V la, lia, Illa, iva, Va or containing R⁶, where R⁶ is selected from (a) hydrogen, (b) -Ci-₈ alkyl, or alternatively two R groups⁶ taken together to form a carbocycle, (с) haloalkyl, (d) -3-14 saturated, unsaturated member, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (e ) -3-14 saturated, unsaturated or aromatic carbocycle member, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound having the formula:

<img file="MX2012004342A_D0028.tif" />

cyclohexyl, cyclopentyl, pyridinyl, dihydropyridyl, cycloheptyl, phenyl, cyclohexadienyl, tetrahydrofuranyl, pyrrolidinyl, cyclohexenyl, furanyl, tetrahydropyridyl, azetidinyl, piperidinyl, piperidenyl, and a single bond; or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound having the formula

II ....

where -GHJ is selected r T 'nu / G — H — J of hydrogen,

<img file="MX2012004342A_D0029.tif" />

<img file="MX2012004342A_D0030.tif" />

HJ _

-FQ

HJ

<img file="MX2012004342A_D0031.tif" />

HJ, \

HJ,

FOR

<img file="MX2012004342A_D0032.tif" />

hj,

HJ

HJ ^ HJ ~ KÍk “KZX 'HJ.v HJ.

or a pharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof.

In some embodiments, the present invention relates to a compound having the formula:

NN 'N' Η H where -GHJ is selected from hydrogen,

<img file="MX2012004342A_D0033.tif" />

<img file="MX2012004342A_D0034.tif" />

<img file="MX2012004342A_D0035.tif" />

<img file="MX2012004342A_D0036.tif" />

HjCHN,

Η, Ν89

<img file="MX2012004342A_D0037.tif" />

or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound having the formula:

<img file="MX2012004342A_D0038.tif" />

where GHJ is selected from hydrogen

<img file="MX2012004342A_D0039.tif" />

<img file="MX2012004342A_D0040.tif" />

or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound containing R⁵, where R⁵ is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) -CF₃, (g) -CN, (h) -N₃(i) -NO₂, (j) -NH₂, (k) -OR⁶, (1) -NHC (= NH) NH₂, (mJ-Cx-e alkyl, (n) -Ci-8 alkenyl, (o) -Ci-s alkynyl, (p) - (Ci-₈alkyl) - (3-14 saturated, unsaturated member, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (q) - (Ci-s alkyl) - (3-14 saturated, unsaturated or aromatic carbocycle member), (r) -haloalkyl, (s) -SR⁶, (t) - 3-14 saturated, unsaturated, or aromatic heterocycle member containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (u) -3-14 saturated, unsaturated, or aromatic carbocycle members ; alternatively two R⁵ Groups are taken together to form a carbocycle, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound containing R⁶ where R⁶ is selected from (a) hydrogen, (b) -Ci-₈ alkyl or, alternatively, two R groups⁶ taken together to form a carbocycle, (c) -haloalkyl, (d) heterocycle -3-14 saturated, unsaturated, or aromatic member containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (e ) -3-14 saturated, unsaturated or aromatic carbocycle member; or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa, or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof , where the -DEF group represents hydrogen.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, V, la, Ha, Illa, IVa, or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof , where W, when present, is O, NR¹, ÑOR¹ or S.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa, or Va, or a pharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof, where X --- Y, when present, is a double bond and X is N e

And it is a carbon atom.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa, or Va, or a pharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof, where R^4th, when present, is H.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa, or Va, or a pharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof, where Z, when present, is NR⁴.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa, or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof , where R⁴ it's H.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa, or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof , which binds to a ribosome.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa, or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof , which binds to the ribosome where the ribosome is a bacterial ribosome.

In some embodiments, the present invention is directed to a compound according to any of the compounds in Table 1 or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, and a pharmaceutically acceptable carrier.

In some embodiments, the present invention relates to a method of treating or reducing the risk of a disease state in a human or animal comprising administering to a human or animal in need of an effective amount of a compound of the invention or a salt pharmaceutically acceptable ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a method of treating a microbial infection in a human or animal, comprising administering to the human or animal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, in the manufacture of a medicament for treating a microbial infection in a human or animal.

In some embodiments, the present invention relates to a method of treating, preventing, or reducing the risk of a microbial infection in a human or animal, comprising administering to the human or animal an effective amount of a compound according to formula I, II, III IV, la, lía, Illa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, in the manufacture of a medicine to treat, prevent or reduce the risk of a microbial infection, in which the microbial infection is selected from the group consisting of:

a skin infection, a Gram positive infection, a Gram negative infection, nosocomial pneumonia, community-acquired pneumonia, after viral pneumonia, hospital-acquired pneumonia / ventilation-associated pneumonia, a respiratory tract infection , such as chronic respiratory tract infections (CRTI), acute pelvic infection, a complicated skin infection and skin structure, one's skin and soft tissue infection (SSTI), including uncomplicated skin and soft tissue infections (uSSTI), and complicated skin and soft tissues, an abdominal infection, a complicated intra-abdominal infection, a urinary tract infection, bacteremia, sepsis, endocarditis, an atrial shunt infection -ventricular, a vascular access infection, meningitis, surgical prophylaxis, a peritoneal infection, bone infection, a joint infection, methicillin-resistant Staphylococcus aureus infection, vancomycin-resistant Enterococci infection, a linezolid-resistant organism infection, a Bacillus anthracis infection, Francisella tularensis infection, an infection with the Yersinia pestis bacteria, and tuberculosis.

In some embodiments, the present invention relates to a method or use wherein the compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, is administered orally, ophthalmic, nasal, oral, parenteral, topical or intravenous.

In some embodiments, the present invention relates to a method of treating, preventing, or reducing the risk of a complicated intra-abdominal infection in a human or animal, comprising administering to the human or animal an effective amount of a compound in accordance with the formula I, II, III, IV, V, la, lia, Illa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or to the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, in the manufacture of a medicament for treating, preventing, or reducing the risk of a complicated intra-abdominal infection, wherein the complicated intra-abdominal infection is selected from polymicrobial infections such as abscesses due to Escherichia coli, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus spp., Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Streptococcus anginosus, Streptococcus constellatus, Enterococcus faecalis, Proteus mirabilis, or Clostridium perfringens.

In some embodiments, the present invention relates to a method of treating, preventing, or reducing the risk of complicated skin and skin structure infection in a human or animal, comprising administering to the human or animal an effective amount of a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or to the use of a compound of the invention , or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, in the manufacture of a medicament for treating, preventing, or reducing the risk of complicated skin and skin structure infection, wherein complicated skin infection and structure of Skin is selected from diabetic foot infections without osteomyelitis due to Staphylococcus aureus (methicillin-resistant and susceptible isolates), Streptococcus agalactiae, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Bacteroides fragilis, Peptostreptococcus species, Porphyromonas osteomyelitis asaccharolytica or bivia

Pre-bottle.

In some embodiments, the present invention relates to a method of treating, preventing, or reducing the risk of community pneumonia in a human or animal, comprising administering to the human or animal an effective amount of a compound in accordance with formula I, II, III, IV, V, la, lia, Illa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or to the use of a compound of the invention, or a pharmaceutically acceptable salt acceptable, ester, tautomer, or prodrug thereof, in the manufacture of a medicine to treat, prevent, or reduce the risk of community-acquired pneumonia, in which non-hospital pneumonia is caused by Streptococcus pneumoniae (penicillin-resistant and susceptible isolates) , including cases with concurrent bacteremia Haemophilus influenzae (including beta-lactamase positive isolates), Moraxella catarrhalis, or atypical bacteria such as Mycoplasma spp.

In some embodiments, the present invention relates to a method of treating, preventing, or reducing the risk of a complicated urinary tract infection in a human or animal, which comprises administering to the human or animal an effective amount of a compound of in accordance with formula I, II, III, IV, V, la, lia, Illa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or to the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, in the manufacture of a medicament for treating, preventing, or reducing the risk of a complicated urinary tract infection, wherein the complicated urinary infection is selected from Escherichia pyelonephritis coli,

100 concurrent bacteremia, or Klebsiella pneumoniae.

In some embodiments, the present invention relates to a method of treating, preventing, or reducing the risk of acute pelvic infection in a human or animal, comprising administering to the human or animal an effective amount of a compound in accordance with formula I, II, III, IV, V, la, lia, Illa, iva or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or to the use of a compound of the invention, or a salt pharmaceutically acceptable ester tautomer, or prodrug thereof, in the manufacture of a medicine to treat, prevent, or reduce the risk of an acute pelvic infection, in which acute pelvic infection including, postpartum endomyometritis, septic abortion, and subsequent surgical gynecological infections, is due to Streptococcus agalactiae, Escherichia coli, Bacteroides fragilis, Porphyromonas asaccharolytica, Peptostreptococcus spp., Or Prevotella bivia.

In some embodiments, the present invention relates to a method of treating, preventing, or reducing the risk of hospital-associated pneumonia / ventilator pneumonia in a human or animal, comprising administering to the human or animal an effective amount of a compound in accordance with formula I, II, III, IV, V, la, lia,

101

Illa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or to the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, in the manufacture of a medicine to treat, prevent or reduce the risk of hospital-acquired pneumonia / pneumonia associated with ventilation, where hospital acquired pneumonia / ventilation associated pneumonia is due to Streptococcus pneumoniae (penicillin sensitive and resistant strains), Staphylococcus aureus (susceptible and methicillin resistant isolates), Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter spp., Stenotroph maltophilia, Haemophilus influenzae (including beta-lactamase positive isolates), or Legionella pneumophilia.

In some embodiments, the present invention relates to a method of treating, preventing, or reducing the risk of a microbial infection associated with an aerobic or facultative gram-positive microorganism in a human or animal, comprising administration to a human or animal. an effective amount of a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or to the use of a

102 compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, in the manufacture of a medicament for treating, preventing, or reducing the risk of a microbial infection, associated with an aerobic or facultative gram-positive microorganism, wherein the aerobic and facultative gram-positive microorganism is selected from:

Staphylococcus aureus (susceptible and methicillin resistant isolates), Streptococcus pneumoniae (susceptible and penicillin resistant isolates), Enterococcus spp. (susceptible and resistant to vancomycin isolates), Streptococcus agalactiae, Streptococcus pyogenes or Staphylococcus epidermidis (susceptible and methicillin resistant isolates).

In some embodiments, the present invention relates to a method of treating, preventing, or reducing the risk of a microbial infection, associated with a facultative and aerobic gram-negative microorganism in a human or animal, comprising administration to the human or animal an effective amount of a compound according to formula I, II, III, IV, V, la, lia, Illa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or to the use of a compound according to formula I, II, III, IV, V la, lia, Illa, IVa, Va, or a pharmaceutically salt

103 Acceptable ester, tautomer, or prodrug thereof, in the manufacture of a medicament for treating, preventing, or reducing the risk of a microbial infection, due to an aerobic or facultative gram-negative microorganism, in which the aerobic gram-negative microorganism and optional is selected from:

Escherichia coli (including isolates that produce ESBL and KPC), Haemophilus influenzae (including positive isolates beta-lactamase), Klebsiella pneumoniae (including isolates that produce ESBL and KPC), Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Morganella morganii, Serratia marcescens, Pseudomonas aeruginosa, Acinetobacter baumannii, Moraxella catarrhalis, Proteus mirabilis, koseri Citrobacter, Haemophilus parainfluenzae, Klebsiella oxytoca (including ESBL and KPC producing strains), Proteus vulgaris, Providencia rettgeri or Providencia stuartii.

In some embodiments, the present invention relates to a method of treating, preventing, or reducing the risk of a microbial infection, associated with an anaerobic microorganism in a human or animal, comprising administering to the human or animal an effective amount of a compound according to formula I, II, III, IV, V, la, lía, Illa, IVa or Va, or a pharmaceutically acceptable salt, ester, tautomer,

104 prodrug thereof, or to the use of a compound according to formula I, II, III, IV, V la, lia, Illa, IVa, Va, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, in the manufacture of a medicine to treat, prevent or reduce the risk of a microbial infection, due to an anaerobic microorganism where the anaerobic microorganism is: Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus species, Porphyromonas asaccharolytica, Prevotella bivia, Bacteroides vivians

In some embodiments, the present invention is directed to a method or use wherein the compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, is administered otically, ophthalmically, nasally, orally, parenterally or topical.

In some embodiments, the present invention relates to a method of synthesizing a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a medical device containing a compound

105 of the invention, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a medical device containing a compound of the invention, wherein the device is a stent.

3. Synthesis of the compounds of the invention

The invention provides methods for preparing the compounds of the invention. The following lb5b Schemes illustrate exemplary routes in general terms for the synthesis of the compounds of the present invention. More specific chemical details are provided in the Examples.

Scheme Ib - Cytosines hnA

Oh

<img file="MX2012004342A_D0041.tif" />

OR

106

Scheme 2b - isocytosine

<img file="MX2012004342A_D0042.tif" />

Scheme 3b - Cytosines with a third ring N

XYZ — OMs

HN ^ N _

O ^ N ^ NHj NaH ^c‘^b‘^to'n ^ n rnco ^c-^b’^to_N^ NO

ON NH,

RCOOH

CB-A

NNO cAiAn ^ r

H

107

Scheme 4b - Cytosines without second double ring bond

NH N NH,

CBA — B

OH 'oh Jhg-nco cb-a._n^

OR

ON NH,

XYZ — OMs _orTO_nTO_nX_n.g-hj

Η H

JHG-COOH [H₂] ^CB-^TO'N-&gt; o

O ^ N ^ N ^ R

H

Hee! _ Π A oX n ^ GHJ H

Scheme 5b Isocytosines without double second ring bond

<img file="MX2012004342A_D0043.tif" />

^C’^B’^TOAND^N'PNH ^θ (ΑΧ ™²

H

Characterization of compounds of the invention

108

Compounds designed, selected and / or optimized by the methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine if the compounds have biological activity. For example, molecules can be characterized by standard assays, including but not limited to those assays described below, to determine if they have predicted activity, binding activity and / or binding specificity.

Additionally, high throughput scanning can be used to accelerate analysis by using such assays. As a result, it may be possible to rapidly examine the molecules described herein for activity, for example, as anti-cancer, antibacterial, anti-fungal, anti-parasitic, or anti-viral agents. Also, it may be possible to test how the compounds interact with a ribosome or ribosomal subunit and / or are effective as modulators (eg, inhibitors) of protein synthesis using techniques known in the art. General methodologies for executing high performance scanning are described, for example, in Devlin (1998) High Performance Scan, Marcel Dekker, and US Patent No. 5,763,263. High performance tests can use one or more techniques of

109 Different tests, including, but not limited to, those described below.

(1) Surface Link Studies. A variety of binding assays can be useful in exploring new molecules for their binding activity. One method includes surface plasmon resonance (SPR) that can be used to assess the binding properties of molecules of interest with respect to a ribosome, ribosomal subunit, or a fragment thereof.

SPR methodologies measure the interaction between two or more macromolecules in real time through the generation of a surface plasmon by quantum mechanics. One device, (BIAcore Biosensor RTM from Pharmacia Biosensor, Piscataway, NJ) provides a focused beam of polychromatic light to the interface between a gold film (provided as a disposable biosensor chips) and an intermediate storage compartment that can be regulated by the user. A hydrogel 100 nm thick composed of carboxylated dextran that provides a matrix for the covalent immobilization of analytes of interest is attached to the gold film. When the focused light interacts with the free electron cloud of the gold film, the plasmon resonance is higher. The reflected light is spectrally depleted resulting in optimally developed wavelengths

110 resonance. By separating the reflected polychromatic light into its component wavelengths (by means of a prism), and determining the depleted frequencies, the BIAcore establishes an optical interface that accurately reports the behavior of the surface generated by resonance of plasmon. When designed as above, the plasmon resonance (and hence the depletion spectrum) is sensitive to mass in the evanescent field (roughly corresponding to the thickness of the hydrogel). If a component of an interaction pair is immobilized to the hydrogel, and the interacting pair is provided through the buffer compartment, the interaction between the two components can be measured in real time based on the accumulation of mass in the evanescent field and its corresponding effects of plasmon resonance measured by the depletion spectrum. This system allows a fast and sensitive real-time measurement of molecular interactions without the need to label any of the components.

(2) Fluorescence Polarization. Fluorescence polarization (FP) is a measurement technique that can be easily applied to protein-protein, protein-ligand, ligandARNo interactions in order to derive IC₅₀^s and Kds of the association reaction between two molecules. In this technique one of the

111 molecules of interest is conjugated to a fluorophore. This is generally the smallest molecule in the system (in this case, the compound of interest). The sample mixture, containing both the ligand-probe conjugate and the ribosome, ribosomal subunit, or fragment thereof, is excited with vertically polarized light. The light is absorbed by the fluorophores in the probe, and re-emits a short time later. The degree of polarization of the emitted light is measured. The polarization of the emitted light depends on several factors, but most importantly on the viscosity of the solution and on the apparent molecular weight of the fluorophore. With proper controls, changes in the degree of polarization of emitted light depend only on changes in the apparent molecular weight of the fluorophore, which in turn depends on whether the probe-ligand conjugate is free in solution, or binds to a receiver. Union testing

<td colspan="2">based on FP</td><td colspan="2">they have a number</td><td colspan="2">of advantages</td>

<td>important,</td><td>including</td><td>the</td><td>IC measurement₅₀^s</td><td>and Kds</td><td>low</td>

<td>true</td><td>terms</td><td>of</td><td colspan="2">homogeneous balance,</td><td>the</td>

<td>speed</td><td colspan="2">analysis</td><td>and equipment</td><td>for</td><td>the</td>

automation, and display capacity in suspensions and cloudy solutions.

(3) Protein synthesis. It is contemplated that, in addition to characterizing the preceding biochemical assays, the compound of interest may also be

112 characterized as a modulator (eg, an inhibitor of protein synthesis) of the functional activity of the ribosome or ribosomal subunit.

Furthermore, more specific protein synthesis inhibition assays can be performed by administering the compound to an entire organism, tissues, organs, organelle, cell, a cellular or subcellular extract, or a purified ribosome preparation and observing its pharmacological properties and inhibitory by determining, for example, its inhibition constant (IC₅o) to inhibit protein synthesis. The incorporation of³H leucine or methionine ³⁵Yes, or similar experiments can be performed to investigate protein synthesis activity. A change in the amount or rate of protein synthesis in the cell in the presence of a molecule of interest indicates that the molecule is a modulator of protein synthesis. A decrease in the rate or amount of protein synthesis indicates that the molecule is an inhibitor of protein synthesis.

(4) Antimicrobial Assays and other Evaluation. Furthermore, the compounds can be tested for anti-proliferative or anti-infective properties at a cellular level. For example, when the target organism is a microorganism, the activity of the compounds of interest

113 It can be assayed for growth of the microorganisms of interest in the media, either containing or lacking the compound. Growth inhibition may be indicative that the molecule may act as an inhibitor of protein synthesis. More specifically, the activity of compounds of interest against bacterial pathogens can be demonstrated by the compound's ability to inhibit the growth of defined strains of human pathogens. For this purpose, a panel of bacterial strains can be assembled to include a variety of target pathogenic species, some containing resistance mechanisms that have been characterized. The use of said panel of organisms allows the determination of the structure-activity relationships not only in terms of potency and spectrum, but also with a view to avoiding resistance mechanisms.

The minimum inhibitory concentrations (MIC) were determined by the microdilution method, generally in a final volume of 100 microliters, according to the protocols described by the standards of the Clinical and Laboratory Institute [CLSI, previously the National Committee for

Clinical Laboratory Standards (NCCLS)]. See CLSI: Methods for Antimicrobial Susceptibility Testing of Bacteria Growing in Aerobic Conditions, the standards approved by the fifth edition. Wayne, PA: NCCLS,

114

2000. The tests can also be carried out in microtiter trays according to conventional methodologies as published by the CLSI. See CLSI. Methods for Antimicrobial Susceptibility Testing of Aerobically Growing Bacteria; Seventh Approved Standard Edition. CLSI Document M7-A7 [ISBN 1-56238-587-9] CLSI, 940 West Valley Road, Suite 1400, New York 19087-1898 EU Wayne, 2006).

The antimicrobial properties of drugs and one of the other compounds can be evaluated in various in vivo mammalian assays, such as mouse or rat peritonitis infectious models, skin and soft tissue models (often referred to as the thigh model) , or a model of mouse pneumonia. There are models of septicemia or organ infection known to those of skill in the art. These efficacy models can be used as part of the evaluation process and can be used as a guide to potential efficacy in humans. Endpoints may vary from reduced bacterial lethality load. By the extreme of the latter, the results are often expressed as a DP50 value, or the drug dose that protects 50% of animals from mortality.

In order to evaluate a compound, such as drugs, measurements of the inhibitory properties of

115 Cytochrome P450 and phase II enzymes that metabolize enzyme activity can also be measured, either using human recombinant enzyme systems or more complex systems, such as human liver microsomes. Furthermore, compounds can be evaluated as substrates for these metabolic enzyme activities as well.

These activities are useful in determining the potential of a compound to cause drug interactions or to generate metabolites that retain or do not have useful antimicrobial activity.

To obtain an estimate of the potential of the compound to be bioavailable orally, tests for solubility and Caco-2 can also be performed. The latter is a human epithelial cell line that allows measurement of drug absorption and passage through a monolayer of Caco-2 cells with increasing frequency within the wells of a well 24 microtiter plate equipped with a membrane 1 miera. Drug-free concentrations can be measured on the basolateral side of the monolayer, evaluating the amount of drug that can pass through the intestinal monolayer. Adequate controls to ensure the integrity of the monolayer and tightening of joints are necessary. Using this same system you can obtain a P-glycoprotein-mediated outflow estimate. P116 glycoprotein is a pump that is located on the apical membrane of cells, forming polarized monolayers. This pump can override active or passive absorption through the Caco-2 cell membrane, resulting in less drug transmission through the intestinal epithelial layer. These results are often made in conjunction with solubility measurements and both of these factors are known to contribute to oral bioavailability in mammals. Measurements of the oral bioavailability of animals and, ultimately, of man using traditional pharmacokinetic experiments will determine absolute oral bioavailability.

Experimental results can also be used to create models that help predict physical-chemical parameters that contribute similar properties to the drug. When this model was verified, the experimental methodology can be reduced, with a greater dependence on the predictability model.

5. Formulation and Administration

The compounds of the invention may be useful in the prevention or treatment of a variety of human or other animal, including mammals and non-mammals, disorders, including, for example, infection

117 Bacterial, fungal infections, viral infections, diarrhea, parasitic diseases, and cancer. It is contemplated that, once identified, the active molecules of the invention can be incorporated into any suitable carrier prior to use. The dose of the active molecule, mode of administration and use of suitable carrier will depend on the recipient and target organism. Formulations, both for veterinary use and for human medical use, of compounds according to the present invention typically include such compounds in association with a pharmaceutically acceptable carrier.

The carrier (s) must be acceptable in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient. Pharmaceutically acceptable carriers, in this regard, are intended to include each and every solvent, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption retarding agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional medium or agent is incompatible with the active compound, its use in the compositions is contemplated. Supplemental active compounds (identified or designed

118 according to the invention and / or known in the art) can also be incorporated into the compositions. The formulations can be conveniently presented in unit dosage form and can be prepared by any of the methods well known in the pharmacy / microbiology art. In general, some formulations are prepared by making the compound in association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

A pharmaceutical composition of the invention must be formulated to be compatible with its intended route of administration. Examples of routes of administration include oral, ophthalmic, otic, nasal, or parenteral, eg, intravenous, intradermal, inhalation, transdermal (topical), transmucosa, and rectal administration. Solutions or suspensions used for parenteral intradermal, or subcutaneous application may include the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl parabens alcohol or methyl; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as acid

119 ethylenediaminetetraacetic; buffers such as acetates, citrates or phosphates and tonicity adjusting agents such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

Useful solutions for oral or parenteral administration can be prepared by any of the methods well known in the pharmaceutical art, which is described, for example, in Remington Pharmaceutical Sciences, (Gennaro, A., ed.), Mack Pub. . , (1990) . Formulations for parenteral administration may also include glycocholate for oral administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration. The parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic. Suppositories for rectal administration can also be prepared by mixing the drug with a non-irritating excipient such as cocoa butter, other glycerides, or other compositions that are solid at room temperature and liquid at body temperatures. The formulations may also include, for example, polyalkylene glycols such as polyethylene glycol, vegetable oils, and hydrogenated naphthalenes. Formulations for direct administration may include

120 glycerol and other high viscosity compositions. Other potentially useful parenteral carriers for these drugs include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for administration by inhalation may contain as excipients, for example, lactose, or they may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Retention enemas can also be used for rectal delivery.

The formulations of the present invention suitable for oral administration may be in the form of: discrete units such as capsules, gelatin capsules, sachets, tablets, troches, or dragees, each containing a predetermined amount of the drug; a powder or granular composition; a solution or suspension in an aqueous liquid or non-aqueous liquid, or an oil-in-water emulsion or a water-in-oil emulsion. The drug can also be administered in the form of a bolus, electorate, or paste. A tablet can be made by compressing or molding the drug optionally with one or more accessory ingredients. The compressed tablets are

121 They can be prepared by compressing, in a suitable machine, the drug in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersing agent. The molded tablets can be made by molding, in a suitable machine, a mixture of the powdered drug and appropriate support moistened with an inert liquid diluent.

Oral compositions generally include an inert diluent or an edible carrier. For the purposes of oral therapeutic administration, the active compound can be incorporated with excipients. Oral compositions prepared using a carrier fluid for use as a mouthwash include the compound in the carrier fluid and are applied orally and shaken and expectorated or ingested. Pharmaceutically compatible binding agents and or adjuvant materials can be included as part of the composition. Tablets, pills, capsules, troches, and the like may contain any of the following ingredients or compounds of a similar nature: a binder such as microcrystalline cellulose, tragacanth gum, or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a slider such as

122 colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin, or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (when soluble in water) or sterile dispersions and powders for extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). It must be stable under manufacturing and storage conditions and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintenance of the required particle size in the case of dispersion, and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol chloride, sorbitol, or sodium in the composition. Absorption

123 Prolonged injection compositions can be accomplished by including an absorption retarding agent in the composition, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients listed above, as necessary, followed by filter sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile carrier containing a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation methods include vacuum drying and freeze-drying which produces a powder of the active ingredient plus any additional desired ingredients from a previously sterilized solution by filtration thereof. .

Formulations suitable for intra-articular administration can be in the form of a sterile aqueous drug preparation that can be in microcrystalline form, eg, in the form of a microcrystalline aqueous suspension. Liposome formulations or biodegradable polymer systems also

124 They can be used to present the drug for both intra-articular and ophthalmic administration.

Formulations suitable for topical administration, including eye treatment, include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments, or pastes; or solutions or suspensions such as drops. Formulations for topical administration to the skin surface can be prepared by dispersing the drug with a dermatologically acceptable carrier, such as a lotion, cream, ointment, or soap. Particularly useful are carriers capable of forming a film or layer on the skin to locate the application and inhibit its removal. For topical administration to internal tissue surfaces, the agent can be dispersed in a liquid tissue adhesive or other known substance to enhance adsorption to a tissue surface. For example, hydroxypropyl cellulose or fibrinogen / thrombin solutions can be used favorably. Alternatively, fabric coatings such as pectin solutions containing the formulations can be used.

For inhalation treatments, the

125 Inhalation powder (self-propellant or spray formulations) distributed with an aerosol can, a nebulizer, or an atomizer can be used. Such formulations may be in the form of a fine powder for pulmonary administration of a powder inhalation device or propulsion of powder dispensing formulations. In the case of self-propellant solution and spray formulations, the effect can be achieved either by choosing a valve having the desired spray characteristics (i.e. being able to produce a spray having the desired particle size) or incorporating the active ingredient as a suspended powder in controlled particle size. For administration by inhalation, the compounds can also be delivered in the form of an aerosol spray from the pressure vessel or

<td>dispenser</td><td>which contains a propellant</td><td>suitable,</td><td>by</td>

<td>example a</td><td>gas such as dioxide</td><td>carbon, or</td><td>a</td>

<td>nebulizer.</td><td></td><td></td><td></td>

<td>The</td><td>systemic administration can</td><td>also be</td><td>by</td>

transmucosal or transdermal medium. For transmucosal or transdermal administration, barrier penetrants appropriate to be permeated are used in the formulation. Such penetrants are generally known in the art, and are included, for example, for administration.

126 transmucosa, detergents and bile salts. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are typically formulated in the form of ointments, ointments, gels, or creams, as generally known in the art.

Active compounds can be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable and biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. The methods for preparing such formulations will be apparent to those skilled in the art. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in the Patent of

EU No. 4,522,811.

The oral or parenteral compositions can be formulated in unit dosage form to facilitate dosing uniformity and administration. Unit dosage form refers to units physically

127 discrete suitable as unit doses for the subject to be treated; each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the unit dosage forms of the invention are dictated by and depend directly on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the composition technique of such an active compound for the treatment of individuals. . Furthermore, administration can be by periodic bolus injections, or can be made more continuous by intravenous, intramuscular, or intraperitoneal administration from an external reservoir (eg, an intravenous bag).

When adherence to a tissue surface is desired, the composition may include the drug dispersed in a fibrinogen-thrombin composition or other bioadhesive. The compound can be painted, sprayed, or otherwise applied to the desired fabric surface. Alternatively, the drugs may be formulated for otic, ophthalmic, nasal, parenteral, or oral administration to humans or other mammals, for example, in therapeutically effective amounts, for example, amounts that provide adequate concentrations.

128 of the drug to target the tissue long enough to induce the desired effect.

When the active compound is to be used as part of a transplant procedure, it can be provided to living tissue or organ to be transplanted prior to removal of tissue or organ from the donor. The compound can be provided to the donor host. Alternatively or additionally, once removed from the donor, the living organ or tissue can be placed in a preservation solution containing the active compound. In all cases, the active compound can be administered directly into the desired tissue, such as by injection into the tissue, or it can be provided systemically, for example, by otic, ophthalmic, nasal, oral or parenteral administration, using any of the methods and formulations described herein and / or known in the art. When the drug comprises part of a tissue or an organ preservation solution, any commercially available preservation solution can be used to advantage. For example, useful solutions known in the art include Collins solution, Wisconsin solution, Belzer solution, Eurocollins solution, and Ringer's lactate solution.

The compounds of the present invention can be administered directly to a tissue locus by

129 applying the compound to a medical device that comes in contact with the tissue. An example of a medical device is a stent, which contains or is coated with one or more of the compounds of the present invention.

For example, an active compound can be applied to a stent at the site of vascular injury. Stents can be prepared by any of the methods well known in the pharmaceutical art, see, for example, Fattori, R. and Piva, T., Drug Extraction Stents in Vascular Intervention, Lancet, 2003, 361, 247-249. ; Morice, MC, A new era in the treatment of coronary heart disease? European Newspaper on the Heart, 2003, 24, 209-211, and Toutouzas, K. et al ,. Sirolimus Extraction Stents: A Review of Experimental and Clinical Results, Z Kardiol, 2002, 91 (3), 49-57. The stent can be made of stainless steel or other biocompatible metal, or it can be made of a biocompatible polymer. The active compound can be attached to the surface of the stent, integrated and released from polymeric materials coated on the stent, or surrounded by and released through a layered airline or stent. The stent can be used to deliver single or multiple active compounds to the tissues adjacent to the stent.

130

The active compound as identified or designed by the methods described herein can be administered to individuals to treat disorders (prophylactically or therapeutically). In conjunction with such treatment, pharmacogenomics (i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug) can be considered. Differences in the metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relationship between the dose and the blood concentration of the pharmacologically active drug. Therefore, a physician or clinician may consider applying the insights gained from relevant pharmacogenomics studies to determine whether to administer a drug, as well as to adapt the dose and / or therapeutic regimen of drug treatment.

In therapeutic use to treat, or combat bacterial infections in mammals, the compounds or pharmaceutical compositions thereof will be administered otically, ophthalmic, nasal, oral, parenteral and / or topically at a dose to obtain and maintain a concentration, that is, an amount, or blood level or tissue level of active component in the submitted treatment of the animal that will be anti-microbial

131 effective. Generally, an effective dosage amount of the active component will be in the range of from about 0.1 to about 100, more preferably from about 1.0 to about 50 mg / kg of body weight / day. The amount administered will probably also depend on variables such as the type and degree of the disease or the indication to be treated, the general health status of the particular patient, the relative biological efficacy of the delivered compound, the formulation of the drug, the presence and types of excipients of the formulation and route of administration. Furthermore, it is to be understood that the initial dose administered may be increased beyond the upper level above in order to rapidly achieve the desired blood level or tissue level, or the initial dose may be less than the optimal and daily dose. It can be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose can also be divided into multiple doses for administration, for example, two to four times per day.

Various disease states or conditions in humans and other mammals are found to be caused or mediated by senseless or absurd mutations.

These mutations cause or mediate the disease state or condition by negatively affecting, for example, the

132 protein synthesis, folding, traffic and / or function. Examples of disease states or conditions in which it is believed that an appreciable percentage of the disease or condition will result in senseless or absurd mutations include hemophilia (factor VIII gene), neurofibromatosis (NFl and NF2 genes), retinitis pigmentosa (human gene USH2A), thick skin diseases such as pruritic hulose Epidermolysis (COL7A1 genes), cystic fibrosis (transmembrane regulatory gene for cystic fibrosis), breast and ovarian cancer (BRCAl and

BRCA2), Duchenne muscular dystrophy (dystrophin gene), colon cancer (repair genes, mainly in MLHl and MSH2), and lysosomal storage disorders such as Neimann-Pick disease (acid sphingomyelinase gene). See Sanders CR, Myers

JK. Lack of meeting of Related Diseases of membrane proteins. Annu Rev Biophys Biomol Struct. 2004; 33: 25-51; National Center for Biotechnology Information (EU) Genes and disease Bethesda, MD: NCBI, NLM ID: 101138560, and Rasko, István; Downes, CS Genes in Medicine: Molecular Biology and Human Genetic Disorders First Edition. London, New York: Chapman &amp; Hall, 1995. NLM ID: 9502404. The compounds of the present invention can be used to treat or prevent a disease state in a mammal caused or mediated by

133 nonsense or nonsense mutations by administration to a mammal in need of an effective amount of the present invention to suppress nonsense or nonsense disease-related mutation.

6. Examples

Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker Avance 300 spectrometer or an Avance 500 spectrometer, or in some cases a GE-Nicolet 300 spectrometer. The common reaction solvents were high performance liquid chromatography (HPLC) grade. , or American Chemical Society (ACS) grade, and anhydrous, obtained by the manufacturer unless otherwise noted. Chromatography or purified by silica gel refers to column chromatography using silica gel (EM Merck, silica gel 60, 230-400 mesh) unless otherwise indicated.

The compounds of the present invention can be prepared using known chemical transformations adapted to the particular situation in question.

Some of the abbreviations used in the following experimental details of the synthesis of the

134 Examples are defined below: ho hr = hour (s); min = minute (s); mol = mol (s); mmol-millimol (s); M = molar; μΜ = micromolar; g = gram (s); pg = micrograms (s); ta = room temperature; L = liter (s); mL = milliliter (s); Et₂O = diethyl ether, THF = tetrahydrofuran; DMSO = dimethyl sulfoxide; EtOAc = ethyl acetate; Et₃N triethylamine; i-Pr₂NEt or DIPEA = diisopropylethylamine; CH₂C1₂ = methylene chloride; CHC1₃ = chloroform; CDC1₃ = deuterated chloroform; CC1₄ - car tetrachloride; MeOH methanol; CD₃OD = deuterated methanol; EtOH = ethanol; DMF = dimethylformamide; BOC = t-butoxycarbonyl; CBZ = benzyloxycarbonyl; TBS = t-butyldimethylsilyl; TBSC1 = t-butyldimethylsilyl chloride; TFA = trifluoroacetic acid; DBU = diazabicycloundecene; TBDPSCl = tbutyldiphenylchlorosilane; Hunig Base = N, Ndiisopropylethylamine; DMAP = 4-dimethylaminopyridine; Cul copper = (I) iodide; MsCl = methanesulfonyl chloride;

NaN₃ = sodium azide; Na₂SW₄ - sodium sulfate; NaHCO₃ sodium bicarbonate; NaOH = sodium hydroxide; MgSO₄ = magnesium sulfate; K₂CO₃ = potassium carbonate; KOH = potassium hydroxide; NH₄OH = ammonium hydroxide; NH₄C1 = ammonium chloride; SiO₂ silica =; Pd-C - palladium on car; Pd (dppf) Cl₂ = dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II).

The compounds of synthesized examples of

135 according to the invention are listed in Table 1. A bold or discontinuous bond is shown to indicate a particular stereochemistry, to a chiral center, while a wavy bond indicates that the substituent can be in any orientation or that the compound is a mixture of the same. It should also be known that, in the interest of conservation space, the chemical structures of some compounds have been divided into two parts with the two connection points of each one indicated by a bond crossed by a wavy line. See, for example, compound 1345, which was made in two parts as:

NH

OCF₃ but it corresponds to the complete chemical structure:

NH

OR'

N

136

The compounds of the present invention can be prepared, formulated, and delivered as salts, esters, and prodrugs. For convenience, the compounds are shown generally, without indicating a particular salt, ester, or prodrug form.

The compounds of the present invention are shown in Table 1. LCMS (Liquid Chromatography Mass Spectrum) data are provided, when available. When the data is not available it will be indicated with NA. LCMS data is provided using the m / z convention in the format, [M + H] +, unless otherwise noted.

Table 1

<td>Comp. No.</td><td>Structure</td><td>LCMS</td>

<td> 100</td><td>NH CH₃H₂NNX NH 0^H nh₂ or XAA N NH₂H</td><td>N / A</td>

137

<td> 101</td><td>NH ch₃„Xxy&gt; or Οχ, ΝΗ 0 X X. X X oX N NH₂Η &lt;χΑ</td><td> 442.30</td>

<td> 102</td><td>NH CH₃ΧχχΧ 0 CK.NH or XXX and Cr NN nh₂h₂n '^/^</td><td> 441.40</td>

<td> 103</td><td>NH CH, OR ¹Η₂Ν ^ Ν ^^^χ^^^^χ'^Ν'^χΧ^χΝΗ 0 &lt;Χ / ΝΗ OX X OX n NH₂h₂n ^ J ^H</td><td> 427.30</td>

<td> 104</td><td>NH CH₃AxrYTr g οχ, νη θ -X Χχ X XO ^ XN NH₂HO ^ X</td><td> 428.20</td>

<td> 105</td><td>NH CH₃A / WXN 'h₂nn ^^^ X γ &lt;nh o ΗΝχ, ΝΗ 0 xX -XX CT NN NH₂nh₂</td><td>N / A</td>

138

<td> 106</td><td>NH CH₃H₂nXn ^^x-^{/ X}AND^XX^^NxAND^X^ NH or &lt;^NH ° oXX^TOnh₂Ά ^H</td><td> 413.30</td>

<td> 107</td><td>NH CH₃^H 0 -5₀ΙλΛη₂NH hnXnh₂</td><td> 469.30</td>

<td> 108</td><td>NH CH₃h₂nn γ γ &lt;NH or Q / ^ NH or -¿and Jk / ZO ^ NN NH_;, z ΰ N H</td><td> 496.40</td>

139

<img file="MX2012004342A_D0044.tif" />

<td> 110</td><td>NH CH₃^Η2Ν-^Ζ^ Ν^{/ Χ}-^{/ Χ}γ^/^^χΝ'γ ^^ΧΝΗ O^NH2 0 0 ^H U /&gt; ΌΗ</td><td> 534.50</td>

<td> 111</td><td>NH CH₃^ Λν ^ ΥΥ ^ νη or ο ^, νη or -XX XX CX NN NH, * —NH</td><td> 478.30</td>

<td> 112</td><td>ρ = Λ_οNH / \ X ° h₂nn χ XX ^ X NH o nh₂ or X. &lt;Λ X² NH₂H</td><td> 451.30</td>

140

<td> 113</td><td></td><td>νη₂</td><td> '^{/ χ}'ν'^&lt;5? Ν Λ Α Ο^ΖΝ ΝΗ₂</td><td> 241.3 0</td>

<td> 114</td><td>JX Η, Ν Ν Η</td><td>νη₂</td><td>^^ Ν ^ Ν Λ Α CK N ΝΗ₂</td><td> 283.2 0</td>

<td> 115</td><td></td><td>νη₂</td><td></td><td> 240.0</td>

<td></td><td></td><td></td><td>XX</td><td> 0</td>

<td></td><td></td><td></td><td>CXA ^ TJH ;,</td><td></td>

<td> 116</td><td></td><td></td><td></td><td> 240.0</td>

<td></td><td>η₂ν '^χχ-''</td><td>νη₂</td><td>^χΧμ^&lt;Χ (Χή ^^ ΧιΗ ;,</td><td> 0</td>

<td> 117</td><td>HcX '' ^</td><td></td><td>'^ νΧΧ</td><td rowspan="2"> 241.1 0</td>

<td></td><td></td><td>νη₂</td><td>Cr Ν ΝΗ₂</td>

<td> 118</td><td>J1X Η, Ν Ν</td><td></td><td>'^^' Ν '^ Χ</td><td> 282.1 0</td>

<td></td><td></td><td>νη₂</td><td>TO THE CT Ν ΝΗ₂</td><td></td>

141

<td> 119</td><td>χχν</td><td></td><td></td><td></td><td rowspan="2"> 331.2 0</td>

<td></td><td></td><td>νη₂</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>CT N ΝΗ₂</td><td></td>

<td> 120</td><td></td><td></td><td></td><td rowspan="2">Η \ ^ Ν ^, ΝΗ₂X</td><td> 438.2</td>

<td></td><td>ΝΗ Ακχ,</td><td>ΗΝ ^^</td><td></td><td> 0</td>

<td></td><td>Η, Ν Ν</td><td></td><td></td><td></td><td></td>

<td></td><td>Η</td><td></td><td>χ</td><td>Ha</td><td></td>

<td></td><td></td><td>C</td><td></td><td>Ν Ν ΝΗ,</td><td></td>

<td></td><td></td><td></td><td></td><td>Η</td><td></td>

<td> 121</td><td></td><td></td><td></td><td></td><td rowspan="2"> 325.1 0</td>

<td></td><td>η₂ν ν</td><td></td><td>Ν^Χ</td><td>X ο</td>

<td></td><td>Η</td><td>ΝΗ₂ χ</td><td></td><td>JLx,.,</td><td></td>

<td></td><td></td><td></td><td></td><td>Η</td><td></td>

<td> 122</td><td>Η₂Ν '~^χ-^χ'</td><td>'γ^{Λχ /}^ 'Ν'</td><td></td><td>Ί θ</td><td> 283.1</td>

<td></td><td></td><td>ΝΗ₂</td><td>X</td><td rowspan="2">1 X Ν ΝΗ₂Η ²</td><td> 0</td>

<td></td><td></td><td></td><td></td><td></td>

<td> 123</td><td></td><td>- ^ Ν ^</td><td></td><td>Ο</td><td> 284.1</td>

<td></td><td></td><td>ΝΗ, X,</td><td>χ &lt;.</td><td>L χ</td><td> 0</td>

<td></td><td></td><td></td><td></td><td>Η</td><td></td>

<td> 124</td><td rowspan="2">ΝΗ i] Η, Ν Ν '^² Η</td><td>νη₂</td><td></td><td></td><td rowspan="2"> 325.2 0</td>

<td></td><td></td><td></td><td rowspan="2">XX Ν Ν ΝΗ, Η</td>

<td></td><td></td><td></td><td></td><td></td>

142

<img file="MX2012004342A_D0045.tif" />

143

<td> 130</td><td colspan="2">ΝΗ il^η2^ν ν '\ ^ \^Η I 0 r οΧλ „,^Η2^Ν\ Υ ^Η</td><td> 382.1 0</td>

<td> 131</td><td></td><td></td><td> 317.0</td>

<td></td><td>η₂ν ^ ~ ^ -</td><td>^^ ΝΗ Τν ,. ΧΛλ CT Ν Ν ΝΗ₂Η</td><td> 0</td>

<td> 132</td><td></td><td></td><td> 273.9</td>

<td></td><td>η₂ν ^</td><td>^Χ- ^ ΝΗ X</td><td> 0</td>

<td></td><td></td><td>λα CK N ΝΗ₂</td><td></td>

<td> 133</td><td>ΝΗ J] χ Η, Ν Ν Η</td><td>νη₂ χΥ &lt;Χ X Ο- ^ Ν ΝΗ, Η</td><td> 326.1 0</td>

<td> 134</td><td>ΝΗ XX</td><td></td><td rowspan="2"> 438.4 0</td>

<td></td><td>² Η</td><td>.ΝΗ X X. X</td>

<td></td><td></td><td>X ο Ν [J ΝΗ,</td><td></td>

<td></td><td></td><td>ΊΜΗ Λ Η₂Ν &lt;ΝΗ</td><td></td>

144

<td rowspan="2"> 135</td><td rowspan="2">η₂ν ^</td><td rowspan="2">νη₂</td><td colspan="2"></td><td rowspan="2">0 Λ Ν ΝΗ₂Η</td><td rowspan="2">Ν / Α</td>

<td> 0'</td><td>Ν Η</td>

<td> 136</td><td>ηο ^</td><td>νη₂</td><td>CT</td><td>'hf Η</td><td>0 Π Ν ΝΗ₂Η</td><td>Ν / Α</td>

<td> 137</td><td></td><td></td><td></td><td></td><td></td><td> 292.1</td>

<td></td><td>η₂ν</td><td>'^ ΝΗ k</td><td>&lt;Αΐ</td><td></td><td></td><td> 0</td>

<td></td><td></td><td></td><td>νΧ</td><td colspan="2">. /F Ν</td><td></td>

<td></td><td></td><td></td><td> 0</td><td colspan="2">χΧ Ν ΝΗ₂</td><td></td>

<td> 138</td><td></td><td></td><td></td><td></td><td></td><td> 335.0</td>

<td></td><td>η₂ν ^</td><td>'' 'ΝΗ Ϋ</td><td></td><td></td><td></td><td> 0</td>

<td></td><td></td><td></td><td>CT</td><td>'Άγ Ν</td><td>,F Ο OR 'Ν ΝΗ₂Η</td><td></td>

<td> 139</td><td></td><td>νκ₂i ^¿</td><td></td><td></td><td></td><td> 259.9</td>

<td></td><td></td><td>Ο, · CK '</td><td>Ά? 0 Ν</td><td>0 he has Η</td><td>νη₂</td><td> 0</td>

145

140

Η, Ν. ,^ν? Ν

Ο

Λ.

CK Ν Ν ΝΗ, Η

141

ΗΝ.

Η, Ν

ΝΗ, ΧΝ

Ν Ύ Ο ¥ Λ Λ

CT N Ν ΝΗ₂Η

143

Η, Ν Ν

<img file="MX2012004342A_D0046.tif" />

. Λ

Ν '

ΝΗ,

Cr Ν ΝΗ,

144

Η, Ν

<img file="MX2012004342A_D0047.tif" />

Ο ϋ

_Ον- '_Ν'' Ν ΝΗ₂Η

145

Η, Ν

Ν ΝΗ,

<img file="MX2012004342A_D0048.tif" />

Ν X 'ΝΗ

Η, Ν ^ Ο

327.0

369.0

349.1

374.2

374.2

146

<img file="MX2012004342A_D0049.tif" />

147

<td> 150</td><td>Η₂Ν— \ /^N-N h₂ñ ·</td><td>&lt;A yy</td><td>jl '^' Y CK</td><td>* ^ A . Xx N</td><td>OR YES nh₂H</td><td> 356.1 0</td>

<td> 151</td><td>NH TO</td><td></td><td></td><td></td><td>nXa Kn</td><td rowspan="2"> 540.4 0</td>

<td></td><td>h₂nn Y ^ -</td><td>'N'</td><td>Ά,</td><td> 0</td><td> /</td>

<td></td><td>H i .NH</td><td></td><td>for.</td><td>.TO</td><td></td><td></td>

<td></td><td>C ⁰</td><td></td><td>N</td><td>NN Η H</td><td>AA</td><td></td>

<td></td><td>nh₂</td><td></td><td></td><td></td><td></td><td></td>

<td> 152</td><td>NH</td><td></td><td></td><td></td><td></td><td> 501.5</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="2"> 0</td>

<td></td><td>H₂NN</td><td>Ύ</td><td></td><td>OR</td><td></td>

<td></td><td>H i .NH</td><td></td><td>V A&gt;</td><td>for</td><td>z = \ _zch₃</td><td></td>

<td></td><td colspan="2">I ⁰</td><td>N</td><td rowspan="2">N H</td><td>N — 6. /) - N Η V // '.</td><td></td>

<td></td><td>TO</td><td></td><td></td><td>CH₃</td><td></td>

<td></td><td>one nh₂</td><td></td><td></td><td></td><td></td><td></td>

<td> 153</td><td>H, N_ x, / x</td><td></td><td></td><td></td><td></td><td> 378.9</td>

<td></td><td> /</td><td>'Ijf</td><td>JL</td><td>N ^ Yi</td><td> 0</td><td> 0</td>

<td></td><td>NHj</td><td></td><td></td><td>-A AL</td><td>for</td><td></td>

<td></td><td></td><td></td><td>or-</td><td>N</td><td>N NH₂H</td><td></td>

<td> 155</td><td>NH</td><td></td><td></td><td></td><td></td><td> 477.3</td>

<td></td><td>Xy / y / -</td><td></td><td></td><td></td><td></td><td>fl</td>

<td></td><td>h₂nn γ ^</td><td></td><td>^ N</td><td>Ύ,</td><td> 0</td><td>or</td>

<td></td><td>Η 1</td><td></td><td></td><td></td><td>II</td><td></td>

<td></td><td>.NH</td><td></td><td></td><td>Ά</td><td></td><td></td>

<td></td><td>X</td><td></td><td>and'</td><td>NN</td><td>li V</td><td></td>

<td></td><td>L</td><td></td><td></td><td>H</td><td>THE</td><td></td>

<td></td><td>η</td><td></td><td></td><td></td><td>Cl</td><td></td>

<td></td><td>NH_Z</td><td></td><td></td><td></td><td></td><td></td>

148

<img file="MX2012004342A_D0050.tif" />

149

<td rowspan="2"> 160</td><td rowspan="2">ΝΗ ιι Η, Ν Ν '' - ^² Η (</td><td rowspan="2">.ΝΗ Λ Ί ΝΗ₂</td><td colspan="2"> '^&lt;Υί 0</td><td rowspan="2"> 494.4 0</td>

<td>ΑΛ Ν Ν ΝΗ Η</td><td>-Q-^FF</td>

<td> 161</td><td></td><td> 0</td><td></td><td></td><td> 338.9</td>

<td></td><td>Η₂Ν_{χ /}^</td><td>Υγ ΝΗ₂ Υυ 0 '</td><td>Υ ^ ΝΗ 0 ΤΑΛ Η</td><td>ΝΗ₂</td><td> 0</td>

<td> 162</td><td>νη₂</td><td>¿Νη₂</td><td></td><td></td><td> 332.0 0</td>

<td></td><td>cY</td><td>'' νη</td><td></td><td></td><td></td>

<td></td><td></td><td>Υ</td><td>ίΤ ^ ΝΗ^χνΆ_νηοΥνΗ₂</td><td></td><td></td>

<td> 163</td><td>ΝΗ D Η, Ν Ν ^ - ^ Η</td><td>.ΝΗ / C.</td><td>ν ^ 7 ~ | ο</td><td>Cl 4_zN — CH₃-ν '</td><td> 481.2 0</td>

<td></td><td></td><td>νη₂</td><td></td><td></td><td></td>

150

<td rowspan="2"> 164</td><td colspan="2">NH</td><td rowspan="2">Α-Ί 0 F. Λ-ζζ ^ F</td><td rowspan="2"> 512.3 0</td>

<td>Η, Ν ^ Ν ^^ ² H</td><td>ΑγΑΆ .NH A ς · nh₂</td>

<td> 165</td><td>NH</td><td></td><td></td><td> 526.2</td>

<td></td><td>FOR</td><td></td><td></td><td rowspan="2"> 0</td>

<td></td><td>Η, Ν N</td><td>AA / A</td><td>X ⁰</td>

<td></td><td>H</td><td>.NH .A C oA</td><td>S-CX</td><td></td>

<td></td><td></td><td>one NH₂</td><td></td><td></td>

<td> 166</td><td>NH</td><td></td><td></td><td> 555.4</td>

<td></td><td></td><td></td><td></td><td rowspan="2"> 0</td>

<td></td><td>h₂nn -</td><td>a ^ a ^_nto</td><td>1 θ</td>

<td></td><td>H</td><td>.NH X &lt;</td><td>Ax_w _f = \</td><td></td>

<td></td><td></td><td>'O^z N</td><td></td><td></td>

<td></td><td></td><td></td><td>\ —N</td><td></td>

<td></td><td></td><td>nh₂</td><td>A-ch₃</td><td></td>

<td> 167</td><td rowspan="2">HA² H</td><td></td><td>'N ^ l O _CHa</td><td> 542.3 0</td>

<td></td><td>.NH</td><td>Ύ - &lt;Y JL X</td><td></td>

<td></td><td></td><td>ς *</td><td>NN and l^H sAⁿ</td><td></td>

<td></td><td></td><td>one nh₂</td><td>νΉ₍</td><td></td>

<td></td><td></td><td></td><td>X /^N</td><td></td>

151

<td> 168</td><td>h₂n Ν '-'Ή γ Ti^H J VL J Λ Η, ΙΨ 0 &lt;^ N '^Z^ N^X^ NH,² H ²</td><td> 416.1 0</td>

<td> 170</td><td>H T »7 0 / JJAX h₂no ^ nn nh₂² H ²</td><td> 402.4 0</td>

<td> 171</td><td>N Α ^ γΑ'ΝΗ zjL xk CT N NH Cr ^ NH Φ · F</td><td> 486.2 0</td>

152

<img file="MX2012004342A_D0051.tif" />

153

<img file="MX2012004342A_D0052.tif" />

154

<img file="MX2012004342A_D0053.tif" />

155

<img file="MX2012004342A_D0054.tif" />

156

<td> 199</td><td>NH JJ Η, Ν Ν '^ γ' ^ N% O (° ^N Λη π^CHaH₂N ^&gt; Η T ΌΗ</td><td> 559.1 0</td>

<td> 202</td><td>NH I H, NN ^ - ^ N Vf&gt;^H J IJL &lt;^ V ^ NH J &lt;Á¿ H₂N CT Ν Λ ^_n.^CH3 _orΗ H</td><td> 590.4 0</td>

<td> 205</td><td>nh₂ nh₂fifteen N X ^ J ^ NH For CT N NH X cf₃</td><td> 517.2 0</td>

157

<td> 207</td><td>ΝΗ Α / X / X / X / X XX Η, Ν Ν ^^ Τ ^ '- ν Υ 0^Η .ΝΗ X Λ J-Ls &lt;CT Ν Ν? ' νη₂</td><td> 624.4 0</td>

<td> 208</td><td>ΝΗ Α / X / X / X / X XX .ΝΗ ₀Α_νΑ_νΑ_ν_ / \ / νη₂</td><td> 613.5 0</td>

<td> 209</td><td>νη₂ νη₂% Ν Λα CT Ν ΝΗ οΛνη 0 Ν ό one ch₃</td><td> 631.5 0</td>

158

<img file="MX2012004342A_D0055.tif" />

159

<img file="MX2012004342A_D0056.tif" />

160

<td> 222</td><td>NH Λ / χ² Η H₂N '</td><td>0 Ν</td><td>XC Η Η</td><td>&lt;Ν ³X</td><td> 590.3 0</td>

<td> 223</td><td rowspan="2">NH Λ Η, Ν lX² Η</td><td></td><td></td><td></td><td> 528.3</td>

<td></td><td>'ΤΌ,</td><td>or</td><td>zv^F</td><td> 0</td>

<td></td><td></td><td rowspan="2">X λ ΗΧ CT</td><td rowspan="2">X Λ 'Ν Ν Ν' Η Η</td><td>ίχ</td><td></td>

<td></td><td></td><td></td><td></td>

<td> 238</td><td></td><td>νη₂</td><td></td><td></td><td> 390.0</td>

<td></td><td></td><td></td><td></td><td></td><td> 0</td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td colspan="2">ΛΛ Cr Ν ΝΗ cAnh</td><td></td><td></td>

<td></td><td></td><td>X</td><td>ή</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>F</td><td></td><td></td>

161

<td> 239</td><td>νη₂ΉΗ οΑ_νηV F</td><td> 447.1 0</td>

<td> 242</td><td>CI η I 1_ΟΧ_ΝΧ_ΝΧ_ΝΧΧ Η Η 1 ocf₃</td><td> 511.3 0</td>

<td> 243</td><td>Cl Η₂Ν ^^^ Ν ^ Υ% Η | one 0 ΖΥ₀Α_ΝΑ_ΝΧ_ΝΑγγι Η Η 1 CI</td><td> 493.2 0</td>

<td> 244</td><td>CI^Η / ° CF₂H γ ^ ΝΗ 0 Γ Υ₀Α_ΝΑ_ΝΧ_ΝΧΧ Η Η</td><td> 493.2 0</td>

162

<td rowspan="2"> 246</td><td rowspan="2">Η₂Ν ^ χ ^</td><td rowspan="2">F^Η υ C</td><td colspan="2">Υ ^ 'ΝΗ 0 ΥΧ Áα XÁJ</td><td rowspan="2"> 495.2 0</td>

<td>) Ν Ν Η</td><td>Ν Υ Η 1 ocf₃</td>

<td> 247</td><td></td><td>F</td><td></td><td></td><td> 438.2</td>

<td></td><td>Η₂Ν ^ '</td><td>Υί</td><td></td><td></td><td> 0</td>

<td></td><td></td><td></td><td>^ΧΝΗ 0</td><td>ο</td><td></td>

<td></td><td></td><td>CrY</td><td rowspan="2">^ Ν ^ Ν^ΧΗ Η</td><td>τ</td><td></td>

<td></td><td></td><td></td><td>ocf₃</td><td></td>

<td> 248</td><td></td><td>F₃c</td><td></td><td></td><td> 488.2</td>

<td></td><td></td><td>Μ</td><td></td><td></td><td> 0</td>

<td></td><td></td><td>Oops</td><td>Υη 0</td><td></td><td></td>

<td></td><td></td><td>CT&gt;</td><td rowspan="2">^ νΑυ Η Η</td><td>τ</td><td></td>

<td></td><td></td><td></td><td>ocf₃</td><td></td>

<td> 249</td><td></td><td>F</td><td></td><td></td><td> 495.2</td>

<td></td><td>Η₂Ν ~ χ ^ | &lt;</td><td></td><td></td><td></td><td> 0</td>

<td></td><td>² Η</td><td>ΧίΧΧγ ςχ</td><td>Υ ^ ΝΗ 0 &gt; ΑΛ</td><td>zv^0CFs„Xx</td><td></td>

<td></td><td></td><td></td><td>Η</td><td>Η</td><td></td>

<td> 251</td><td></td><td></td><td></td><td></td><td> 503.3</td>

<td></td><td>ΥΧ Η₂Ν ^^</td><td></td><td>Ύνη 0</td><td>ΥΎι</td><td> 0</td>

<td></td><td></td><td>&lt;Υ</td><td colspan="2"></td><td></td>

<td></td><td></td><td></td><td></td><td>ocf₃</td><td></td>

163

<td rowspan="2"> 252</td><td rowspan="2">HjN ^</td><td rowspan="2">H</td><td colspan="2">F TO</td><td rowspan="2"> 479.1 0</td>

<td> 0*</td><td>Ynh or YY AÁAAi^{H H} ¿1</td>

<td> 255</td><td></td><td></td><td>F</td><td></td><td> 443.2</td>

<td></td><td>H₂N '^^x</td><td>H</td><td>Cl</td><td>Y'NH 0 ΆπΑ-γθ ^</td><td> 0</td>

<td> 256</td><td colspan="2">h₂n ^ A</td><td>γγγ kC 0</td><td>'' ΥΎη or YY&gt; Η Η ocf₃</td><td> 534.4 0</td>

<td> 257</td><td></td><td></td><td>Cl</td><td></td><td> 462.2</td>

<td></td><td></td><td>^H 1</td><td>AND</td><td></td><td> 0</td>

<td></td><td></td><td></td><td>yy \ ¿</td><td rowspan="2">^ ΝΗ 0 ΆΎγγ</td><td></td>

<td></td><td></td><td></td><td>DC</td><td></td>

<td> 259</td><td></td><td></td><td>cf₃</td><td></td><td> 529.2</td>

<td></td><td>h₂n ^ '</td><td>H</td><td>γΥ \TO (AND</td><td>ΥΎη ο ΥΥ^{Η Η} ί,</td><td> 0</td>

164

<td rowspan="2"> 260</td><td rowspan="2">H₃CS ^ / X</td><td rowspan="2">ν ' H</td><td colspan="2">Cl</td><td rowspan="2">TO ocf₃</td><td rowspan="2"> 528.2 0</td>

<td>Ax c?</td><td>γ ^ ΝΗ 0 ^ nA_nTO_n, Η H</td>

<td> 265</td><td></td><td></td><td>F</td><td></td><td></td><td> 465.2</td>

<td></td><td></td><td>X H</td><td>or</td><td rowspan="2">X ^ NH 0 AÁA ' Η H</td><td>TO</td><td> 0</td>

<td></td><td></td><td></td><td></td><td>T F</td><td></td>

<td> 266</td><td></td><td></td><td>cf₃</td><td></td><td></td><td> 515.3</td>

<td></td><td></td><td>H</td><td>Ta or"</td><td rowspan="2">ΧΆη 0 ^ νΑ_νΆ_νλ Η Η</td><td>TO</td><td> 0</td>

<td></td><td></td><td></td><td></td><td>F</td><td></td>

<td> 267</td><td></td><td></td><td>Cl</td><td></td><td></td><td> 476.3</td>

<td></td><td>^h3^cs^/\_nH</td><td></td><td colspan="2">fl or₀Α_νΑ_νΛ_ν^. Η H</td><td>OR,</td><td> 0</td>

165

<td rowspan="3"> 268</td><td rowspan="3">H₃CS. χ-χ³ - Ν Η</td><td colspan="3">CI</td><td rowspan="3"> 498.1 0</td>

<td colspan="2">ΊΓι ΧΧΑη 0</td><td rowspan="2">Υ F</td>

<td> 0^</td><td>Τν ^ ν ^ Ν Η Η</td>

<td> 269</td><td></td><td>cf₃</td><td></td><td></td><td> 545.3</td>

<td></td><td>Η₂Ν '^^χΧ^ Ν ^ Η</td><td>Χί XX ο</td><td>XX 0 Χχ Η</td><td>one? ocf₃</td><td> 0</td>

<td> 270</td><td></td><td>cf₃</td><td></td><td></td><td> 527.3</td>

<td></td><td rowspan="2">Η₂Ν - '' Χ X^Η</td><td></td><td></td><td></td><td> 0</td>

<td></td><td colspan="2">'' '^ Υ - Χ''ΝΗ 0</td><td>^ t - ^. OCF₂H</td><td></td>

<td></td><td></td><td></td><td>Η Η</td><td></td><td></td>

<td> 271</td><td></td><td>CI</td><td></td><td></td><td> 514.2</td>

<td></td><td>Η</td><td>Χί χχ 0 *</td><td>Χ ^ ΝΗ Ο</td><td>Τ&gt;</td><td> 0</td>

<td></td><td></td><td></td><td></td><td>ocf₃</td><td></td>

<td> 273</td><td></td><td>cf₃</td><td></td><td></td><td> 529.2</td>

<td></td><td>Η</td><td>Τι ^ XjX ^ X cr</td><td>Χ'ΝΗ 0 '' ΓΓ'Ν ^ 'Ν' Η Η</td><td>α</td><td> 0</td>

166

<td rowspan="2"> 274</td><td rowspan="2"></td><td colspan="2"></td><td rowspan="2">9 ocf₃</td><td rowspan="2"> 474.0 0</td>

<td>&lt;and</td><td>Η Η</td>

<td> 275</td><td></td><td></td><td></td><td>F one</td><td rowspan="2"> 444.0 0</td>

<td></td><td></td><td></td><td>^ ΝΗ Ο (&lt;</td><td></td>

<td></td><td></td><td>cr</td><td>'N ^ N ^ hT</td><td></td><td></td>

<td></td><td></td><td></td><td>Η Η</td><td>Τ F</td><td></td>

<td> 276</td><td></td><td></td><td></td><td>F</td><td> 448.0</td>

<td></td><td>Η</td><td>\TO</td><td>γ ^ ΝΗ Ο</td><td>i ^ V^F</td><td> 0</td>

<td></td><td></td><td></td><td>^ί5* \. .Χ \. , χ</td><td rowspan="2">V</td><td></td>

<td></td><td></td><td>ο^χ</td><td>Ν Ν Ν</td><td></td>

<td></td><td></td><td></td><td></td><td>F</td><td></td>

<td> 277</td><td></td><td></td><td></td><td></td><td> 478.0</td>

<td></td><td>Η</td><td>V</td><td>υ ^ νη 0</td><td></td><td> 0</td>

<td></td><td></td><td>ο</td><td></td><td>'Τ</td><td></td>

<td></td><td></td><td></td><td>Η Η</td><td>ocf₃</td><td></td>

167

<img file="MX2012004342A_D0057.tif" />

168

<img file="MX2012004342A_D0058.tif" />

169

<img file="MX2012004342A_D0059.tif" />

170

<img file="MX2012004342A_D0060.tif" />

171

<img file="MX2012004342A_D0061.tif" />

172

<img file="MX2012004342A_D0062.tif" />

173

<td rowspan="2"> 305</td><td rowspan="2">ι ^ΗOCF 3 Η₂(Ψ</td><td rowspan="2">γ</td><td colspan="2">Α&gt; ^ ΝΗ 0 I ha.</td><td rowspan="2">9 ocf₃</td><td rowspan="2"> 738.0 0</td>

<td>Ο Ν Ν Η</td><td>Ν Η</td>

<td> 307</td><td></td><td>F</td><td></td><td></td><td></td><td> 536.3</td>

<td></td><td></td><td>Υί</td><td></td><td></td><td></td><td> 0</td>

<td></td><td rowspan="2">η₂ν ^ Υ</td><td>ΑΑ</td><td>A ™ 0</td><td>Ο</td><td></td><td></td>

<td></td><td> 0^</td><td>Γ_νΥ_νΙν^χ</td><td>τ</td><td>ki</td><td></td>

<td></td><td></td><td></td><td></td><td>CI</td><td></td><td></td>

<td> 308</td><td></td><td>F</td><td></td><td></td><td></td><td> 552.4</td>

<td></td><td>η₂ν ^^^ Υ</td><td>Ά</td><td></td><td></td><td></td><td> 0</td>

<td></td><td>η, ν ^ Α</td><td>υ</td><td>Υ ^ ΝΗ 0</td><td>Α</td><td>Ίΐ</td><td></td>

<td></td><td></td><td>ο⁵</td><td rowspan="2">Ακ, Α'μΑ'κ Ν Ν Ν Η Η</td><td>V</td><td>J</td><td></td>

<td></td><td></td><td></td><td colspan="2">ocf₃</td><td></td>

<td> 311</td><td></td><td>F</td><td></td><td></td><td></td><td> 522.3</td>

<td></td><td></td><td></td><td></td><td>F</td><td></td><td> 0</td>

<td></td><td rowspan="2">η₂ν ^ Υ</td><td>ΑΑ</td><td>A® 0</td><td>Α</td><td>AND^F</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>Η Η</td><td>Τ F</td><td></td><td></td>

<td> 312</td><td>νΥΎ</td><td></td><td></td><td></td><td></td><td rowspan="2"> 531.0 0</td>

<td></td><td></td><td colspan="2">^ Α ^ νη ο</td><td></td><td></td>

<td></td><td rowspan="2">η₂ι &lt;</td><td></td><td></td><td>Α</td><td></td><td></td>

<td rowspan="2"></td><td rowspan="2">cr</td><td rowspan="2">Ν Ν Ν Η Η</td><td rowspan="2">Τ OCF</td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

174

<td rowspan="2"> 313</td><td rowspan="2">i &lt; ^ΗV-NH</td><td rowspan="2">/ Ζ. er</td><td colspan="2">^ ΝΗ O ^F'Y ^' Z^FζλΙΧ</td><td rowspan="2"> 468.0 0</td>

<td>Ν Ν Ν Η Η</td><td>ρ</td>

<td> 314</td><td>1 1 Η Υ-ΝΗ</td><td>OR.</td><td>Ζ ^ ΝΗ 0</td><td></td><td> 500.0 0</td>

<td></td><td></td><td></td><td rowspan="2">'^ Ν ^ Ν ^ Ν' '' Η Η</td><td>II</td><td></td>

<td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2">τ ocf₃</td><td rowspan="2"></td>

<td></td>

<td> 315</td><td>Ο</td><td></td><td></td><td></td><td> 462.0</td>

<td></td><td>ΗοΛ / 'ν' /</td><td></td><td></td><td></td><td> 0</td>

<td></td><td>Η</td><td>ΙΑ</td><td>Ζ ^ 'ΝΗ 0</td><td>xt^F</td><td></td>

<td></td><td></td><td></td><td rowspan="2">Α Λ. Ν Ν Ν Η Η</td><td>χχ</td><td></td>

<td></td><td></td><td></td><td></td><td></td>

<td> 316</td><td>CH]</td><td></td><td></td><td></td><td> 488.0</td>

<td></td><td></td><td>γγ</td><td></td><td></td><td> 0</td>

<td></td><td>³ Η</td><td></td><td>Υ ^ ΝΗ 0</td><td></td><td></td>

<td></td><td></td><td> 0'</td><td>Λ, ΑιΧ</td><td>ÁJ</td><td></td>

<td></td><td></td><td></td><td>Η Η</td><td>one ocf₃</td><td></td>

<td> 317</td><td>ch₃</td><td></td><td></td><td></td><td> 458.0</td>

<td></td><td>h₃c ^^^/^ n '^xx</td><td>V ^ l</td><td></td><td></td><td> 0</td>

<td></td><td>Η</td><td>THE</td><td>Υ ^ ΝΗ o ^F</td><td>Af^F</td><td></td>

<td></td><td></td><td></td><td rowspan="2">XXX ' Η Η</td><td>XX</td><td></td>

<td></td><td></td><td></td><td></td><td></td>

175

<td> 319</td><td>Τ ^ νη o Η Η 1 OCF₃</td><td> 511.0 0</td>

<td> 320</td><td>OH NH₂TO/ N Ah ON NH cA ^ nh Ϋ F</td><td> 519.0 0</td>

<td> 321</td><td>OH NH₂λ and N ΛΛ CT Ν NH oah xY /^0CF3 σ</td><td> 549.0 0</td>

176

<img file="MX2012004342A_D0063.tif" />

177

<img file="MX2012004342A_D0064.tif" />

178

<img file="MX2012004342A_D0065.tif" />

179

<img file="MX2012004342A_D0066.tif" />

180

<img file="MX2012004342A_D0067.tif" />

181

<img file="MX2012004342A_D0068.tif" />

182

<img file="MX2012004342A_D0069.tif" />

183

<img file="MX2012004342A_D0070.tif" />

184

<img file="MX2012004342A_D0071.tif" />

185

<img file="MX2012004342A_D0072.tif" />

186

<img file="MX2012004342A_D0073.tif" />

187

<img file="MX2012004342A_D0074.tif" />

188

<img file="MX2012004342A_D0075.tif" />

189

<img file="MX2012004342A_D0076.tif" />

190

<td rowspan="2"> 365</td><td rowspan="2">ΝΗ X XX η₂ν ν - 'ch₃η₂ν ^</td><td rowspan="2">Λ</td><td colspan="2"></td><td rowspan="2"> 590.0 0</td>

<td>'' ^ Υ ^ 'ΝΗ 0_ΟΑ_ΝΑ-_ΝΑ_Ν. Η Η</td><td>Ό ocf₃</td>

<td> 366</td><td>ΝΗ 1 / XX Η₂Ν ν</td><td></td><td></td><td></td><td> 560.0 0</td>

<td></td><td>ch₃HjN ^</td><td></td><td>Α'χ, ^ 'μη q ^F'x_οΑ_ΝΑ_ΝΧ_Νχ Η Η</td><td>α;</td><td></td>

<td> 368</td><td colspan="2">„Ο</td><td rowspan="2">^ ΝΗ 0 ΥΥι υλΧ¹Η Η 1 ocf₃</td><td></td><td> 427.1 0</td>

<td></td><td></td><td></td><td></td><td></td>

<td> 369</td><td>η₂ν ^^</td><td>ο</td><td colspan="2">- ^ ΥΥ ^ ΝΗ Ο ΥΧΐ_οΑ_ΝΥχ_ΝΑ_ΝχΧΑ</td><td> 484.1 0</td>

<td></td><td></td><td></td><td></td><td>ocf₃</td><td></td>

<td> 370</td><td>νη₂i ^¿</td><td></td><td></td><td></td><td> 525.3</td>

<td></td><td> 1</td><td>F</td><td></td><td></td><td> 0</td>

<td></td><td>Η; Ν — ξ</td><td>Αί</td><td></td><td></td><td></td>

<td></td><td></td><td> 0'</td><td>ύΑ^η ΚνΑ ΑΧΆ JlA</td><td>₂och₃OCHu</td><td></td>

191

<td rowspan="2"> 372</td><td rowspan="2">Ζ- \ &gt; ζ / &lt;Μ / I</td><td rowspan="2">ΎΆ χχ 0 *</td><td colspan="3">ΆνΗ ο ΑΧ Σλ λ Á.J</td><td rowspan="2"> 596.0 0</td>

<td>Ν Ν Η</td><td colspan="2">Ν γ Η 1 ocf₃</td>

<td> 373</td><td></td><td></td><td>ACE</td><td></td><td></td><td> 509.0</td>

<td></td><td>υ Ν</td><td>Η</td><td colspan="2"> 0</td><td>^ΡΎΎ^Ρ</td><td> 0</td>

<td></td><td></td><td></td><td></td><td rowspan="2">ΑΑ Η</td><td rowspan="2">Η</td><td></td>

<td></td><td></td><td></td><td></td><td></td>

<td> 374</td><td>Ο</td><td></td><td></td><td></td><td></td><td> 520.0</td>

<td></td><td>ϊ η₂ν ν '</td><td></td><td>ΎΎ</td><td></td><td></td><td> 0</td>

<td></td><td>² Η</td><td>Η</td><td>χχ</td><td>Ά ^ ΝΗ</td><td>ο ΑΛ</td><td></td>

<td></td><td></td><td></td><td></td><td colspan="2"></td><td></td>

<td></td><td></td><td></td><td></td><td>Η</td><td>Η 1</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>ocf₃</td><td></td>

<td> 376</td><td></td><td></td><td>• cf₃</td><td></td><td></td><td> 486.1</td>

<td></td><td>Η₂Ν</td><td rowspan="2">Η</td><td>Αι</td><td></td><td></td><td> 0</td>

<td></td><td></td><td>ΧΛ</td><td>Υ ^ ΝΗ</td><td>| Χ&gt;</td><td></td>

<td></td><td></td><td></td><td></td><td>Α.Α ^.</td><td>HA</td><td></td>

<td></td><td></td><td></td><td>ο</td><td>Ν Ν Η</td><td>τ cf₃</td><td></td>

<td> 381</td><td></td><td></td><td></td><td></td><td></td><td> 427.1</td>

<td></td><td>η₂ν</td><td>&lt;L</td><td colspan="2">^ Υ ^_ΝΗ 0</td><td></td><td> 0</td>

<td></td><td></td><td></td><td>Χκ - &lt;Χ</td><td></td><td>Α</td><td></td>

<td></td><td></td><td></td><td>οΆι</td><td>'' ν'ίψ Η Η</td><td>ocf₃</td><td></td>

192

<img file="MX2012004342A_D0077.tif" />

193

<img file="MX2012004342A_D0078.tif" />

194

<td> 394</td><td>or Λ _ΛH₂N^H j tJL A 0 AA «A oXaA τ ocf₃</td><td> 577.0 0</td>

<td> 395</td><td>NH₂CT ^ NH Αλ O ^ N ^ NH οΑμη TO F</td><td> 490.0 0</td>

<td> 397</td><td>A ΑΑζΛ_{νη o} xtx h₂X AnAAA^{H H} ocf₃</td><td> 545.0 0</td>

<td> 398</td><td>^nc^ AⁿAOl A ^ ΑγΤ'ΜΗ Q H₂t &lt;οΑν ^ Α^ΧΝ^ζΑ /^{H H} ocf₃</td><td> 544.0 0</td>

195

<img file="MX2012004342A_D0079.tif" />

196

<td rowspan="2"> 404</td><td rowspan="2">νη₂η₂ν — ι</td><td colspan="2">F /^νΎΑ.</td><td rowspan="2">xC^p3</td><td rowspan="2"> 534.1 0</td>

<td></td><td>-ΑΑ1 Η Ν</td>

<td> 405</td><td></td><td></td><td></td><td></td><td> 498.2</td>

<td></td><td>Η₂Ν '^Χ^^χχ</td><td>Α</td><td>Ά'Ύη Ο</td><td>rAi</td><td> 0</td>

<td></td><td></td><td>0 X</td><td>Ια λ.</td><td>Ο</td><td></td>

<td></td><td></td><td>ο</td><td>'Ν Ν Ν Η Η</td><td>Τ ocf₃</td><td></td>

<td> 406</td><td></td><td></td><td></td><td></td><td> 512.1</td>

<td></td><td>η₂ν '^χ^^χΧ</td><td>θΊΓ</td><td>CH₃υΑη _ο</td><td>rA</td><td> 0</td>

<td></td><td></td><td>5 χ Ο '</td><td rowspan="2">Η Η</td><td>τ</td><td></td>

<td></td><td></td><td></td><td>ocf₃</td><td></td>

<td> 407</td><td></td><td></td><td></td><td></td><td> 498.1</td>

<td></td><td>Η₂Ν ^^</td><td colspan="2">Άΐΐ i</td><td>χφ</td><td> 0</td>

<td></td><td></td><td></td><td>Η Η</td><td>ocf₃</td><td></td>

<td> 408</td><td></td><td></td><td></td><td></td><td> 482.0</td>

<td></td><td>η₂ν '^χ^^</td><td>Ά kXxX</td><td>Α ^ ΝΗ ο (</td><td>Αί</td><td> 0</td>

<td></td><td></td><td>0 X</td><td>ΙΑ ΑχΙ</td><td>TO THE</td><td></td>

<td></td><td></td><td>CX</td><td>Ν Ν Ν</td><td>Υ Ό</td><td></td>

<td></td><td></td><td></td><td></td><td>α</td><td></td>

197

<td> 409</td><td>„Ρ X Χτ χ jO Ν Ν Η Η 1 ocf₃</td><td> 441.0 0</td>

<td> 410</td><td>^Η*^Ν..... Ογ ^ ΝΗ or rVX or JL &lt;Α χ JxJj CT N Ν Ν Η Η 1 ocf₃</td><td> 441.0 0</td>

<td> 412</td><td>F ΗΝ-Ο cX'I'Xn ^ A / Η</td><td> 408.1 0</td>

<td> 413</td><td>Η₂Ν '^^{χ /}^ 'ΝΗ Χ% Χγ ^_ΝΗ □ ₀A ^ n^{&lt;! í}^ 'N' ^ N^x^^x^^X'CF₃Η Η</td><td> 497.0 0</td>

<td> 414</td><td>_FXX ^_NH 0 ^ Y ° X ^^CH3 ₀Χ_Νχ λ _nAx Η Η 1 νο₂</td><td> 500.0 0</td>

198

<td> 415</td><td>Η₂Ν '^^Χχ^^Χ'ΝΗ_ρ-ΧΧγ ^_ΝΗ θ Η Η 1 OMe</td><td> 486.0 0</td>

<td> 416</td><td>Η₂Ν^χΧ'^χ^ 'ΝΗ 5ol x Ο ^ Ν ^ Ν '^' Ν'η ^ Η Η 1 OMe</td><td> 486.0 0</td>

<td> 417</td><td>pJOXxh or f-yQ ₀ΧγΧγΧν · Χ ^ ° Η H</td><td> 506.0 0</td>

<td> 418</td><td>what^{H H} M</td><td> 476.0 0</td>

199

<td> 419</td><td>H_ZN '^XX'“'^X'^V'NH SfA cf ° ΧΎ^ΑηΆ Cl</td><td> 513.0 0</td>

<td> 420</td><td>_ΡΧλγχ_{ΝΗ o} XY^CICl</td><td> 507.0 0</td>

<td> 421</td><td>H₂N '^XX«^^K'NH_ρΑ / \ γ \_{ΝΗ o} YXi οΑγΧ ^ Χ, γ \&gt; · γΧ_α</td><td> 473.0 0</td>

<td> 422</td><td>nh₂h 1 i^Ιχ-^{/ Ν}Υ^Γ^ ΝΗ 0 YY | oAaaXJ Η Η 1 OCF₃</td><td> 498.1 0</td>

<td> 423</td><td>H₂N '' - '^x-^X~^XNH_FÁ / \ xT '_NH 0 Y \ X^CIοΧγ-ΧΪ</td><td> 473.0 0</td>

200

<img file="MX2012004342A_D0080.tif" />

201

<td> 429</td><td>ΝΗ JL Η₂ιΧ | Χ</td><td></td><td>ο &lt;Χ -Ν. / X / X, and κ ΝΗ 0 8 Λχλ</td><td>ocf₃</td><td> 540.2 0</td>

<td> 431</td><td>ΝΗ Η₂Νχ ΗΝ—</td><td colspan="2">ΗΝ— &lt;1 Χν γ ·^χΝΗ 0 οΑ_ν&lt;^_ν^_νΗ Η</td><td>τ ocf₃</td><td> 498.1 0</td>

<td> 432</td><td>η₂ν '^' ^^χ</td><td>Ύ</td><td>ΑΡχ^Ρ^ ΧΧ'ΝΗ 0</td><td>£? ocf₃</td><td> 495.1 0</td>

<td> 433</td><td>HjN ^^ '^'</td><td></td><td>γχ^ρΧ'ηΧ'ΝΗ 0 οΑΑΑ- ^ Η Η</td><td>q. Cl</td><td> 479.1 0</td>

<td> 434</td><td>HaN ^^^</td><td>Ύ</td><td>'DC..</td><td>LL</td><td> 465.0 0</td>

202

<td> 435</td><td></td><td>X Γ</td><td>X C?</td><td>Ύ ^ ΝΗ 0 ίΧΥ Η Η</td><td> 457.0 0</td>

<td> 436</td><td>Η₂Ν '^Ζ~^Χ'^χΖ~</td><td>X</td><td></td><td></td><td rowspan="2"> 463.0 0</td>

<td></td><td></td><td>F</td><td></td><td>X / θ¹yy 'νη or ^ kr οΧ ^ Αχ_ΗχΧ</td>

<td></td><td></td><td></td><td></td><td>F</td><td></td>

<td> 437</td><td></td><td>'X</td><td>ΊίΧ</td><td></td><td rowspan="2"> 507.0 0</td>

<td></td><td></td><td></td><td>ΛΧ</td><td></td>

<td></td><td></td><td></td><td>C</td><td>XXVX CI</td><td></td>

<td> 438</td><td>νη₂</td><td></td><td></td><td></td><td> 426.1</td>

<td></td><td>ι</td><td></td><td></td><td></td><td> 0</td>

<td></td><td>Ύ</td><td>J</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>CT</td><td>What and and</td><td></td>

<td> 439</td><td>νη₂</td><td></td><td></td><td></td><td> 444.1</td>

<td></td><td>S</td><td></td><td>F</td><td></td><td> 0</td>

<td></td><td>X Η</td><td>| ί</td><td>Χ&gt; |</td><td></td><td></td>

<td></td><td></td><td></td><td> 0&lt;</td><td>XX XjXf Η N</td><td></td>

203

<img file="MX2012004342A_D0081.tif" />

204

<td> 445</td><td>η₂νΆΑ ^_νηor [íX Η HW / Ν — S</td><td> 469.1 0</td>

<td> 446</td><td>Η₂Ν ^ \ Α-_νηρΧααχΑη _ο ζ \₀Α_νΑ_νΛ_ν&gt; αΛα \^{Η Η}ch₃</td><td> 508.1 0</td>

<td> 448</td><td>or λ-ΝΗ^ην\ Χαχ- \ Ζααα_{νη ο} ζ \ ₀Χ_ΝΧ_ΝΧ_ΝΧχ^{Η Η} Α OCF₃</td><td> 530.0 0</td>

<td> 449</td><td>c_FAaa_nh q AaaA Η Η 1 F</td><td> 501.0 0</td>

205

<td rowspan="2"> 450</td><td rowspan="2">η₂ν '^'</td><td rowspan="2">Η F</td><td colspan="3">^^ V ^ NH OX</td><td rowspan="2"> 463.0 0</td>

<td></td><td colspan="2">Η H</td>

<td> 451</td><td></td><td></td><td></td><td></td><td></td><td> 507.0</td>

<td></td><td></td><td>^Η JL</td><td rowspan="2">cr'n</td><td colspan="2">^XNH 0 ΧΧ⁰'</td><td> 0</td>

<td></td><td></td><td></td><td>Η H</td><td></td><td></td>

<td> 452</td><td>ΝΗ</td><td></td><td></td><td></td><td></td><td> 517.0</td>

<td></td><td>η₂νΑ_ν.</td><td>'ΎΧΎ' '</td><td></td><td></td><td></td><td> 0</td>

<td></td><td></td><td>and</td><td>M</td><td>Y ^ NH O</td><td>^ \. CN</td><td></td>

<td></td><td></td><td></td><td></td><td>TO_nTO_nTO_nx</td><td>KJ '</td><td></td>

<td></td><td></td><td></td><td></td><td>Η H</td><td></td><td></td>

<td> 453</td><td>ΝΗ</td><td></td><td></td><td></td><td></td><td> 560.0</td>

<td></td><td>^Η2ΝΛ '</td><td></td><td>Ύ&gt;</td><td></td><td></td><td> 0</td>

<td></td><td>Η</td><td>and</td><td></td><td>ΥΧ ^ ΝΗ 0</td><td>Λ</td><td></td>

<td></td><td></td><td rowspan="2">HjN ^</td><td></td><td></td><td rowspan="2">AA_CI</td><td></td>

<td></td><td></td><td></td><td>Η H</td><td></td>

<td> 454</td><td>Η₂Ν ^</td><td rowspan="2"></td><td>ΥΊ</td><td></td><td>F -V</td><td rowspan="2"> 427.0 0</td>

<td></td><td></td><td>THE</td><td>'X'NH N— \</td><td rowspan="2">J "^F</td>

<td></td><td></td><td></td><td>(X</td><td>W?</td><td></td>

<td></td><td></td><td></td><td></td><td>H</td><td></td><td></td>

206

<td> 455</td><td>η₂ν ^</td><td>¥ Α_ΝΗ θ ο ^ ν ^ ν ^ νΑ Η Η 1 ocf₃</td><td> 455.1 0</td>

<td> 456</td><td>νη₂</td><td></td><td> 497.2</td>

<td></td><td>ηνΑ ^ Η</td><td>¥¥ χ \_νη θ Yy ocf₃</td><td> 0</td>

<td> 457</td><td>Η₂Ν '^Χχ-^χ</td><td>^ Ν^{/ Χ}γ^ΖΑ ΝΟ₂^ηΛΥ_γ,„_ο λ^{Η Η} CI</td><td> 490.1 0</td>

<td> 458</td><td>νη₂ \</td><td>Ά « ^to Α ο ^ -ν ^ νΥ ΛΑ^ρ</td><td> 444.0 0</td>

<td> 459</td><td>η₂ν ^^</td><td>^ΧΝΗ Α</td><td> 513.0 0</td>

<td></td><td></td><td>_FOh-_NH ο αΑ Η Η</td><td></td>

207

<td rowspan="2"> 461</td><td rowspan="2">Η₂Ν '^χ~ 'Χ ^</td><td rowspan="2">Η ν '</td><td colspan="3"></td><td rowspan="2"> 513.0 0</td>

<td> 0</td><td>y ^ 'NH Ο ^ AAA^XΗ Η</td><td>ςτ^αI</td>

<td> 462</td><td></td><td></td><td></td><td></td><td></td><td> 465.0</td>

<td></td><td>η₂ν^χΧ-</td><td>Η V '</td><td>γΑ Ά = ^</td><td rowspan="2">Υ ^ ΝΗ 0 TO_NTO_NJk_Nx Η Η</td><td>σ:</td><td> 0</td>

<td></td><td></td><td></td><td></td><td>Τ ^FF</td><td></td>

<td> 463</td><td></td><td></td><td></td><td></td><td></td><td> 493.0</td>

<td></td><td>Η₂Ν ^ Χ ^</td><td>η J ν '</td><td></td><td>«Υη ο ΑΑΑ ^ Η Η cr</td><td>Ο,</td><td> 0</td>

<td> 464</td><td></td><td></td><td></td><td></td><td></td><td> 493.0</td>

<td></td><td>Η₂Ν ^^Χχ^’</td><td>^Η 1</td><td>Ά cY</td><td>^ 'ΝΗ Ο^χ'ν ^ ν'^χ^ ν^/'Η Η</td><td>V-</td><td> 0</td>

<td></td><td></td><td></td><td></td><td></td><td>CI</td><td></td>

<td> 465</td><td></td><td>'' lYXr</td><td>Χη</td><td></td><td></td><td> 538.0</td>

<td></td><td rowspan="2">ΝΗ one Η₂Ν Η</td><td>Α</td><td></td><td rowspan="2">Χ'ΝΗ 0 ΑΑΑ- ^ Η Η</td><td>Α</td><td> 0</td>

<td></td><td></td><td></td><td></td><td></td>

208

<td rowspan="3"> 466</td><td rowspan="3">Η₂Ν · ^^ NH χ η₂ν ν Η</td><td rowspan="3"></td><td colspan="5">γ</td><td rowspan="3"> 554.0 0</td>

<td colspan="2">ο</td><td rowspan="2">χ—- ~ Χ Ν Η</td><td rowspan="2">ί</td><td rowspan="2">X</td>

<td></td><td>ΛΑ Η</td>

<td> 467</td><td>Η₂Ν^Χ</td><td>Χι^ζ</td><td>Ό 0</td><td colspan="3">Ύ ^ ΝΗ νΑΑ X Α Α &lt;Χ Ν Ν ° Η</td><td>-F</td><td> 445.1 0</td>

<td> 468</td><td></td><td>νη₂</td><td></td><td></td><td></td><td></td><td></td><td> 483.2</td>

<td></td><td></td><td>s</td><td></td><td></td><td></td><td></td><td></td><td> 0</td>

<td></td><td>η₂ν—</td><td> \_)^Ν^</td><td>ΊΠ</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>THE</td><td>ΧΝΗ</td><td colspan="2">Η 7 ^ /</td><td>,F</td><td></td>

<td></td><td></td><td></td><td>&lt;Υ</td><td>Ν Ν Η</td><td>&lt;Α Ν</td><td>and</td><td>F</td><td></td>

<td> 469</td><td></td><td>νη₂</td><td></td><td></td><td></td><td></td><td></td><td> 483.2</td>

<td></td><td></td><td>s</td><td></td><td></td><td></td><td></td><td></td><td> 0</td>

<td></td><td>η₂ν—</td><td></td><td>ΥΊ</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>ΑΑ</td><td>Υνη</td><td>Η Α Ν ^ /</td><td></td><td>,F</td><td></td>

<td></td><td></td><td></td><td>&lt;Υ</td><td>Ν Ν Η</td><td>&lt;Α Ν</td><td>and</td><td>T</td><td></td>

<td> 470</td><td>η₂Υ</td><td>Η₂! Ψ</td><td>GOVERNESS ΧΥ 0 '</td><td colspan="3">F xyh nAs_ / Χαα_οΗ</td><td>-F</td><td> 484.1 0</td>

209

<td rowspan="2"> 471</td><td rowspan="2">Η</td><td colspan="2">F</td><td rowspan="2"> 445.0 0</td>

<td>Αχ γΑ θ ''</td><td>Α ΙΧυ Η</td>

<td> 472</td><td></td><td>F</td><td>CI</td><td rowspan="2"> 548.1 0</td>

<td></td><td>Η₂Ν '^^κ-^{/ Λχ}Ν ^ Υ &lt;</td><td>ά.</td><td>X</td>

<td></td><td> 1</td><td></td><td>/ V-CH,</td><td></td>

<td></td><td></td><td>χΑυ</td><td>Χ ^ νη νΑ_?</td><td></td>

<td></td><td>η₂ιτ</td><td>&lt;Α</td><td>ΑΤΆ</td><td></td>

<td></td><td></td><td></td><td>Η</td><td></td>

<td> 473</td><td>ηΧ'Ά'ιΥ</td><td>γΑ</td><td></td><td rowspan="2"> 447.2 0</td>

<td></td><td></td><td>ΥΑ</td><td>\ α_νη νΑ __ /</td>

<td></td><td>Η, ΝΓ</td><td></td><td>I j ι A / A Η ^Η</td><td></td>

<td> 474</td><td></td><td></td><td></td><td> 489.3</td>

<td></td><td>Γ Η₂Ν^ΧΊ \ |^/~ '' - ^ Ύ | '</td><td></td><td>Α ^ χ</td><td> 0</td>

<td></td><td>Η J</td><td>ίγ</td><td>αυα ^ νη νΑΧ</td><td></td>

<td></td><td>Η₂ΙΨ</td><td></td><td>J 1 11 / οΆ ν''Ν Η ^Η</td><td></td>

<td> 475</td><td>ΝΗ</td><td></td><td></td><td> 544.0</td>

<td></td><td>χ ___ η₂ν ν ^^ Υ ^ Α</td><td>ΑΥ</td><td></td><td> 0</td>

<td></td><td>Η J</td><td>γΑ</td><td>r-- ο 0</td><td></td>

<td></td><td>η₂ν ^</td><td>ο *</td><td>Η ^Η</td><td></td>

210

<td> 476</td><td>ΝΗ Η₂Ν Ν ^ Χ Η H₂hT</td><td>to</td><td>to</td><td>f ^ 'NH Ο Η ^Η</td><td> '—</td><td> £</td><td>ί CI</td><td> 588.0 0</td>

<td> 477</td><td>ΝΗ Λ η₂ν ^^χν '^ ~' ' Η Η₂Ν^χ</td><td> /</td><td>ίΓ ^ ί Υγ ^ ο '</td><td>'γ ^ ΝΗ ο Η ^Η</td><td>CI-</td><td></td><td>? CI</td><td> 588.0 0</td>

<td> 478</td><td rowspan="2">Τ / γ - η₂ν ν ^ Η Η₂Ν ^</td><td></td><td></td><td></td><td></td><td></td><td></td><td> 588.0</td>

<td></td><td>π</td><td>ύ</td><td>^ ΝΗ Ο Η ^Η</td><td> —/</td><td>C</td><td>C,</td><td> 0</td>

<td> 479</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 479.0</td>

<td></td><td>Η₂Ν^χ'~^Χ-^χ</td><td>Η ΐ '</td><td>aa θ ''</td><td>γ ^ ΝΗ Η ^Η</td><td> £</td><td>? CI</td><td></td><td> 0</td>

<td> 480</td><td>Η₂Ν '^^χ^'</td><td>Η</td><td>ο</td><td></td><td>CI</td><td>to</td><td></td><td> 479.0 0</td>

<td></td><td></td><td></td><td>ο '</td><td>Η ^Η</td><td>to</td><td>\ CI</td><td></td><td></td>

211

<td> 481</td><td>ΛΑ ». Aj- Η Η</td><td> 493.1 0</td>

<td> 482</td><td>Η₂Ν '^^Χ-^ζ^^ΧΝ^/ΑΑΑ F^Η 1JL 1 ο ΑΑ cA ^ aX ^ N ^ YaR, Η Η</td><td> 497.0 0</td>

<td> 483</td><td>Η₂Ν^χΖΥ-^ζΖ^ Ν^χΖ^ Υ &lt;^ΖΑ&gt; ι ΝΗ_Ζ^Η 1/1 ^ I ; Ά / \ Υ \ η ο ΑΑ ο-ΧαΆΆ '-' α ^ Η Η 1 CI</td><td> 459.9 0</td>

<td> 484</td><td>ΝΗ Π Η, Ν Ν ^^ Ν ^ Ά _λΟρ 0 ΑΑ οΧαα-Α Η Η 1 ocf₃</td><td> 538.2 0</td>

<td> 485</td><td>_F 4¼ ο Λ ο-ΧαλΑτ Η Η</td><td> 456.0 0</td>

212

<td rowspan="2"> 486</td><td rowspan="2"></td><td rowspan="2">'N ^ X H</td><td colspan="2">to the</td><td rowspan="2">CN OR</td><td rowspan="2"> 436.2 0</td>

<td>&lt;r</td><td>and NH or Η H</td>

<td> 487</td><td></td><td></td><td></td><td></td><td></td><td> 418.1</td>

<td></td><td></td><td>n</td><td>to cY</td><td>Xnh Xi LrJy H</td><td>/.CF₃</td><td> 0</td>

<td> 488</td><td></td><td></td><td>F</td><td></td><td></td><td> 436.0</td>

<td></td><td>h₂n^/^^x^'</td><td>'N ^&gt; H</td><td>X &lt;r</td><td>Xnh r / a AND_Nto_Naa H</td><td>/ CF₃</td><td> 0</td>

<td> 489</td><td></td><td></td><td>F</td><td></td><td></td><td> 493.1</td>

<td></td><td>h₂n ^ - ^</td><td>'N'X</td><td>ixi</td><td></td><td></td><td> 0</td>

<td></td><td>H₂N ^</td><td>J</td><td>aa cy '</td><td>Xnh Χ LazU Ν N H</td><td>TO^F3</td><td></td>

<td> 490</td><td rowspan="2">NH j¡ H₂N N '^ -' H H₂N</td><td rowspan="2"> 1</td><td>F</td><td></td><td></td><td rowspan="2"> 535.2 0</td>

<td></td><td>c</td><td>ax'NH X ΛΑΛ H</td><td>\ .CF₃AND</td>

213

<td> 491</td><td>ΗΝ / -NH η₂ν \ —i— OCF3</td><td> 512.1 0</td>

<td> 492</td><td>η₂ν \ —Ν V— '^Ν\//_Νη ο Aw OCF3</td><td> 470.1 0</td>

<td> 493</td><td>Ν \\ &lt;7 J Λ η α ο ^ ν ^ ν ^ ν Η ^Η</td><td> 408.0 0</td>

<td> 494</td><td>η₂ν '^χ^ - ^^ νη ΧΑγ ^ ΝΗ 0 ^ V^N°²οΧχχΑΐ Η Η 1 CI</td><td> 490.0 0</td>

<td> 495</td><td>Η₂Ν '^^{χ /}^ 'ΝΗ γΑγί ^ ΝΗ 0 ύΧΛθ²_οχχ_ΝΑ_ΝΧΙ Η Η 1 ch₃</td><td> 470.0 0</td>

214

<td> 496</td><td>_FXJXx_nh θ r &lt;^ r^cl_οί_Ν^_ΝΛιΑ / Η Η 1 Cl</td><td> 479.0 0</td>

<td> 497</td><td>XV Λ Η Η 1 Cl</td><td> 513.0 0</td>

<td> 499</td><td>^ χΧ ^ ΝΗ jj H hr</td><td> 396.0 0</td>

<td> 500</td><td>^ xx ^ x x- ~ XX^H3 H, N Ν&gt; XX^H ί JL XXXnh or XXi Aaaaí Η Η 1 ocf₃</td><td> 491.1 0</td>

<td> 501</td><td>H₂N ^ X^x^-^x^ 'N^/^ | L. χΝχ xX. χ-Χ X nh or fX&gt; I Λ Λ ΛΑ O ^ N ^ NNY CI Η Η 1 F</td><td> 552.0 0</td>

215

<img file="MX2012004342A_D0082.tif" />

216

<td> 509</td><td>η₂ν.</td><td> 381.9 0</td>

<td> 510</td><td>ΗΝγΝΗ₂ΗΝ Α ^ Α ^ Α jpi^h αΓα ₀Α_να_να JLa Η</td><td> 423.8 0</td>

<td> 512</td><td>F Η₂Ν^/~'^χ'^χ'Α^χΑι * 1 η [| one ΑΖ \ γ ^_{ΝΗ 0}Η Η 1 ocf₃</td><td> 523.1 0</td>

<td> 513</td><td>ΝΗ F H₂N'I'N^x~^xxTO^xAlh Η Η || one ^^ ΑΖΑη O ALREADY ΛΑΑιΑψ Η Η 1 ocf₃</td><td> 565.1 0</td>

217

<img file="MX2012004342A_D0083.tif" />

218

<td> 518</td><td>Η₂Ν '^ «^Χ</td><td>TO</td><td>^ NH 0 H</td><td>/? ocf₃</td><td> 484.0 0</td>

<td> 519</td><td>NH</td><td></td><td></td><td></td><td> 526.0</td>

<td></td><td>Λ Η, Ν N^z H</td><td>or</td><td>Y ^ NH</td><td></td><td> 0</td>

<td></td><td></td><td> 0*</td><td colspan="2">AA_nx_nOh</td><td></td>

<td></td><td></td><td></td><td></td><td>ocf₃</td><td></td>

<td> 520</td><td>H₂N ^ \</td><td></td><td></td><td></td><td> 440.0</td>

<td></td><td></td><td></td><td>'NH O</td><td>rr^F</td><td> 0</td>

<td></td><td></td><td colspan="2">ΑΛΑ 0 NNN</td><td>V</td><td></td>

<td></td><td></td><td></td><td>Η H</td><td>F</td><td></td>

<td> 521</td><td></td><td></td><td></td><td></td><td> 436.0</td>

<td></td><td>^H2^N\AND\</td><td>ΥΊ</td><td>NH 0</td><td>XX</td><td> 0</td>

<td></td><td></td><td colspan="2">oA_n^&lt;X_nX_n&lt;</td><td>γΑι</td><td></td>

<td></td><td></td><td></td><td>Η H</td><td>F</td><td></td>

<td> 522</td><td></td><td></td><td></td><td></td><td> 469.0</td>

<td></td><td>H₂N ^ xx</td><td>Ύ</td><td>'' NH O</td><td></td><td> 0</td>

<td></td><td></td><td>TO</td><td rowspan="2">^ N ^ N Η H</td><td>V</td><td></td>

<td></td><td></td><td></td><td>ocf₃</td><td></td>

219

<img file="MX2012004342A_D0084.tif" />

220

<img file="MX2012004342A_D0085.tif" />

221

<td> 534</td><td>Η Τ ΝΗ</td><td>C</td><td>γ ^ ΝΗ 0 Λν ^ ν ^ Η</td><td>V ocf₃</td><td> 512.0 0</td>

<td> 535</td><td>^Η2Ν. ^ / \</td><td></td><td></td><td>ff</td><td> 440.0</td>

<td></td><td></td><td>ι 1</td><td></td><td>LF</td><td> 0</td>

<td></td><td></td><td colspan="2">Ο</td><td>&lt;Τ</td><td></td>

<td></td><td></td><td>CT</td><td rowspan="2">'ν νΆ Η Η</td><td>AND</td><td></td>

<td></td><td></td><td></td><td>F</td><td></td>

<td> 536</td><td>^Η2^Ν\/\,</td><td></td><td></td><td></td><td> 438.0</td>

<td></td><td></td><td></td><td></td><td></td><td> 0</td>

<td></td><td></td><td colspan="2"> 0</td><td>Οι</td><td></td>

<td></td><td></td><td>(Τ '</td><td rowspan="2">ΑΧ / Η Η</td><td>FOR</td><td></td>

<td></td><td></td><td></td><td>F</td><td></td>

<td> 537</td><td>^Η2^ΝΧ ^^ Χ</td><td></td><td></td><td></td><td> 469.0</td>

<td></td><td></td><td>XX,</td><td> 0</td><td>ΥΊ</td><td> 0</td>

<td></td><td></td><td>0-J</td><td rowspan="2">'' Ν ^ 'Ν ^' Ν ' Η Η</td><td>T</td><td></td>

<td></td><td></td><td></td><td>ocf₃</td><td></td>

<td> 538</td><td></td><td></td><td></td><td>F</td><td> 454.0</td>

<td></td><td></td><td></td><td>Χ'ΝΗ 0</td><td>Ax</td><td> 0</td>

<td></td><td></td><td></td><td></td><td>ÁJ</td><td></td>

<td></td><td></td><td>(Τ</td><td>Ν Ν Ν Η Η</td><td>T F</td><td></td>

222

<td> 539</td><td>F Η, Ν '^' ^ 'ν'ΧΧ h || one Or OCF₃^{H H} or</td><td> 537.1 0</td>

<td> 540</td><td>NH F JL 1 H₂NN ^^ NY² Η H || one ^^ X ^ NH 0 OCF₃₀ΎΎ / Χ 'Α^{H H} or</td><td> 579.1 0</td>

<td> 541</td><td>H₂N ^^ Y Oh - '^Νγ ^_ΝΗ N-yY /^FΑνΑη \ Αζ ^ ρ H</td><td> 433.1 0</td>

<td> 545</td><td>jr H₂NN ^ - ^^^ Ν''η F ΑγΥ_ΝΗ or Jv^FoX_NTO_NTO_NXj Η Η 1 F</td><td> 495.0 0</td>

<td> 546</td><td>H^ΗΝγ^Ν-χ ^ \ ^ -_Ν/ \ F^NHz ΑΑγ'ΝΗ ₀ Jy οΛΑ ^ νΧ Η Η</td><td> 481.0 0</td>

223

<td rowspan="2"> 547</td><td rowspan="2">Η^ΗΝ· Ψ^Ν- ^ νη₂</td><td colspan="3">ΆΙ</td><td rowspan="2">9, F</td><td rowspan="2"> 480.0 0</td>

<td colspan="2"></td><td>'Ϋ' ΝΗ 0 υ_νΑ_νΧ_νχ Η Η</td>

<td> 548</td><td>Η</td><td></td><td></td><td></td><td></td><td> 511.0</td>

<td></td><td>^ΗΝ&lt;ΧΧ^ΝΧ. νη₂</td><td></td><td>γ</td><td>b'Y'NH 0</td><td></td><td> 0</td>

<td></td><td></td><td></td><td> 0'</td><td rowspan="2">Α_νΑνΑ_νΗ Η</td><td>Υ</td><td></td>

<td></td><td></td><td></td><td></td><td>ocf₃</td><td></td>

<td> 549</td><td></td><td></td><td>Ί</td><td></td><td></td><td> 452.0</td>

<td></td><td></td><td>Α</td><td>Α</td><td>Υ'ΝΗ 0</td><td>Αι</td><td> 0</td>

<td></td><td></td><td></td><td></td><td rowspan="2">_ΝΑ_ΝΑ_Ν&gt; Η Η</td><td>aA_ci</td><td></td>

<td></td><td></td><td></td><td></td><td>F</td><td></td>

<td> 550</td><td>Η₂Ν '^^χχ</td><td></td><td>γ</td><td>γ ^ ΝΗ Ο</td><td>ALREADY</td><td> 483.0 0</td>

<td></td><td></td><td></td><td>X</td><td>Χ ^. ί ^ Α,&gt; χΛ. , χ</td><td>TO</td><td></td>

<td></td><td></td><td></td><td> 0^χ</td><td>Ν Ν Ν Η Η</td><td>T ocf₃</td><td></td>

<td> 551</td><td rowspan="2"></td><td></td><td></td><td></td><td></td><td> 449.0</td>

<td></td><td>Η 1^{Ν &lt;}Χζ</td><td>ϊι</td><td></td><td>HA</td><td> 0</td>

<td></td><td></td><td></td><td></td><td>χ Α Α, Χ</td><td>M</td><td></td>

<td></td><td></td><td></td><td>cr</td><td>Ν Ν Ν Η Η</td><td>I F</td><td></td>

224

<td> 552</td><td colspan="2">Χ-γ γγ_{ΝΗ 0}Η Η</td><td>Α F</td><td> 447.0 0</td>

<td> 553</td><td></td><td></td><td></td><td> 478.0</td>

<td></td><td>Η, Ν Ν ΥΧ Η 1^Νχ</td><td>ΑΑνη ο IA Α Cr N Ν Ν Η Η</td><td>Τ ocf₃</td><td> 0</td>

<td> 554</td><td>F</td><td></td><td></td><td> 515.1</td>

<td></td><td colspan="2">Η, Ν^Ζ~^Χ- ^ νΆχ1^Η UA-. ΝΗ Ο</td><td>F r0 ^^F</td><td> 0</td>

<td></td><td>cr</td><td>Η Η</td><td>Α^ζΗ</td><td></td>

<td> 555</td><td>F</td><td></td><td></td><td> 479.0</td>

<td></td><td>Η, Ν^{/ Χ}'·^/'' νΆΆ^Η Αλ</td><td>τΑΥιη 0</td><td></td><td> 0</td>

<td></td><td>&lt;Α</td><td>^χνΆ^χΗ Η</td><td>^ Α^ζΗ</td><td></td>

<td> 556</td><td>F</td><td></td><td></td><td> 465.0</td>

<td></td><td>H, N^{/ X}x^{/ X}N^ZVAND | 1^Η Α 0</td><td>'Α ^ ΝΗ 0 TO_NTO_NTO_N^ Η Η</td><td>Α ^^ΝHIAa</td><td> 0</td>

<td></td><td></td><td></td><td>W</td><td></td>

225

<td> 573</td><td></td><td></td><td>F</td><td></td><td></td><td></td><td> 410.0</td>

<td></td><td>HjN^X</td><td></td><td>Άί</td><td></td><td></td><td></td><td> 0</td>

<td></td><td></td><td></td><td>TO</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>XaJL</td><td>TO\</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>Η H</td><td></td><td></td><td></td>

<td> 574</td><td></td><td></td><td>F</td><td></td><td></td><td></td><td> 507.1</td>

<td></td><td>h₂n ^</td><td rowspan="2">'^ n ^ Aí' ^H 1</td><td>η</td><td></td><td></td><td></td><td> 0</td>

<td></td><td></td><td>Jy</td><td>Ύιη 0</td><td></td><td>F</td><td></td>

<td></td><td></td><td></td><td></td><td>AA ^^</td><td></td><td>TO</td><td></td>

<td></td><td></td><td></td><td></td><td>Η H</td><td></td><td>γ ¥_ρ</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>F</td><td></td>

<td> 577</td><td></td><td></td><td>F</td><td></td><td></td><td></td><td> 494.1</td>

<td></td><td>h₂n ^</td><td>^{X / X}N^Z</td><td>Υί</td><td></td><td></td><td></td><td> 0</td>

<td></td><td></td><td>H</td><td>ALREADY</td><td>Ά ^ ΝΗ NH</td><td>TO</td><td>• j</td><td></td>

<td></td><td></td><td></td><td></td><td>uses. , A. .x '</td><td>C</td><td> )</td><td></td>

<td></td><td></td><td></td><td> 0</td><td>Ν Ν N</td><td>AND</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td colspan="2">ocf₃</td><td></td>

<td> 582</td><td>NH</td><td></td><td>F</td><td></td><td></td><td></td><td> 549.1</td>

<td></td><td rowspan="2">I H₂NN ^ H</td><td rowspan="2">H</td><td>Άα</td><td></td><td></td><td></td><td> 0</td>

<td></td><td>YAx</td><td>«^ NH 0</td><td></td><td>F</td><td></td>

<td></td><td></td><td></td><td>CT</td><td></td><td></td><td>TO</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>\TO</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>F</td><td></td>

226

<td rowspan="2"> 583</td><td colspan="2">NH</td><td rowspan="2">Q, F</td><td rowspan="2"> 494.0 0</td>

<td>H₂N νΆΑ H</td><td>ΧγΑ O_ORX_NX_NX_N^ Η H</td>

<td> 584</td><td>NH</td><td></td><td></td><td> 525.0</td>

<td></td><td>χ h₂n nA</td><td>to ^_n/\</td><td></td><td> 0</td>

<td></td><td>H</td><td>XX ^ NH 0</td><td></td><td></td>

<td></td><td></td><td rowspan="2">_QX_NX_NX_N- Η Η</td><td>TO</td><td></td>

<td></td><td></td><td>ocf₃</td><td></td>

<td> 585</td><td>NH X η₂ν ^ ά</td><td>x ^ N ^ H</td><td>TO\ N &lt;% ^ A 0 *</td><td>χ_ΝΗ or^λΑ^Λιτ</td><td>F</td><td> 489.0 0</td>

<td> 588</td><td></td><td></td><td>F</td><td></td><td></td><td> 409.1</td>

<td></td><td>H₂N ^ A</td><td></td><td>Xl &lt;Α</td><td>X'NH NA \ Α ^ Χο</td><td></td><td> 0</td>

<td> 589</td><td></td><td></td><td>F</td><td></td><td></td><td> 423.0</td>

<td></td><td>Η₂νΆ</td><td>Ax H</td><td>one Wo-</td><td>XN NA % X_NX ° H</td><td></td><td> 0</td>

227

<td rowspan="3"> 593</td><td colspan="2">ΝΗ</td><td colspan="2" rowspan="2"></td><td rowspan="3"> 489.1 0</td>

<td rowspan="2">Λ Η, Ν Ν² Η</td><td rowspan="2">Η</td>

<td>^^ Χ ^ ΝΗ Ο cXnYnYn ^ Η Η</td><td>ςι, F</td>

<td> 594</td><td>ΝΗ Λ η₂ν ν Η</td><td>Η</td><td>XX- ΝΗ 0 ct'nA'nYn Η Η</td><td>9 OCF₃</td><td> 520.1 0</td>

<td> 599</td><td>Η₂Ν ^^</td><td>Η -χ</td><td colspan="2">?Ν? Η Η 1 ocf₃</td><td> 484.1 0</td>

<td> 605</td><td>ΝΗ Λ. Η, Ν Ν² Η</td><td>Η</td><td>ΧΧγ ^ ΝΗ 0 _ΟΑΥ ^_Ν-Χ_Ν- Η Η</td><td>9 ocf₃</td><td> 526.1 0</td>

<td> 607</td><td>Η₂Ν^Χ''^^/</td><td>F^χΝ ^ χΧ Η</td><td colspan="2">F JLX ^ J ·⁶ΝΗ νΧ_ / cYn ^ n ^ YA / Η ^Η</td><td> 472.2 0</td>

228

<td rowspan="3"> 608</td><td colspan="3">F</td><td colspan="3" rowspan="2">F</td><td rowspan="3"> 473.0 0</td>

<td rowspan="2"></td><td rowspan="2">Η</td><td rowspan="2">\ Χ ΑΧΑΑπ ν (ΤίΧνΑ / · Η</td>

<td>5 ο</td><td></td><td>- ^ F</td>

<td> 619</td><td></td><td></td><td>Η</td><td></td><td></td><td></td><td> 454.1</td>

<td></td><td></td><td></td><td>, ν.</td><td></td><td></td><td></td><td></td>

<td></td><td>η₂νΆ</td><td></td><td>YJ</td><td>F</td><td></td><td></td><td rowspan="2"> 0</td>

<td></td><td></td><td></td><td>Χ^χΝχ[Α^χΝΗ 0</td><td>TO</td><td>ν</td><td>,F</td>

<td></td><td></td><td></td><td>11 X</td><td>X</td><td>J</td><td></td><td></td>

<td></td><td></td><td></td><td>Η Η</td><td>one F</td><td></td><td></td><td></td>

<td> 652</td><td>ΝΗ</td><td></td><td></td><td></td><td></td><td></td><td> 586.1</td>

<td></td><td>I Η, Ν</td><td>Ν ^ ~</td><td>Χ ^ Χ</td><td></td><td></td><td></td><td> 0</td>

<td></td><td>H</td><td>Η</td><td>ΑγΑπ □</td><td>Ά &lt;</td><td></td><td>Ax^F</td><td></td>

<td></td><td></td><td></td><td>Αχ Αχ Αχ Αχ</td><td></td><td></td><td>• \ X.</td><td></td>

<td></td><td></td><td></td><td>CT Ν Ν Ν</td><td></td><td>F^x</td><td></td><td></td>

<td></td><td></td><td></td><td>Η Η</td><td></td><td></td><td></td><td></td>

<td> 680</td><td></td><td></td><td></td><td></td><td></td><td></td><td> 557.1</td>

<td></td><td colspan="2">to ^_n</td><td></td><td></td><td></td><td></td><td> 0</td>

<td></td><td>NH</td><td></td><td>| | Χ \ α_νη or ^Fx</td><td>'Χ'</td><td></td><td>-F</td><td></td>

<td></td><td> 1</td><td></td><td>XX X</td><td></td><td></td><td></td><td></td>

<td></td><td>Η, Ν Ν '*</td><td></td><td>(Τ Ν Ν Ν</td><td>'' Ά '</td><td></td><td>F</td><td></td>

<td></td><td>Η</td><td></td><td>Η Η</td><td></td><td></td><td></td><td></td>

<td> 710</td><td>η, νΆΆ</td><td></td><td>[Αχ</td><td></td><td></td><td></td><td> 516.1</td>

<td></td><td>² Η</td><td></td><td>Αα_ΝΗ 0</td><td rowspan="2">Ν ^ F*</td><td></td><td>γ</td><td> 0</td>

<td></td><td></td><td></td><td>&lt;ΑΑνΑ ^ Η Η</td><td></td><td>TO_F</td><td></td>

229

<td> 712</td><td>ΝΗ JL Η, Ν Ν '^ ~² Η</td><td>^η ΧΛ</td><td>Ανη ο /-.μ^- ΧΑνΛ ^. Η Η ^h</td><td>Ά ^ Ά</td><td> 558.2 0</td>

<td> 735</td><td rowspan="2">ΝΗ Λ Η, Ν Ν '^² Η</td><td></td><td></td><td></td><td> 572.3</td>

<td></td><td>ο</td><td>JXV&gt; Η Η</td><td>X</td><td> 0</td>

<td></td><td></td><td></td><td></td><td>/ - \ FF</td><td></td>

<td> 739</td><td>ΝΗ Λ Η, Ν Ν ² Η</td><td>Η | ||</td><td></td><td></td><td> 533.2 0</td>

<td></td><td></td><td></td><td>Α ^ ΝΗ Ο</td><td>Λ</td><td></td>

<td></td><td></td><td></td><td></td><td>LÁp</td><td></td>

<td></td><td></td><td></td><td></td><td>F</td><td></td>

<td> 747</td><td>ΝΗ 0 Η₂Ν² Η</td><td></td><td>NHI 0 1—7 ^ 8 αλΑ ^ηΗ Η</td><td>LL</td><td> 587.1 0</td>

230

<img file="MX2012004342A_D0086.tif" />

231

<img file="MX2012004342A_D0087.tif" />

232

<td> 1302</td><td colspan="2">H₂N^/aa</td><td>to cr</td><td>Άνη ^ a</td><td colspan="2">AQ Η H i HN ^ ch₃</td><td> 385.1 0</td>

<td> 1303</td><td>H₂N '</td><td>aa</td><td></td><td></td><td></td><td></td><td rowspan="2"> 400.1 0</td>

<td></td><td></td><td>xxx cr</td><td colspan="2">Xnh or AA H</td><td>X. hT H</td><td>^ / \ ^. NH₂</td>

<td> 1304</td><td>h₂n '</td><td>aa</td><td></td><td></td><td></td><td></td><td> 400.1</td>

<td></td><td></td><td>ax cr</td><td colspan="2">Xnh or -aa H</td><td>,3 H</td><td>^ / \ ^ NH₂</td><td> 0</td>

<td> 1305</td><td></td><td colspan="2">^hinXi 0 ^</td><td>Xs N</td><td colspan="2">Ax NN &lt;- ^ Η H</td><td> 342.9 0</td>

<td> 1308</td><td></td><td>H HaN ^^ N</td><td></td><td rowspan="2">H</td><td>ar</td><td></td><td> 484.8 0</td>

<td></td><td></td><td></td><td></td><td>for</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>cr</td><td>N</td><td></td>

<td></td><td></td><td></td><td></td><td>0 to_N</td><td>to</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>Η H</td><td>AND</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>CH</td><td></td><td></td>

233

<img file="MX2012004342A_D0088.tif" />

234

<img file="MX2012004342A_D0089.tif" />

235

<td rowspan="2"> 1317</td><td rowspan="2">There ^</td><td colspan="2">h ⁰</td><td rowspan="2"> 386.9</td>

<td>ΥΧν 0 &lt; Η Η H</td><td>X-,</td>

<td> 1318</td><td></td><td></td><td></td><td> 500.6</td>

<td></td><td>Η h₂nn² Η</td><td>ΧΎΥ-Υι ^H YY</td><td>or</td><td></td>

<td></td><td></td><td></td><td>YY Xy H</td><td></td>

<td></td><td></td><td>'ÁA_n*AC Η H</td><td>- \ ^ nh₂</td><td></td>

<td> 1319</td><td>H₂N ^</td><td>X'nXY,^H To the</td><td> 0</td><td> 457.1</td>

<td></td><td></td><td></td><td>^ 'N II c</td><td></td>

<td></td><td></td><td></td><td>nA Η ^Γ</td><td></td>

<td></td><td></td><td>Α^Λν &lt;Ο ^ - H H</td><td>\ ^ NH₂</td><td></td>

<td> 1320</td><td>NH OR H₂NY</td><td>~ ΑΆί</td><td>OR</td><td> 499.4</td>

<td></td><td></td><td>AA</td><td></td><td></td>

<td></td><td></td><td></td><td>Vk H ^J</td><td></td>

<td></td><td></td><td>XiA_n&lt;Oⁿ' Η H</td><td></td><td></td>

236

<img file="MX2012004342A_D0090.tif" />

237

<img file="MX2012004342A_D0091.tif" />

238

<td> 1337</td><td>ΝΗ Π HjN N ^ NY: Η Η | ΆΌ Η Η i</td><td>Ί ° Υή to Η χ ^^ΝΗ2</td><td> 512.8</td>

<td> 1338</td><td></td><td></td><td> 413.8</td>

<td></td><td></td><td>/ X</td><td></td>

<td></td><td>^ ιΆν ^ Μ Η Η Η</td><td> ? ^ΗΝ\ ΥΥ ^^ΝΗ2</td><td></td>

<td> 1339</td><td>ΝΗ Λ ΥΥ ΑΧ</td><td></td><td> 516.3</td>

<td></td><td></td><td>II 'η ^^ ΝΗ</td><td></td>

<td></td><td>'Χ, ΑνΌυ Η Η</td><td>y ^ ch₃</td><td></td>

<td> 1340</td><td>Η, Ν ^ '' - Η \ Α</td><td></td><td> 473.8</td>

<td></td><td>AC</td><td>Μ /</td><td></td>

<td></td><td>λα_ν-Ο - / - Η Η</td><td>.CH₃S</td><td></td>

239

<img file="MX2012004342A_D0092.tif" />

240

<td> 1347</td><td>ΐ-UQ Η Η 1 ocf₃</td><td>^xnX ^</td><td> 484.0</td>

<td> 1348</td><td>/ X hX &amp;</td><td>Xnh</td><td> 541.1</td>

<td></td><td>χχ Oh</td><td></td><td></td>

<td> 1353</td><td>NH Λ H; NN^Z^^{/ X}N^Z^% Η H % / 0</td><td>Y ^ NH XX^N /'</td><td> 529.7</td>

<td></td><td>XX-CX Η H</td><td>// x / OH</td><td></td>

241

<td rowspan="2"> 1354</td><td colspan="2">^¿ u 1 II</td><td rowspan="2"> 489.4</td>

<td>YY Η Η</td><td>^ ΝΗ Α γ ^ °^Η</td>

<td> 1355</td><td>η₂ν — NOW</td><td></td><td> 386.1</td>

<td></td><td colspan="2">ΥνΗ &lt;AX</td><td></td>

<td></td><td>λΑ &lt;0 ^ Η Η</td><td>^ νη₂</td><td></td>

<td> 1356</td><td>ΑΑ</td><td></td><td> 485.5</td>

<td></td><td>Η Η Υγ</td><td>χ '' ΥΎ'νη oA_NTO</td><td></td>

<td></td><td>ΥΥΥ Η Η</td><td>^v^^xnh₂</td><td></td>

<td> 1357</td><td>η ^ ΥΥ</td><td></td><td> 439.0</td>

<td></td><td colspan="2">Α-Υ ^ νη ο ΥΥ οΑ_νΑ_νΑ_νυΑ Η Η i</td><td></td>

<td></td><td></td><td>ΗΝ ^ cf₃</td><td></td>

242

<td> 1358</td><td>ΝΗ TO Η, Ν Ν Η</td><td>Η /TO Η Η</td><td>ΑΑ \ Χ &lt;_νη-A Α CR N 9 ΗΝ ^ cf₃</td><td> 538.1</td>

<td> 1362</td><td>ΝΗ Λ Η, Ν Ν</td><td></td><td>AA</td><td> 536</td>

<td></td><td></td><td></td><td>αα ^_νηA Α cX ν, γ</td><td></td>

<td></td><td></td><td colspan="2"></td><td></td>

<td></td><td></td><td></td><td> °\</td><td></td>

<td></td><td></td><td colspan="2">^ηΑ</td><td></td>

<td></td><td></td><td></td><td>CHA νη₂</td><td></td>

<td> 1363</td><td>Η₂Ν ^</td><td rowspan="2">Η</td><td>γΑι</td><td> 493</td>

<td></td><td></td><td>οΑ_νΑ</td><td></td>

<td></td><td></td><td>ΑχΑ</td><td> 9</td><td></td>

<td></td><td></td><td></td><td> \</td><td></td>

<td></td><td></td><td></td><td>ην ^ ήη₂</td><td></td>

243

<img file="MX2012004342A_D0093.tif" />

244

<img file="MX2012004342A_D0094.tif" />

245

<td> 1383</td><td>^Η UU ν ' τ, Ο. Η Η</td><td>Υ^ΧΝΗ TO - ^ NHj</td><td> 442.8</td>

<td> 1384</td><td>ΛΑ</td><td></td><td> 484.8</td>

<td></td><td> υ</td><td>Ύ ^ νη ΑνΑ</td><td></td>

<td></td><td>λΆΑΑ Η Η</td><td>^ \ χΝΗ₂</td><td></td>

<td> 1385</td><td></td><td></td><td> 526.8</td>

<td></td><td> UL</td><td></td><td></td>

<td></td><td>Υ</td><td>Ύ ΝΗ ΐγ</td><td></td>

<td></td><td>ΆνΑΑ Η Η</td><td>Η . .Ν. , ΝΗ₂Π ΝΗ</td><td></td>

<td> 1386</td><td>η₂ν^{/ χ}'^/ΆΆΥΥ^Η ΥΑ</td><td></td><td> 443.0</td>

<td></td><td></td><td>Υ ^ ΝΗ Α /</td><td></td>

<td></td><td>GO 'Η Η</td><td> \/^ΝΗ2</td><td></td>

246

<td rowspan="2"> 1387</td><td colspan="2">ΝΗ</td><td rowspan="2"> 543.3</td>

<td>OR Η, Ν '^Ζ^ Ν^/Η</td><td>'Ύ ^ ι Α /^ΝγΑ-_ΝΗΆ0 ΝΗ ο ^ Αη₃</td>

<td> 1388</td><td>ΝΗ</td><td></td><td> 544.3</td>

<td></td><td>Λ Η₂Ν ^ Ν ^ Η</td><td>'ΑΓ' ^^ν^ νη □ Μ</td><td></td>

<td></td><td></td><td>9 chili</td><td></td>

<td></td><td></td><td>'/ ΛνΧα^Γ Η Η 1 \ ΝΗ οΑνη₂</td><td></td>

<td> 1389</td><td>HjN ^^ -</td><td>Υχ^ΝγΑ ^_ΝΗ</td><td> 502.4</td>

<td></td><td></td><td>oÁ ^</td><td></td>

<td></td><td></td><td>9 to</td><td></td>

<td></td><td>Αν Η</td><td>^Λ| ΓΤ Ύ ΝΗ οΧη₂</td><td></td>

247

<img file="MX2012004342A_D0095.tif" />

248

<img file="MX2012004342A_D0096.tif" />

249

<img file="MX2012004342A_D0097.tif" />

250

<img file="MX2012004342A_D0098.tif" />

251

<td rowspan="2"> 1429</td><td colspan="3">ΝΗ Λ / ν _{Λ Λ}</td><td rowspan="2"> 516.1</td>

<td> -₂·- _Η</td><td>^Η VL Q ' H₃CxxCH₃Ν ο^ηο- · Α Η Η</td><td>γΧ'ΝΗ XX</td>

<td> 1430</td><td>Η₂Ν '^Χ^</td><td></td><td></td><td> 474.6</td>

<td></td><td></td><td colspan="2">kx JX</td><td></td>

<td></td><td></td><td>(τ '</td><td>Ν ^ Ζ</td><td></td>

<td></td><td></td><td>H₃C _zCH₃Ν₀^Ηθ'·· Α&gt;</td><td></td><td></td>

<td></td><td></td><td>Η Η ³</td><td></td><td></td>

<td> 1445</td><td>ΝΗ 0</td><td></td><td></td><td> 516.0</td>

<td></td><td>² Η</td><td>^Η L1</td><td></td><td></td>

<td></td><td></td><td></td><td>'ΧΧΐΗ XX</td><td></td>

<td></td><td></td><td colspan="2">ΑΛνΧΟ \ Α ^^ΝΗtwo Η Η</td><td></td>

252

<img file="MX2012004342A_D0099.tif" />

<td rowspan="2">3000b</td><td colspan="2">NH</td><td rowspan="2"> 498.00</td>

<td>X H, NN^xH</td><td>oAA Η H</td>

<td>3001b</td><td>NH one h₂nn H</td><td>ΑγΧ οΑ_ΝΧγ</td><td> 492.30</td>

<td></td><td></td><td>α-Α_νΧ ^ Α ^^ νη₂Η Η</td><td></td>

<td>3002b</td><td>NH II H₂NN² H</td><td>^ΖΆ ,,.</td><td> 498.80</td>

<td></td><td></td><td>CrAtA</td><td></td>

<td></td><td></td><td>ΛΟΧ „, u_y_</td><td></td>

253

<td></td><td></td><td></td>

<td>3003b</td><td>NH jl H₂N Ν '^^ Ν ^ ύ /' ?!² Η H 1 ll AX / cr n jx_ς π I | h₃c ch₃AA_n, VXXh₂Η Η</td><td> 513.60</td>

<td>3004b</td><td>NH Λ H₂NN Η H ^ A ^ NH &lt;AnA ° XA ÁAAX Η Η 1 ° \ / \ χΝΗ₂</td><td> 576.30</td>

<td>3005b</td><td>cf₃, vz NHV _(b)X NH χ H₂NN ^^ - ^^ N ^ V ^ X^{H H} XA v &lt;&gt; °^b&gt; AA O ^ N ^ l _(tQa)or X% X^FaΧΑΧΑ Η Η 1 (He</td><td>418.30 [M + 2H] + / 2</td>

254

<td></td><td colspan="3"></td><td></td>

<td>3006b</td><td rowspan="2">NH Ϊ H₂NN '-'X H</td><td></td><td></td><td> 480.90</td>

<td></td><td>H</td><td>XX cr ν χ</td><td></td>

<td></td><td>XnA '</td><td>xr</td><td>X XV -x^NHtwo N</td><td></td>

<td></td><td></td><td></td><td>\ / NH₂</td><td></td>

<td></td><td rowspan="2">NH II h₂nn ' H</td><td></td><td></td><td></td>

<td>3007b</td><td>ΝΆγ H X.</td><td>^ Ά ^ ΝΗ (/TO</td><td> 538.30</td>

<td></td><td>άΑ^χ</td><td> ¥</td><td>Oh</td><td></td>

<td></td><td></td><td> °\/\</td><td>χΝΗ₂</td><td></td>

<td>3008b</td><td>NH Λ XV H₂NN ^^ H</td><td>Ν ^ χγ H</td><td>j)</td><td> 517.80</td>

<td></td><td></td><td></td><td>AA⁵O- ^ N ¢ -</td><td></td>

<td></td><td colspan="2">YnA'O Η H</td><td>F \ XxX^NH2</td><td></td>

<td>3009b</td><td>OR</td><td>¥ A</td><td></td><td> 474.80</td>

<td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>&lt;and</td><td>AA</td><td></td>

<td></td><td colspan="2">and A XX Y'N Ν 'Αχ \ Η H</td><td>F χΤχ ^ ΝΗ ;,</td><td></td>

255

<img file="MX2012004342A_D0100.tif" />

<td>3011b</td><td>NH J] _</td><td>γΑ</td><td>Π</td><td></td>

<td></td><td></td><td>Λχ</td><td>II</td><td></td>

<td></td><td></td><td></td><td>οΛνΧ '·</td><td></td>

<td></td><td>^ νΧν'Ά^χΗ Η</td><td>F</td><td>^, νη₂</td><td></td>

<td>3012b</td><td>NH or _ HjN N ^^/^ N ^^X</td><td></td><td>η</td><td></td>

<td></td><td></td><td></td><td>II Χ ^^ ΝΗ crXz / x</td><td></td>

<td></td><td>Λ-Ο ' Η Η</td><td>F</td><td>^ .νη₂</td><td></td>

<td>3013b</td><td colspan="3"></td><td> 615.6</td>

256

<td rowspan="2"></td><td colspan="2">-nn A XX X. H₂NN² H OH</td><td rowspan="2">^XN ' H OR.</td><td rowspan="2">r</td><td rowspan="2">CV NH oA_nXl '^xn^xSch₃~ x ^ nh₂</td><td rowspan="2"></td>

<td>H</td><td>H</td>

<td rowspan="2">3014b</td><td>NH OR Η, Ν N² H</td><td rowspan="2"></td><td>^XN ' H</td><td rowspan="2"></td><td rowspan="2">to\ &lt;JL aU Cr NA</td><td rowspan="2"> 592.3</td>

<td></td><td></td>

<td></td><td></td><td></td><td></td><td colspan="2">OR-^CF2</td><td></td>

<td></td><td></td><td> 0</td><td></td><td>TO</td><td> 3</td><td></td>

<td></td><td></td><td></td><td></td><td colspan="2">° χ / \ χ^ΝΗ2</td><td></td>

<td rowspan="2">3015b</td><td>NH J] Η, Ν N² H</td><td rowspan="2"></td><td>^ N ' H</td><td rowspan="2"></td><td rowspan="2">OkxΛ. Ά O &lt;^ N Ax</td><td rowspan="2"> 576.3</td>

<td></td><td></td>

<td></td><td></td><td>TO H</td><td></td><td>i</td><td>TO'</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>3016b</td><td colspan="5"></td><td> 537.1</td>

257

<td rowspan="2"></td><td rowspan="2">-Rff^-OR Η, Ν ^ Ν ' ² H</td><td rowspan="2">Λ Η</td><td colspan="2">Η</td><td rowspan="2">CV ηΥ 'ΝΗ • X -ί&gt; υ CT N ^ Α · ^ Χη₂</td><td rowspan="2"></td>

<td>X</td><td>ς 0.</td>

<td>3017b</td><td>NH</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Η, Ν N</td><td></td><td></td><td></td><td>τΧγ</td><td></td>

<td></td><td>H</td><td></td><td>Η</td><td></td><td>UL · ....</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>Α · Χ O ^ N rY</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>χ ^ θχ</td><td></td>

<td></td><td></td><td></td><td>Ο</td><td>X</td><td>X ^CF3</td><td></td>

<td></td><td></td><td>^ Ν</td><td>Α^χ</td><td>S</td><td>ί</td><td></td>

<td></td><td></td><td>Η</td><td>Η</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>'' - ^ 'ΝΗ,</td><td></td>

<td>3018b</td><td>NH</td><td></td><td></td><td></td><td></td><td> 626.0</td>

<td></td><td>Λ Η, Ν Ν</td><td></td><td>^^ Ν</td><td></td><td>ιίΑ</td><td></td>

<td></td><td>² Η</td><td></td><td>Η</td><td></td><td>ΑΑγ-_ΝΗ</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>&lt;rA</td><td></td>

<td></td><td></td><td> 0</td><td>and</td><td colspan="2">x / 0CF₃</td><td></td>

<td></td><td>and</td><td>Λ</td><td>νΑ</td><td></td><td></td><td></td>

<td></td><td>Η</td><td></td><td>Η 1</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>og</td><td>λ</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td colspan="2">νη₂</td><td></td>

<td>3019b</td><td colspan="5"></td><td> 568.0</td>

258

<td rowspan="2"></td><td rowspan="2">NH X H, NN H ¿NAt Η H</td><td rowspan="2">'^' N^/H 9</td><td colspan="2">\TO\ a \ a_nh</td><td rowspan="2"></td>

<td>'^ SCHj Χ \ ^. ΝΗ₂</td><td>A &lt;</td>

<td>3020b</td><td>NH</td><td></td><td></td><td></td><td> 600.6</td>

<td></td><td>Λ</td><td></td><td></td><td></td><td></td>

<td></td><td>Η, Ν N</td><td></td><td>Χ ^ Ί</td><td></td><td></td>

<td></td><td>H</td><td>H</td><td>ux</td><td rowspan="2">TO_nhΝ Ά</td><td></td>

<td></td><td></td><td></td><td>(T</td><td></td>

<td></td><td>Άν-</td><td>X</td><td>rx</td><td></td><td></td>

<td></td><td>Η H</td><td>TO</td><td>AA /^NH2</td><td></td><td></td>

<td>3021b</td><td rowspan="2">NH X H, NN H</td><td rowspan="2"></td><td></td><td></td><td></td>

<td></td><td>ΎΧ</td><td></td><td></td>

<td></td><td></td><td></td><td colspan="2">^ Άνη</td><td></td>

<td></td><td></td><td></td><td>(Τ '</td><td>ÑA</td><td></td>

<td></td><td></td><td></td><td colspan="2">Oh</td><td></td>

<td></td><td></td><td></td><td>ΛΑ</td><td></td><td></td>

<td></td><td></td><td></td><td>OC</td><td></td><td></td>

<td></td><td>OR</td><td>r ~~</td><td> ~\</td><td></td><td></td>

<td></td><td colspan="2"></td><td>; n ^ x ^</td><td>NH₂</td><td></td>

<td></td><td>H</td><td>H</td><td></td><td></td><td></td>

<td>3022b</td><td colspan="4"></td><td></td>

259

<td></td><td rowspan="2">NH OR _ Η, Ν N Η H</td><td></td><td></td>

<td></td><td>AA ^ NH₀AA</td><td></td>

<td></td><td>1S⁵ XJ TN ^ N Η H</td><td>CH₃S^H3 ^^ΝΆχ ^^ΝΗ2</td><td></td>

<td>3023b</td><td>NH X H, N^X^ N '' ^^^XN ' Η H</td><td>For oA_nA ^</td><td></td>

<td></td><td></td><td>Oh , - &lt;H&gt;</td><td></td>

<td></td><td>Η H</td><td>/ Ax^nhz</td><td></td>

<td>3024b</td><td>NH X _ H₂NN Η H</td><td>FOR aa ^_nh</td><td> 593.2</td>

<td></td><td>AJ Η H</td><td>TO? O ^ / \ ^ NH₂</td><td></td>

<td>3 02 5b</td><td colspan="2"></td><td> 592.4</td>

260

<td></td><td>-nn- Η, Ν N H</td><td>ΊΑ H</td><td>X</td><td>CT N ^</td><td></td>

<td></td><td colspan="2">XAn ' Η H</td><td colspan="2">r ^ N „ and O ^ x ^ NH,</td><td></td>

<td>3026b</td><td>NH χ H₂NN H</td><td>N ^ H</td><td>x / ' TO</td><td>X X ^ NH Ha</td><td> 593.0</td>

<td></td><td>0 for_NJ Η H</td><td>X ' 0,</td><td>J</td><td>H ^ N / CH₃TO 0 ^ nh₂</td><td></td>

<td>3027b</td><td rowspan="2">NH TO h₂nn ^^ 'H</td><td>'N^X</td><td>A ^</td><td>ll</td><td></td>

<td></td><td></td><td>TO</td><td>II • 'γΧ οΑ_νΧ &lt;</td><td></td>

<td></td><td></td><td></td><td></td><td>F</td><td></td>

<td></td><td>0 9 A 9-n ^ n 'Η H</td><td>.c</td><td>TO /^N—</td><td>ch₃A ^ NH₂</td><td></td>

<td>3028b</td><td colspan="4"></td><td></td>

261

<img file="MX2012004342A_D0101.tif" />

<img file="MX2012004342A_D0102.tif" />

262

<td></td><td>NH Ϊ Η, Ν N H H H</td><td>ΑΆ H X \ V'X /</td><td>Ol CT TO^cfr^-0CH,</td><td>Ah to AA '· 3 , nh₂</td><td></td>

<td>3032b</td><td rowspan="2">NH II h₂n H</td><td rowspan="2">A ^ H</td><td></td><td></td><td></td>

<td></td><td>XX</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>TO N TR</td><td></td>

<td></td><td>0 Xn ^ n '' ' Η H</td><td>d</td><td colspan="2">/ -cf₃-0 CH₃^ X ^ nh₂</td><td></td>

<td>3033b</td><td rowspan="2">NH X h₂nn ^ Η</td><td>A ^</td><td>'AA</td><td></td><td></td>

<td></td><td></td><td>XXX</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>Oh-</td><td></td>

<td></td><td></td><td>r ~</td><td>, ch₃TO or</td><td></td><td></td>

<td></td><td>άΧν '· ^ Η Η</td><td> ,/^N</td><td>TO-</td><td> 2</td><td></td>

<td>3034b</td><td colspan="4"></td><td></td>

263

<img file="MX2012004342A_D0103.tif" />

264

In other embodiments, the compounds of the present invention do not encompass a compound having the structure:

<img file="MX2012004342A_D0104.tif" />

The compounds of the present invention can be made using chemical synthesis techniques well known to those skilled in the art.

Example 1 - Synthesis of Isocytosines

NH

<img file="MX2012004342A_D0105.tif" />

[4- (2-Amino-4-oxo-l, 4-dihydro-pyrimidin-5-yl) -benzyl] - (3-tert-butoxycarbonylamino-propyl) -carbamic acid tert-butyl ester: For a solution of the acrylate (1.43 g, 3.00 mmol) in EtOH (12 ml), guanidine carbonate (278 mg, 3.30 mmol) and sodium methoxide in methanol (0.5 M, 6.6 ml, 3.3 mmol) were added respectively. The mixture is heated to 90 ° C and allowed to stir overnight. The reaction mixture is cooled to room temperature, where the solid formed was filtered off and the filtrate was concentrated. The crude product was purified by flash chromatography.

265 using a N NH solvent gradient system₃ in MeOH: CH₂Cl₂, to give the desired white solid product (1.95 mmol, 65%). [M + 23] - 496.2.

0-20% 2 as a

<img file="MX2012004342A_D0106.tif" />

{3- [tert-Butoxycarbonyl-4- {4-oxo-2- [3- (2-trifluoromethoxyphenyl) -ureldo] -l, 4-dihydro-pyrimidin-5-yl} -benzyl) -amiono] propyl} - carbamic tert-butyl ester acid:

For a solution of the isocytosine derivative (0.913 g, 1.93 mmol) in dimethylformamide (10 ml), 2 (trifluoromethoxy) phenyl isocyanate (0.30 ml, 2.2 mmol) was added, and the reaction was left stirring at room temperature for two hours . The reaction mixture was concentrated. The crude product was purified by flash chromatography with a 0-20% 2N NH solvent gradient system₃ in MeOH: CH₂Cl₂, to isolate the desired product as a white solid (1.60 mmol, 83%). [M + l] = 577.1.

<img file="MX2012004342A_D0107.tif" />

1- (5- {4 - [(3-Amino-propylamino) -methyl] -phenyl} -4-oxo-l, 4266 dihydro-pyrimidin-2-yl) -3- (2-trifluoromethoxy-phenyl) -urea :

The urea derivative (1.07 g, 1.58 mmol) was suspended in dichloromethane (50 ml) and for this added trifluoro acetic acid (20 ml). The reaction was left stirring at room temperature for one hour. The volatiles were evaporated and the isolated product was a clear oil (1.32 gx TFA salt). [M +1] = 477.1.

NBoc

XM BocHN Ν '

OCF₃

Et₃N, DMF Boc₂0

BocHN

<img file="MX2012004342A_D0108.tif" />

^ NH O zaX ^{H H} 0CF3

Guanidine derived:

For a solution of the free amine (1) (0.661 g, 0.811 mmol) in dimethylformamide (10 ml), triethylamine (0.901 ml, 6.45 mmol) and 77.27'bis- (benzyloxycarbonyl) -1Hpirazol-l-carboxamidine ( 2), respectively, and the reaction was left stirring at room temperature overnight. For the mixture, di-tert-butyl (0.201 g, 0.921 mmol), water (5 ml) and tetrahydrofuran (5 ml) were added and allowed to stir at room temperature for 2 hours. The reaction mixture was diluted in EtOAc (100 ml), washed with saturated brine (2 x .50 ml) and the organic layer was dried (Mg₂SW₄), filtered and concentrated. The crude product was purified by flash chromatography with a

267 solvent gradient of 0-7% 2 N NH³ in MeOH: CH₂Cl2, to isolate the desired product (3) as a clear oil (0.35 mmol, 43%). [M + l] = 719.3.

<img file="MX2012004342A_D0109.tif" />

<img file="MX2012004342A_D0110.tif" />

Final analog:

The guanidine analog (3) (0.291 g, 0.351 mmol) was diluted in CH2CI2 (10 ml), to this added trifluoric acetic acid (3 ml) and the reaction was left stirring at room temperature for one hour. The volatiles were evaporated, the crude was dissolved in water (10 ml) and HC1 1.0 N (5 ml) then concentrated. The residue was redissolved in water (10 ml), then filtered, frozen and lyophilized, to isolate the desired product as a HCl salt (4) (0.184 g). [M + l] = 519.1; 'ή NMR (D20): δ 7.80-7.77 (m, 2H), 7.60 (s, 1H), 7.40-7.13 (m, 4H), 7.09 (m, 2H), 6.94 (s, 1H) , 4.08 (s, 2H), 3.18 to 3.14 (m, 2H), 3.3 to 3.1 (m, 2H),

1.92-1.82 (m, 2H).

Example 2 - Antimicrobial Activity

The compounds of the present invention were tested for antimicrobial activity.

268

These data are presented in Table 2. The compounds are carried out against the Eschericia coli strain ATCC25922 by a standard microdilution assay to determine the minimum inhibitory concentrations (MIC). The data is presented where a + indicates that the compound has a MIC value of 16 micrograms / ml or less and a indicates that the compound has a MIC value greater than 16 micrograms / ml. An N / A means that the data is not available. It will be recognized by those skilled in the art that the compounds can be evaluated with other bacterial organisms and that the presentation of data for activity against Escherichia coli is illustrative and in no way intended to limit the scope of the present invention. The compounds of the present invention can be tested against a range of other microorganisms, depending on the desired yield activity to be collected. Furthermore, the representation and section of +, and N / A of a cut-off value of 16 micrograms / ml is also illustrative and is not intended in any way to limit the scope of the present invention. For example, a is not intended to indicate that the compound necessarily lacks activity or utility, but rather that its MIC value against the indicated microorganism is greater than micrograms / ml 16.

Table 2.

269

<td>Compound Number</td><td>E. coli ATCC25922 MIC</td>

<td> 100</td><td> -</td>

<td> 101</td><td> -</td>

<td> 102</td><td> -</td>

<td> 103</td><td> -</td>

<td> 104</td><td> -</td>

<td> 105</td><td> -</td>

<td> 106</td><td> +</td>

<td> 107</td><td> -</td>

<td> 108</td><td> -</td>

<td> 109</td><td> +</td>

<td> 110</td><td> +</td>

<td> 111</td><td> -</td>

<td> 112</td><td> -</td>

<td> 113</td><td> -</td>

<td> 114</td><td> -</td>

<td> 115</td><td> —</td>

<td> 116</td><td> -</td>

<td> 117</td><td> -</td>

<td> 118</td><td> -</td>

<td> 119</td><td> -</td>

<td> 120</td><td> -</td>

<td> 121</td><td> -</td>

<td> 122</td><td> -</td>

<td> 123</td><td> -</td>

<td> 124</td><td> -</td>

<td> 125</td><td> -</td>

<td> 126</td><td> -</td>

<td> 127</td><td> -</td>

<td> 128</td><td> -</td>

<td> 129</td><td> -</td>

<td> 130</td><td> -</td>

<td> 131</td><td> -</td>

<td> 132</td><td> -</td>

<td> 133</td><td> -</td>

<td> 134</td><td> -</td>

<td> 135</td><td> -</td>

<td> 136</td><td> -</td>

<td> 137</td><td> -</td>

<td> 138</td><td> -</td>

<td> 139</td><td> -</td>

<td> 140</td><td> -</td>

<td> 141</td><td> -</td>

<td> 143</td><td> -</td>

270

<td>Compound Number</td><td>E. coli ATCC25922 MIC</td>

<td> 144</td><td> -</td>

<td> 145</td><td> -</td>

<td> 146</td><td> -</td>

<td> 147</td><td></td>

<td> 148</td><td> -</td>

<td> 149</td><td> -</td>

<td> 150</td><td> -</td>

<td> 151</td><td> -</td>

<td> 152</td><td> -</td>

<td> 153</td><td> -</td>

<td> 155</td><td> -</td>

<td> 156</td><td> -</td>

<td> 157</td><td> -</td>

<td> 158</td><td> -</td>

<td> 159</td><td> -</td>

<td> 160</td><td> -</td>

<td> 161</td><td> -</td>

<td> 162</td><td> -</td>

<td> 163</td><td> +</td>

<td> 164</td><td> -</td>

<td> 165</td><td> -</td>

<td> 166</td><td> -</td>

<td> 167</td><td> -</td>

<td> 168</td><td> +</td>

<td> 170</td><td> -</td>

<td> 171</td><td> -</td>

<td> 172</td><td> +</td>

<td> 173</td><td> -</td>

<td> 174</td><td> -</td>

<td> 175</td><td> -</td>

<td> 176</td><td> +</td>

<td> 177</td><td> -</td>

<td> 178</td><td> -</td>

<td> 185</td><td> +</td>

<td> 186</td><td> -</td>

<td> 187</td><td> -</td>

<td> 188</td><td> -</td>

<td> 189</td><td> -</td>

<td> 190</td><td></td>

<td> 191</td><td> +</td>

<td> 199</td><td> +</td>

<td> 202</td><td> +</td>

<td> 205</td><td> -</td>

<td> 207</td><td> -</td>

<td> 208</td><td> +</td>

<td> 209</td><td> +</td>

271

<td>Compound Number</td><td>E. coli ATCC25922 MIC</td>

<td> 210</td><td> +</td>

<td> 211</td><td> —</td>

<td> 212</td><td> +</td>

<td> 213</td><td> -</td>

<td> 214</td><td> -</td>

<td> 215</td><td> +</td>

<td> 222</td><td> +</td>

<td> 223</td><td> —</td>

<td> 238</td><td> -</td>

<td> 239</td><td> —</td>

<td> 242</td><td> +</td>

<td> 243</td><td> +</td>

<td> 244</td><td> —</td>

<td> 246</td><td> +</td>

<td> 247</td><td> -</td>

<td> 248</td><td> -</td>

<td> 249</td><td> +</td>

<td> 251</td><td> +</td>

<td> 252</td><td> +</td>

<td> 255</td><td> -</td>

<td> 256</td><td></td>

<td> 257</td><td> —</td>

<td> 259</td><td> +</td>

<td> 260</td><td> -</td>

<td> 265</td><td></td>

<td> 266</td><td> +</td>

<td> 267</td><td> -</td>

<td> 268</td><td> —</td>

<td> 269</td><td></td>

<td> 270</td><td> -</td>

<td> 271</td><td> —</td>

<td> 273</td><td> -</td>

<td> 274</td><td></td>

<td> 275</td><td> -</td>

<td> 276</td><td> —</td>

<td> 277</td><td> -</td>

<td> 278</td><td> -1-</td>

<td> 281</td><td> —</td>

<td> 282</td><td> -</td>

<td> 283</td><td> -</td>

<td> 284</td><td> -</td>

<td> 285</td><td> -</td>

<td> 286</td><td> —</td>

<td> 287</td><td> —</td>

<td> 290</td><td> -</td>

<td> 291</td><td> -</td>

272

<td>Compound Number</td><td>E. coli ATCC25922 MIC</td>

<td> 294</td><td> +</td>

<td> 295</td><td> -</td>

<td> 297</td><td> +</td>

<td> 299</td><td> -</td>

<td> 300</td><td> -</td>

<td> 301</td><td> -</td>

<td> 302</td><td> -</td>

<td> 303</td><td> +</td>

<td> 304</td><td> +</td>

<td> 305</td><td> -</td>

<td> 307</td><td> +</td>

<td> 308</td><td> +</td>

<td> 311</td><td> -</td>

<td> 312</td><td> +</td>

<td> 313</td><td> -</td>

<td> 314</td><td> -</td>

<td> 315</td><td> -</td>

<td> 316</td><td> -</td>

<td> 317</td><td> -</td>

<td> 319</td><td> -</td>

<td> 320</td><td> -</td>

<td> 321</td><td> —</td>

<td> 322</td><td> -</td>

<td> 323</td><td> -</td>

<td> 324</td><td> +</td>

<td> 325</td><td> -</td>

<td> 326</td><td> -</td>

<td> 327</td><td> -</td>

<td> 328</td><td> -</td>

<td> 329</td><td> -</td>

<td> 330</td><td> -</td>

<td> 331</td><td> -</td>

<td> 332</td><td> +</td>

<td> 334</td><td> +</td>

<td> 336</td><td> -</td>

<td> 337</td><td> +</td>

<td> 338</td><td> +</td>

<td> 339</td><td> -</td>

<td> 340</td><td> -</td>

<td> 341</td><td> -</td>

<td> 342</td><td> -</td>

<td> 343</td><td> +</td>

<td> 344</td><td> +</td>

<td> 345</td><td> -</td>

<td> 346</td><td> +</td>

<td> 347</td><td> -</td>

273

<td>Compound Number</td><td>E. coli ATCC25922 MIC</td>

<td> 348</td><td> -</td>

<td> 349</td><td> +</td>

<td> 350</td><td> +</td>

<td> 351</td><td> +</td>

<td> 352</td><td> +</td>

<td> 353</td><td> -</td>

<td> 354</td><td> -</td>

<td> 355</td><td> +</td>

<td> 356</td><td> +</td>

<td> 357</td><td> -</td>

<td> 358</td><td> -</td>

<td> 359</td><td> -</td>

<td> 361</td><td> +</td>

<td> 363</td><td> -</td>

<td> 364</td><td> -</td>

<td> 365</td><td> +</td>

<td> 366</td><td> -</td>

<td> 368</td><td> -</td>

<td> 369</td><td> -</td>

<td> 370</td><td> -</td>

<td> 372</td><td> -</td>

<td> 373</td><td> —</td>

<td> 374</td><td> -</td>

<td> 376</td><td> -</td>

<td> 381</td><td> -</td>

<td> 382</td><td> +</td>

<td> 383</td><td> -</td>

<td> 384</td><td> -</td>

<td> 385</td><td></td>

<td> 386</td><td> -</td>

<td> 387</td><td> -</td>

<td> 388</td><td> -</td>

<td> 389</td><td> -</td>

<td> 394</td><td> +</td>

<td> 395</td><td> -</td>

<td> 397</td><td> —</td>

<td> 398</td><td> -</td>

<td> 399</td><td> -</td>

<td> 401</td><td> +</td>

<td> 403</td><td> -</td>

<td> 404</td><td> —</td>

<td> 405</td><td> -</td>

<td> 406</td><td> -</td>

<td> 407</td><td> -</td>

<td> 408</td><td> -</td>

<td> 409</td><td> -</td>

274

<td>Compound Number</td><td>E. coli ATCC25922 MIC</td>

<td> 410</td><td> -</td>

<td> 412</td><td></td>

<td> 413</td><td> -</td>

<td> 414</td><td> -</td>

<td> 415</td><td> -</td>

<td> 416</td><td> -</td>

<td> 417</td><td> -</td>

<td> 418</td><td> -</td>

<td> 419</td><td> +</td>

<td> 420</td><td> +</td>

<td> 421</td><td> -</td>

<td> 422</td><td> -</td>

<td> 423</td><td> -</td>

<td> 424</td><td> -</td>

<td> 425</td><td> -</td>

<td> 427</td><td> -</td>

<td> 428</td><td> -</td>

<td> 429</td><td> -</td>

<td> 431</td><td> -</td>

<td> 432</td><td> +</td>

<td> 433</td><td></td>

<td> 434</td><td> -</td>

<td> 435</td><td> -</td>

<td> 436</td><td> +</td>

<td> 437</td><td> -</td>

<td> 438</td><td> +</td>

<td> 439</td><td> +</td>

<td> 441</td><td> -</td>

<td> 443</td><td> -</td>

<td> 444</td><td> -</td>

<td> 445</td><td> -</td>

<td> 446</td><td> -</td>

<td> 448</td><td> -</td>

<td> 449</td><td> -</td>

<td> 450</td><td> +</td>

<td> 451</td><td> +</td>

<td> 452</td><td> +</td>

<td> 453</td><td> +</td>

<td> 454</td><td> +</td>

<td> 455</td><td> -</td>

<td> 456</td><td> -</td>

<td> 457</td><td> -</td>

<td> 458</td><td> +</td>

<td> 459</td><td> -</td>

<td> 461</td><td> -</td>

<td> 462</td><td> -</td>

275

<td>Compound Number</td><td>E. coli ATCC25922 MIC</td>

<td> 463</td><td> +</td>

<td> 464</td><td> -</td>

<td> 465</td><td> -</td>

<td> 466</td><td> -</td>

<td> 467</td><td> +</td>

<td> 468</td><td> +</td>

<td> 469</td><td></td>

<td> 470</td><td> +</td>

<td> 471</td><td> +</td>

<td> 472</td><td> -</td>

<td> 473</td><td> -</td>

<td> 474</td><td> +</td>

<td> 475</td><td> -</td>

<td> 476</td><td> -</td>

<td> 477</td><td> -</td>

<td> 478</td><td> -</td>

<td> 479</td><td> -</td>

<td> 480</td><td> 4-</td>

<td> 481</td><td> -</td>

<td> 482</td><td> -</td>

<td> 483</td><td> -</td>

<td> 484</td><td> -</td>

<td> 485</td><td> -</td>

<td> 486</td><td> -</td>

<td> 487</td><td> -</td>

<td> 488</td><td> -</td>

<td> 489</td><td> -</td>

<td> 490</td><td> -</td>

<td> 491</td><td> -</td>

<td> 492</td><td></td>

<td> 493</td><td> +</td>

<td> 494</td><td> -</td>

<td> 495</td><td> -</td>

<td> 496</td><td> +</td>

<td> 497</td><td> +</td>

<td> 499</td><td> -</td>

<td> 500</td><td> +</td>

<td> 501</td><td> -</td>

<td> 502</td><td> -</td>

<td> 503</td><td> -</td>

<td> 504</td><td> -</td>

<td> 505</td><td> -</td>

<td> 509</td><td> -</td>

<td> 510</td><td> -</td>

<td> 512</td><td> -</td>

<td> 513</td><td> -</td>

276

<td>Compound Number</td><td>E. coli ATCC25922 MIC</td>

<td> 514</td><td> -</td>

<td> 515</td><td> -</td>

<td> 516</td><td> -</td>

<td> 517</td><td> -</td>

<td> 518</td><td> -</td>

<td> 519</td><td> -</td>

<td> 520</td><td> -</td>

<td> 521</td><td> -</td>

<td> 522</td><td> -</td>

<td> 523</td><td> -</td>

<td> 524</td><td> -</td>

<td> 525</td><td> -</td>

<td> 526</td><td> -</td>

<td> 527</td><td> -</td>

<td> 530</td><td> -</td>

<td> 531</td><td> -</td>

<td> 532</td><td> -</td>

<td> 533</td><td> -</td>

<td> 534</td><td> -</td>

<td> 535</td><td> -</td>

<td> 536</td><td> -</td>

<td> 537</td><td> -</td>

<td> 538</td><td> -</td>

<td> 539</td><td> +</td>

<td> 540</td><td> -</td>

<td> 541</td><td> -</td>

<td> 545</td><td> -</td>

<td> 546</td><td> -</td>

<td> 547</td><td> -</td>

<td> 548</td><td> -</td>

<td> 549</td><td> -</td>

<td> 550</td><td> -</td>

<td> 551</td><td> -</td>

<td> 552</td><td> -</td>

<td> 553</td><td> -</td>

<td> 554</td><td> -</td>

<td> 555</td><td> -</td>

<td> 556</td><td> -</td>

<td> 573</td><td> -</td>

<td> 574</td><td> -</td>

<td> 577</td><td> -</td>

<td> 582</td><td> -</td>

<td> 583</td><td> -</td>

<td> 584</td><td> -</td>

<td> 585</td><td> -</td>

<td> 588</td><td> 4-</td>

277

<td>Compound Number</td><td>E. coli ATCC25922 MIC</td>

<td> 589</td><td> -</td>

<td> 593</td><td> +</td>

<td> 594</td><td> +</td>

<td> 599</td><td> -</td>

<td> 605</td><td> -</td>

<td> 607</td><td> -</td>

<td> 608</td><td> -</td>

<td> 619</td><td> -</td>

<td> 652</td><td> -</td>

<td> 680</td><td></td>

<td> 710</td><td> -</td>

<td> 712</td><td> -</td>

<td> 735</td><td> -</td>

<td> 739</td><td> -</td>

<td> 747</td><td> +</td>

<td> 779</td><td> -</td>

<td> 780</td><td> -</td>

<td> 1283</td><td> -</td>

<td> 1291</td><td> -</td>

<td> 1294</td><td> -</td>

<td> 1295</td><td> -</td>

<td> 1296</td><td> -</td>

<td> 1297</td><td> -</td>

<td> 1302</td><td> -</td>

<td> 1303</td><td> -</td>

<td> 1304</td><td> -</td>

<td> 1305</td><td> -</td>

<td> 1308</td><td> -</td>

<td> 1311</td><td> -</td>

<td> 1312</td><td> -</td>

<td> 1313</td><td> -</td>

<td> 1314</td><td> -</td>

<td> 1315</td><td> -</td>

<td> 1317</td><td> -</td>

<td> 1318</td><td> +</td>

<td> 1319</td><td> -</td>

<td> 1320</td><td> +</td>

<td> 1321</td><td> +</td>

<td> 1322</td><td> -</td>

<td> 1323</td><td> -</td>

<td> 1331</td><td> -</td>

<td> 1332</td><td> +</td>

<td> 1333</td><td> -</td>

<td> 1337</td><td> +</td>

<td> 1338</td><td> -</td>

<td> 1339</td><td> -</td>

278

<td>Compound Number</td><td>E. coli ATCC25922 MIC</td>

<td> 1340</td><td> -</td>

<td> 1341</td><td> -</td>

<td> 1345</td><td> -</td>

<td> 1346</td><td> -</td>

<td> 1347</td><td> -</td>

<td> 1348</td><td> -</td>

<td> 1353</td><td></td>

<td> 1354</td><td> -</td>

<td> 1355</td><td> -</td>

<td> 1356</td><td> +</td>

<td> 1357</td><td> -</td>

<td> 1358</td><td> -</td>

<td> 1362</td><td> -</td>

<td> 1363</td><td> -</td>

<td> 1364</td><td> -</td>

<td> 1375</td><td> +</td>

<td> 1376</td><td> +</td>

<td> 1377</td><td> +</td>

<td> 1378</td><td> +</td>

<td> 1382</td><td> +</td>

<td> 1383</td><td> -</td>

<td> 1384</td><td> +</td>

<td> 1385</td><td> +</td>

<td> 1386</td><td> +</td>

<td> 1387</td><td> -</td>

<td> 1388</td><td> -</td>

<td> 1389</td><td> -</td>

<td> 1394</td><td> +</td>

<td> 1395</td><td> +</td>

<td> 1396</td><td> +</td>

<td> 1401</td><td> +</td>

<td> 1402</td><td> +</td>

<td> 1403</td><td> -</td>

<td> 1407</td><td> +</td>

<td> 1409</td><td> +</td>

<td> 1419</td><td> +</td>

<td> 1420</td><td> +</td>

<td> 1424</td><td> +</td>

<td> 1425</td><td> +</td>

<td> 1429</td><td> -</td>

<td> 1430</td><td> -</td>

<td> 1445</td><td> +</td>

<td> 1454</td><td> +</td>

<td>3000b</td><td> +</td>

<td>3001b</td><td> +</td>

279

<td>3002b</td><td> +</td>

<td>3003b</td><td> +</td>

<td>3004b</td><td> +</td>

<td>3005b</td><td> +</td>

<td>3006b</td><td> +</td>

<td>3007b</td><td> +</td>

<td>3008b</td><td> +</td>

<td>3009b</td><td> -</td>

<td>3010b</td><td> +</td>

<td>3011b</td><td> +</td>

<td>3012b</td><td> +</td>

<td>3013b</td><td> +</td>

<td>3014b</td><td> +</td>

<td>3015b</td><td> -</td>

<td>3016b</td><td> +</td>

<td>3017b</td><td> -</td>

<td>3018b</td><td> -</td>

<td>3019b</td><td> +</td>

<td>3020b</td><td> +</td>

<td>3021b</td><td> -</td>

<td>3022b</td><td> -</td>

<td>3023b</td><td> -</td>

<td>3024b</td><td> -</td>

<td>3025b</td><td> +</td>

<td>3026b</td><td> -</td>

<td>3027b</td><td> +</td>

<td>3028b</td><td> +</td>

<td>3029b</td><td> +</td>

<td>3030b</td><td> +</td>

<td>3031b</td><td> -</td>

<td>3032b</td><td> -</td>

<td>3033b</td><td> -</td>

INCORPORATION BY REFERENCE

The full description of each of the patent documents and scientific articles mentioned in this document is incorporated by reference for all purposes.

EQUIVALENTS

280

The invention can be carried out in other specific forms without departing from the scope or essential characteristics thereof. Accordingly, the foregoing embodiments are to be considered in all illustrative and non-limiting respects in the invention described herein. The scope of the invention is indicated by the appended claims rather than by the foregoing description, and all changes that fall within the meaning and scope of the claims are intended to be included therein.

281