Antimicrobial compounds and methods of making and using the same.

PATENT TITLE No. 349718

Owner (s): MELINTA THERAPEUTICS, INC.

Address: 300 George Street, Suite 301, New Haven, Connecticut, 06511, USA

Name: ANTIMICROBIAL COMPOUNDS AND METHODS FOR MANUFACTURING AND USING THEM.

Classification: CIP: C07D487 / 04; A61K31 / 519; A61P31 / 00; A61P31 / 04; C07D403 / 10

CPC: C07D487 / 04; A61F2 / 82; C07D471 / 08; C07D491 / 048; C07D519 / 00;

A61F2250 / 0067

Inventor (s): ERIN M. DUFFY; ASHOKE BHATTACHARJEE; HARDWIN O'DOWD; FRAME

DEVIVO; ZOLTAN F. KANYO; JACEK G. MARTINOW; IK-HYEON PAIK; *

REQUEST

Number: International Presentation Date:

MX / a / 2015/017605 ....... October 15, 2010

Divisional File Number: MX / a / 2012/004340

...... PRIORITY*

<td>Country:</td><td>Date:</td><td>Number:</td>

<td>US</td><td>March 16, 2010</td><td> 61/314,287</td>

<td>US</td><td>October 16, 2010</td><td> 61/252,478</td>

Validity: Twenty years

Expiration Date: October 15, 2030

Issue Date: August 10, 2017.

The reference patent is granted based on articles 1^or, 2nd section V, 6th section III, and 59 of the Industrial Property Law.

In accordance with article 23 of the Industrial Property Law, this patent is valid for twenty years, non-extendable, counted from the filing date of the international application and will be subject to payment of the fee to keep the rights in force.

Whoever signs this title does so based on the provisions of articles 6^or fractions lll and 7^or bis 2 of the Industrial Property Law (Official Gazette of the Federation (DOF) 06/27/1991, amended on 08/02/1994, 10/25/1996, 12/20/1997, 05/17/1999, 01/26/2004, 06/16/2005, 01/25/2006, 05/06/2009, 06/01/2010, 06/18/2010, 06/28/2010, 01/27/2012 and 09 / 04/2012), articles 1, 3 »fraction V subsection a), 4^or and 12th sections I and III of the Regulations of the Mexican Institute of Industrial Property (DOF 12/14/1999, amended on 07/01/2002, 07/15/2004, 07/28/2004 and 09/07/2007) ; Articles 1, 3^or. 4^or, 5 »section V subsection a), 16 sections I and III and 30 of the Organic Statute of the Mexican Institute of Industrial Property (DOF 12/27/1999, amended on 10/10/2002, 07/29/2004, 08/04 / 2004 and 09/13/2007); 1^or, 3rd and 5th^or Subsection a) of the Agreement that delegates powers to the Deputy General Directors, Coordinator, Divisional Directors, Heads of Regional Offices, Divisional Deputy Directors, Departmental Coordinators and other subordinates of the Mexican Institute of Industrial Property. (DOF 12/15/1999, amended on 02/04/2000, 07/29/2004, 08/04/2004 and 09/13/2007).

This document is signed with an advanced electronic signature (FIEL), based on articles 7 BIS 2 of the Industrial Property Law; 3 of its Regulations, and 1 fraction lll, 2 fraction V, 26 BIS and 26 TER of the Agreement establishing the guidelines for the use of the Payment and Electronic Services Portal (PASE) of the Mexican Institute of Industrial Property, in the procedures indicated.

THE DIVISIONAL DIRECTOR OF PATENTS

NAHANNY CANAL REYES

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MX / 2017/65206

IMPI

INSTI n / ra MEXICAN

D «M rRCr.'INDUSTRIAL AGE

<img file="MX349718B_D0002.tif" />

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 March 16, 2010; and US Provisional Patent Application No. 61 / 358,201 filed 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

<img file="MX349718B_D0003.tif" />

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 as strains of cells or microorganisms resistant to effective therapeutic agents today 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 developed. Resistant bacteria can cause serious and even fatal results for infected patients. See, eg, Lowry, FD Antimicrobial Resistance: Staphylococcus aureus Example, J. Clin. Invest., Vol. 111, no. 9, pp. 1265-1273 (2003); and Gold, HS and Moellering, RC, Jr., Antimicrobial Drug Resistance, N. Engl. J. Med., Vol. 335, pp. 1445-53 (1996).

The discovery and development of new antibacterial agents have for decades been a major focus in many pharmaceutical companies. 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 of particular concern, 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 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, thus providing an effect

<img file="MX349718B_D0004.tif" />

<img file="MX349718B_D0005.tif" />

INSTITUTO MkXICANi I

DE LA ί · Τ.Ο. ·! Ε!, Λ '·&gt; INI USTRIAL antimicrobial. In fact, some antibiotic compounds such as erythromycin, clindamycin, and linezolid are known to bind to the ribosome.

The present invention uses a framework based on the drug design approach for the discovery and development of new antimicrobial agents. This approach begins with high-resolution X-rays through ribosome crystals to engineer new classes of antimicrobial compounds that have specific chemical structures, ribosome-binding characteristics, and antimicrobial activity. This structure-based approach to drug discovery is described in the following publication: Franceschi, F. and Duffy, EM, Design of the drug based on the Structure found in the ribosome, Biochemical Pharmacology, vol. 71, pp. 1016-1025 (2006).

Based on this structure based approach to 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

<img file="MX349718B_D0006.tif" />

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY provide better activity, espeoi ^ lmanbc ·¹· versus¹resistant strains of bacteria, than current antibiotic compounds.

The present invention utilizes a framework-based approach to drug design for the discovery and development of new antimicrobial agents. This approach begins with high-resolution X-ray ribosome crystals to engineer new classes of antimicrobial compounds that have specific chemical structures, ribosome binding characteristics, and desired antimicrobial activity. This approach to drug discovery based on this structure is described in the following publication: Franceschi, F. and Duffy, EM,

Drug design based on the structure found in the ribosome, Biochemical Pharmacology, vol. 71, pp. 1016-1025 (2006).

The present invention therefore fills an ongoing important need to provide new antimicrobial agents, in particular for antimicrobial agents, which have activity against resistant bacterial pathogens.

BRIEF DESCRIPTION OF ΙΛ 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, Noxides, and prodrugs of these compounds.

The present invention provides compounds having the structure:

D — E — F -A

C - B — A - R

L____ (where I—— is a chemistry selected from:

<img file="MX349718B_D0007.tif" />

<img file="MX349718B_D0008.tif" />

where Vy represents a 5 to 7 fused member saturated, unsaturated or aromatic carbocycle or system of

<img file="MX349718B_D0009.tif" />

heterocyclic ring. · ''¹ where T¹ is a carbon or N atom, such that when T¹ is N, -DEF is absent, where T² is a carbon or N atom, such that when T² is N, -GHJ is absent, where both T¹ and T² they are not both simultaneously N, where V is independently selected from -CR^4th-oN-,

W is O, NR¹, GOR¹, 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-₈ alkyl) 0- and Hambas 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 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 0, NR⁴, S (0)_n, or NH,

R¹ is selected from H and Ci-₈ I rent,

R² is selected from H and Ci-₈ I rent,

R³ is selected from H and Ci ~₈ I rent,

R⁴ is selected from H and Ci-₈ I rent,

R^4th is selected from H and Ci-₈ I rent,

<img file="MX349718B_D0010.tif" />

IMPIg

MEXICAN INSTITUTE

OF PROPERTY C = W:

INDUSTRIAL ^ 1.

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

H - J - &lt; ^H—J, 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, (or). - (Ci-₈ alkyl) -, (c) - (C₂-8 alkenyl) -, (d) - (C₂-b alkynyl) -, where

i) 0-4 carbon atoms in any of (b) (d) immediately above are optionally replaced by a fraction selected from the group consisting of -0 -, - S (O) _p, -NR⁶-, - (C = 0) -, S (O) PNR⁶-, - NR⁶S (O) p, y-NR⁶SW)_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 are optionally substituted with - (Ci-8 alkyl) -R groups⁵;

(e) -O-, (f) -NR⁶-, (g) -S (O)_P-, (h) -C (O) -, (i) -C (0) 0-,

<img file="MX349718B_D0011.tif" />

<img file="MX349718B_D0012.tif" />

INSTITUTE ME7JCAMO DE LA PkOPiiDAD INDUSTRIAL (j) -OC (O) -, k) -0C (0) 0-, (1) -C (0) NR⁶-, (m) -NR⁶C0 -, (n) NR⁶C (O) NR⁶-, (o) - C (= NR⁶) -, (p) -C (= NR⁶) 0-, (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 (0) -, (y) OC (= S) -, (z) -C (= S) O-, (aa) -NR⁶ (CNR⁶) NR⁶-, (bb) -CR⁶R⁶C (O) -, (cc) -C (0) NR⁶ (CR⁶R⁶) _t-, (dd) a 3-14 member saturated, unsaturated or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (ee) a 3-14 member saturated, unsaturated or aromatic carbocycle , 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 member saturated, unsaturated or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (c) a 3-14 member saturated, unsaturated or aromatic carbocycle, where (b) or (c) is optionally substituted with one or more R groups⁵;

<img file="MX349718B_D0013.tif" />

IMPI

MEXICAN INSTITUTE

I HEARD THE INDUSTRIAL PHOH'DAD (d) - (Ci-₈ alkyl) -, (e) - (C₂_₈ alkenyl) -, (f) - (C₂_ ₈ alkynyl) -, where

i) 0-4 carbon atoms in any of (d) - (f) immediately above is optionally substituted by a moiety selected from the group consisting of -O-, -S (O)_p-, -NR⁶-, - (C = O) -, C (= NR⁶) -, -S (O) pNR⁶-, -NR⁶S (O) p-, and -NR⁶SW)_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 are 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) -N0₂, (k) -NR⁶ (CR⁶R⁶) _tR⁸, (1) -OR⁸, (m) -S (O) p (CR⁶R⁶) tR⁸, (n) -C (O) (CR⁶R⁶) _tR⁸, (o) -OC (O) (CR⁶R⁶) tR⁸, (p) -SC (O) (CR⁶R⁶) tR⁸, (q) C (0) O (CR⁶R⁶) tR⁸, (r) -NR⁶C (O) (CR⁶R⁶) tR⁸, (s) C (0) NR⁶ (CR⁶R⁶) tR⁸, (t) -C (= NR⁶) (CR⁶R⁶) tR⁸, (u) C (= NNR⁶R⁶) (CR⁶R⁶) tR⁸, (v) -C (= NNR⁶C (O) R⁶) (CR⁶R⁶) tR⁸, (w) -C (= N0R⁸) (CR⁶R⁶) tR⁸, (x) -NR⁶C (0) 0 (CR⁶R⁶) tR⁸, (y) OC (0) NR⁶ (CR⁶R⁶) tR⁸, (z) -NR⁶C (O) NR⁶(CR⁶R⁶) tR⁸, (aa) -

<img file="MX349718B_D0014.tif" />

NR⁶S (O) p (CR⁶R⁶) tR⁸, (bb) -S (O) pNR⁶NR⁶S (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 ^ g alkyl group, (mm) a C2-8 alkenyl group, (nn) a C2-8 alkynyl group, (or or) a 3-14 member saturated, unsaturated or aromatic heterocycle containing one or plus 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 [(CR⁶R⁶) tR⁸] [C = O (CR⁶R⁶) tR⁸], (ss) (CR⁶R⁶) tN [(CR⁶R⁶) tR⁸] [(CR⁶R⁶) tR⁸], (tt) (CR⁶R⁶) tNR⁶ (C = O) (CR⁶R⁶) tR⁸/ (uu) -haloalkyl, (vv) C (0) (CR⁶) [(CR⁶R⁶) tR⁸] R⁸, (ww) - (CR⁶R⁶) tC (O) NR⁸R⁸, (xx) - (CR⁵R⁶) tC (O) O (CR⁶R⁶) tR⁸, (yy) -NR⁶C (O) CR⁸R⁸R⁸, (zz) -N [(CR⁶R⁶) tR⁸] C (O) R⁸, and (aaa) -S (O) PNR⁸R⁸;

wherein (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) -NO2 , (j) -NR⁶R⁶, (k) -OR⁸, (1) -NR⁶ (CNR⁶) NR⁶R⁶, (m) -Ci-8 alkyl, (n) -Ci-₈alkenyl, (or) -Ci-₈ alkynyl, (p) - (Ci-₈ alkynyl) - (3-14 member saturated, unsaturated, or aromatic heterocycle that Instituto Mexicano

MLAI 'PROPERTY'^x. ". i

INDUSTRIAL '- &lt;. " U -—Cx '' contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (q) - (Ci-₈alkyl) - (3-14 member saturated, unsaturated or aromatic carbocycle), (r) -haloalkyl, (s) -SR^fi, (t) -3-14 saturated, unsaturated, or aromatic 5-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 ; alternatively, two R groups⁵ come together to form a carbocycle;

1Ό where (m) a (r) and (t) a (u) is optionally substituted with one or more R⁸;

R⁶ is selected from (a) hydrogen, (b) -Ci-₈ alkyl or alternatively two R groups⁶ are taken together to form a carbocycle, (c) -haloalkyl, (d) -3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and ( e) -3-14 member saturated, unsaturated or aromatic carbocycle;

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

R⁷ 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, (or) -Ci-₈ alkynyl, (p) - (Ci-₈ alkyl) - (3-14 member saturated, unsaturated, or aromatic heterocycle that

<img file="MX349718B_D0015.tif" />

<img file="MX349718B_D0016.tif" />

ΐΝΓΓΓτνίο AHxa.Year

Vt tA PF.O? ÍLIMU iHO '/ rrRiAL contains one or more heteroatoms selecciorrát ^ á ^' ^ re ^^ 'e ^ ™ * - ^^ group consisting of nitrogen, oxygen and sulfur), (q) - (Cl8 alkyl ) - (3-14 saturated, unsaturated or aromatic carbocycle), (r) -haloalkyl, (s) -NR R, (t) OR⁸, (u) - (CR⁶R⁶) _tNR⁶R⁸, (v) -CR⁶R⁸R⁸, (w) -SR⁶, (x) -3-14 member saturated, unsaturated or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (y) -3-14 member saturated, unsaturated or aromatic carbocycle, (z) (CR⁶R⁶) tC (O) NR⁸R⁸, (aa) -S (O) PR⁸, (bb) -NR⁶C (0) NR⁶R⁶, (cc) NR⁶C (O) R⁶, and (dd) -C (= NR⁶) NR⁶R⁶; .

where (m) a (q) and (x) a (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) -NO2 , (j) -NR⁶R⁹, (k) -OR⁹, (1) -NR⁶ (CNR⁶) NR⁶R⁶, (m) -Ci-8 alkyl, (η) -Οχ-8 alkenyl, (o) -Ci-₈ alkynyl, (p) - (Ci-₈ alkyl) - (3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (q) - (Ci-₈alkyl) - (3-14 member saturated, unsaturated or aromatic carbocycle), (r) -3-14 member saturated, unsaturated or aromatic containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, ( s) -3-14 member saturated, unsaturated or aromatic carbocycle,

<img file="MX349718B_D0017.tif" />

<img file="MX349718B_D0018.tif" />

(t) -haloalkyl, (u) -C (O) (CR⁶R⁶) _tR⁹, (v) -SR⁶,

OC (Ó) (CR⁶R⁶)_tR⁹, (x) -NR⁶C (O) NR⁶R⁹, (and) -NR⁶C (O) R⁹, (z) NR⁶ (CNR⁹) (NR⁶R⁶), (aa) -ONR⁶ (CNR⁶) NR⁶R⁶, (bb) -C (= NR⁹) NR⁶R⁶, (cc) -S (O) pR⁹, (dd) - (CR⁶R⁶) tc (O) NR⁶R⁹, (ee) - (CR⁶R⁶) tOR⁹, and (ff) - (CR⁶R⁶)_tNR⁶R⁹;

where (m) a (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) 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 member saturated, unsaturated or aromatic containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (r) -3-14 member saturated, unsaturated or aromatic carbocycle, (t) - (CR⁶R⁶) tOR⁶, (u) -O (CR⁶R⁶) tNR⁶R¹⁰, (v) -C (O) R⁶, (w) -SR⁶, (x) -C (O) OR¹⁰, (and) -S (O) PR⁶, (z) - (C ^ g alkyl) - (3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (aa) - (Ci -8 alkyl) - (3-14 member saturated, unsaturated, or aromatic carbocycle), (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;

in which (n) to (r) and (z) through (aa) is

<img file="MX349718B_D0019.tif" />

IMPIIR

INSTITUTO MEXICANO DE LA FROPiP.DAP industriai 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 (O) (CR⁶R⁶) tNR⁶R⁶, (n) -Ci5 ₈ rented, (or) -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 ) 10 haloalkyl, (t) - (CR⁶R⁶) tOR⁶, (u) -O (CR⁶R⁶) tNR⁶R⁶, (v) C (O) R⁶, (w) -SR⁶, (x) -C (O) OR⁶, (and) -S (O) PR⁶, (z) - (Ci-8 alkyl) - (3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (aa) - (Ci -8 alkyl) - (3-14 member saturated, unsaturated or aromatic carbocycle), (bb) -O (CR⁶R⁶) tOR⁶, (cc) C (= NR⁶) NR⁶R⁶, (dd) -ONR⁶R⁶, (ee) -NR⁶C (O) NR⁶R⁶, (ff) O (CR⁶R⁶) tOR⁶, (gg) -NR⁶C (O) R⁶, and (hh) - (CR⁶R⁶) _tNR⁶R⁶;

optionally, wherein either the group -DEF or the group -GHJ is absent, but both -DEF and -GHJ are not simultaneously absent;

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

<img file="MX349718B_D0020.tif" />

<img file="MX349718B_D0021.tif" />

<img file="MX349718B_D0022.tif" />

IMPI

INSTITUTE ME »JCAt! O

Say LA FRO.'IEDAD INDUSTRIAL

Furthermore, the invention provides methods for synthesizing the above compounds. After 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, intravenously, otic ophthalmic, nasal, or topical, to provide an effective amount of the compound to the human or animal.

The above 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 agents

INSTITUTO MEXICANO OS tA WCHC &amp; AU INDUSTRIAL ----------- antimicrobials, more particularly as antibacterial agents.

The present invention includes the pharmaceutically acceptable salts, esters, tautomers, N-oxides and prodrugs thereof.

The compounds described herein can have asymmetric centers. Compounds of the present invention containing 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 the processes used to prepare compounds of the present invention and the

<img file="MX349718B_D0023.tif" />

INSTITUTO MEXICANA DE LA PROPIED · .i) INDUSTRIAL intermediates made in the same are considered part 3e 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 the atoms that occur in the present compounds. Isotopes are atoms that have the same atomic number but different mass numbers. By way of general example and without limitation, hydrogen isotopes include tritium and deuterium. The isotopes of car are C-13 and C-14. g When any variable (for example, R) occurs 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 it is selected regardless of the definition of R⁶. Furthermore, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds within the normal valence of a designated atom.

A chemical structure showing a

<img file="MX349718B_D0024.tif" />

IMPI

MEXICAN INSTITUTE

DE The industrial PROFILE representation dotted line 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 span a bond connecting two atoms in a ring, then that substituent can be bonded to any atom in the ring. When a substituent is on the list without indicating the atom through which said substituent is attached in the remainder 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, where appropriate, can be converted into ΛΓ-oxides by treatment with an oxidizing agent (for example, MCPBA and / or hydrogen peroxides) . Therefore, the shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its derivative M-oxide (N ~&gt; 0) derivative, as appropriate.

An approach to developing better agents μ&gt;,

<img file="MX349718B_D0025.tif" />

anti-proliferative and anti-infective 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-eguivalent 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 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 the aminoacyl, peptidyl, and exit sites. The aminoacyl site or an A site accommodates the entrant

<img file="MX349718B_D0026.tif" />

MEXICAN INSTITUTE

PE THE industrial PROPERTY aminoacyl-TARN 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.

1. Definitions

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 stereoisomers that are not superimposable mirror images are called enantiomers, or sometimes optical isomers. A carbon atom attached to four non-identical substituents is called a chiral center.

Chiral isomer means a compound with al. minus one chiral center. It has two enantiomeric forms of

<img file="MX349718B_D0027.tif" />

₂₂ IMPI

Mexican INSTITUTE

OF THE PROPERTY

INDUSTRIAL 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 2 enantiomeric pairs^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. The substituents attached to the chiral center under consideration are classified according to the Sequence Rule of Cahn, Ingold and Prelog. (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 the hindered rotation around double bonds. These configurations are differentiated in their names by the prefixes cis and trans,

<img file="MX349718B_D0028.tif" />

<img file="MX349718B_D0029.tif" />

INSTITUTO MEXICANO DE LA KtO.'raC'AD INDUSTRIAL 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 atropic isomers thereof. Atropic isomers are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic Isomers owe their existence to a restricted rotation caused by impeding the rotation of large groups around a central bond. Such atropic isomers typically exist as a mixture, however, as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic 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 forms.

<img file="MX349718B_D0030.tif" />

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 enol and imine form and the keto and enamine form and geometric isomers and mixtures thereof. All tautomeric forms are included within the scope of the present invention. Tautomers exist as mixtures of an established tautomer 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 equilibrium of the tautomers can be achieved. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertable by tautomerizations is called

<img file="MX349718B_D0031.tif" />

<img file="MX349718B_D0032.tif" />

<img file="MX349718B_D0033.tif" />

INSTITUTE MtXlO.U ·) DE LA ιΉνίΕΓΑΓ »INDUSTRIAL tautomerism.

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

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: enol ketone, amide-nitrile, lactam-lactim, amide tautomerism of imidic acid in heterocyclic rings (eg, in the nucleobases guanine, thymine, and cystosine), amine-enamine, and enamine. An example is included below for illustrative purposes and the present invention is not limited to this example:

<img file="MX349718B_D0034.tif" />

<img file="MX349718B_D0035.tif" />

<img file="MX349718B_D0036.tif" />

Ttt τ iwrrnrn.) Mexican de IA rRCEfE'jAD INDU-tuial

The terms "crystal polymorphs" or "polymorphs or crystalline forms" mean crystal structures in which a compound (or salt or solvate thereof) can crystallize in different crystalline packing regimes, all of which have the same elemental composition. Different crystal forms generally have different X-ray diffraction patterns, infrared spectrals, melting points, density hardness, crystal shape, optical and electrical properties, stability, and solubility. The recrystallization solvent, crystallization rate, storage temperature, and other factors can cause a crystal shape to dominate. 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 a car, oxygen, or nitrogen atom, is substituted with a selection from the indicated group, provided that the normal valence of the atom designated is not exceeded, and that substitution results in a stable compound. When a substituent is keto (i.e. = O), then 2 hydrogens on the atom are double ring substituted, as used herein, they are double bonds that form between two adjacent ring atoms (e.g. C = C, C = N, N = N, etc.)

As used herein, the term "anomeric car" means the acetal character 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, n-heptyl, and n-octyl.

As used herein alkenyl is intended to include hydrocarbon chains of either straight or branched configuration and one or more unsaturated car-car linkages that can occur at any stable point along the chain, such as ethenyl and propenyl. For example alkenyl C₂-6 is intended to include the C alkenyl groups₂, C₃, C₄, C₅, C₆.

As used herein, alkynyl

<img file="MX349718B_D0037.tif" />

it is intended to include hydrocarbon chains of one or another straight 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, C alkynyl₂_₆ is intended to include C alkynyl groups₂, C₃, C₄, C₅, C₆.

Furthermore, alkyl, alkenyl and alkynyl are intended to include moieties that are diradicals, that is, having two points of attachment, an example of which in the present invention is when D is selected from these chemical groups. A non-limiting example of such an alkyl moiety that is a diradical is -CH₂CH₂-, that is, a C alkyl group₂ which is covalently linked through each terminal carbon atom to the rest of the molecule. Alkyl diradicals are also known as alkylenyl radicals. Alkenyl diradicals are also known as alkenylenyl 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. C 3-8 cycloalkyl is intended to include C cycloalkyl groups₃, C₄, C₅, Ce, C₇, C₈.

As used in the present counterion it is

<img file="MX349718B_D0038.tif" />

I; &amp; 4 D τ λ '«vm,_rc vk \ i_VOC,,

L. LA J^:.^rU) ”Lr A) íncl'suíal x

<img file="MX349718B_D0039.tif" />

used to mean a positively or negatively charged species present in conjunction with an oppositely charged ion. 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 contractions include ammonium chloride, bromide, hydroxide, acetate, sulfate, and.

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

As used herein, haloalkyl is intended to include straight-chain, branched, saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (e.g. -C_vF_w where v = 1 to 3 and w = 1 to (2v + 1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, pentafluoroethyl, trichloromethyl, and pentachlorethyl.

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 0χ-₆, is meant 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, Ce, C7, Ce. Examples of alkoxy include, but are not

<img file="MX349718B_D0040.tif" />

institutu. .tAic. · .-. or

OF LA Ι'ΚΟίΊΚ.ΟΛΟ industrial limits 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 C_X-6, is intended to include Ci, C alkylthio groups₂, C₃, C₄, C₅, Cg. Cl-6 alkylthio is intended to include Ci, C alkylthio groups₂, C3, 10 c₄, c₅, c₆, c₇, c₈.

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 15 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, cyclohexenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0] bicyclooctane, [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

<img file="MX349718B_D0041.tif" />

<img file="MX349718B_D0042.tif" />

F

Η

<img file="MX349718B_D0043.tif" />

INSTITUTO MEXICANO DE LA ΡΗ.ΟΠΠ&gt; · η INDUSTRIAL in the definition of carbocycle (for example, [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 substituents described for the ring may also be present on the bridge. Spiro and fused rings (eg, naphthyl and tetrahydronaphthyl) are also included.

As used herein, the term "heterocycle" means, unless otherwise indicated, a monocyclic, bicyclic, or tricyclic ring composed 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 composed of carbon atoms and one or more ring heteroatoms, for example 1 or 1-2 or 1-3 or 1 heteroatoms -4 or 1-5 or 1-6, independently selected from nitrogen, oxygen and sulfur, and including any bicyclic or tricyclic group that in any of the above defined heterocyclic rings is fused or attached to a second ring (eg, a benzene ring). Nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., N 0 and S (0)_p, where p =

<img file="MX349718B_D0044.tif" />

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 tri valence of the nitrogen atom). 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 resulting 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 on 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 (ie, 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 recited substituents for the ring may also be present on the bridge. Spiro and fused rings are also included.

As used in the present, the term

<img file="MX349718B_D0045.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY Heterocycle aromatic or heteroaryl is intended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-membered 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 (eg 2,3-dihydroindole), although both can be (eg 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). 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's in the aromatic heterocycle is no more than 1.

Examples of heterocycles include, but are not limited to, acridinyl, azabicyclooctanonyl, azepanyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranol, benzothiophenyl, benzoxazolyl, benzoxazolinol, benzothiazolyl, benztepanyl, benzetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranol, benzothiophenyl, benzoxazolyl, benzoxazolinol, benzothiazolyl, benztetriazolyl, benzisioxazolyl, benzodiazolidazolexazolyl, benzodiazoloxyloxiazolyl, benztetriazolyl, benzoxazolinol, benzothiazolyl, benztetriazolyl. carbazola,

WICKED

INSTITUTO MEX! CAN &lt;&gt; W -tó '-. ·'. h

Dt THE PROPERTY

INDUSTRIAL

4aH-carbazole, carbolinyl, chromanyl, chromenyl, cinnolinyl, cycloheptyl, decahydroquinolinyl, dihydrobenzodioxinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofide

[2,3-¿&gt;] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolidinylimine, imidazolinyl, imidazolyl, imidazolonyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3 / iso-indolyl, isaturanoyl, iso-bindazolidinyl, isaturanoyl, iso-binindazolyl, isaturanoyl, iso- bindazolyl, isaturanyl, isoindoline, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, methylbenzotriazolyl, methylfuran, methylimidazole, methylthiazolyl, morpholinyl, naphthyridinyl, octahydroisoquinoline, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolidinonyl, oxazolyl., Oxindolyl, phenanthridine, phenanthroline, phenazinyl, phenothiazine, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperazinyl, piperazinyl, piperazinyl, piperazinyl, , piperidinyl, piperidenyl, piperidinyl, 4piperidinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl pyrroldionyl, pyrrolidinyl, pyrrolidinonyl, pyrrolinyl, 2H-pyrrolyl, quinazolinyl pyrrolyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,. tetrahydrofuranyl,

<img file="MX349718B_D0046.tif" />

tetrahydroisoquinolinyl, tetrahydroqul rrotT * tetrazolyl, 6H-1, 2,5-thiadiazinyl, 1,2,3-thiadiazolyl,

1,2,4 thiadiazolyl, 1,2,5 thiadiazolyl, 1,3,4 thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, thiomorpholinyl dioxidyl, triazinyl, triazolopyrimidinyl, 1,2,3, triazolyl, 1, 2, 3 triazolyl 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 the tissues of humans 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 parent compound is modified by the manufacture of acid or basic salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acid residues such as

<img file="MX349718B_D0047.tif" />

<img file="MX349718B_D0048.tif" />

tNSTiTUTC¹ MEXICAN PROPERTY? INDUSTRIAL carboxylic acids, and the like. Pharmaceutically acceptable salts ____ include conventional non-toxic salts or quaternary ammonium salts of the parent 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 inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethanesulfonic sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic. , disulfonic ethane, sulfonic ethane, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycol-sanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxamic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsilic, nitric, oxalic, pantothenic pamoic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, sulfuric, subacetic, succinic sulfuric, tannic, tartaric, and sulfonic toluene.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic fraction by conventional chemical methods.

Generally, such salts can be prepared by making ι Μ ρ I '· &lt;' '· *' '&lt;· »

INSTITUTO MkXICAiN »&gt;&gt;, &lt;-.....&gt;. &lt;'4

ΠΙ Ι.Λ PltOHEDAl · · ·&gt;

.NWSTKIM reacting the free acid or forms of ... base — of · - «βΐββ— 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. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed. , Mack Publishing Company, Easton, PA, EU, p. 1445 (1990).

Thus, prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (eg, solubility, bioavailability, manufacturing, etc.) the compounds of the present invention can be provided in prodrug form. Thus, the present invention is intended to cover prodrugs of the currently claimed compounds, methods of delivery thereof, and compositions containing the same. 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 handling or in vivo, to the compound.

<img file="MX349718B_D0049.tif" />

<img file="MX349718B_D0050.tif" />

INSTITUTO MtXICAN'J gave the original INDUSTRIAL pnornoAf '. Prodrugs include compi ipst cls ---- present invention where a hydroxy, amino or sulfhydryl group is attached to any group that, when the prodrug of the present invention is administered to a mammalian subject, cleaves to form a free hydroxyl, amino free or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.

As used herein, "stable compound and stable structure" is intended to denote a compound that is robust enough to survive isolation to a useful degree of purity from a reaction mixture, and formulation into 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) is undergoing a surgical or invasive 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 can also be

<img file="MX349718B_D0051.tif" />

<img file="MX349718B_D0052.tif" />

INSTITUTO MEXICANO DE LA PROPERTY INPHSTKIAL considered in need of perioperative prophylaxis.

As used herein, the term "treat" 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 infection. get an infection. Prevention can also include inhibiting, that is, stopping the development, of an infection.

As used herein, the term "reducing the risk of," as used herein, means reducing the likelihood or probability of an infection occurring, for example when the patient or subject is predisposed to infection or in risk of getting an infection.

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

As used herein, the term "effective amount" refers to an amount of a

<img file="MX349718B_D0053.tif" />

IMPI

INSTITUTO MIXICaN.

Say LA PRlIUhlMb

INDUSTRIAL 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 patient or subject sufficient to elicit biological activity, eg, anti-infectious 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 an infection due to a surgical procedure or an invasive medical procedure.

It should be further understood that the representations of Hydrogen Bond Acceptor - Hydrogen Bond Acceptor - Hydrogen Bond Donor and Hydrogen Bond Acceptor - Hydrogen Bond Acceptor Hydrogen Bond Acceptor indicate the relative orientation of the acceptors and hydrogen bond donor and are not intended to limit that these groups are directly connected to each other as atoms or

<img file="MX349718B_D0054.tif" />

<img file="MX349718B_D0055.tif" />

INSTITU Ιι^-1 MEXICANO DE LA PROPERTY INDUSTRIAL Additional groups of atoms may be included among such groups.

In the description, the 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 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 combination of compounds, of the present invention present in or on a receptor in an amount sufficient to elicit biological activity, eg, activity. anti-microbial, anti-fungal activity, anti-viral activity, anti-parasitic activity, anti-diarrhea activity, and / or anti-proliferative activity. The combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. 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

<img file="MX349718B_D0056.tif" />

INSTITUTO MEXICANO DE LA EROntUAU INDUSTRIAL sole agent. In general, an effect * - ^ liiérgi'CC 'f is most clearly demonstrated at suboptimal concentrations of the compounds. The synergy may be in terms of lower cytotoxicity, increasing 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 microhelix binding site" refers to the ribofunctional locus of the large ribosomal subunit occupied by the RNA microhelix of Formula III. The RNA microhelix binding site defines at least part of or overlaps with the E site.

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

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

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

<img file="MX349718B_D0057.tif" />

<img file="MX349718B_D0058.tif" />

INSTITUTO MSXICAN '.' D £ THE INDUSTRIAL rROHXTY of peptide bond formation.

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 oxazolidinone ring of linezolid is attached.

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 charge 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 the 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 ribosome ribosome or, (c) a combination of both. As used herein and in reference to the RNA microhelix, the terms a portion of or a portion of the structure

<img file="MX349718B_D0059.tif" />

"three-dimensional" means a portion of the three-dimensional RNA microhelix structure, including charge distribution and hydrophilicity / hydrophobicity characteristics, formed by 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 microhelix

RNA, (ii) the accessible solvent atoms of the RNA microhelix, or (iii) a combination thereof.

All percentages and ratios used herein, unless otherwise indicated, 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 process steps, it is contemplated that the compositions of the The present invention also consist essentially of, or consist of, the cited 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 steps or order to perform certain actions is irrelevant as long as the invention remains operable.

<img file="MX349718B_D0060.tif" />

<img file="MX349718B_D0061.tif" />

INSTITUTO MEXICANO DS Ι.Λ rKOriSUAO INDUSTRIAL

Also, two or more steps be carried out simultaneously.

two. Compounds of the invention

The present invention provides compounds having the structure:

<img file="MX349718B_D0062.tif" />

where L —- J is a chemical fraction selected from:

<img file="MX349718B_D0063.tif" />

where represents a saturated, unsaturated or aromatic carbocyclic fused 5 to 7 member or heterocyclic ring system, where T¹ is a carbon or N atom, so

<img file="MX349718B_D0064.tif" />

INSTITUTO MLXíCaNO PE LA P ^ PISDaP 'Nr&gt; usi w¡al

<img file="MX349718B_D0065.tif" />

so when T¹ is N, -DEF is absent, where T² is a carbon or N atom, such that when T² is N, -GHJ is absent, where both T¹ and T² they are not both simultaneously N, where V is independently selected from -CR^4th-oN-,

W is O, NR¹, GOR¹, 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-8 alkyl) -0 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 0, NR², and S (0)_n and Y is CR³, and when XY is a double bond, X is N and Y is a carbon atom,

Z is selected from the group consisting of 0, NR⁴, S (0) _n, or NH,

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

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

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

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

<td>R^4th</td><td>I know</td><td>Choose</td><td>of</td><td>H</td><td>Y</td><td>C1-;</td><td>8 alkyl,</td>

n is 0, 1, or 2, or a pharmaceutically acceptable salt, ester,

<img file="MX349718B_D0066.tif" />

iMPI

MEXICAN INSTITUTE

OF THE l'KOHEL'AD

INDUSTRIAL tautomer, or prodrug thereof.

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

In some embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof, where - 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 compound or a pharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof, wherein the hydrogen bonding acceptor moieties and the hydrogen bonding donor moieties in the orientation of Hydrogen Bond Acceptor - Hydrogen Bond Acceptor - Hydrogen Bond 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 as there may be other intermediate atoms or groups of atoms between the bond donor

<img file="MX349718B_D0067.tif" />

<img file="MX349718B_D0068.tif" />

NS; ΊΪ ·. '-'I.XiCANí · ΙΗ The íKOPIFOaí InHUSTJUAL of hydrogen or acceptor fractions. "

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

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

In some embodiments, the present invention relates to a compound or a pharmaceutically acceptable 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.

In some embodiments, the present invention relates to a pharmaceutically compound or salt.

<img file="MX349718B_D0069.tif" />

<img file="MX349718B_D0070.tif" />

ÍNSTi'T'JTC í.J -. /. CANO

D * LA fr / i / uS »Acceptable RAL, ester, tautomer, or pro-drug thereof, en. . R ....... .

where - is a chemical fraction comprising at least three hydrogen-accepting moieties.

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

Hydrogen Bond - Hydrogen Bond Acceptor.

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

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

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

IΜ P r

INL »ljSTil_Ai where each hydrogen bond acceptor moiety is tádeñTr ^ Tte ~~ = - = approximately 3 A of at least one hydrogen acceptor moiety other bond.

In some embodiments, the present invention relates to a compound or a pharmaceutically acceptable 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 fused multiple ring structure.

In some embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof, wherein said hydrogen-accepting moieties are independently selected from the group consisting of a carbonyl group, a thiocarbonyl group, imine group, imine substituted alkyl group, sulfoxide group, sulfone group, oxime group, oxime substituted alkyl group, hydrazone group, a monoalkyl or dialkyl substituted hydrazone group, an oxygen ether (-0-) group, a sulfur, also known as a thioether group (-S-), 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

<img file="MX349718B_D0071.tif" />

INSTITUI l.uíiOtfn. OS LA ΜΟΗΙΙίΑυ INDUSTRIAL refers to a compound of a pharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof, wherein the hydrogen bond donor moiety is selected where said hydrogen bond donor moiety is selected from the group that It consists of a hydroxy group, a thiol group, an amino group, and a monosubstituted amino group.

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

<img file="MX349718B_D0072.tif" />

where W is O, NR¹, GOR¹, 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 S (0)_n and Y is CR³, and when X --- y is a double bond, X is N and Y is a carbon atom or S (O)_n

Z is selected from the group consisting of O, NR⁴

R¹ is selected from H and alkylCl-8,

R² is selected from H and alkylCiR is selected from H and alkylCiR⁴ is selected from H and alkylCi and n is 0, 1, or 2.

In some embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof, wherein W is O, NR¹, GOR¹, or S; where R⁴ is selected from hydrogen and Ci-₆.

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

JWb UXTlCuCl.

where Z is selected from the group consisting of 0, NR⁴, or S (0) _n; R⁴ is selected from hydrogen and Ci-6 alkyl,

<img file="MX349718B_D0073.tif" />

n is 0, 1, and 2.

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

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

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

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

R comprises a moiety of pyrrolocystosin or a derivative thereof.

In some embodiments, the present invention relates to a pharmaceutically compound or salt.

<img file="MX349718B_D0074.tif" />

INSTI ΓϋΤ &lt;&gt; MEXICAN Ϋ

OF THE PROPERTY í

INDUSTRIAL 'acceptable, ester, tautomer, or pro-drug thereof, where R⁴ it is hydrogen.

In some embodiments, the present invention relates to an acceptable compound, ester, tautomer, where

R or a pharmaceutically salt or one of its prodrugs, in which it comprises the structural moiety.

<img file="MX349718B_D0075.tif" />

<img file="MX349718B_D0076.tif" />

<img file="MX349718B_D0077.tif" />

<img file="MX349718B_D0078.tif" />

where

<img file="MX349718B_D0079.tif" />

represents a 5 to 7 saturated, unsaturated or carbocyclic aromatic fused member or system of

Τ 1 \ / Τ Τ '&lt;7Γ _

INSTITUT 'ι ΜίΧ'Ο V&gt;^¿íí &lt;6 ^ - Ύ'Α &lt;Έ la zropisdaij i _ _ INDUSTRIAL Xg?

□ 5 heterocyclic ring, where V is independently selected from -CR^4th-oN-,

W is O, NR¹, GOR¹, 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-₈ alkyl) 0- and Hambas 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 0, NR², and S (0) ne 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 (0) n, or NH,

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-₈I rent,

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

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

<img file="MX349718B_D0080.tif" />

<img file="MX349718B_D0081.tif" />

where Vx represents a 5 to 7 saturated, unsaturated or aromatic carbocyclic fused member or heterocyclic ring system, where T¹ is a carbon or N atom, such that when T¹ is N, -DEF is absent, where T² is a carbon or N atom, such that when T is N, -GHJ is absent, where both T¹ and T² they are not both simultaneously N, where V is independently selected from -CR^4th-oN-,

W is O, NR¹, GOR¹, or S, alternatively W = is selected from the combination of HO-and H both attached to the same carbon atom or the combination of (Cj-g alkyl) © - and Hambas 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 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 NH,

R¹ is selected from H and Ci-₈ I rent, ^{, eXlr}-AN_t.

'DCUSTRIAL

R² is selected from H and Ci-8 alkyl, R³ is selected from H and ϋχ_8 alkyl, R⁴ is selected from H and Ci-8 alkyl, R^4th is selected from H and Ci-8 alkyl, n is 0, 1, or 2, alternatively-GHJ is selected from

<img file="MX349718B_D0082.tif" />

where each H and J are 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 single bond, (b) - (Ci-₈ alkyl) -, (c) - (C₂-₈ alkenyl) -, (d) - (C₂-s 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 = O) -, S (O) PNR⁶-, - NR⁶S (O) p-, y-NR⁶SW)_p-, NR⁶, ii) any of (b) - (d) immediately by

<img file="MX349718B_D0083.tif" />

IMPI

MEXICAN INSTITUTE

DE LA 7ROFIEDAD INDUSTRIAL above is optionally substituted with one or more R groups⁵, and iii) any of (b) - (d) immediately above are optionally substituted with (Ci-8 alkyl) -R groups⁵;

(e) -0-, (f) -NR⁶-, (g) -S (O)_p-, (h) -C (0) -, (i) C (0) 0-, (j) -0C (0) -, k) -0C (0) 0-, (1) -C (O) NR⁶-, (m) -NR⁶CO-, (n) -NR⁶C (0) NR⁶-, (or) -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 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 314 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:

<img file="MX349718B_D0084.tif" />

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

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

i) the carbon atoms 0-4 in any of (d) - (f) immediately above is optionally replaced 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 (0) _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-₈alkyl) - R groups⁵;

and (g) - (CR⁶R⁶)_t-,

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

<img file="MX349718B_D0085.tif" />

IMPI

MEXICAN INSTITUTE

OF LA PSOPIEUAD INDUSTRIAL (a) hydrogen, (c) F, (d) Cl, (e) Br, (f) I, (g) -CF₃, (h) -CN, (i) -N₃(j) -N0₂, (k) -NR⁶ (CR⁶R⁶) tR⁸, (1) -OR⁸, (m) -S (0) p (CR⁶R⁶) tR⁸, (n) -C (O) (CR⁶R⁶) tR⁸,(or)-

0C (0) (CR⁶R⁶) tR⁸, (p) -SC (0) (CR⁶R⁶) tR⁸, (q) -C (0) 0 (CR⁶R⁶) tR⁸, (r) -NR⁶C (O) (CR⁶R⁶) tR⁸, (s) -C (O) NR⁶ (CR^SR⁶) tR⁸, (t) C (= NR⁶) (CR⁶R⁶) tR⁸, (u) -C (= NNR⁶R⁶) (CR⁶R⁶) tR⁸, (v) C (= NNR⁶C (O) R⁶) (CR⁶R⁶) tR⁸, (w) -C (= N0R⁸) (CR⁶R⁶) tR⁸, (x) NR⁶C (O) O (CR⁶R⁶) tR⁸, (and) -OC (O) NR⁶ (CR⁶R⁶) tR⁸, (z) NR⁶C (O) NR⁶(CR⁶R⁶) tR⁸, (aa) -NR⁶S (0) p (CR⁶R⁶) tR⁸, (bb) S (0) pNR⁶ (CR⁶R⁶) tR⁸, (cc) -NR⁶S (0) pNR⁶ (CR⁶R⁶) tR⁸, (dd) -NR⁶R⁸, (ee) -NR⁶ (CR⁶R⁶) R⁸, (ff) -OH, (gg) -NR⁸R⁸, (hh) -OCH3, (ii) -S (0) pR⁸, (jj) -NC (0) R⁸, (kk) -NR⁶C (NR^C) NR^CR⁸, (11) a C ^ galkyl group, (mm) a C2_ group₈ alkenyl, (nn) a group C₂_₈ alkynyl, (oo) a 3-14 member saturated, unsaturated 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 [(CR⁶R⁶) tR⁸] [C = 0 (CR⁶R⁶) tR⁸], (ss) (CR⁶R⁶) tN [(CR⁶R⁶) tR⁸] [(CR⁶R⁶) tR⁸], (tt) (CR⁶R⁶) tNR⁶ (C = 0) (CR⁶R⁶) tR⁸, (uu) -haloalkyl, (vv) C (0) (CR⁶) [(CR⁶R⁶) tR⁸] R⁸, (ww) - (CR⁶R⁶) tC (0) NR⁸R⁸, (xx) (CR⁶R⁶) tC (O) 0 (CR⁶R⁶) tR⁸, (yy) -NR⁶C (0) CR⁸R⁸R⁸, (zz) N [(CR⁶R⁶) tR⁸] C (0) R⁸, and (aaa) -S (O)_PNR⁸R⁸;

<img file="MX349718B_D0086.tif" />

wherein (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, (or) -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 member saturated, unsaturated or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and (u) 3-14 member saturated, unsaturated or aromatic carbocycle; alternatively, two R groups⁵ are taken together to form a carbocycle where (m) through (r) and (t) through (u) are 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 member saturated, unsaturated, or aromatic heterocycle which contains one or more heteroatoms selected from the group consisting

<img file="MX349718B_D0087.tif" />

of nitrogen, oxygen and sulfur and (e) member-3-14 saturated, 'unsaturated or aromatic carbocycle;

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, (or) ~ Ci-₈ alkynyl, (p) - (Ci-₈ alkyl) - (3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (q) - (Ci-₈alkyl) - (3-14 member saturated, unsaturated or aromatic carbocycle), (r) -haloalkyl, (s) -NR⁶R⁸, (t) -OR⁸, (u) (CR⁶R⁶) _tNR⁶R⁸, (v) -CR⁶R⁸R⁸, (w) -SR⁶, (x) -3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (y) -3-14 member saturated, unsaturated, or carbocycle aromatic, (z) CR⁶R⁶) tC (O) NR⁸R⁸, (aa) -S (O) PR⁸, (bb) -NR⁶C (0) NR⁶R⁶, (cc) NR⁶C (O) R⁶, and (dd) -C (= NR⁶) NR⁶R⁶;

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

R⁸ is selected from a (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) -C ^ g alkylated ', (n) -Ci-g alkenyl, (o) -Ci-g alkynyl, (p) - (Ci-₈ alkyl) (3-14 member 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) -3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (s) -3-14 member saturated, unsaturated or aromatic carbocycle, (t) -haloalkyl, (u) C (0) (CR⁶R⁶) tR% (v) -SR⁶, (w) -0C (0) (CR⁶R⁶) tR⁹, (x) NR⁶C (0) 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) 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 (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) C (0) (CR⁶R⁶) tNR⁶R⁶, (n) -Ci-₈ alkyl, (or) -Ci-₈ alkenyl, (p) -Ci-g alkynyl, (q) -3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (r) -3-14 member saturated, unsaturated, or carbocycle

<img file="MX349718B_D0088.tif" />

aromatic), (s) -haloalkyl, (t) - - (CR⁶R⁶) tOR ° ', fuT - O (CR⁶R⁶) tNR⁶R¹⁰, (v) -C (O) R⁶, (w) -SR⁶, (x) -C (O) OR¹⁰, (and) S (O) PR⁶, (z) - (Ci-g alkyl) - (3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (aa) - (Cx_₈ alkyl) - (3-14 member saturated, unsaturated or aromatic carbocycle), (bb) -O (CR⁶R⁶) tOR⁶, (cc) -C (= NR⁶) NR⁶R⁶, (dd) -ONR⁶R⁶, (ee) NR⁶C (O) NR⁶R⁶, (ff) -0 (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) -N02 , (j) -NR⁶R⁶, (k) -OR⁶, (1) -NR⁶ (CNR⁶) NR⁶R⁶, (m) -C (O) (CR⁶R⁶) tNR⁶R⁶, (n) -CX8 alkyl, (o) -CX-8 alkenyl, (p) -Cx_8 alkynyl, (q) -314 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen , oxygen, and sulfur, (r) -3-14 member saturated, unsaturated or aromatic carbocycle, (s) haloalkyl, (t) - (CR⁶R⁶) t0R⁶, (u) -O (CR⁶R⁶) tNR⁶R⁶, (v) C (O) R⁶, (w) -SR⁶, (x) -C (O) OR⁶, (y) -S (O) pR⁶, (z) - (C_x_₈ alkyl) - (3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur),

IMPI

Mexican INSTITUTE -1. · Df La PSOPiírtAP

INDUSTRIAL (aa) - (Ci-8 alkyl) - (3-14 member saturated, unsaturated or carbocycle aromatic), (bb) -0 (CR⁶R⁶) tOR⁶, (ce) C (= NR⁶) NR⁶R⁶, (dd) -ONR⁶R⁶, (ee) -NR⁶C (0) 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, but both -DEF and GHJ are not simultaneously absent;

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

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

(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 carbocycle aromatic member, or ( c) a single bond, where (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,

<img file="MX349718B_D0089.tif" />

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

i) 0-4 carbon atoms in any of (a) - (C) immediately above are optionally substituted by a fraction selected from the group consisting of -O -, - S (O)_p-, - NR⁶-, - (C = O) -, C (= NR⁶) -, - S (O) pNR⁶-, and -NR⁶S (O)_pNR6, ii) any 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-_toalkyl) -R⁵ groups. .

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

The invention relates to a pharmaceutically acceptable salt, ester, tautomer, or prodrug of a compound according to formula- I, II, III, IV, la, lia, Illa, IVa.

In some embodiments, the present invention is

<img file="MX349718B_D0090.tif" />

IMPI ^

INSTITUT O MEXICaN ·&gt; OE La PR (? Ned_TO|, industrial refers to a compound according to formula I, II, III, IV, la, lia, Illa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, where A is:

(a) a 4-7 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (b) a 4-7 member saturated, unsaturated, or aromatic carbocycle, or (c) a single bond, where (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, la, lia, Illa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein A is azepanyl , cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl, cyclohexadienyl, dihydropyridyl, furanyl, tetrahydrofuranyl, tetrahydropyridyl, azetidinyl, pyrrolidinyl, piperidinyl, or piperidenyl;

wherein A is optionally substituted with one or more R groups⁵.

Alternatively, the present invention relates to a compound according to formula I, II,

MEXICAN INSTITUTE. Π8 LA PROFISDAÜ Cwr-JtXj f gQ industual

III, IV, la, lia, Illa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein A is a single bond.

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

i) 0-4 carbon atoms is optionally substituted by a fraction selected from -O-, S (O)_P, -NR⁶-, - (C = O) -, - 5 (O) pNR^s-, or - (NR⁶SO) pNR6-, ii) (a) B is optionally substituted with one or more R5 groups, and / or iii) (a) B is optionally substituted with - (Ci-₈ alkyl) -R⁵ .

Alternatively, the present invention relates to a compound according to formula I, II, III, IV, la, lía, Illa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, in which B is a bond simple.

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

<img file="MX349718B_D0091.tif" />

IMPI

MEXICAN INSTITUTE

I HEARD THE INDUSTRIAL rXOPIEPAP

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

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, la, lia, Illa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein G is (a) a 3-14 member saturated, unsaturated, or aromatic heterocycle 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 bond;

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, la, lia, Illa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein G is s (a) a 4-7 member saturated, unsaturated, or aromatic heterocycle containing one or more

<img file="MX349718B_D0092.tif" />

IMPl £

INSTITUTO MEXICANO DE LA MOPltDAD INDUSTRIAL heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (b) a saturated, unsaturated, or aromatic carbocycle 4-7 member, or (c) a single bond;

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, la, lia, Illa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein G is azepanyl , cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl, cyclohexadienyl, dihydropyridyl, furanyl, tetrahydrofuranyl, tetrahydropyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperidenyl, or a single bond.

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

<img file="MX349718B_D0093.tif" />

where CBA -, - DEF, -GHJ, W, X, Y, Z, V, T¹ and T² previously defined * Í ^! 7^&gt;^^Twq · a pharmaceutically acceptable ual, ester, tautomer, or prodrug thereof.

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

-F

G -H — J where CBA -, - DEF, -GHJ, W, X

Y, Z, and V are as defined above, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

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

^ E ~ F

C— B—

G -HJ (la), where CBA -, - DEF, and GHJ have been defined above, or a pharmaceutically acceptable salt,

IMPIAS

MEXICAN INSTITUTE

SAY THE PROPIBILITY

INDUSTRIAL ester, tautomer, or prodrug thereof.

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

<img file="MX349718B_D0094.tif" />

wherein CBA -, - GHJ, W, X, Y, and Z are as defined 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="MX349718B_D0095.tif" />

wherein CBA -, - GHJ, W, X, Y, Z, and V 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 formula2__F

<img file="MX349718B_D0096.tif" />

<img file="MX349718B_D0097.tif" />

MtXICAN-&gt; INSTITUTE OF INDUSTRIAL PROPERTY wherein CBA -, - DEF, W, X, Y, Z, and V 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:

<img file="MX349718B_D0098.tif" />

wherein CBA -, - DEF, -GHJ, W, X, Y, Z, and V 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:

E —F

<img file="MX349718B_D0099.tif" />

<img file="MX349718B_D0100.tif" />

MEXICAN INSTITUTE

OF THE industrial DEPTH at which CBA -, - DEF, -GHJ, W, X, Y, Z, V, T¹and T² are defined as in formula II 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="MX349718B_D0101.tif" />

wherein CBA -, - DEF, -GHJ, W, X, Y, Z, and V 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="MX349718B_D0102.tif" />

<img file="MX349718B_D0103.tif" />

IMPI

INSTITUID MEXICAN 'i DE LA PROPIEDAD INDUSTRIAL where CBA -, - DEF, and GHJ have been defined 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="MX349718B_D0104.tif" />

wherein CBA -, - GHJ, 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="MX349718B_D0105.tif" />

wherein CBA -, - GHJ, W, X, Y, Z, and V 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="MX349718B_D0106.tif" />

wherein CBA-, -DEF, W, X, Y, Z, and V 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="MX349718B_D0107.tif" />

wherein CBA -, - DEF, W, X, Y, Z, and V 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="MX349718B_D0108.tif" />

<img file="MX349718B_D0109.tif" />

&gt; · 1 .. »/ ívHtDAl, INDUSTRIAL

<img file="MX349718B_D0110.tif" />

wherein CBA -, - DEF, -GHJ, W, X, Y, Z, V and K are defined as in formula III, 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="MX349718B_D0111.tif" />

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

In some embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof, wherein it represents a saturated, non-saturated six-melt

<img file="MX349718B_D0112.tif" />

saturated or carbocyclic aromatic or a heterocyclic ring system.

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

<img file="MX349718B_D0113.tif" />

wherein CBADEF, -GHJ, W, X, Y, ZV, and K are defined as in formula III; and Q¹, Q², Q³ and Q⁴ are independently selected from a nitrogen atom, a carbon atom, or CH, where-DEF, and GH-J-, when present, are attached to a carbon atom; 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="MX349718B_D0114.tif" />

<img file="MX349718B_D0115.tif" />

wherein CBADEF, and GHJ are defined as in formula III, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

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

.E —F

D

<img file="MX349718B_D0116.tif" />

^Z (IV) where CBA -, - DEF, -GHJ, W, X, Y, Z, V and K are defined as in formula IV, 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="MX349718B_D0117.tif" />

<img file="MX349718B_D0118.tif" />

i

MPIS (TUTO MEXICANO DE LA PROPIEDAD INDUSTRIAL where CBA -, - GHJ, W, X, Y, Z, V and K are defined as in formula IV, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

In some embodiments, the present invention relates to a compound according to formula IV, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, wherein it represents a saturated, unsaturated, or carbocyclic aromatic fused six-member or ring system. heterocyclic.

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

<img file="MX349718B_D0119.tif" />

where CBA -, - DEF, -GHJ, W, X, Y, Z, V and K are defined as in formula IV, and are Q¹, Q², Q³ and Q⁴independently selected from a nitrogen atom, a carbon atom, or CH, where -DEF, and GHJ-, when present, are each attached to a carbon atom; or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

<img file="MX349718B_D0120.tif" />

<img file="MX349718B_D0121.tif" />

INZHTUT '&gt; MlXICANu Or. THE INDUSTRIAL XROI'ltüAD ____,. ,_L __, _ ./yes

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

<img file="MX349718B_D0122.tif" />

wherein CBADEF, and GHJ are defined as in formula IV, 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="MX349718B_D0123.tif" />

wherein A is (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 -carbocycle member, not saturated or aromatic

INSTITUTO M'XICAN ·.) J *

OF LA PHOFISDaD industrial aff · * -¾ ^ (c) a single bond, where (a) or (b) is optionally substituted with one or more R groups⁵;

B is (a) - (Ci-₈ alkyl) -, (b) - (C₂-₈ alkenyl) -, (c) - (C₂_₈ alkynyl) -, or (d) a single bond, where

i) 0-4 carbon atoms in any of (a) - (c) immediately above are optionally replaced by a fraction selected from the group consisting of -0 -, - S (0) -_p, -NR⁶-, - (C = 0) -, C (= NR⁶) -, -S (O) PNR⁶-, y-NR⁶S (O) pNR⁶-, ii) any 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-₈alkyl) -R⁵, Y

C is selected from (a) NH₂, (b) -NHC (-NH) NH₂ and hydrogen (c), 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="MX349718B_D0124.tif" />

IMPI

DK LA PR: wejad INDUSTRIAL

<img file="MX349718B_D0125.tif" />

wherein CBADEF, and GHJ are defined as in formula I, II, III and IV, 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="MX349718B_D0126.tif" />

wherein A is azepanyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl, cyclohexadienyl, dihydropyridyl, furanyl, tetrahydrofuranyl, tetrahydropyridyl, azetidinyl, pyrrolidinyl, piperidinyl, or where Aperidenyl is optionally or more substituted in piperidenyl groups R⁵;

<img file="MX349718B_D0127.tif" />

or, A is a single bond;

B is (a) - (Ci-e alkyl) -, where

i) 0-4 carbon atoms in (a) immediately above is optionally substituted by a fraction selected from the group consisting of -0-, S (0) p -, - NR⁶-, - (C = 0) -, -S (O) pNR⁶-, and -NR⁶S (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 - (Ci-8 alkyl) -R groups⁵;

or, B is a single bond;

C is (a) NH₂, (b) -NHC (= NH) NH₂ or (c) hydrogen.

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

<img file="MX349718B_D0128.tif" />

. where CBA-is selected from:

hydrogen,

<img file="MX349718B_D0129.tif" />

<img file="MX349718B_D0130.tif" />

<img file="MX349718B_D0131.tif" />

<img file="MX349718B_D0132.tif" />

IMPI

INSTITUTO MIXICANO Of LA nOMfOAD INOUSTÍIAL

<img file="MX349718B_D0133.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="MX349718B_D0134.tif" />

where G is s (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 member or aromatic carbocycle, or (c) a single bond;

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

<img file="MX349718B_D0135.tif" />

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

<img file="MX349718B_D0136.tif" />

wherein G is azepanyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl, cyclohexadienyl, dihydropyridyl, furanyl, tetrahydrofuranyl, tetrahydropyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperidenyl, single bond, or a pharmaceutically acceptable ester, or a salt bond , tautomer, or prodrug thereof. .

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

<img file="MX349718B_D0137.tif" />

where -GHJ is selected from:

<img file="MX349718B_D0138.tif" />

.1 v -1 j¡ Λ

INSU ruiOMMICaNi r »£ THE LEVEL. ·· ÍNWSTIilAL hydrogen,

<img file="MX349718B_D0139.tif" />

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

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

'15

<img file="MX349718B_D0140.tif" />

<img file="MX349718B_D0141.tif" />

hydrogen,

<img file="MX349718B_D0142.tif" />

<img file="MX349718B_D0143.tif" />

<img file="MX349718B_D0144.tif" />

<img file="MX349718B_D0145.tif" />

<img file="MX349718B_D0146.tif" />

<img file="MX349718B_D0147.tif" />

IMPI

MEXICAN INSTITUTE

DE LA FHOPI1DAO INDUSTRIAL '***** «i ·» »»

<img file="MX349718B_D0148.tif" />

<img file="MX349718B_D0149.tif" />

<img file="MX349718B_D0150.tif" />

<img file="MX349718B_D0151.tif" />

<img file="MX349718B_D0152.tif" />

<img file="MX349718B_D0153.tif" />

<img file="MX349718B_D0154.tif" />

nh₂

<img file="MX349718B_D0155.tif" />

<img file="MX349718B_D0156.tif" />

<img file="MX349718B_D0157.tif" />

ΙΜ

ΝΗΤτυτυ. · „, You the nfCrALt» * '' ipíntríTct * »

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<img file="MX349718B_D0161.tif" />

<img file="MX349718B_D0162.tif" />

<img file="MX349718B_D0163.tif" />

<img file="MX349718B_D0164.tif" />

<img file="MX349718B_D0165.tif" />

<img file="MX349718B_D0166.tif" />

<img file="MX349718B_D0167.tif" />

<img file="MX349718B_D0168.tif" />

<img file="MX349718B_D0169.tif" />

<img file="MX349718B_D0170.tif" />

<img file="MX349718B_D0171.tif" />

<img file="MX349718B_D0172.tif" />

<img file="MX349718B_D0173.tif" />

<img file="MX349718B_D0174.tif" />

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

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

<img file="MX349718B_D0175.tif" />

where -GHJ is selected from:

NC

<img file="MX349718B_D0176.tif" />

<img file="MX349718B_D0177.tif" />

<img file="MX349718B_D0178.tif" />

<img file="MX349718B_D0179.tif" />

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ί Μ Ρ ϊ

INSTITUTE .'1CX1CANO Γ- «CTjT» ', **!

'OF LA ΡΚΟΡΙΕΙΜΩ O—— INDUSTRIAL --------

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<img file="MX349718B_D0185.tif" />

<img file="MX349718B_D0186.tif" />

<img file="MX349718B_D0187.tif" />

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

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

NH

<img file="MX349718B_D0188.tif" />

IMPI

INSTITUTE mlXICanu JA

Ot LA EROnUMU Λμ, ΙΜ JÍM industrial where B is Ci-₈ alkyl, where the 0-4 carbon atom is optionally substituted with NH, where each -HJ is independently selected from CF₃, OCF₃, and - (Cl-8) alkyl-NH₂, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.

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

<img file="MX349718B_D0189.tif" />

<img file="MX349718B_D0190.tif" />

where each -HJ is independently selected from CF₃, OCF₃, And ci-₈) alkyl-NH₂, 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, (m) -Ci-₈alkyl, (n) -Ci-₈ alkenyl, (or) -Ci-₈ alkynyl, (p) - (Ci-₈alkyl) - (3-14 member saturated, unsaturated, or heterocycle

<img file="MX349718B_D0191.tif" />

aromatic 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 member saturated, unsaturated or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (u) -3-14 member saturated, unsaturated, or aromatic carbocycle ; 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-_to alkyl or alternatively two R groups⁶ are taken together to form a carbocycle, (c) -haloalkyl, (d) saturated, unsaturated, or aromatic -3-14 member heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (e ) -3-14 member saturated, unsaturated or aromatic 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, la, lia, Illa, IVa or a pharmaceutically acceptable salt, ester, tautomer, or one of its prodrugs, wherein W, when currently, it is 0, NR¹, GOR¹, or S.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, la, lia, Illa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or one of its prodrugs, wherein X --Y, when present, is a double bond and X is N and Y is a carbon atom.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, la, lia, Illa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof, where R⁵ is OR⁶, and R⁶ is CE³.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, la, lia, Illa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof, where R⁵ is CF3.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, la, lia, Illa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof, where- G- HJ is selected from,

H - J ^G\

<img file="MX349718B_D0192.tif" />

100

IMPI

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL where each one -HJ ah btíltRJ 010773 independently between -0-CF³ and - (Ci-g alkyl) -NH².

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, la, 5lia, Illa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or one of its prodrugs, where R^4th, when currently, it is hydrogen.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, la, 10lia, Illa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or one of its prodrugs, wherein Z, when currently, is NR⁴.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, la, 15lia, Illa, IVa, or a pharmaceutically acceptable salt, ester, tautomer, or pro-drug thereof, where R⁴ it is hydrogen.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, la, 20lia, Illa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or a prodrug thereof, which binds to a ribosome.

In some embodiments, the present invention relates to a compound according to formula I, II, III, IV, la, 25 Ha, Illa, or IVa, or a pharmaceutically acceptable salt,

101 ΙΜ i

101 . Mexican institute V j Jí^c SAY OWNERSHIP

INDUSTRIAL ester, tautomer, or one of its prodrugsWwsT ^^ we ^ se - '^ awe ^^ pi -— ribosome in which the ribosome is a bacterial ribosome.

In some embodiments, the present invention relates 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, which comprises 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 is

102

<img file="MX349718B_D0193.tif" />

refers 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 for treating, preventing or reducing the risk of a microbial infection in a human or animal, which comprises administering to the human or animal an effective amount of a compound according to formula I, II, III IV, la, lia, 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 a human or animal, 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, post viral pneumonia, hospital acquired pneumonia / ventilation associated pneumonia, a respiratory tract infection such as chronic infections of the

<img file="MX349718B_D0194.tif" />

103

IMPI

MEXICAN INSTITUTE

DE L »INDUSTRIAL PROrttPAD respiratory tract (CRTI), acute pelvic infection, a complicated skin infection and skin structure, a skin and soft tissue infection (SSTI), including uncomplicated skin and tissue infections (uSSTI), and complicated skin and soft tissues, an abdominal infection, a complicated intra-abdominal infection, a urinary tract infection, bacteremia, septicemia, endocarditis, an atrio-ventricular shunt infection, a vascular access infection, meningitis, guirurgical prophylaxis, a peritoneal infection, bone infection, a joint infection, methicillin-resistant Staphylococcus aureus infection, vancomycin, a linezolid-resistant infection of the body, a Bacillus anthracis infection, a Francisella tularensis infection, an infection with the bacteria Yersinia pestis, and tuberculosis.

In some embodiments, the present invention relates to a method for treating, preventing, or reducing the risk of a complicated intra-abdominal infection in a human or animal, which comprises administering to the human or animal an effective amount of a compound according to formula I, II, III, IV, la, lia, Illa, or IVa, or a salt

<img file="MX349718B_D0195.tif" />

104

IMPÍ

INSTITUTO MEXICANO DE Ι.Λ pharmaceutically acceptable industrial property, 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 a complicated intra-abdominal infection in a human or animal, in which the complicated intra-abdominal infection is selected from 'polymicrobial infections such as abscesses due to Escherichia coli, Clostridium clostridio forme, Eubacterium lentum, Peptostreptococcus spp., Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotacus, Bacteroides thetaiotamis 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, la, lia, Illa, or IVa, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof, or to the use of a compound of the invention, or a pharmaceutically salt acceptable, ester, tautomer, or prodrug thereof, in the manufacture of a

<img file="MX349718B_D0196.tif" />

105

IMPI

MEXICAN INSTITUTE

Of LA / SoriEDAD. INDUSTRIAL drug to treat, prevent or reduce the risk of complicated skin and skin structure infection, where complicated skin infection and skin structure is selected from diabetic foot infections without osteomyelitis due to Staphylococcus aureus (susceptible and resistant isolates to methicillin), Streptococcus agalactias, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Bacteroid.es fragilis, Peptostreptococcus species, Porphyromonas osteomyelitis asaccharolytica or Prevotella bivia.

In some embodiments, the present invention relates to a method for treating, preventing, or reducing the risk of community pneumonia in a human or animal, which comprises administering to the human or animal an effective amount of a compound according to formula I , II III, IV, la, lia, Illa, or IVa, 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 drug to treat, prevent or reduce the risk of community-acquired pneumonia, in which extra-hospital pneumonia is caused by Streptococcus pneumoniae (susceptible isolates

106

<img file="MX349718B_D0197.tif" />

and penicillin resistant), including cases with concurrent bacteremia Haemophilus influenzas (including beta-lactamase positive isolates), Moraxella catarrhalis, or atypical bacteria such as Mycoplasma spp.

In some embodiments, the present invention relates to a method for treating, preventing, or reducing the risk of a complicated urinary tract 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, lia, Illa, or IVa, 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 to treat, prevent, or reduce the risk of a complicated urinary tract infection, wherein the complicated urinary tract infection is selected from 'Escherichia coli pyelonephritis, concurrent bacteremia, or Klebsiella pneumoniae.

In some embodiments, the present invention relates to a method for treating, preventing, or reducing the risk of an acute pelvic infection in a human or animal, comprising administering to the human or animal an effective amount of a compound according to the formula I, II III, IV, la, lía, Illa, or IVa, or a salt

107

<img file="MX349718B_D0198.tif" />

pharmaceutically acceptable 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 an acute pelvic infection, in which the acute pelvic infection (including, for example, postpartum endomyometritis, septic abortion and subsequent surgical gynecological infections) is due to Streptococcus agalactias, Escherichia coli, Bacteroides fragilis, Porphyromonas asaccharolytica, Peptostreptococcus spp., Or Prevotella bivia.

In some embodiments, the present invention relates to a method for treating, preventing, or reducing the risk of hospital pneumonia / ventilator associated pneumonia 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, lia, Illa, or IVa, 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 to treat, prevent or reduce the risk of hospital acquired pneumonia / ventilation associated pneumonia,

108

<img file="MX349718B_D0199.tif" />

wherein hospital acquired pneumonia / ventilation associated pneumonia is due to Streptococcus pneumoniae (penicillin sensitive and resistant strains), Staphylococcus aureus (methicillin resistant and susceptible isolates), Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter spp. , Stenotrophomonas maltophilia, Haemophilus influenzae (including beta-lactamase positive isolates), or Legionella pneumophilia.

In some embodiments, the present invention relates to a method for treating, preventing, or reducing the risk of a microbial infection, due to an aerobic or facultative gram-positive 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, la, lia, 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 medicament to treat, prevent, or reduce the risk of a microbial infection, due to an aerobic or facultative gram-positive microorganism, wherein the gram-positive microorganism -positive aerobic or facultative is selected from:

<img file="MX349718B_D0200.tif" />

109

IMPI

MtXIONO INSTITUTE

O £ THE INDUSTRIAL ARLIPIETY

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

In some embodiments, the present invention relates to a method for treating, preventing, or reducing the risk of a microbial infection, due to an aerobic and facultative 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, la, lia, Illa, or IVa, 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 to treat, prevent, or reduce the risk of a microbial infection, due to an aerobic or facultative gram-positive microorganism, in which the microorganism gram-negative aerobic and facultative is selected from:

Escherichia coli (including isolates that produce ESBL and KPC), Haemophilus influenzae (including

<img file="MX349718B_D0201.tif" />

110

IMPI

INSTITUTO MEXICANO I&gt; E LA PROPILOAD INDUSTRIAL beta-lactamase positive isolates), Klebsiella pneumoniae (including isolates producing ESBL and KPC), Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Morganella morganii, Serratia marcescens, Morabainella aeriiiiine Pseudomonasiii Pseudomonas catarrhalis, Proteus mirabilis, Citrobacter koseri, Haemophilus parainfluenzae, Klebsiella oxytoca (including ESBL and KPC producing strains), Proteus vulgaris, Providencia rettgeri and stuartii Providencia.

In some embodiments, the present invention is. refers to a method for treating, preventing, or reducing the risk of a microbial infection, due to an anaerobic microorganism in a human or animal, which comprises the administration to the human being or animal an effective amount of a compound according to formula I, II,

III, IV, la, lia, Illa, or IVa, 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 20 of the same, 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 25 ovatus, Bacteroides thetaiotaomicron, Bacteroides

<img file="MX349718B_D0202.tif" />

111

MEXICAN INSTITUTE

OF THE INDUSTRIAL PROPERTY uniforms, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus species, Porphyromonas asaccharolytica, Prevotella bivia, Bacteroides vulgates, Clostridium perfringens, or Fusobacterium spp.

In some embodiments, the present invention relates to a method for treating or reducing the risk of a microbial infection in a human or animal, which comprises administering to the human or animal an effective amount of a compound according to formula I, II, III, IV, la, Ha, Illa, or IVa, 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 of the same, in the manufacture of a medicine to treat, prevent or reduce the risk of a microbial infection, where the microorganism is Legionella pneumophilia.

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 otic, ophthalmic, nasal, oral, parenteral. 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,

<img file="MX349718B_D0203.tif" />

112

IMPI

INSTITUTO mil.Cano I heard the tautomer industrial PROPERTY, or prodrug thereof.

In some embodiments, the present invention relates to a medical device containing 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 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 Schemes la5a 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.

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113

IMPI

MEXICAN INSTITUTE

D € INDUSTRIAL PROPERTY

Scheme la - Pir r ilod tos inas · _XOh

Oh

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<img file="MX349718B_D0206.tif" />

BZ

<img file="MX349718B_D0207.tif" />

<img file="MX349718B_D0208.tif" />

<img file="MX349718B_D0209.tif" />

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OMe

OMe

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Or OMe

OMe

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<img file="MX349718B_D0215.tif" />

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114

IMPI

IΝΓΠΤΙΠΌ iwyumiAi

Scheme 3a - Triazolisocytosines

OMe

<img file="MX349718B_D0218.tif" />

<img file="MX349718B_D0219.tif" />

NaOMe / MeOH, 50 ° C

<img file="MX349718B_D0220.tif" />

Scheme 4a - Triazolisocytosines

<img file="MX349718B_D0221.tif" />

<img file="MX349718B_D0222.tif" />

<img file="MX349718B_D0223.tif" />

115

IMPI

MEXICAN INSTITUTE

OF THE «. INDUSTRIAL TRADE

<img file="MX349718B_D0224.tif" />

Scheme 5a [6,5,6] -pyrroloisotosins

OMe

<img file="MX349718B_D0225.tif" />

<img file="MX349718B_D0226.tif" />

<img file="MX349718B_D0227.tif" />

Pd (PPh₃)₄/ K₂CO3

HjO / Dioxane

<img file="MX349718B_D0228.tif" />

Four. Characterization of compounds of the invention

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.

116

<img file="MX349718B_D0229.tif" />

matter to determine whether 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 whether they have predicted activity, binding activity, and / or binding specificity.

In addition, high-throughput scanning can be used to speed up analysis by using such assays. As a result, it may be possible to rapidly screen 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 ribosomal or ribosomal subunit and / or are effective as modulators (eg, inhibitors) of protein synthesis using techniques known in the art. General methodologies for performing high throughput exploration are described, for example, in Devlin (1998) High Throughput Exploration, Marcel Dekker, and US Patent No. 5,763,263. High throughput tests may utilize one or more different testing techniques, including, but not limited to, those described below.

(1) Surface Link Studies. A variety of binding assays can be useful in the

<img file="MX349718B_D0230.tif" />

117

ΙΜΡΙ (

MEXICAN INSTITUTE ¹

OF INOUSTRJAL PROPERTY exploration of new molecules for your '

One method includes surface plasmon resonance (SPR) that can be used to assess the binding properties of molecules of interest with respect to a ribosomal, 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 from 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 Username. A 100 nm thick hydrogel 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 cloud of free electrons in the gold film, the plasmon resonance is higher. The reflected light is spectrally depleted resulting in wavelengths that are optimally developed by resonance. By separating the polychromatic reflected light into its component wavelengths (by means of a prism), and determining which frequencies are exhausted, the BIAcore establishes an optical interface that

<img file="MX349718B_D0231.tif" />

118

IMPI,

INSTIT UTO MRXICa.H.

UE LA PELONEbAL · INDUSTKJAL accurately reports the behavior of the surface generated by plasmon resonance. When designed as above, the plasmon resonance (and hence the depletion spectrum) is sensitive to mass in the evanescent field (which roughly corresponds to the thickness of the hydrogel). If a component of an interacting pair is immobilized to the hydrogel, and the interacting partner 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 as measured by the depletion spectrum. This system allows rapid 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 IC₅or^s and Kds of the association reaction between two molecules. In this technique one of the molecules of interest is conjugated with a fluorophore. This is generally the smallest molecule in the system (in this case, the compound of interest). The sample mixture, which contains both the ligand-probe conjugate and the

<img file="MX349718B_D0232.tif" />

119

IMPI ΐ '^ ιτυτν mucamo THE MUHIUAD INUUiTkJAL subunit of the ribosome, ribosomal or fragment thereof, se. excites with vertically polarized light. The light is absorbed by the fluorophores in the probe, and re-emits a short time afterwards. 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 the apparent molecular weight of the fluorophore. With proper controls, changes in the degree of polarization of the emitted light depends 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. Binding assays based on FP have a number of important advantages, including IC measurement.₅₀^S and Kds under true homogeneous equilibrium conditions, the speed of analysis and automation equipment, and display capacity in suspensions and cloudy solutions.

(3) Protein synthesis. It is contemplated that, in addition to the characterization of the preceding biochemical assays, the compound of interest may also be characterized as a modulator (eg, an inhibitor of protein synthesis) of the functional activity of the ribosome or ribosomal subunit.

In addition, more protein-specific assays

<img file="MX349718B_D0233.tif" />

Inhibition of synthesis can be accomplished by administering the compound to a whole organism, tissues, organs, organelle, cell, a cellular or subcellular extract, or a purified ribosome preparation and observing its pharmacological and inhibitory properties by determining, for example, its inhibition constant (IC₅₀) to inhibit protein synthesis. The incorporation of³H leucine or methionine ³⁵S, 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 Trials and other Evaluation. In addition, compounds can be tested for anti-proliferative or anti-infective properties on a cellular level. For example, when the target organism is a microorganism, the activity of the compounds of interest can be assayed by growth of the microorganisms of interest in media either containing or lacking the compound. Growth inhibition may be indicative that the molecule can

<img file="MX349718B_D0234.tif" />

<img file="MX349718B_D0235.tif" />

121 (Η | Λ TílIJAi. INDUSTRIAL act as an inhibitor of protein synthesis. More specifically, the activity of the 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 structure-activity relationships not only in terms of potency and spectrum, but also with a view to obviating resistance mechanisms.

Minimum inhibitory concentrations (MIC) were determined by the microdilution method, usually in a final volume of 100 microliters, according to the protocols described by the standards of the Clinical and Laboratory Institute [CLSI, formerly the National Committee for Clinical Laboratory Standards (NCCLS)]. See CLSI: Methods for Antimicrobial Susceptibility Testing of Aerobic Growing Bacteria, Standards Approved by the Fifth Edition. Wayne, PA: NCCLS, 2000. Assays can also be carried out in microtiter trays according to conventional methodologies as published by the CLSI. See CLSI.

Methods for Antimicrobial Susceptibility Testing

IMPI

INSTITUTE MSXiCAIlD Y '

OF THE PROPERTY C '- = ur --- LL &lt;' '/ INDUSTRIAL of the Bacteria that Grow Aerobically; Standard Edition Seventh Approved. 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 other compounds can be evaluated in various in vivo tests in mammals, such as a mouse or rat peritonitis infectious models, skin and soft tissue models (often referred to as the thigh model). , or a mouse pneumonia model. There are septicemia or organ infection models 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. End points may vary from reducing bacterial load to lethality. At the extreme of the latter, the results are often expressed as a DP50 value, or the dose of drug that protects 50% of the animals from mortality.

In order to evaluate a compound, such as drugs, measurements of the inhibiting properties of '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 liver microsomes

123

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INSTITUTE Μ ¿Ma.a DE LA PMFIEDAM INDUSTRIAL Humans. Furthermore, compounds can be evaluated as substrates for these metabolic enzymatic 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 orally bioavailable, solubility and Caco-2 tests can also be performed. The latter 10 is a human epithelial cell line that allows the measurement of drug uptake and passage through a monolayer of Caco-2 cells with increasing frequency within the wells of a 24-well microtiter plate equipped with a 1 micron membrane. 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. Proper controls to ensure monolayer integrity and bond tightness are necessary. Using this same system one can obtain a P-glycoprotein-mediated efflux estimate. Pglycoprotein is a pump that is located in the apical membrane of cells, forming polarized monolayers. This pump can nullify active or passive absorption across the Caco-2 cell membrane, resulting in transmission

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I Μ ΡI INSTITUTO MEXICANO DE LA FROFISDaD INDUSTRIAL of minor drug through the epithelial layer⁴intestinal. These results are done. often in conjunction with solubility measurements and both of these factors are known to contribute to oral bioavailability in mammals. Measurements of oral bioavailability in animals and eventually man by traditional pharmacokinetic experiments will determine absolute oral bioavailability.

The experimental results can also be used to create models that help predict physico-chemical parameters that contribute to similar drug properties. When this model is verified, the experimental methodology can be shortened, with a greater reliance on model predictability.

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 mammalian and non-mammalian, disorders, including, for example, bacterial infection, 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 carrier.

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125

The dose of the active molecule, mode of administration, and use of a suitable carrier will depend on the recipient and target organism. Formulations, for both veterinary use and 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 sense, are intended to include any and all 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 media or agent is incompatible with the active compound, its use in the compositions is contemplated. Supplemental active compounds (identified or designed in accordance with the invention and / or known in the art) can also be incorporated into compositions. The formulations can be conveniently presented in unit dosage form and can be prepared by

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FROM INDUSTRIAL PROPERTY any of the methods well known in the art of pharmacy / microbiology. 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), transmucosal, 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 alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; 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 acid

<img file="MX349718B_D0239.tif" />

hydrochloric or sodium hydroxide. —— · ——- - Solutions useful for oral or parenteral administration can be prepared by any of the methods well known in the art of pharmacy, described, for example, in Remington Pharmaceutical Sciences, (Gennaro, A., ed.), Mack Pub .., (1990). Formulations for parenteral administration may also include glycollate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration. The parenteral preparation can be enclosed in ampoules, disposable syringes, or multi-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 can also include, for example, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, and hydrogenated naphthalenes. Formulations for direct administration can include glycerol and other high viscosity compositions. Other potentially useful parenteral carriers for these drugs include ethylene vinyl acetate copolymer particles, osmotic pumps, infusion sets

<img file="MX349718B_D0240.tif" />

implantables and liposomes. Formulations for administration by inhalation can contain as excipients, for example, lactose, or they can 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.

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 lozenges, 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, electary, or paste. A tablet can be made by compression or molding of the drug optionally with one or more accessory ingredients. Compressed tablets 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 agent.

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MEXICAN INSTITUTE of dispersant industrial property. Molded tablets can be made by molding, in a suitable machine, a mixture of the powdered drug and appropriate carrier 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 mouth rinse 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, gum tragacanth, or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or cornstarch; a lubricant such as magnesium stearate or Sterotes; a glidant such as 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 dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL ™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the 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. Prolonged absorption of injectable compositions can be accomplished by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

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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 listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation include vacuum drying and freeze drying which produces a powder of the active ingredient plus any additional ingredients desired from a previously sterilized solution by filtration thereof. .

Formulations suitable for intra-articular administration may be in the form of a sterile aqueous drug preparation which may be in microcrystalline form, eg, in the form of a microcrystalline aqueous suspension. Liposome formulations or biodegradable polymer systems can also be used to present the drug for both intra-articular and ophthalmic administration.

Formulations suitable for topical administration, including the treatment of

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IΜ ΡI INSTITUTO MIXICaNo DE LA TkOPliPAP INDUSTRIAL

132 eyes, 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 surface of the skin 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 localize 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 formulations can be used.

For inhalation treatments, inhalation powders (self-propellants or spray formulations) dispensed with an aerosol can, a nebulizer, or an atomizer can be used. Such formulations can be in the form of a fine powder.

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THE INDUSTtIAL PJiCNJTUAn for the pulmonary administration of a powder inhalation device or the 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 that has the desired spray characteristics (i.e., being capable of producing a spray that has 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 as an aerosol spray from the pressure container or dispenser containing a suitable propellant, eg, a gas such as car dioxide, or a nebulizer.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, appropriate penetrants for the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, and bile salts. Transmucosal administration can be achieved 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,

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Ot THE INDUSTRIAL PROPERTY 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. Methods for the preparation of 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 US Patent No. 4,522,811.

Oral or parenteral compositions can be formulated in unit dosage form for ease of administration and uniformity of dosage. Dosage unit form refers to physically discrete units suitable as unit doses for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for shapes

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INDUSTRIAL dosage unit 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 art of compounding such an active compound for the treatment of individuals. Furthermore, administration can be by periodic bolus injections, or it 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 of the drug to target the tissue for a time sufficient to induce the desired effect.

When the active compound is to be used as part of a transplantation procedure, it can be provided to the living tissues or organ to be transplanted.

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OR »INDUSTRIAL rtOHETY prior to tissue removal or ORGD'HU of the · · -ΕΊ compound can be provided to the donor host. Alternatively or, in addition, once extracted 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 to the desired tissue, such as by injection into the tissue, or it can be delivered systemically, for example, by otic, ophthalmic, nasal, oral, or parenteral administration, using any of the following methods and formulations described herein and / or known in the art. When the drug comprises part of a tissue or 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 applying the compound to a medical device that is contacted 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 Coronary Disease Treatment? European Journal of 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 bound to the surface of the stent, integrated and released from polymeric materials coated on the stent, or surrounded by and released through a layered carrier or stent. The stent can be used to deliver single or multiple active compounds to the tissues adjacent to the stent.

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

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INDUSTRIAL the relationship between the genotype of an individual and the response of that individual to a foreign compound or drug) can be considered. Differences in therapeutic metabolism 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 knowledge gained in relevant pharmacogenomics studies to determine whether to administer a drug, as well as tailoring 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 otic, ophthalmic, nasal, oral, parenteral, and / or topically at a dose to obtain and maintain a concentration, ie, an amount, or blood level or tissue level of active component in the treatment subjected to the animal that will be effective antimicrobial. Generally, an effective dosage amount of the active component will range 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

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CS INDUSTRIAL PROPERTY 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 drug formulation, the presence and types of excipients of the formulation and the 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 optimal and the 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 nonsense or absurd mutations. These mutations cause or mediate the disease state or condition by adversely affecting, for example, protein synthesis, folding, trafficking, and / or function. Examples of disease states or conditions in which an appreciable percentage of the disease or condition is believed to result in nonsense or nonsensical mutations include hemophilia (factor VIII gene), the «η INSTITUTO MEXICANO * · *^υ !&gt; e currency C »a» = Í4EL £ and industrial neurofibromatosis (genes NF1 and NF2), retinitis pigmentosa (human gene USH2A), hullous skin diseases such as pruritic hullosa Epidermolysis (genes COL7A1), cystic fibrosis (gene transmembrane regulator of cystic fibrosis), breast and ovarian cancer (BRCA1 and BRCA2), Duchenne muscular dystrophy (dystrophin gene), colon cancer (repair genes, mainly in MLH1 and MSH2), and lysosomal storage disorders such as Neimann-Pick disease (acid sphingomyelinase gene). See Sanders CR, Myers JK. Lack of Disease Related Membrane Protein Assembly. Annu Rev Biophys Biomol Struct. 2004; 33: 25-51; National Information Center

Biotechnology (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 nonsense or nonsense mutations by administration to a mammal in need of an effective amount of the present invention to suppress the nonsense mutation. or absurd related to the disease state.

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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. Common reaction solvents were high performance liquid chromatography (HPLC) grade , or American Chemical Society (ACS) grade, grade, and anhydrous, obtained by the manufacturer unless otherwise noted. Silica gel chromatography or purified refers to column chromatography using silica gel (EM Merck, silica gel 60, 230-400 mesh) unless otherwise noted.

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 examples are defined below: h or hr = hour (s); min = minute (s); mol = mol (s); mmol = millimole (s); M = molar; μΜ = micromolar; g = gram (s); gg = microgram (s); ta = room temperature; L = liter (s); mL = milliliter (s); Et₂O = diethyl ether, THF = tetrahydrofuran; DMSO =

<img file="MX349718B_D0251.tif" />

dimethylsulfoxide; 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; TBDPSC1 = t-butyldiphenylchlorosilane; Hunig Base = N, N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; Which copper = (1) 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; Yes₂ silica =; Pd-C = palladium on car; Pd (dppf) Cl₂ = dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II).

Example compounds synthesized in accordance with the invention are listed in Table 1. A bold or dashed bond is shown to indicate a particular stereochemistry, to a chiral center, while a wavy bond indicates that the substituent may be in any orientation. or that the compound is a mixture

143

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thereof. 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 being indicated by a link crossed by a wavy line. See, for example, compound 755, which was elaborated in two parts as:

<img file="MX349718B_D0253.tif" />

. - The compounds of the present invention can be prepared, formulated, and delivered as salts, asters, and prodrugs. For convenience, the compounds are shown_M4

INST1TUTO Μ £ X! CA ΝΟ ΥΥΥ-ΤίΥ&gt; Α

OF INDUSTRIAL PROPERTY in a general way, without indicating a gai-p ^ pniar. ester, or prodrug form.

Compounds of the present invention are shown in Table 1. LCMS [liquid chromatography mass spectrum) data is provided, where available. When 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. Do not.</td><td>Structure</td><td>LCMS</td>

<td> 142</td><td>NH₂'TT í '' N ' J.: / ONN</td><td> 241.00</td>

<td> 154</td><td>H₂N n ..... 'y 1 AND h₂non pj</td><td> 355.10</td>

<td> 169</td><td>H₂N - N- Y! F ^N , _/OR . h₂nonn) - &lt; h₂n o-ch₃</td><td> 456.20</td>

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<td> 179</td><td> 1' ^N 'f -^X......-_λH₂NONN OH</td><td> 461.30</td>

<td> 180</td><td>h, nn Ij 'N τ -V. . 'i L: · -......,, - f h₂non N ΓΊ</td><td> 449.20</td>

<td> 181</td><td>J jTIV-X Z^CH3 H₂NT S— '</td><td> 486.10</td>

<td> 182</td><td>N H₂NNN _;7 . .-J¹ ~ N-- ..... 1 ^N 1 H₂NONN</td><td> 486.10</td>

<td> 183</td><td>0 HZ— \) 2 / X z N z</td><td> 459.20</td>

<td> 184</td><td>I z I / N »/ z :</td><td> 435.00</td>

<td> 192</td><td>I M z I / N / z &lt;K^Z,M 2Z z) 0 or ' δ I</td><td> 572.30</td>

<td> 193</td><td>H₂M n, - | .¹ ! - ¹¹ ·. 'Or 7 'N · r' ·,. /. 1 - ί '1' '·&gt;' H_?NONN ---- HN —7 O</td><td> 558.30</td>

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<td> 194</td><td>NH, J HN NH NH, ! ..... J N ' 1 . TL .. N Γ^{Ο N} H</td><td> 397.20</td>

<td> 195</td><td>N ..... x., JL ......, ....... or 1 - N. λ 1 L ....... λ XN H₂NONN ^! hn— &lt; </td><td> 551.30</td>

<td> 196</td><td>H₂NN - i J ... .-- ·. or 1 '.....'. 1 T w i- &lt; h₂nonn --- HN. J. Í-ⁿ4</td><td> 583.30</td>

<td> 197</td><td>H₂NN .-^J t— .o 'N - [-', .______ / and __ H₂N or NN --- '' HN—: NH</td><td> 557.30</td>

<td> 198</td><td>H₂N ^ 'N ^ &gt; N '/ k _ - - o rn - '' r'-xi xo i L - $ '' —τ h₂nonn / _{HN NH}</td><td> 593.20</td>

<td> 200</td><td>\ _ θ '' N '^ r A / ~ ·. HO λ Λη ./^^sH₂NONN 'HN NH</td><td> 611.30</td>

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<td> 201</td><td>X z - \ / '—z \ Y ( ΐ Γ 11 X, .X T ζ, ωα vyj °</td><td> 619.40</td>

<td> 203</td><td>H₂N '^ N' X '' ' 1 L il _ rn H₂N d Ν'Ύ HN-Yll</td><td> 583.10</td>

<td> 204</td><td>I X 'z X / N&gt; / z &lt; ° Y γγ zz X 0 z / X &lt;y or X GJ</td><td> 571.30</td>

<td> 206</td><td>1 1 i Vr-N ^ i / L · ' ^v'· / \' H₂N CrN^x N - 'HN——'</td><td> 597.70</td>

<td> 216</td><td>nh₂HN ^ NH NH₂k J. X and N Όγ. „- o ~ N 7 X / \ __ / 1 / x ΟΝ 'N -NH 0 N _HlY</td><td> 625.30</td>

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<td> 217</td><td>nh₂HN 'NH NH₂eleven Ί 1 ' N . = P Λ t /% ONN - nh Π / HN.</td><td> 559.30</td>

<td> 218</td><td>. h₂nn] | Γ ' ^{i? i} N -⁼. - / —COOH H₂NONN - . Π</td><td> 475.20</td>

<td> 219</td><td>nh₂HN NH NH₂OR ¹N L i '' ------ i ONN 'Ó NH N &lt;</td><td> 661.40</td>

<td> 220</td><td>nh₂HN NH NH₂eleven Ί f N ' Ό ~ o ONN - O NH Π HN -</td><td> 635.50</td>

«·** »*»

149

<img file="MX349718B_D0259.tif" />

<td> 221</td><td>νη₂ΗΝ NH ΝΗ, L ..... J 1 j Ν 1. ^ Τ · ..... ν- / .1 1&gt; “Τ Γ ~ Ρ_οτ -_Ν'Ν - Ο ΝΗ . π _______. (&gt; ΗΝ—</td><td> 653.30</td>

<td> 224</td><td> ·^Ν Γ 'ιι Ν γ-Λ - Ρ Λ 1 -% - Ο Ν - ΗΝ— ΝΗ π λ /</td><td> 443.80</td>

<td> 225</td><td>1. ό f ζι Ηζ Ζ— \ ) ζ / CN / r ζ ν I</td><td> 683.40</td>

<td> 226</td><td>Η₂Ν '' Ν '' '' · .- / =. ο I ~ I Χ.Μ Μ Η₂Ν ο Ν Ν 'Ν—, ΝΗ k. ° i ch₃</td><td> 652.49</td>

<td> 227</td><td>FOR-. .--- Ν,,; η ϊ Τ '- Η .- · ΟΝ 'Η - ΗΝ ΝΗ Π</td><td> 501.20</td>

150

228

<img file="MX349718B_D0260.tif" />

585.30'

229

230

231

232

<img file="MX349718B_D0261.tif" />

<img file="MX349718B_D0262.tif" />

<img file="MX349718B_D0263.tif" />

COOH

<img file="MX349718B_D0264.tif" />

<img file="MX349718B_D0265.tif" />

h₃cs

572.40

651.70

637.30

667.60

<img file="MX349718B_D0266.tif" />

151

IMPI

MEXICAN INSTITUTE

FROM WOFIWA »INDUSTRIAL

<td> 233</td><td>- 'Ν' '' ^ r'P / \ II 0 chi X τ / -T H₂N 0 NN - N, NH^H (\ --- / /-Do not-</td><td> 706.60</td>

<td> 234</td><td>nh₂HN NH^L1 NH .......... 0 N - NH Π / HN— ''</td><td> 542.40</td>

<td> 235</td><td>'TT. or 'Ν' ~ T '^. · '\ T-0 ! &gt; ... l Τ 'Λ JT / -' H₂N 0 N (j - · ' ^N NH / &lt;; ^ Cl \ you</td><td> 753.70</td>

<td> 236</td><td>H₂NN · ' ,¹ TA,₇.. .___ or _N 'ύ-λ / \ ii _, or L? '- is - \ H₂N Ο Ν N 'N (NH . f T scf₃</td><td> 783.50</td>

152

<img file="MX349718B_D0267.tif" />

IMPI

INSTITUTO M EX ÍCA A '&lt;' O »LA PROPIcDaI. · Industry.

<td> 237</td><td>(Ί X ° i 1 0 ω '-' F ^zi// f. (z &gt; ........ í -^/=\ ° / Z.— , / \ ______λ. z , CM I zz *¹</td><td> 715.60</td>

<td> 240</td><td>HN — NA &lt;.. N NH ' , 1 XM / ~ x ONN -^z NH ΓΊ _____y / \ HN—</td><td> 524.40</td>

<td> 241</td><td>r 0. z - 1 T l 9 ¹zz V ......... ( 'z z- b Z— ' Μ Z-- ' r /^Z-X ·. z T</td><td> 556.40</td>

<td> 245</td><td>nh₂Me /' XM / —X Fr⁰CT NN - NH Ó H</td><td> 513.10</td>

<img file="MX349718B_D0268.tif" />

153

IMPI

INSTITUTE MF.X1CANO

OS INDUSTRIAL PROPERTY

<td> 250</td><td>Cl NH - N 'j- &lt;- / - ^ύii ' ^s θ ON ** --- NH NH</td><td> 573.30</td>

<td> 253</td><td> 11 ^F\ NH or H</td><td> 537.60</td>

<td> 254</td><td>CI ^^ - ^^ NH LJL / \ ^ - ° NH OR H</td><td> 537.30</td>

<td> 258</td><td> ^^Htwo ^ VryT-O N- ^⁷H</td><td> 479.20</td>

<td> 261</td><td>F - NH L. .. Ϊ 'll -. ° 1 J. \ ® _{or N} N - NH ". ' HN—</td><td> 573.40</td>

154

<img file="MX349718B_D0269.tif" />

IMPI

INSTITUTO MEXICANO • E Ι.Λ SRONEDAI INDUSTRIAL ·

<td> 262</td><td>F '^^{X / X}'NH Η 'or H</td><td> 539.30</td>

<td> 263</td><td>h₂n AND] \ / \ _L ·⁰(ΛιΟ HN— (NH ΓΊ \ /</td><td> 580.70</td>

<td> 264</td><td>I M z X TZ ex _ü&gt; = O^z0</td><td> 606.40</td>

<td> 272</td><td>nh₂ F [ TO I i. Wo N '-r-Ύ / \ _or° X &lt;- 'XX θ '' NN --- 'NH Π __ HN— '</td><td> 531.30</td>

<td> 279</td><td>"Π / \ .--- Z / I , ---------- &lt; ς. -η_or X / z.) X \ _____ X 'í, z Γ j xx&gt; I or</td><td> 575.30</td>

<img file="MX349718B_D0270.tif" />

155

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<td> 280</td><td>F ^{NH F}it. ... or ”X„ ~^;. ONN NH H __ HN ^z</td><td> 539.30</td>

<td> 288</td><td>jQ OR ] ^ /^Xzi T</td><td> 408.20</td>

<td> 289</td><td>H₃N NH . N · 1 ... - \ 9 ONNN -χ^H 'Or</td><td> 397.20</td>

<td> 292</td><td></td><td> 442.20</td>

<td> 293 </td><td>H, N NH L .. to. 'ϊ TONN -^H NH -</td><td> 411.20</td>

<td> 296</td><td>rt U. υ o ^^λζι f Z &lt;N I</td><td> 458.20</td>

156

<img file="MX349718B_D0271.tif" />

<td> 298</td><td>H₂N NH J .ι. ? -.......... \ ο ΟΝ Ν^Η Ν-_λ'' ^ F</td><td> 441.20</td>

<td> 306</td><td>I Νί ζ Η Η HZ. χΊ 71 ^^^^^^ 71</td><td> 428.20</td>

<td> 309</td><td>I Ζ 0¹Η ΙΖ ο 1 Ο ^ Α Ό</td><td> 458.20</td>

<td> 310</td><td>Η₂Ν 'ΝΗ Τ i. _j Ν [? —F 0 'Ν Ν</td><td> 428.20</td>

<td> 318</td><td>η γ ^ ο 1 ^Λ^^ ζτ Η = Ζ-- 'Ζ--' U- τ</td><td> 517.30</td>

<img file="MX349718B_D0272.tif" />

<img file="MX349718B_D0273.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PEOHtOAD

158

<td> 542</td><td>HA, N Γ ~ \^N 1 ° ^N H</td><td> 326.20</td>

<td> 559</td><td>h₂n _n j , 1 .., L // ........^F ° ^N N -</td><td> 370.10</td>

<td> 560</td><td>h₂n »- ^ - / = \^FN '---' Π</td><td> 384.00</td>

<td> 561</td><td>0 T</td><td> 298.90</td>

<td> 562</td><td></td><td> 368.00</td>

<td> 563</td><td>H, NNY '”' i h 1. | '·' N j. 1 / ONN</td><td> 297.00</td>

<td> 564</td><td>NH h₂nn - n γ '^{H H} L 1. '' 'Y ^' N · '·'. \ L ° ^N H</td><td> 339.70</td>

<td> 565</td><td>H_?NY ..... P O 'N</td><td> 368.00</td>

159

<img file="MX349718B_D0274.tif" />

<td> 566</td><td>χ ___^H LH J Λ XX / Y^F</td><td> 410.10</td>

<td> 567</td><td>^{H2N N} , _ 'Γ, L - / ^F ° ^N N -</td><td> 370.90</td>

<td> 571</td><td>zz and Z⁰\ O ZZ ✓&gt;)</td><td> 274.00</td>

<td> 572</td><td>NH H₂NNN.]² H | | ONN</td><td> 315.90</td>

<td> 580</td><td>H-iC ^ _ ^ =. X / ^FO ^ NN VV</td><td> 243.80</td>

<td> 581</td><td>H₃c_x _. =, or n — γ \_Η</td><td> 352.00</td>

<td> 586</td><td>h₂n. __nQ |_orX_nXh</td><td> 325.90</td>

<td> 587</td><td>h₂n '^^x~^x^ n '^^x&gt; / = ^ cXhr-N</td><td> 323.90</td>

<img file="MX349718B_D0275.tif" />

160

IMPIAS

INSTITUTO MEXICANO OE LA noriidad industrial

<td> 590</td><td></td><td> 312.00</td>

<td> 591</td><td>hn- ^ / ^ X ϊΎΧ o ^ NT PI</td><td> 241.00</td>

<td> 596</td><td>ÍA X 1 and IZ I (N I</td><td> 368.00</td>

<td> 597</td><td>(Q. / A or I</td><td> 254.80</td>

<td> 600</td><td>HjN _____ ^N \ ' Μ N / ' .eleven OR' ^N H</td><td> 340.00</td>

<td> 601</td><td>Η, Ν '^^^ Ν' ^ ΧΧΧ / ““ X cAn ^ n</td><td> 348.10</td>

<td> 602</td><td>I N z IZ TZ^Zo ° \ = &lt;H</td><td> 391.00</td>

<td> 609</td><td>H₂NNT⁵^ 11 ^H L 1 Js. X / -^{0 N} H</td><td> 408.00</td>

<img file="MX349718B_D0276.tif" />

161

IMPI

MEXICAN INSTITUTE

FROM MOFIEDAP industrial

<td> 610</td><td>H₂NN 'ri | kx Jk. x OCH, N ONH ΓΊ</td><td> 342.00</td>

<td> 611</td><td>I z IZ ^z) \ TZ or or TI</td><td> 442.00</td>

<td> 612</td><td>I wz IZ 3 \ _z IZ J 0</td><td> 380.00</td>

<td> 613</td><td>os ° . H₂NN / / kx - L, - _% N 7 1 - ONN</td><td> 445.00</td>

<td> 616</td><td> I^H j 1 II , ¾</td><td> 396.70</td>

<td> 617</td><td>h₂n— ^ B ^ Yjl _ I 1 / v?^-</td><td> 454.00</td>

<td> 618</td><td>NH H₂N^for^ N^/^^{/ X}'N ^^XY^yes?&gt;] ^H L Λ I 1/4 / O ^ NN</td><td> 496.00</td>

<img file="MX349718B_D0277.tif" />

162

IMPI

MEXICAN INSTITUTE

GIVE THE INDUSTRIAL PROPERTY

<td> 620</td><td>H₂NN '', H ι .1 and O Ν Ν N Π</td><td> 375.00</td>

<td> 621</td><td>H₂NN 7 Z² H | \ /ⁿ ................. Ο Ν Ν</td><td> 387.90</td>

<td> 622</td><td>______ Η, Ν · ​​Ν; j^Η 1 _ '' Ν '. Ο Ν Ν π</td><td> 394.00</td>

<td> 623</td><td>_Η2ν ν ι - Ν —'Χ '' ι .. - &lt;&gt; · Ο Ν Ν - Π</td><td> 378.00</td>

<td> 624</td><td>Μ 1 χ 1 Μ ζχ ζ Ν I</td><td> 341.00</td>

<td> 625</td><td>η₂ν ν ·. Ν,^CH' ; Γ-ΝΗ₂Ο Ν Ν CH₃Γΐ</td><td> 355.00</td>

<td> 626</td><td>η₂ν ν,¹ 1 ... ο^-- ' ' ° ' ^Ν Η</td><td> 404.00</td>

<td> 628</td><td>τ ν °^{Η Η} 1 χ J jOO⁷ο ^ ν ^ ν ΓΊ</td><td> 487.00</td>

<img file="MX349718B_D0278.tif" />

163

IMPI

MEXICAN INSTITUTE

OF THE PROPERTY fr.'CUSTRIAL

<td> 629</td><td>NH TO. ..... .... ... H₂NNN] 'n^{H H} L l. * - * - · * ... Ϊ ^sON and ' ΙΊ</td><td> 422.00</td>

<td> 630</td><td>NH Η H 1 // ° ^^Ν Η</td><td> 446.00</td>

<td> 631</td><td>I ζ ΧΖ ο 2 = / Χ ± 0 1 W</td><td> 452.00</td>

<td> 632</td><td>ΝΗ Λ ... ... ... .... Η₂Ν Ν Ν Ύ '¡1² Η Η X .. = Ο Τ 'Ν /&gt; · 7 , 1 A .- "X ~ ^s ° Ο Ν Ν ^CH3 η</td><td> 494.10</td>

<td> 633</td><td>^Η L JL ^^ νΆλ X ± / ΓΤ'ΚΤ'Ν ⁷υ ΙΝ Η</td><td> 375.00</td>

<td> 634</td><td>Η, Ν Ν Χ.Α_ν. · Χ ch₃ L .L - / / —rχ Ο Ν ¹ CH₃</td><td>Ν / Α</td>

<td> 635</td><td>ΝΗ^Η k ^ XXVO ^ η₂ν ^ crA ^ N '-' CH₃^£ Γι</td><td> 551.10</td>

<img file="MX349718B_D0279.tif" />

<img file="MX349718B_D0280.tif" />

164 mu institute; 08 THE RRO. INDUSTRY

<td> 636</td><td>NH í. . . H₂NN 'N - p N-NH N ' ⁱ'i' '' ^S N NH₂á .1 0 N *</td><td> 468.00</td>

<td> 637</td><td>NH J „....... H₂NNN, |^{H H} L. N η t. / \ ONNM NH = O ~ 'N O ^ _</td><td> 558.00</td>

<td> 640</td><td>Η, Ν Ν ^ - ^ N |]^H J IX zx JX \ / ^BrH₂N cr NN '---</td><td>N / A</td>

<td> 644</td><td>H₂N^x^^x-^x^^S'N^x^^XAnd ^^{! X}S ^H L 1 . o ^ n ^ n M^H NH X^orO HN ~ ^</td><td> 515.00</td>

<td> 645</td><td>- z? II T&gt; ' ·. , 'i ] - ξ r Item or z z- &lt; '= &lt;' Or (\; ----- / ZI ( ) _ zx r. · z— · z M X</td><td> 557.00</td>

165

<td> 646</td><td>h, n 'ν ^Η ί Ιι .. Ν : ί χ Ο Ν Ν</td><td> 338.90</td>

<td> 647</td><td>η₂ν ν Ν 'Ν 1 ^_w^{? ΝΗ2}0 Ν Ν</td><td> 314.00</td>

<td> 648</td><td>Η₂Ν 'Ν&gt; Η: 'Ν' '' '·&gt;: ___. = \ ___ ° Ο Ν Pj ΗΝ—: ΝΗ</td><td> 500.00</td>

<td> 649</td><td>Η₂Ν Ν! I^Η ί- Μ ₌ _ ^χ^ - Ν '/ /' ' ] | '----- X. ΝΗ Ο Ν Ν - '</td><td> 455.00</td>

<td> 650</td><td>ΝΗ J .. ... .. .. η₂ν ν ν γ ΐ | -^;-Γ ^ ν -, = rx ^ΝΗί —y / &lt;,^Ν 7 Ο Ν Ν ^; 'ΝΗ₂ΓΊ</td><td> 539.20</td>

<td> 653</td><td>ΝΗ 11 .. ~ ... ... Η₂Ν ν Ν Ύ '' ίι^{Η Η} L .1. ... = ο: ΓΜ Μ ΟΝ Ν Ν 'ΟΗ</td><td> 529.20</td>

<td> 654</td><td>ΝΗ j _, _ Η_?Ν Ν '- Ν ι' ύ Η Η^k-'X ................ 'Μ θ Ν Ν ^Ν- Η: '. Ο</td><td> 529.10</td>

<img file="MX349718B_D0281.tif" />

166

IJMí Ρ1 INSTITUTO MEXICANO DE LA «.OPILAD INDUSTRIAL

<td> 655</td><td>NH eleven- HgN NN ·· - 'η H Π: | J 1 - / ONN --- ί N- . '—NH</td><td> 500.00</td>

<td> 661</td><td>NH H₂N nn γ u ' 1 ¹ N ^N · .eleven _ ' - ONN ΓΊ</td><td> 381.00</td>

<td> 662</td><td>Ó Z ^ ZZ H 4 z / \ ° w ΖΣ X</td><td> 393.00</td>

<td> 663</td><td>NH H, N '^X^ 'N ^' '' - '' '”' '' N H ^H_rΛ Χ, / νν O ^ N 'N</td><td> 435.50</td>

<td> 665</td><td>^H₂N · N |^; II _ N ___ / \ or NN 'í --- (^N- N CH₃H₃C.</td><td> 500.2</td>

<td> 666</td><td>►? z ΣΖ H TZ \ or I or</td><td> 543.00</td>

<img file="MX349718B_D0282.tif" />

167

IMPI

MEXICAN INSTITUTE

Dli LA ΙΈΩΊΕΝαι, inoujtmial

<td> 5</td><td> 668</td><td></td><td>^H L</td><td>X Ύβ-</td><td>/ = \ 0 ν — ν N—. &lt;x</td><td> 489.10</td><td></td>

<td></td><td> 670</td><td>r H</td><td>^H L</td><td></td><td> /=\ 0</td><td> 622.30</td><td></td>

<td> 10</td><td></td><td></td><td></td><td>οΑ^Λν</td><td>^ o</td><td></td><td></td>

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

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

<td> 15</td><td> 673</td><td>h₂n N</td><td>H l</td><td>\ y ° / = / o 12 X&gt;</td><td>/ = \ P v — 0 'M—. \ ZF</td><td> 531.10</td><td></td>

<td> 20</td><td> 677</td><td>h₂n ' </td><td>'NH</td><td>'N J -L / O- Ν N</td><td>/ —Yes^N~, - N ch₃</td><td> 472.00</td><td> —</td>

<td></td><td> 678</td><td>r</td><td></td><td></td><td></td><td> 514.00</td><td></td>

<td></td><td></td><td>JL^H2N N</td><td>H</td><td></td><td> /=\</td><td></td><td></td>

<td> 25</td><td></td><td></td><td></td><td>qA_nTO</td><td>PPj H \, Y)</td><td></td><td></td>

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

168

<img file="MX349718B_D0283.tif" />

<td> 679</td><td>^H/ ^ - ch₃o ^ n ^ n HJ π</td><td> 409.10</td>

<td> 682</td><td>H₂NN - 'hee^H ^ .. 1 ....., ^ ......_, or j J '/ —1 / &lt; ONN ^N-. Π. —NH</td><td> 486.10</td>

<td> 683</td><td>NH il. . . .. H₂NNN,!² Η H h / - \ P 1 Λ / - \ O 'NN' ^NM. NH</td><td> 528.00</td>

<td> 684</td><td>NH J. _ ....., - .. H₂^N N nij L. i- .... - O |^; N | J: \ / O. N ΰ --- N-- Π - / \ —N N—, OR</td><td> 641.30</td>

<td> 687</td><td>Η, Ν ^ - ^ Ν ^ ΧΧ _NH\ _ / O ^ NT'N ^ NH π</td><td> 424.00</td>

<td> 688</td><td>NH .eleven .... ...... , ...^H^^N N - N | &lt; _NH^N .....&gt; or^; NNN = O</td><td> 570.00</td>

169

<img file="MX349718B_D0284.tif" />

<td> 5</td><td> 692</td><td>ΝΗ Λ. Η, Ν Ν² Η</td><td>Ν Η</td><td>L ii Τ ^Ν° Ν Ν</td><td>- 0 \__Y Ν '.0 ñh₂</td><td> 556.10</td>

<td></td><td> 693</td><td>ΝΗ II η₂ν 'ν Η</td><td>'Ν Η</td><td>'”Ί - Ν-</td><td> .·⁼. Ρ</td><td> 542.10</td>

<td> 10</td><td></td><td></td><td></td><td>Ο ^Ν Η</td><td> ------^&gt;! Ν (/^{= Ο}—</td><td></td>

<td></td><td> 697</td><td>η₂ν '</td><td>Ν ^Η</td><td>/ X Ί and — ζ ζ '&gt;,,. / \ ΧΖ ή 1' _or-</td><td>= Ο 'II, ​​0 /-5'' /- - '' Ν ΝΗ</td><td> 694.10</td>

<td> 15</td><td></td><td></td><td></td><td></td><td>\ Xci</td><td></td>

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

<td></td><td> 698</td><td>HjN ^</td><td>Η</td><td>X χ</td><td> 0</td><td>Ν / Α</td>

<td> 20</td><td></td><td></td><td></td><td>O ^ Xn-í '^ - n^OR Η</td><td>«—Ν— \ Q. 0</td><td></td>

<td></td><td> 699</td><td>Η₂Ν ^</td><td>Χ ^ Χ | &lt;'Η</td><td>Xsá ^ x Τ X</td><td> /=\ 0</td><td>Ν / Α</td>

<td></td><td></td><td></td><td></td><td>Ο '^ Ν' ^ Ν π</td><td></td><td></td>

<td> 25</td><td></td><td></td><td></td><td></td><td>'—Ν_χch₃</td><td></td>

<img file="MX349718B_D0285.tif" />

<img file="MX349718B_D0286.tif" />

170

ΙΝ ^ Τ, υΤυ.MEXICANO ui LA PROMEIMD mOUSTklAL

<td> 700</td><td>HjN '^ Ν^{/ Χ}^ Ν^{/ Χ}&lt;\ HH \ r ° o</td><td> 577.10</td>

<td> 701</td><td>H_ZN 'N' t '.i^H 1 7·. ,-^Λ·. - = - · ... ^ = Or 'N , x, Χ,., ~ Λ. / ............... ONN - N Π. ' '. -DO NOT , s-ch₃0</td><td> 564.10</td>

<td> 702</td><td>NH H₂NNN '' i Η H : ^N -^orONN ^NΠ /. ^NH</td><td> 543.10</td>

<td> 703</td><td>X____ H ^HΛλΜΜ or</td><td> 567.20</td>

<td> 704</td><td>NH H_ZNNN: '' and '' 'N ___ ..⁼'.___? ONN —N '- + F F</td><td> 563.20</td>

171

<img file="MX349718B_D0287.tif" />

<td> 705</td><td>H, N '^^XN '^X^^XX'N^{/ X}Y^yes!T | Η Η</td><td> 528.10</td>

<td> 706</td><td>ΝΗ ] [ Η₂Ν ' ^νΝ '^ΧΧ^^^χΝ^χ^’'^&gt;^^χ'η Η Η, | '^' ΤΤΑΓμ θ 'Ν Ν Ν ΓΊ, \ Ν ch₃</td><td> 542.30</td>

<td> 709</td><td>Η, Ν ^ Ν '' ' Η 1 .i ^ΝΗ / "Λ Ο Ν]] λ - &lt;; AF^Η 0</td><td> 436.00</td>

<td> 711</td><td>Η, Ν ν 'A Η -¾. =. 0 Ν / \ 0 α Λ Ο '- ^ Ν ^ Ν ^' · Ν ΝΗ Π; \ \ ' Κ &gt;</td><td> 590.10</td>

<td> 713</td><td>X ό (ί ^^ ζχ 0 /⁼\ ° W ζχ ζχ Μ ζ Μ X</td><td> 572.30</td>

<img file="MX349718B_D0288.tif" />

<img file="MX349718B_D0289.tif" />

172

INSTITUTO MEXICANO Df LA PROPlilüAD INDUSTRIAL

<td> 716</td><td>NH TO . . ... ... H₂NNN 11 ^M ..... *. . . 0 p N '', _____ '._____ / ON ü - ^NΠ -DO NOT 'S CH_:¡OR</td><td> 606.20</td>

<td> 717</td><td>h₂nn^H 1 II. No. , .1 '—X Xx / - γ. CNN ---- HN&gt; ΓΊ; ____ /</td><td> 551.20</td>

<td> 719</td><td>NH eleven .. ... ,. . Η HI || NH N ^;r ..... .i 1 ^;.........- χ .........'..... ONN —NH</td><td> 466.00</td>

<td> 720</td><td>NH eleven .. ... . H₂NNN | - p^N_N^θ0 NN - N— HjC '—OH</td><td> 517.10</td>

<td> 721</td><td>NH .11. . H₂NNN 'X^H H¹ jfX) c ONN N--. Π —N N N '</td><td> 606.30</td>

<td> 722</td><td>NH ... ,,. H₂NN - N 'A Ί ' ' 1 · -_{or N} N --- HN N</td><td> 585.20</td>

173

<img file="MX349718B_D0290.tif" />

<td> 723</td><td>Η, Ν 'Ν γ \ ί. 1. . .. „0 - I Ι.Μ π 0 Ν Ν ΗΝ Ν 0 ΓΊ \ _______ '</td><td> 502.20</td>

<td> 724</td><td>ΝΗ eleven Η, Ν^{/ Αχ}Ν^/^ Α^χ_Ν— ^{Η Η} L 1 ΛΧλΟΑο</td><td> 593.30</td>

<td> 725</td><td>ΝΗ 1 . . . . Η₂Ν Ν '·' Ν Η Η Ιί fifteen.. -_χ Q Ν^ζ \ II, ο । '---------:' ξ _______ g'- __________, ΟΝ Ν ^ή—^? Ν Η / · .. / 7 CI CI</td><td> 736.20</td>

<td> 726</td><td>Η₂Ν ~ Ν X | ΐ 1, ! , - ο and '' 'χΑχ^-VA ° C Ν Ν ^λ—/ _{Ν ΝΗ}Μ / \ / Y \ ό</td><td> 620.20</td>

<td> 727</td><td>ΝΗ Α η₂ν 'ν ^Χ '' Α^{Η Η} 1, ί. .. - ο 'Ν' / II, Ο 1 1 --¾ η / - \ ϋ Ν Ν '-^; Ν— ΝΗ Η ·, / 0 ¹</td><td> 662.30</td>

<img file="MX349718B_D0291.tif" />

<img file="MX349718B_D0292.tif" />

174

INSTITUTO MEXICAN »'DE IA PROPERTY INDUSTRIAL

<td> 728</td><td>NH ..... Λ. ,, χ -x -. H₂N Ν 'N r' ñ^{H H} L i. - _ or N V'X / \ ΙχΟ .1 .1. i /^s / \ O Ν Ν _N- _NH</td><td> 632.30</td>

<td> 734</td><td>H; NN 'γΑ^H L if . &lt;-1. - 0. / O Ν N / -^H 0 ch₃</td><td> 404.80</td>

<td> 736</td><td>NH i ... ....... ... _ Η, Ν N '' N 0^H " OR......_N..... _ 0 | ·· Ν Λ. / _____7, ____ 0 Ν Ν N-0 NH HjC </td><td> 556.10</td>

<td> 737</td><td>η, ν ν ^^ ν υ ^ Λ² Η H 1XX&gt; ^ O ^ N ^ N HN-O^H / —Ch₃h₃c</td><td> 517.20</td>

<td> 742</td><td>H, N Ν '^H L. 'L. .. m .... - 'O -i -L. 7 — v /, A or 'Ν N' - 'N'í'. NH</td><td> 498.20</td>

<td> 743</td><td>^H k 1 . or ___ \ Ϋ y &lt;yJL^/ i</td><td> 525.10</td>

<img file="MX349718B_D0293.tif" />

175

IMPÍ

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<td> 744</td><td>NH^hM ^ XXX Π H 1 -. OR ___ \? X / \ ί! ' 1</td><td> 567.20</td>

<td> 745</td><td>NH H₂^N Ν N. No. . L '--V. ) ------ τ / ( υ Ν Ν ^v Ν X N Η</td><td> 540.20</td>

<td> 746</td><td>I N z IZ O \ = ~ 'or τζ 0 O-CZ&gt; = O 0</td><td> 523.10</td>

<td> 755</td><td>NH Ί H₂N ν N - n Η H: | ΏΎΧ- O Ν N or _z—_z ., =, X Ν Ν vy F -5- · Λ '' ΐχ ./ N —NH</td><td> 706.50</td>

<td> 756</td><td>NH H₂NNN ' Η H। | i Γ '·' -χ o N t¡ ΓΊ ... or i X ' ¹ or^—F·'--------'· N NH F3C X x. S 7 7</td><td> 768.00</td>

<img file="MX349718B_D0294.tif" />

176 i A4 p I

INSTITUTO MEXICANO IH La ^ ROí; edaí&gt; industrial

<td> 757</td><td>NH and ....... H_;, NN 'N i,&gt; H H k-, λ. _ - or N 'X- &lt;' \ II. OR J .1 .-- T / -y ON ~ ^N NH —N</td><td> 669.00</td>

<td> 758</td><td>NH H₂NNN γ · - ^ 'Α^{H H} L 11. or NN ' , =. OR &gt; / \ II.&gt; Or ? rr S ----------^:- * 'N— (NH / \ -or</td><td> 676.00</td>

<td> 759</td><td>NH eleven ........ H₂NN - N IJ ........ I θ 'NN - O s ^z \ 11 .. or 1—^s / - '' '- N NH / ΑΛ. F₃c S Cl</td><td> 802.00</td>

<td> 760</td><td>H ...... ^ .4 .. ...,._x Oh ϊ: i: i ..... 'τ ΓΑ 4 A' N ^N ---- Η N— F -^NH</td><td> 595.30</td>

<img file="MX349718B_D0295.tif" />

177

IMPI&gt; ”7 TUTO MEXICANO '*» A FROFIEDAÍ)' Mm / STRlAL

<td> 761</td><td>NH ,, _mTO ^{0 H}H_to.NN 'N 1'&gt; Λ .. ii LJ, .. _ -^L- Ν '___ / \ /% 0 N ^N ' ( ’⁼Η N—. F NH</td><td> 637.30</td>

<td> 762</td><td>NH h₂n^x^ n '^^x^^ 'n^{/ x}&gt;^^íXi Η Η Γ II / “Ά ° / - \ 1 1 7 ~ Λ Xs— N p o ^ n ^ n V / «VJ</td><td> 565.20</td>

<td> 764</td><td>H₂NN Η X. · 'N' ,1 ... ^— \ 0 N ^N 0— H</td><td> 356.00</td>

<td> 766</td><td>^{H? N} 'h' ll Ί _ O • X 1 N. · ---. ·. i '-Y ^NHONN - \^H_N TO</td><td> 527.30</td>

<td> 767</td><td>X ΓΌ z IZ \ „Ó 4 -L &lt;Λ = Ο / í T 1 ° ΓΛ ΐ Ί QX ^ O &lt;J yz j¹ i X / / \ zz Γ</td><td> 770.00</td>

<img file="MX349718B_D0296.tif" />

<img file="MX349718B_D0297.tif" />

178

INJTI1 UTO MhX'C'.N'.l

ÍV LA KKOPIrDAD

INUCSTAlAl.

<td> 768</td><td>NH .1 .. . H₂NN 'NX^{H H} L l N 'XX A. X_N TO- ONN &gt; ~ ° W —S, -.^{, J} N — NH VO or</td><td> 726.00</td>

<td> 769</td><td>NH H Η Γ o ^ n ^ n KA-tz- ' 4 Λ = Ν</td><td> 710.00</td>

<td> 770</td><td>NH .eleven ... . ... ... Η, Ν N - 'N'। Η H i ¡| 'N' S .i 1 A O 'Ν N ΓΊ or p · '\ ¹ &gt; OR γ · 'x&gt; —s; .-Y - N - ί NH OR F</td><td> 716.00</td>

<td> 771</td><td>Ί ..... Γ '1 . 1 z AONN --- ”N h₃c —oh</td><td> 475.20</td>

<img file="MX349718B_D0298.tif" />

<img file="MX349718B_D0299.tif" />

179

KSTI TUTO MEXICANO 02 LA PSOFIEDAD IHEUSTR'-A '.

<td> 772</td><td>NH II ......... H₂NNN r 7]^{H H} LL - θα 1 I \ o NN —- HN— NH H \ ___</td><td> 578.30</td>

<td> 773</td><td>Η, Ν NA ¡i^H L 1 - ₌ or _or^! yix — í m - ONN HN NH ΓΊ '/</td><td> 536.20</td>

<td> 775</td><td>^ O '¹ΟΓ zx'z- '¹) (* - 2 — X Z X</td><td> 458.20</td>

<td> 778</td><td>Η, Ν Ν ^^ Ν γΧ _ Η Η 11 1 θ Λ ^N\ O ^ N ^ N \^H -O / ^ H NX</td><td> 569.40</td>

<td> 784</td><td>X M 2 X2 X .y Q o ^ b</td><td> 459.00</td>

<td> 785</td><td>NH Ll. ....... H₂NNN -A '.^{H H} or. Ί,. N। Λ to 0 N Η NS H - o</td><td> 501.00</td>

<img file="MX349718B_D0300.tif" />

<img file="MX349718B_D0301.tif" />

180

INS rnuT ·) Y.FXtCANO

L&gt; IA PROPERTY

INDUSTRIAL

<td> 786</td><td>Γ. ... . H₂NN '' Ν 'x ^ X, H ^H L^N TT XHS · ⁷⁼T? OR -? χ / ”...... '' N - NH ~ N '/ W^s z τ - CF;</td><td> 819.00</td>

<td> 787</td><td>I N&gt; z '. ^ = Z / I , 12 -vw \ 1 .' '^x'X' ·. '' , It " J 1 T ° - yes Γ Ί o 'OZ z Z / τ ^ 2 X Y .</td><td> 743.00</td>

<td> 788</td><td>NH Ϊ - H₂N Ν X- 'N Η H^L^ A, = xo _or&lt;- γ _N / '^&gt; 9 i. τ γ, qX Ά ^ Ν Ν V Π \ 'NH</td><td> 564.20</td>

<td> 789</td><td>I fO z) xz / /..........T /&gt; \\ \ 'o: - =⁷f 'T z ⁷&gt; Y í 1 . C jl ί, T ° X x · '·'</td><td> 522.00</td>

181

<img file="MX349718B_D0302.tif" />

INSTITUTO MEXICANO OF LA PRGPILDaD INDUSTRIAL

<td> 790</td><td>NH H₂N Ν ^^ - ^^ Ν ^ γΧγ Η Η 1 | l or °</td><td> 698.30</td>

<td> 791</td><td>N z IZ or O \ = / H iz Y _vcr 6</td><td> 656.30</td>

<td> 796</td><td>,, 0 CH₃h₂n N ¡i ___., H '' —N TO _N --Ch₃A A ..^;^. / ^{0 N} «........ Ν _λNH</td><td> 529.00</td>

<td> 797</td><td>NH AQ, ch₃h₂nn ^^ n X ^ XX ' H H /-\^CH' Ο ^ Ν ^ ΠΜ. '—NH</td><td> 571.00</td>

<td> 799</td><td>h₂n ν X '' | ¡ ¹ J .'-_N^J, - 0 t X- / - / A OR^! N ü - ^HN~ ° Π</td><td> 502.20</td>

<img file="MX349718B_D0303.tif" />

<img file="MX349718B_D0304.tif" />

182

<td> 800</td><td>ΝΗ Η, Ν Ν Ν '&gt; Η Η I 0 Ν Ν π . . =.⁰'' —ΗΝ—: ο</td><td> 544.30</td>

<td> 801</td><td>ΝΗ Η₂Ν Ν '-' ν '' &lt; ^{Η Η} ... 1 ... ~, ϊ Σ Ηακ Ν &lt;=. ο X&gt; ........ S ⁰ ............., - Ν ΝΗ / Ν</td><td> 697.00</td>

<td> 802</td><td>ΝΗ 1 . ........^ΗΧ Ν - Ν · | ϊ Χ ^ Χ ' . Ο Ν Ν '₌ Ο &gt; \ ΐαο ~ Η, —S '.— '·' ^; Ν— 'ΝΗ Q ) Ρ h₃c</td><td> 680.00</td>

<img file="MX349718B_D0305.tif" />

183

IMPI

INSTITUI D MEXICANO

OF PKOPIETY

INDUSTRIAL

<td></td><td> 803</td><td>i zx \ 1 ..... K f í: Γ 'V' ^z° / -. \ or 1 .—_to or ω --- ' / / ΓΊ 5_" ^X- z fM I</td><td> 769.00</td><td></td>

<td></td><td> 804</td><td>1. 8 '0 p C i 9 ZI 1 zi '</td><td>N / A</td><td></td>

<td></td><td> 805</td><td>I 1 AVJ * \ AA $</td><td>N / A</td><td></td>

<td></td><td> 806</td><td>H₂NN j ''^N'- ONN ' j. -⁰ O. .;&gt; - S NH^and '—HN /</td><td>N / A</td><td> 1</td>

<img file="MX349718B_D0306.tif" />

<td> 807</td><td>'.- •' χ - · · - γ, - Η₂Ν Ν γ ιί^Η L 1 „ ΟΗ- Ο - Ν Ν é.^/=\ ° ο i \,; ^{Yes ΝΗ} . ^: ΗΝ—</td><td>Ν / Α</td>

<td> 808</td><td>ΝΗ Η, Ν ^ η ^Η 1 II ΤΤ7- (τ'Ά 'Ν ΓΊ / = \ Ρ Q νη₂</td><td> 542.30</td>

<td> 809</td><td>1 υννν X ^ zr d / = \ ° Γ $ ζ CN Ζ</td><td> 523.20</td>

<td> 810</td><td>ζ Μ ζ ρ _ο ν ^ / 'ϊ</td><td> 453.00</td>

<td> 813</td><td>m /^zb 4 ζ / = ¿O Ό ΖΙ Η ζ IM Τ</td><td> 497.10</td>

185

<img file="MX349718B_D0307.tif" />

«NST1TUTO Μ u« ομϊζϊ:

<td> 814</td><td>η, ν^{χχ /}^ ν^/ΥΧ^Η LJ1 ^ 4. '\ Ο ^^ Ν '' Ν ΝΗ Π «J ο ΗΝ— '</td><td> 424.00</td>

<td> 815</td><td>I ro ζ Η ΙΖ χζ ' X; 5</td><td> 466.00</td>

<td> 816</td><td>Η, Ν '^Χ^^{χ /}^ Ν '^Χ^ γί^:&gt;&gt; ^Η X 1 οΑΑ Αμη b ΗΝ— '</td><td> 424.00</td>

<td> 817</td><td>ΝΗ eleven " .. . Η₂Ν Ν '' Ν γ-Χ^{Η Η} . Ν. - 'Ν ____ Ο Ν Κ ΝΗ \ ΗΝ—^Ζ</td><td> 466.00</td>

<td> 819</td><td>Η, Ν ^^^ Ν '^ ΧΧ^Η L 11 Ο '^ ΙΨ ^ Ν υ Ν _Η (^N i-CH,) —ΝΗ H₃C</td><td> 514.30</td>

<img file="MX349718B_D0308.tif" />

186

IMPI

ΙΝ.Π ll'UTO MEXICAN

Oh LA PROmOAO industrial

<td> 820</td><td> • ZI ·. / · Z « 'i. / X --- í OK b Λζ ./ 1 ['z ) —V P._. .-two. 4-0 / T - £ "LJ '.ΛΛΛ / ( 1 ZI x / z Λ X</td><td> 556.30</td>

<td> 821</td><td>^H l 1 ZXH o ^ n ^ n S ΓΊ z = \ / ° () -^ch= '—NH</td><td> 500.20</td>

<td> 822</td><td>NH II H₂NN _N Ύ'-η^{H H} I. II. J .1 '.....? ONN ' Π , - or &lt;N- ( ^CH3 \—_NH</td><td> 542.30</td>

<td> 823</td><td>H₇N^x^^ - ^^ N '^x^ X^{: í :: í}X₁^H LX / 5 o ^ n ^ n ⁵r— NH. 4Q p -s &amp; S — NH ° \\ O</td><td> 536.10</td>

<img file="MX349718B_D0309.tif" />

187

IMPI

1Ν &lt;ΤΙ ι UTO XtCANO

ΓΛ INDUSTRIAL PROPERTY

<td> 824</td><td>[ll vix 9 \ / _HN—Z NH</td><td>Ν / Α</td>

<td> 825</td><td>H₂^N n ' Ο Ν Ν , =. Ρ ~ f ',. '· Γ ^. '' -^J ,^Ν~ \ — '-----------------, F</td><td> 532.20</td>

<td> 826</td><td>ΝΗ -_:.Ν Ν Ν 'ίι² Η Η || . Y 'Ν: 1 .L Ο Ν Ν &gt; 7 / \ - Ν— \ —Ν \ F.</td><td> 574.30</td>

<td> 827</td><td>Η, Ν '' Ν '' -τ ''. I Η 1 ΧΜ Μ ' _ο. _Ν Ν --- ΗΝ ΟΗ</td><td> 461.20</td>

<img file="MX349718B_D0310.tif" />

188

IMPI

MEXICAN INSTITUTE

IN THE PRQPIEUaI »INDUSTRIAL

<td> 828</td><td>NH Y H₂n 'N - N - j^{H H} k 1. 'T ΓΜ- ° Ν N / = O '' '-i - c _H^X_N- -OH</td><td> 503.10</td>

<td> 829</td><td>&lt;- c^{H, N} 'I 1 ..... or '[I —i&gt; - or N - HN ~ ^NHH</td><td> 501.40</td>

<td> 830</td><td>H₂NN i H k- J. OR - N r '' i - 0 J. / ....... k \, k Sf NH O N ..... N ---- N ¹ . Γ. .or</td><td> 634.30</td>

<td> 831</td><td>Η, Ν N t]^H L.1 _ o - N r '। OR eleven :¹—V -^s —^NHON ²- N— . OR</td><td> 634.30</td>

<td> 834</td><td>H₂NN '' I^H L 1. N -'i- J. ,, l \, O 'Ν N' —N; Yes H₂</td><td> 438.00</td>

<td> 835</td><td> _ ^{H H} i ii * nh₂</td><td> 480.00</td>

<img file="MX349718B_D0311.tif" />

<img file="MX349718B_D0312.tif" />

189

INSTITUTO Ml.'UC. '. I'O rt Ι.Λ i'PGI'IEDAD INDUSTRIA'.

<td> 836</td><td>NH H_?NNN γ ^ · | Η H [j NH Io _ O 'NN -----,. · ------' 0-V'H 0</td><td> 578.30</td>

<td> 837</td><td>NH TO ..... ~ ^N A ~ «...... f) Ιϊ&gt; NN ₌ 0 5 / . H θ Ή .. ^^sl .— ·. '' N—; NH i \ NN C₂H₅</td><td> 714.00</td>

<td> 838</td><td>NH • L ~ ~ h₂nnnj.^{H H} k 1 - 'IA t 0 Ν N . --- 0^H? \ t.0 - N— (NH _: . . ...Y A v. —N</td><td> 697.00</td>

190

<img file="MX349718B_D0313.tif" />

<td> 839</td><td>NH II ... .....^HzN n - N γ 'N' 'γ'ϊ. &gt; J ... I rr⁰ NN c ⁰ OR -íH / i — S '· - '' '--- N — i NH N—</td><td> 703.00</td>

<td> 840</td><td>NH . 'N Ό' Λ '= i .1 go 0 NN __ 0 &gt; 11.0 i — x ^s '/ N— \ NH &lt; C)</td><td> 688.00</td>

<td> 841</td><td>c 'zx \ / &lt;^{7 ;}z W i Γ ^ \ ^Ο Γ 1 £, =: ^ 4 1 .. JO \ \ ο-φ ^zzx i / ⁵ J ZX • x.-u- z χ¹</td><td> 750.00</td>

<img file="MX349718B_D0314.tif" />

<img file="MX349718B_D0315.tif" />

191

INSTITUTO AUXICANO Oí LA PROUEOad INbtISIRlAL

<td> 842</td><td>NH 11 ~ .... ' h₂n ν ν 'ι Ίι² Η Η 1 j | ......... r \ i '⁷γ Υ _ | _ O Ν N ' . .____ OR yj '........., __ ii ao? \ //^s._ / \ - &lt;— _N—, _NH\ '-----------------' CN</td><td> 645.00</td>

<td> 843</td><td>NH H₂NNN i 'i^{H H} L l .. Ν τ 'S .i .1 -p- _ O ° ^N H &gt; / \ -O -------- S. ·, ---------- · .. N NH ;-or H₂N</td><td> 663.00</td>

<td> 844</td><td>^{H H} L II s / = \ ÍL.O '---' ....... 2 X - o</td><td> 676.40</td>

<td> 845</td><td>Jt__ Η.Ν ^ νΧΧΧ ^ Ν ^ ΆΥ^{H H} 1 JL o- ^ n ^ n "HXX^-Ύ &lt;~^nh? \ Y \__or</td><td> 676.40</td>

192

IMPI 6 'NSTIFblV MEXICAN X □ t PROPERTY C'. INDUSTRIAL

<td> 846</td><td>h₂nn^H Χ λ .. - N 'T' í&gt; .1 / ί- ο NN - or _ S. - '1 LO A, S NH^? 'N-Ά) / O or /</td><td> 636.30</td>

<td> 847</td><td>I z 1 \ or ° η^Λ° or OJ __ / or XZ vvv 1</td><td> 487.20</td>

<td> 848</td><td>NH .1 4 ... / 4. Or .4 ... h₂n ν '' γ ¡i^H L 11. .. ...... 'A' N '·' '3 XX / Το 'NN Π . ,, = 4. 0 TT, /, --- {.., NH 'HN— (N '' nh₂</td><td> 585.30</td>

<td> 849</td><td>X z 1 zz ww 1</td><td> 438.00</td>

193

<img file="MX349718B_D0316.tif" />

<img file="MX349718B_D0317.tif" />

INSTITUTO VtX'C.ANO Dt LA PRONLDAD INDUSTRIAL

<td> 850</td><td>NH H₂NNN&gt; '' 1 Η Η 1 | ONN 'ΙΊ : nh, ' Ν</td><td> 480.00</td>

<td> 851</td><td>Λ / Τ Λ / V '' 21 C '' Z r, '' - v _ v, ·&gt; O j, O \ · \ // z— 'O- ω ( 1^zi Ii 'ή \ 'r. ) v'WV , 1 r ^ZIz.— </td><td> 678.40</td>

<td> 852</td><td>I z IZ 3 γς Q Ó I</td><td> 536.20</td>

<td> 853</td><td>Λίνν R! / = (^ ° o If O cz CM X</td><td> 550.30</td>

<img file="MX349718B_D0318.tif" />

<img file="MX349718B_D0319.tif" />

194

INSTITUTO MEXICANO ΩΓ LA moPIH) AT&gt; INDUSTRIAL

<img file="MX349718B_D0320.tif" />

856

<img file="MX349718B_D0321.tif" />

195

<img file="MX349718B_D0322.tif" />

i; ύ β ό fr

1 1

INSTITUTE · μ?. ·; Ονο

DF LA ΓΚΟΠΕ:) AD industrial

<img file="MX349718B_D0323.tif" />

<img file="MX349718B_D0324.tif" />

κ. \ * ί «. · Λΐ. '. τΑΑί .. *: ν wsvr = w_T» i ». ιζ—. ♦ .. ·. »

196

<img file="MX349718B_D0325.tif" />

<td> 862</td><td>NH H₂NNN '' Y'X hh | || n ^ -Ύ. | or NN &lt; / = or? ⁷ \ II, 0 /^;~^s' '—\ ^S - 'N \ NH Ί NN. NN</td><td> 738.00</td>

<td> 863</td><td>NH Η, Ν NN Ύ .i² η hj || Ύγη ONN Π 0 A.M^ífl ,— ^Y DO NOT / 1 — sch₃ Cl</td><td> 803.00</td>

<td> 864</td><td>NH J1. ... ..^{H H} L 1. N Ύ '' \ é O 'N ñ - or 5 &lt;\ II. 0 '' HN Ó.</td><td> 579.00</td>

197

<img file="MX349718B_D0326.tif" />

<td> 865</td><td>ΝΗ Λ .. ... ... ... Η₂Ν Ν Ν Υ Η Η |^Ν » Ο Ν Ν ΓΊ , .------ · ο 7 / \ Η 0 .&gt; - s. · - &lt;-¹ Ν— 'ΝΗ / —Sch₃</td><td> 768.00</td>

<td> 866</td><td>ΝΗ Λ. .. ......... Η, Ν Ν Ν 7,² Η Η] .ι .1 ' Ο Ν Ν ' , = ο ^Η? 7 \ II .Ο -η 'Ν — ΝΗ '\ _____ / [&gt; -1 ^Ν</td><td> 709.00</td>

<td> 867</td><td>Ο ^^ Ν ^^ Ν '- / \&gt; Η η₂ν</td><td> 447.30</td>

<td> 871</td><td>JC Η₂Ν Ν ^^^/^ Ν''Υ ^ ηΐ ² Η Η [1 Υθγ π ? A / ~ υ / \ -^J ΗΝ— &lt;ΝΗ</td><td> 578.30</td>

<img file="MX349718B_D0327.tif" />

<img file="MX349718B_D0328.tif" />

198

INSTITUTO MEXICANO Dt LA ΡΚΟΡΙΓΏΑ1 'INUUSTkiAL

<td> 872</td><td>NH II. . HoN Ν N 7 ii² Η H | || ° Ν N --OR _x ...... Yk ° 'N--, í CH, '--- NH h₃c</td><td> 592.20</td>

<td> 873</td><td>1 ΛΥ. ϊ F j '1 1 I^Z η ° 1 - 0 - z / o = &lt;p : '·'. · (Í 1 ,^ZI X 1 Z &lt;N z</td><td> 516.30</td>

<td> 874</td><td>^H 1 II ° Ν N 7 — H 5¾ / \ __ / o or ^λ—NH</td><td> 619.00</td>

<td> 875</td><td>I ro ZH IZ ^ZZ^ 2</td><td> 661.00</td>

<img file="MX349718B_D0329.tif" />

<img file="MX349718B_D0330.tif" />

199 institute / mexican

Say THE INDUSTRIAL PROPERTY

<td> 876</td><td>X M z Vz / X xz \ 1 / . _Ύ„·. / «1 i ^}1, ω = Ο / iy τ ° / ν '1' 1 ti ' or ' ^H7 ! \ XZ _w</td><td> 769.00</td>

<td> 877</td><td>X z Λ — Z - X w- ^IZor &lt; . . A or - I i FY¹ &gt; íj, or i — zz β xz 1. -, ..</td><td> 727.00</td>

<td> 878</td><td>NH^H4'........ Ν γΧγ_ /⁼\ uo / -¹ N— \ NH O = b oc₂h₅</td><td> 704.00</td>

<img file="MX349718B_D0331.tif" />

<img file="MX349718B_D0332.tif" />

200

INSTITUTO vEXICAN; &gt; Df LA PkOFIEJAll INDUSTRIAL

<td> '879</td><td>«J-'UV.P · F ^ΖΣ&gt; ..... ' , 77 fO_z . or. or - 'í' ⁰/ - 'θ l 'X' - ' w 1 1 i Ο = ω y zz A. - IJ . TO '. ΛΛ, V ! '| ZI z = / z CM T</td><td> 771.00</td>

<td> 880</td><td>NH 1.......... Η, Ν N 'N,^{H H} L l. 1 1 '........ ί- ο 'NN ΓΊ , - or^c,. ii or ..... í ..... c s- ... '' '........... N ...... &lt;O OR F</td><td> 717.00</td>

<td> 881</td><td>^H2^N HTI - ~ / NH eleven ^v x ^Hr O 'NNS M! \ J or</td><td> 488.10</td>

<td> 882</td><td>NH eleven. ... .... ....... ..... Η, Ν NN^H . N .. o A r</td><td> 501.10</td>

<td> 883</td><td>H₂N ^^ - ^^ '- L ___ í JL 2— \ / -^Br</td><td> 461.10</td>

201

<img file="MX349718B_D0333.tif" />

<td> 884</td><td>η.ν ν yy _H3c ........................ Ο Ν Ν</td><td> 376.90</td>

<td> 885</td><td>ΝΗ^ΗίΝ S ..... ^ ΣΣΣ ....... _ - Γ Ν '. '\ 1 ί --Λ / ---^Br ° ^Ν Ή ~</td><td> 493.10</td>

<td> 886</td><td>/ = ° \ ~ X. XX /^—\ X—^ΒγΓΊ</td><td> 453.20</td>

<td> 887</td><td>ΝΗ Η, Ν '^ Ν' ^ - ^ Χ ϊ | ? - 6&gt; -sy— ν ην — ς \ η</td><td> 501.30</td>

<td> 892</td><td> 1 ^Η2Ν Í1. ! 1 Ί X Ο Ν Ν₍ ----- Ο ί RO ? '% ν^s . ' ^ν ’ ⁵--- 'ΗΝ— \ ΝΗ'</td><td> 550.17</td>

<td> 893</td><td>I ΙΟ ζ ΙΖ / vpv) δ J ζ_Λ= ° Σο δ Σ ί 1</td><td> 592.30</td>

202

<img file="MX349718B_D0334.tif" />

Say INDUSTRIAL PROPERTY

<td> 894</td><td>h₂nnpj Ύ ..... ONN OH O / - &gt; N ..._Λ; \ oh N -NH</td><td> 589.00</td>

<td> 895</td><td>Λ.'Ύ ...... ^zZ— / = \ ⁰ δ 0 1. OR A - I i, i * í ziz i ' ^¡zx. 1. .. z, 1 T . Ha r zi^z~ - ' z I HEARD r</td><td> 631.00</td>

<td> 896</td><td>Cl ci / ... ... .. ... / H, N - N - 'Ί) - Y Y-Π M O 'NN “S n 7th OR</td><td> 646.30</td>

<td> 897</td><td>NH h₂n^x&gt;^ n '^x^^ n-- ^{H H} L JL jOch „__ or "?TO \ /-\ N — ς NH F.₃c- ^_n, nh</td><td> 754.00</td>

203

<img file="MX349718B_D0335.tif" />

<td> 898</td><td>ΝΗ eleven. . . . . Η₂Ν Ν Ν 'ν' ¡)^{Η Η} L i ...... t Τ Π- ° ^Ν..... Η ξ. ⁼\ ° ... ο 7 &lt;·, f — S '--- '' - 'Ν —... Ο' \ _______,^{? Cl}CI</td><td> 737.00</td>

<td> 899</td><td>Γ. .^ΗϊΝ Η ....... Η ...... Γ 11 V, - _Ν ν. - Λ J--._NΤ ο ^Ν Η Ο ¿—And and --- S '.^C Ν--¹ ΝΗ Ν— / \ \ / —Ν ch₃</td><td> 718.00</td>

<td> 900</td><td>ο '—ΝΗ</td><td> 529.40</td>

<td> 901</td><td>ΝΗ eleven . . ....... Η₂Ν Ν Ο Ί- 'ΐι η ι. I. _____ 'V' Ν / ...... „ [J ^-----.? Βγ Ο Ν Ν '</td><td> 497.10</td>

<td> 902</td><td>Η₂Ν '^^^' Ο '^ γ ^^ ϊ | /⁼\ = JL JL / ^ΒΓ</td><td> 455.00</td>

204

INSTITUTO MEXICANO DE LA NOPIEDALl INDUSTRIA!

<td> 905</td><td>X z xz 5</td><td> 431.20</td>

<td> 906</td><td>NH .—, Ii. .. ..,. . / / H₂NN 'NA' ^x| ur ^ == Η H ^HsC o Ν N</td><td> 473.20</td>

<td> 907</td><td>h ^H eleven FOR Π ύ ^^οηnh₂</td><td> 489.20</td>

<td> 910</td><td>z \ ,.4. J-, x ¿J ”I τ - '. x X // X X 0 x 1 X j V / ¡\ TZ Ά</td><td> 612.00</td>

205

<img file="MX349718B_D0336.tif" />

IMPI

INSTITUTO MEXICANO DF! -A INDUSTRIAL PROPERTY

<td> 911</td><td>NH II ......^HzN Η Η [II , 1 .1 'x- ON O --- nh₂/ —Ν; - - - &lt;'--- O / N—, NH</td><td> 654.00</td>

<td> 912</td><td>NH^H V z = x θ hn— \ ih</td><td> 502.20</td>

<td> 913</td><td>NH 1 . H₂NN Ν Ύ 'n Η H | | [ 'ⁱ⁵'N' V '⁷ í i .1 c- Cl ^N H α;_r &lt;! NH -ξ- r - —S- or °</td><td> 688.20</td>

<td> 914</td><td>I N z ° ° ²w ^IZ\7</td><td> 605.00</td>

<img file="MX349718B_D0337.tif" />

206

IMPI

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

<td> 915</td><td>F H₂N N '^ x ^' '' N '^ AAA | H ^H 1 II Γ7 / ^ bZX ° TO or.</td><td> 647.00</td>

<td> 918</td><td>^H L 1 aOCHu in h __ CF, HN- \ h</td><td> 554.30</td>

<td> 922</td><td>Γ ....... ... HN N 'Ν A π^{H H} L 11. x ··· n ..y_ O 'Ν N ^¿i&gt; / ^ λ θ .o “A .M / - '^{i 7}—/ _NHb- F₃C</td><td> 770.00</td>

<td> 923</td><td>- / H₂N 'ν' '|| '^H / r- '-A Χ' / NH b - ⁿ ’ ° ^N H ^ñ or or</td><td> 586.30</td>

<img file="MX349718B_D0338.tif" />

<img file="MX349718B_D0339.tif" />

207 I instituted ·. · ·&gt; ϊχιο · .. · ιυ nt la ¡· Ι! ο: ·: εοαι&gt; INDUSTRIAL

<td> 924</td><td>Γ '' 4 * 4 4 * '.. 4- · ^ O. H₂NNN&gt; Η H^N &gt; τ ° NN =. 0 ? , ·. 11 ^ 0 -ξ-κ.? - s _; ' ^λ HN — I NH . /</td><td> 558.30</td>

<td> 925</td><td>NH r -'- 4 ··. .... HN N - t. OR · 4. 4 0. .. - 0 '' N γ ·, / '...... H ^ O ONN -^Z HN NH H ___ /</td><td> 541.20</td>

<td> 926</td><td>X I f ZT ZI ZI ^zT</td><td> 530.30</td>

<td> 927</td><td>Η₂Ν '^Χ^^^ΧΟ '^Χ^ γΤ \ -, == 0 X JL / \ O ^ N ^ N HN— &lt;NH H \ /</td><td> 501.00</td>

<td> 928</td><td>NH Λ 4 ...... rr Η, Ν N '0 r ·' η^h I. Y .. Neither 1 f rr or NN • Π 4, = O 2 - '\ 7 '—9 HN- · NH</td><td> 543.30</td>

<img file="MX349718B_D0340.tif" />

208

IMPI

MEXICAN INSTITUTE

OF THE PROPERTY

INDImTRiAL

<td> 930</td><td>NH 11 H_?N Ν N 'ί^{H H} J .. Ν -χ-'λ L .1, 1 x^_O Ν 'N^OR .X '\ NH -íx N _J κ \ / S -. * 0 0</td><td> 628.40</td>

<td> 931</td><td>X not z O Λ) 1 O / = / O ° g</td><td> 487.30</td>

<td> 932</td><td>NH or . . ... .. Η, Ν N x OY 'í^H . i]._nX · - p'- 'N :,' '. P I, -L -............. 0 7 Ι- ΟΝ N - N, ΓΊ _x- NH</td><td> 529.30</td>

<td> 933</td><td>fi Y PQ / ¹X</td><td> 651.00</td>

209

<img file="MX349718B_D0341.tif" />

<img file="MX349718B_D0342.tif" />

<img file="MX349718B_D0343.tif" />

210

IΜ ΡI

MEXICAN INSTnnTO

DF THE INDUSTRIAL PROPERTY

<td> 937</td><td>NH Η, Ν N '' Ν Λ h Η Η I] Ϊ 'i O Ν 'N Π , ch₃N —OH N—- —NH</td><td> 601.00</td>

<td> 939</td><td>I NJ z IZ $ saw IZ 0 / -iP or z- / ii V or</td><td> 488.80</td>

<td> 940</td><td>NH Λ. . .... ..... H₂NN Ν γ || ....... O Ν N O CH₃N -Xi) OH &gt; b / ·? --- /^N—NH</td><td> 615.00</td>

<td> 943</td><td>NH TO η₂ν n - ν γ g, Η Η 1 | or ^N N ' = - OR _ S / λ ~ F '/ Ν N— H \. ,</td><td> 624.73</td>

211

<img file="MX349718B_D0344.tif" />

<td> 944</td><td>ΝΗ J). η₂ν Ν ν^{Η Η} L 1 .. 'Ν' Α, 1, 1 ΟΝ Ν_r CF₃ΗΝ - \ ΝΗ</td><td> 596.40</td>

<td> 945</td><td>χχχθνο ο / CI CI</td><td> 637.00</td>

<td> 946</td><td>I 'ζ \ __ / '\\ ο Ή '^Ην ί Λ ............. \ ΙΖ ' 1 ο .. '· ζ · Η - \ Ο / Ί J (\ '-'Ζ τ</td><td> 589.00</td>

<td> 947</td><td>Ν η^Η eleven ΧΐχΟή ^ Ο</td><td> 603.00</td>

212

<img file="MX349718B_D0345.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<td> 948</td><td>h₂n -yn J .7. '—7 so /_NHO Ν N ^: N .J ΓΊ i '' N '!</td><td> 604.00</td>

<td> 949</td><td>1 i I KJ z&gt; 5 zz J Γ} or yVVV »1</td><td> 731.00</td>

<td> 951</td><td>NH eleven ... ... .. . H₂N Ν 'Ν X HH: | '' ΓΤΧΣ &amp; Ν N what ch₃) —Ν N h '· \ / f N — and —NH</td><td> 648.00</td>

<td> 952</td><td>Z N3 Z zz IZ oo 2 = 7 H ZZ η _______1</td><td> 498.20</td>

<img file="MX349718B_D0346.tif" />

<img file="MX349718B_D0347.tif" />

213

<td> 957</td><td>1 X '' ΖΙ ^!/ \ ' Ϊ Ζ \; OR. ,: ζ — X 'X . ^ν· ¹ 1 Ο. . . &lt;1 X f χ 1 '&lt;—- O, J ,, I / Ζ 'ζ '/ J ... ζ 1 • Γ ° ϊ 1.&gt;, Χ ζχ X / Ζ — Á ζ Ν τ</td><td> 665.40</td>

<td> 958</td><td>ΝΗ Η₂Ν Ν '' X^{Η Η} L 1. ο Ν Ν 8 Ζ '' 1 -X Χχο. · - ·_χ- Ν ΝΗ ΗΟ k, ''</td><td> 662.00</td>

<td> 959</td><td>H₃x ^ Τιΐ ^Η L i Λ.Χ 'ΓΊ χθχθ^Η</td><td> 618.00</td>

<img file="MX349718B_D0348.tif" />

214

I ο ρτ, Λλ k 1

Mexican INSTITUY OF INDUSTRIAL PROPERTY

<td> 960</td><td>A, ~ a zi H i. &lt; ^z \ \ 'TO - &lt;^Z OO \ ... ^z/ \ TO-^z- z ⁷ ° 'J. Yes: . X ZT X Z z I heard X</td><td> 679.00</td>

<td> 961</td><td>^H2N^ T ^ χοχΓΊ 4. / Χ-Λ. , ο Ν</td><td> 611.00</td>

<td> 962</td><td>HE HAS.. Ν | 1 χΐχχΓΊ ¡) = Ν \ - L. _χο Ν</td><td> 625.00</td>

<img file="MX349718B_D0349.tif" />

215

ΙΜΡΙ6

MEXICAN INSTITUTE OF INDUSTRIAL LITTLE

<td> 963</td><td>NH 1 ' , A., Α'Α. ΑΆ H₂N ν - N 1-^{H H} L1 and χΥγ OΝ N ^sΠ F XX O / - N, H^N—NH</td><td> 665.00</td>

<td> 964</td><td>1 JW H Jk npv 0 ZT TT 1 ZX X</td><td> 662.40</td>

<td> 965</td><td>^h*ⁿ i νΎ Ap o</td><td> 477.20</td>

216

<img file="MX349718B_D0350.tif" />

<td> 966</td><td>NH Η H₃N Ν Ν Η ' Ν Ο Ν Η ^ Τ-7-, Ο ^^{eleven Ο} ~ ? Λ /: S: '. &gt; Ο '' / -^ζ ν— ΝΗ \ CI CI</td><td> 712.00</td>

<td> 967</td><td>ΝΗ Η₂Ν Ν 'Ν Η | ; | ° η₌ ο S 'L.0 Χχ. ys; , - \ '' 'Ν - ΝΗ \ \</td><td> 664.00</td>

<td> 968</td><td>^η ΈΧ j — Χ-Ι- Ο ^ Ν Ν 1 · Ο “\ 7θ &lt;^Ηto</td><td> 641.00</td>

<img file="MX349718B_D0351.tif" />

217

Τ Λ VI 1 Χ'Ι Τ 1

INSTITUI '.) .MEXICAN

Dt THE iP.OEIFJIAD

INOUST1IAL

<td> 969</td><td>NH H_?N Ν N^H ί 11. '..... IΓΗ- 0- VN &lt;= O S \ ME - | Y ./--se.⁷ 'N NH / \</td><td> 608.00</td>

<td> 970</td><td>NH Η, Ν N 'x' N ^ 'X', i^H «L 11 τχι ON “ 'F Q / - ( Vn f ,. = {H \\ __ p N ™ —NH</td><td> 607.00</td>

<td> 971</td><td>NH eleven ...... . H_?NN Ν Ύ '^{H H} L 11. N '7 1&gt; 1 .X '"0 O 'Ν' N n O / cf₃ Xn / ^ \ ^H^—-Y /) / / .1 N— .. NH</td><td> 625.00</td>

218

<img file="MX349718B_D0352.tif" />

INSTITUTO MtXICANO Pt LA PMOPIÍDAD INDUSTRIAL

<td> 974</td><td>NH H₂NNN Ύ T^{H H} L i. . J 1 ONN ocf₃. HN / 'b</td><td> 543.10</td>

<td> 975</td><td>NH Jl .. .. 4 .4 H_?NN '' N 'or Ί Η H | I'llX 0 NB ocf₃e, ---- XX - ' '1 ;! or</td><td> 528.20</td>

<td> 977</td><td>NH eleven . . . . Four. H₂NN - NYN γγ_ OH, Α M ONN , = 0 í \ II 3 / —so '-4 / 1 HN / 4, Ύ 1 Χ, ο-ΝΗ</td><td> 546.70</td>

219

<img file="MX349718B_D0353.tif" />

<td> 978</td><td>NH or . . . . H2N Ν Ν Ύ'Α Η π /, A, -¼ .. '[1.A._F O Ν ^N^F___ H f ^ / F. O&gt; = &gt; -N ' CH / &lt;j N—., NH</td><td> 655.40</td>

<td> 979</td><td> 0^X/ A.,. 1 ,. ,or 1 J / '1 / - ¼ -A v T js : -. .- · · - - &gt;; a ° 1 II .1 9 / Y x ..ν · .η., I /^{HI 1}Z =^zz CM X</td><td> 736.40</td>

<td> 980</td><td>'NH jl. _ H₂NN - - N ^ '-A' -J^{H H} L. 1 ... ..... N '- //. 1 AA " ... you 'Ν N' ί T _ , 1 / NH -A Ν 'J S. k °</td><td> 636.60</td>

<img file="MX349718B_D0354.tif" />

220 - ··. ·· J.; '

INSTITUID ΙΙΛΙ &lt;&gt; x: V'- l · ΠΕ LA MOhhMAi 'Á.

INrMISTRlAt X '“&lt;··

<td> 981</td><td>NH Λ ...., ,, ...^{H: N} a 'κ γ ..... ¡ ° ^N H ^?toⁿ 21 J s T a No. NH</td><td> 645.00</td>

<td> 982</td><td>NH H₂NN ^N I k A to L, k -. ΐ I H- O Ν N - Λ \ H / / —F o; = z . / '^N3 Π H -5-(, /? N ^. / \ NH</td><td> 637.00</td>

<td> 983</td><td>h₃c ... ... HC Γ 1 h₃c _N . .1 _N . OR ^N'H - Á ° .. Ά á ^s ° / NH - ^N x ' í ί ci^rCl</td><td> 665.00</td>

<img file="MX349718B_D0355.tif" />

222

987

<img file="MX349718B_D0356.tif" />

INSTITUTO MÍXICAW DE LA PROPERTY C

INDUSTRIAL "

988

989

<img file="MX349718B_D0357.tif" />

632.00

767.00

647.00

<img file="MX349718B_D0358.tif" />

<img file="MX349718B_D0359.tif" />

223

1Μ ΡI &amp;

Mexican INSTITUTE IIP LA ZROEIEOAD INDUSTRIAL

<td> 990</td><td>. X N9 IZ A = z / X xz / b- - ··. / \ JSJ Sj,. · '· 1&gt; = ') - / / í / - 'xz °^MZ) ° X, z ..... i. 'or' - / X / · -z 'd ____ // xZ</td><td> 648.10</td>

<td> 991</td><td> ?^H . . . . H₂N Ν 'Ν Y ΐ^{H H} x 1 .., Ύ ^ 'Χ^ζ..χ ΓΛ ° ^N " f NH ' T _r \ j NH ΐΎ or^?'°</td><td> 627.40</td>

<td> 992</td><td>NH TO .... H₂NN 'Ν X Η H ll 0- NN Π ..F X \ / NH Ύ, NJ No. 0</td><td> 666.50</td>

<img file="MX349718B_D0360.tif" />

<img file="MX349718B_D0361.tif" />

224

994

INSTITUTO MEXICAN) DE LA PROPIÉDAO INDUSTRIAL

638.40

996

<img file="MX349718B_D0362.tif" />

NH

NH jl H₂NNH

<img file="MX349718B_D0363.tif" />

<img file="MX349718B_D0364.tif" />

<img file="MX349718B_D0365.tif" />

752.00

646.40

225

<img file="MX349718B_D0366.tif" />

ΊΝ.'ΊΊΤυΤβ MEXICAN »e la r» orieoA9 INDUSTRIAL

<img file="MX349718B_D0367.tif" />

<img file="MX349718B_D0368.tif" />

226

IMPI

MEXICAN INSTITUTE

DF THE industrial PROPERTY

<img file="MX349718B_D0369.tif" />

227

<img file="MX349718B_D0370.tif" />

<td> 1003</td><td>। v UW Λ Ο¹ / ⁷Ζ ζ — χ Μ * Α ₅V / 'Α' _Γ- \ / '° k,. X i ζχ ° ' ^ΖΙί III / · '. , ·&gt; · \ ¹ζχ ¹X / ζ = ζ I</td><td> 720.00</td>

<td> 1004</td><td>ΝΗ J .......... . ,. Η₂Ν Ν X Ν&gt; Η 1 || Τ ΤΜ Ο Ν Ν = 0 S / \ IUO Υ / ^ 9, -— \ - 'Ν ΝΗ X, ^ Ν^-Ν °</td><td> 686.00</td>

<td> 1005</td><td>ΝΗ Λ ..... Η₂Ν '' 'ν' 'Ν ^ Ά' 1^{Η Η} L Λ ... X J&gt; _ ο ^Ν Η Ν X.¹··. _r /. ΝΗ Ν'Χ. Α '' Αο 0</td><td> 649.60</td>

<img file="MX349718B_D0371.tif" />

228

IMPI insti rim&gt; Mexican OF LA PROPERTY INDUSTRIAL

<td> 1009</td><td>I i Λ 1</td><td> 659.00</td>

<td> 1010</td><td>1 , Ό 'X / V C zr \ / / Ά b A (\%;&gt; 1 ΙοΌ 7— '' ', \ or or A ° L⁷^ ' zz o = »' / (.-¹ } 1 \ 1 _zxZ = r z CN X</td><td> 740.40</td>

<td> 1011</td><td>NH O H₂N^/^ N^x^^X^^ N '^ V ^&gt; i Η H [Jl O ^ N ^ N -L / \ _ ^ o N ^ -</td><td> 702.00</td>

229

<img file="MX349718B_D0372.tif" />

<td> 1012</td><td>ΝΗ I ... .. -. ... Η₂Ν Ν Ν 'ι Η Η_Ν τ ..-&gt; 1 ... ι. ^ζ 5 ° ^Ν Η ' ι X F₃CO ι_r \ / ΝΗ ? χ Ν 'Μ' S ¿°</td><td> 718.50</td>

<td> 1013</td><td>ΝΗ 1 . η₂ν Ν Ν τ ι . ^Η Η ¹. | i I 'Χ- . Ο Ν Ν . II Ί. Ο₂Ν '| e \ [ ^ΝΗ-Σ ^Ν - ^J- -8 =. ό °</td><td> 680.50</td>

<td> 1015</td><td>ΝΗ CF, Η, Ν ^^ Η Η I 1 Ο ^ Ν ^ Ν _ | _ / \ -s ^ °&gt; ___κ* 'ΗΝ 7 ΝΗ</td><td> 646.30</td>

<td> 1017</td><td>ΝΗ Ο ΗυΝ- Ν Ν Μ^;; Ίΐ Η Η 1 Ι)^Ν_Ν ° ^Ν Η - - Ν — ΝΗ 1 ^λ—^ζΝ '' / /</td><td> 717.40</td>

<img file="MX349718B_D0373.tif" />

230

IMPI

INSTITUTO MEXICANO Dí LA PROPERTY industrial

<td> 1018</td><td>T^{H H} L 1 - \ ξ 40 p Xs — n (° \\ X___ or \ |</td><td> 632.40</td>

<td> 1019</td><td>1. . ZI \ / / TO _ z &lt;z&gt;. M by \ iz 0 4 ¿P- &lt;I 'j / o \ .... .....- / - IZ. ! , Ά \ or; ZI .A \ -I 1 4. 4 ' /. Ϊ &lt;Um- ' 'twenty-one X z ^ -. z CN X</td><td> 703.00</td>

<td> 1020</td><td>I 'b / XZ TO H XZ 0 σ 0 X</td><td> 601.00</td>

<td> 1021</td><td>Ϊ J / X / - ° / NH ^ NN Xz ~ cf₃</td><td> 669.00</td>

<img file="MX349718B_D0374.tif" />

<img file="MX349718B_D0375.tif" />

231

IHtXISTUlAl

<td> 1022</td><td>H, C. . ? I j^CH= ° ... .eleven. - /. .77 ° / NH O Ν N 'N' π. / 'N - XO N</td><td> 639.00</td>

<td> 1023</td><td>NH^{H H} [II O ^ NN / - NH_VP Ύ P</td><td> 626.00</td>

<td> 1024</td><td>NH .......1 . ... . .. ... .. HgN ν 'N r ñ Η H | l [ 'I x&gt; ° Ν N Ν X ^MI¹ .7 . \ Γ NH -7 NJ 5 \ / -^x 6 'OO</td><td> 636.40</td>

<td> 1027</td><td>NH I. .. ... ...... .... H₂NN - N - Ν 'ΧτΎ s _ .. / .. .o— O Ν N NH ζ / ' -¾— ('· ---- 'or ^{s N} | · 'J Or. . N -</td><td> 703.40</td>

<img file="MX349718B_D0376.tif" />

232

IMPI

INSTITUTO MFXICANt

OF THE industrial PROPERTY

<td> 1028</td><td>NH II ... ... . H₂N Ν 'N' /, 1 Η H i | - TO ^z.._ TO. ocf₃ on N J ,, ^HΆ- .. _-- ·· .._t '/ NH TO\ ^N TO —S o °</td><td> 732.30</td>

<td> 1029</td><td>NH OR ... ...... . H₂N Ν 'N / X^{H H} | | - N a O Ν N ' ΓΊ or NH At i ° N— NH</td><td> 627.40</td>

<td> 1034</td><td>oAXACAyAA ζΛ h₃co</td><td> 641.00</td>

<td> 1035</td><td>^HíN _ or - A. I '--X ³⁰ NH θ 'Ν N -' N .J ΓΊ / ' Ν N 1 \</td><td> 587.00</td>

<img file="MX349718B_D0377.tif" />

<img file="MX349718B_D0378.tif" />

2. 3. 4 Mexican institute DE ΙΑ Ρ »ΟΧΙΕΙ&gt; ΛΓ&gt; INDUSTRIAL

<td> 1040</td><td>NH 1 . ...... H_?NN 'Ν XX² Η H ^! || Ι1ΓΉ- 0 NN ΓΙ cf₃—N ,, =; h c \\: pv - N — v —NH</td><td> 611.00</td>

<td> 1043</td><td>NH .1 ...... . N: '7' 7_F .1 Χχ^F ONN - ΓΊ / Γ Γ — N . , = &lt;'H two · \ -&gt; ...... yv / -------- &lt; N—, —NH</td><td> 641.30</td>

<td> 1044</td><td>NH TO ....... B ~ HX '' -nX ^ 1 O Ν N NH -Α "\ ; T / / \ . Ν — 7 * - ( / / 'F —NH</td><td> 651.40</td>

235

<img file="MX349718B_D0379.tif" />

INSTITUTO MEXICANO Oí LA PROPERTY INDUSTRIAL

<td> 1045</td><td>NH «. . - H₂NNN N '^ _ c A. ...-- .i ' __R_F you 'N o) -^/FAn Ye ^H. Ή) r \\ // N \ '—N H</td><td> 661.30</td>

<td> 1046</td><td>NH 1. .. ... .. ... H₂NN - NA || Η HL | [, -N- NH₂ , A- A_n &lt; 1² O- Ν N. Ν 'N L .1 L t / NH 0— \ Ν ', Α '' —S. or ⁰</td><td> 665.30</td>

<td> 1047</td><td>NH TO HjN N ^^ 'N ^ Rt Η Η 1 II P r \</td><td> 688.40</td>

<img file="MX349718B_D0380.tif" />

236

INSTITUTO MEXICANO r&gt; E la raoriFDAi 'INDUSTRIAL

<td> 1048</td><td>OR NH II 11 H₂N Ν 'L JL _^H jOCM- O »SZ ~ | Π , ____. o έ n ^ o -K r ~ &lt;- * HN— &lt;NH</td><td> 578.30</td>

<td> 1049</td><td>NH II. . ... Η, Ν Ν N ......, | H ^H II. . 'X- n Ά' ^r&gt; JJ i- ° ^N H ch₃ F N =: N— NH</td><td> 651.40</td>

<td> 1050</td><td>NH H₂N Ν Ν V ¡1 η π | | [ ______ .1 ..... ? O Ν N Π A] Ί N \; &gt; -NH</td><td> 631.00</td>

<td> 1051</td><td>h₂n VY | N '1' &lt;&gt;. . · 'Λ _ r- · * 1 1 · \ .....- s = o / nh O Ν N - 'NJ / ch₃l¹</td><td> 618.00</td>

<img file="MX349718B_D0381.tif" />

237

IMPI

INSTITUTO MEXICANO Of LA PROPERTY

INDUSTRIAL

<td> 1052</td><td>H, CX ..³ N^Z^H 1 | l / \\ _n / -Ά Ί J / - / - ^ = ° Γ NH O ^ N ^ NW</td><td> 605.00</td>

<td> 1053</td><td>H₂N: i 11 .'— xs = o Γ nh O Ν N - NJ π, - Γ '% F</td><td> 615.00</td>

<td> 1054</td><td>H-&gt; C.^H I 1 ΧφΥχ?</td><td> 652.00</td>

<td> 1057</td><td>r ____ H, rf TTT^{H H} 1 II OH "Ky^{1 F}or^x—NH</td><td> 615.30</td>

238

<img file="MX349718B_D0382.tif" />

<td> 1059</td><td>NH Η, Ν NN Ni^{H H} ilo^-or NN ' &lt;= - 0 / \ II í t - so \/ 1 HN. .....^NH</td><td> 530.30</td>

<td> 1060</td><td>NH II .. ./. .. Η, Ν NNV ¡i^{H H} 1 l | . '' 'K'&gt;^F O 'NN .--- / Π '\ __ / NH , N— \ / \, —NH</td><td> 623.00</td>

<td> 1061</td><td>NH_or „11. ......... _.... ^H*^N η Η X ¡¡_s CF₃ on N ^&lt;j--NH χ^,_&lt;S '*? N —NH</td><td> 694.30</td>

<img file="MX349718B_D0383.tif" />

<img file="MX349718B_D0384.tif" />

239

MEXICAN INSTITUTE

DE LA r? .O?! COAD

INDUSTRY!.

<img file="MX349718B_D0385.tif" />

240

<img file="MX349718B_D0386.tif" />

<td> 1065</td><td>^Η2^Ν - | &gt; ', 1 X 1. '&gt; ³⁰ νη Ο _Ν Ν - Ν. J Π ' Ν-Α Ύ V ....</td><td> 638.00</td>

<td> 1066</td><td>Η, Ν ' • ^k ν '^ \ b 1 L - \ ^s ο 'νη Ο Ν Ν '--- Ν / π; / -Ο</td><td> 591.00</td>

<td> 1067</td><td>η₂ν - '' '&gt; : 1 '&gt; s-ο; _ΝΗΟ Ν Ν ----- 'Ν J / Ν 'Λ • ι ' (Α</td><td> 638.00</td>

<td> 1068</td><td>ΝΗ 1ί. ....... Η₂Ν ν '' Ν ¡,. Η Η | || ΤΧα ο 'Ν' Ν : ---- Π / A ^_Fο, &gt; —Ν , Η Ν - χ —</td><td> 665.40</td>

<img file="MX349718B_D0387.tif" />

241

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

<td> 1069</td><td>NH .1 ... ..... ... .... H₂NN - NY 7^{H H} L. L .. N ^%Yj O Ν Ί ⁵ ----7 9. /=⁷7 NH 5 / ^ Y and 7 N— NH ___</td><td> 687.00</td>

<td> 1074</td><td>NH J. .. H_?NNN - || ν'Ύύ s .1 Λ -X^{0 N} H ° .— 'F N / -F S 3Λ /^N~ '—NH</td><td> 647.30</td>

<td> 1075</td><td>NH O^{H H} l 1 Π -ox ° _ ^ -⁹ HN — í NH</td><td> 592.20</td>

<img file="MX349718B_D0388.tif" />

242

IMPI

INSTITUTO MEXICANO DE LA PROPIaüAI »INDUSTRIAL

<td> 1076</td><td>NH .1 .... .... ..... ... H₂NN ..... N 7- '7, Η Η 1] O Ν N __ / —NH Y- &lt;&lt;. ? · ·&gt; \\ ______z'X_________ or ^{s N}b (' 1 'b,^NDO NOT</td><td> 710.40</td>

<td> 1077</td><td>NH H₂N '^' N '^x^ - ^ 'Ν' ^ 'Ύ' ^ Υι Η Η 1 i ZTXMo ^ rZ ^ N ⁵^N\ ⁰ 1</td><td> 689.40</td>

<td> 1078</td><td>HN O .yes. ... JL .-. h₂nnp¡ and - N '7 _&gt; _ OR^; N ^ N ' Π / —NH '\ &gt; _ \ / ¿0 And .............-.......- · 7 || 7 —S — N II&gt;. ⁰ / , ίι — n</td><td> 649.40</td>

243

<img file="MX349718B_D0389.tif" />

<td> 5</td><td> 1079</td><td>h₃c^J NH</td><td>N ON</td><td>[ H</td><td> /--_λ Q., 0 —so / ............ N • /</td><td>NH</td><td> 634.00</td>

<td></td><td></td><td></td><td></td><td></td><td>N l</td><td>, r^Oh</td><td></td>

<td></td><td> 1080</td><td>Or .11 h₂n</td><td>r 'n</td><td></td><td></td><td></td><td> 631.00</td>

<td> 10</td><td></td><td></td><td>1 hour Ϊ ON</td><td>~ NH</td><td>or . P so Γ P. - N</td><td>NH</td><td></td>

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

<td></td><td> 1081</td><td>h₂n</td><td>1 II</td><td></td><td></td><td></td><td> 613.00</td>

<td> 15</td><td></td><td></td><td>ON</td><td>'NH</td><td>OR \ ³⁰ Γ -----¹ N -</td><td>NH</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>i</td><td>Oh</td><td></td>

<td> 20</td><td> 1085</td><td>h₂n</td><td> N , 0 J. ON</td><td>'NH</td><td>OR x —s — o 'HN</td><td></td><td> 555.10</td>

<td></td><td></td><td>i:</td><td>i Γ F</td><td></td><td> 1</td><td>I NH</td><td></td>

<td></td><td> 1087</td><td>h₂n</td><td>N</td><td>TX</td><td></td><td></td><td> 390.10</td>

<td> 25</td><td></td><td></td><td>ON</td><td>NH</td><td>or-\</td><td>nh₂</td><td></td>

244

<img file="MX349718B_D0390.tif" />

<td> 1088</td><td>^HjN T ..... II ° ^N H q " Oh</td><td> 377.00</td>

<td> 1089</td><td>NH II H₂NNN | N Γ'Τ-- | ° °^N H ' C1 F^F = O d · 11 SO * 7 7 1 "HN k NH</td><td> 672.40</td>

<td> 1090</td><td>_H r τ² n ν γ- y .....'...... i! : ONH^Q .... “A / —υ / nh^C \\ 'r --- N / j ------ Γ .-- ocf₃F</td><td> 784.00</td>

<td> 1091</td><td>I N z T - ' IJI „0 \,_;or. . W / \ . 'z 1 z' . i 0 a \ \ λ ---, M A '\ IZ J or \ r oz 'z -0 --- I 0 I 1 w</td><td> 658.00</td>

<img file="MX349718B_D0391.tif" />

245

IMPI

MEXICAN INSTITUTE

DP THE PROPERTY

INDUSTRIAL

<td> 1092</td><td>X 1 X or σΧ / ΧΙΌ ' 4 ⁷ Ί V &lt;r vj \ \ / bo \. ^zí ^z '/ m² A o ' / = (or. A ) _ / 'L_tTO z CM x</td><td> 620.00</td>

<td> 1093</td><td>N^H 0 . Λ _ 1_ΛH₂N Ν Ν V 'ri^{H H} 1 1 ^N 'or ^N Ή - ==^{7 0}SW; _NHor '1 and F</td><td> 730.00</td>

<td> 1094</td><td>^H₂Nyyy oAhfY ^H &gt;) / - ° h₃co-'</td><td> 435.00</td>

<img file="MX349718B_D0392.tif" />

246

IMPI

INSTITUTE MKX1C / .NO

Say THE INDUSTRIAL PKOPIEUAD

<img file="MX349718B_D0393.tif" />

<td> 1095</td><td>HN O k jl ΰ h T 'II Á X- 'i ° N- N ' , —NH P? - —SN II Or, ' N— OR</td><td> 657.40</td>

<td> 1097</td><td>X z '^ -z / I TZ \ / You-⁷ / ---- .. / Γ i | '=' or XN o) I 1 1 — z^{z M} Z) &gt; O v ____ / '&gt; =: z --- - ·_Τ1 X WU '</td><td> 654.30</td>

<td> 1098</td><td>HN O 1 . X „. H₂NN - N I T&gt; ONN , —NH 4-, ? V YN 1 \ o / i ~ ^NN = '</td><td> 650.30</td>

247

<img file="MX349718B_D0394.tif" />

<td> 1099</td><td>₀Α, / Χζ ΟΗ</td><td> 391.00</td>

<td> 1100</td><td>I Μ Ζ \ / ' 7 1 . Q Υ^-/γ ...... Ζ k «π 5 J. 'Ο</td><td> 377.00</td>

<td> 1101</td><td>ΝΗ II. . Η, Ν Ν 'Ν V η Η Η 'ι_Ν- 'y-'7 .__ / = 1 ₀1 »- _!; '-γ 1st H₃CO-</td><td> 534.00</td>

<td> 1102</td><td>ΝΗ Λ, ο. Η, Ν Ν Ν&gt;^{Η Η} . 1 . - and γγ_ ο ^ -ν '^' ν &gt; / = Λ? , ο Υ1 - --- ΗΝ ΝΗ</td><td> 580.30</td>

248

<img file="MX349718B_D0395.tif" />

IMPI

MEXICAN INSTITUTE

OF THE INDUSTRIAL THOniETTY

<td> 1103</td><td>NH OO Η, Ν NNJ Η Η 1 1 ο ^ ν ^ ν ΓΊ / = χ Ο „ν. ^ ° .__. ΗΝ — C ΝΗ</td><td> 628.20 ’</td>

<td> 1104</td><td>Η Η₂Ν Ν. _ Γ Η Τ ..... i ÑH -Η- 'Ν' r- · - Ϊ .1 ...... L. ί Ο Ν Ν . / =. 9 Η / 1 \ / ^Ν ' ^ΝΗο</td><td> 564.30</td>

<td> 1105</td><td>^Η₂Ν- γ - Ν 'Ζ - \ __ / y ΟΝ Ν / ^Η 0 -ΟΗ</td><td> 391.00</td>

<td> 1106</td><td>CM I ζ Ol V Ζ ^ ζι Ηζ ζ CM I</td><td> 390.10</td>

<td> 1107</td><td>Ij 1 Ζ ί Μ ζ Μ τ</td><td> 459.00</td>

<img file="MX349718B_D0396.tif" />

<td> 1108</td><td>Η HN Ν .... .... .... .. .. Ύ - Ν - Ν -τ '. &gt; I η „'s ΝΗ, OH J. μ&gt;² Ο Ν Ν Π_t 9 - ,. :-SW 2 τ ... 1. ΗΝ-. f 1. ΝΗ</td><td> 532.20</td>

<td> 1109</td><td>ΗΝ HN 'V Α ΟΗ .. 7 / ⁸⁰ο Ν Ν - _ΗΝ Τ '1 , ΝΗ</td><td> 515.10</td>

<td> 1110</td><td>ΝΗ JI ... Η₂Ν ν ν - Η Η L 1] . · - '·. ..'two?. _. Ν 'Τ θ 'Ν' 'Ν ^F^Η ρ^ΟΗ</td><td> 490.10</td>

<td>lili</td><td>jOct — CR Ζ «u Rv Ν — CH₃h₃c</td><td> 404.10</td>

<td> 1112</td><td>ΝΗ Ο IL L, η₂ν ν Ν^ΝΟ Ν Ν CH₂Π</td><td> 380.40</td>

<img file="MX349718B_D0397.tif" />

250

IMPI

INSTITUI '' MEXICAN '&gt;

PE LA PROI'ILDAD

INDUSTRIAL

<td> 1113</td><td>'1 K9 z \ 7 or V -z; \. X / zZi í X. . .. /. z 'or - OR I ω</td><td> 418.00</td>

<td> 1114</td><td>X z '-—z' X xz / ₍ xz 'X Xo Ϊ Q ' . ... .. ω O „₂Item ^z ° &lt;} Ύ r 'I' r \ z ¿L 1 zz „1 "Ozr " ¹ Ύ '</td><td> 757.00</td>

<td> 1115</td><td>or 'x OXN ' , - or ? / \ II ..o /&gt; --- S, ---- &lt;-^J N-; NH / \ ___ / FX OCF₃</td><td> 685.00</td>

251

<img file="MX349718B_D0398.tif" />

<td> 1116</td><td>JX Μ 1 z 0. °¹ · 1 TO ^{ω C} 0 (A Z \_x · / or \ Z; IZ to 2 _ UV z j. 1 or Π w</td><td> 669.00</td>

<td> 1117</td><td>^H2N _ ¹'N' '_____ \ O Ν N -^/Q ..... · .. f --------- \ —Ν NH</td><td> 459.00</td>

<td> 1118</td><td>HN O &gt; 1. .. 1 H₂N Ν 'Ν γ Ί i 1 /......i O Ν N NH 3 _ Q ____ T '\ II. SN II \ Or; N --NH</td><td> 656.30</td>

<td> 1119</td><td>^HN N^h₂ñ ii¹ X, 1 '' '' Ν '' Ά ''&gt; Λ -A '? O&gt; Ν N § _ / “.__ ° θ __ í HN— (NH</td><td> 604.30</td>

252

<img file="MX349718B_D0399.tif" />

<td> 1120</td><td>O ^ N ^ N j _ / = \ _ x ° ξ V Τ^-X / - \ '-' UN— (NH</td><td> 562.20</td>

<td> 1121</td><td>H₂N^XXXX XX^H $ ° H₃c</td><td> 405.00</td>

<td> 1122</td><td>T Η₂ν'ή^ζ''''-^/ή'υΧ² H ^H | l 1 o ^ n ^ n 7 = X 0 8 / \ II H / \ —s — N— &lt; _YNH ? \ / II V '-' 0</td><td> 550.30</td>

<td> 1123</td><td>Η, Ν ^ ΧΧΧ THE /-^NHσ-OCpQ or ^ Vx. or 1 Ό 9. F</td><td> 617.00</td>

<img file="MX349718B_D0400.tif" />

253

IMPI

IbS I l IL'TU miAICaiMo of INDUSTRIAL property

<td> 1124</td><td>NH O Ιί. . 1 Η Η X II Ν Ύ '&gt; Λ J. ~ P ° Ν N __ NH c .-- \ ^λ_ό_; .&gt; '/ n ^ SN ° w or Ί N X cf₃</td><td> 768.00</td>

<td> 1125</td><td>NH O J ... .. IL .. H₂NN - N ^ · 'Γ 0 Ν N - H , --- NH 40 'vJ'^or^®~^N° L NN \\ _____! ' ch₃</td><td> 714.00</td>

<td> 1126</td><td>hey ... η₂ν ΎΥ L 1. .—^N.H ONN v_ / oV^N° l Ί N ch₃</td><td> 615.00</td>

254

<img file="MX349718B_D0401.tif" />

IΜ ΡI iNSrtru iu muican *

01 'THE m ^ lEIIAD INPUSTUtAL

<img file="MX349718B_D0402.tif" />

<td> 1129</td><td>h₂n '' y ' '.T f ..... ° ^N H _Q~ NH h₃c</td><td> 390.10</td>

<td> 1130</td><td>NH Η, Ν Ν ~ Ν γ n Η H | || ..... ^N 'X ° ^N ñ - or s. · » ,._z—S— -¹ Ó '—NH₂</td><td> 523.10</td>

<td> 1131</td><td>O Ν N -^H Q p H ^ C</td><td> 405.00</td>

τ

255

IMPI

MEXICAN INSTITUTE

LE LA ΡΚΟΙΊΕΟλο industrial

<img file="MX349718B_D0403.tif" />

<td> 1132</td><td>«ΛΑλ Ζ or c Ó</td><td> 614.20</td>

<td> 1136</td><td>or X Η₂Ν ^H z = x O O ^ N ^ N HN— (NH Π \ /</td><td> 552.10</td>

<td> 1137</td><td>NH Q Ϊ or X η η I II οΧΥ £ Α ^ Α η-o “FÁ # - / - \^? ΗΝ - ¿ΝΗ</td><td> 594.20</td>

<td> 1138</td><td>, ΝΗ η₂ν— -μ 'ζ. · * Α ζ Ζ X. ..... _ ο ^Ν ..... Ζ -γ · -,. = ¿= O ο Ν ΗΝ^Υ Ί¹ , ÑH</td><td> 590.20</td>

<td> 1139</td><td>/.....Ν 'ι ^;J 1 .. 11 ..... .—, ο - '' Ν I \ ____ / - \ II Α _Ν ι⁰Ο Ν Ν ΗΝ. i 1 . . ΝΗ</td><td> 448.20</td>

<td> 1140</td><td>Ν ι. ' ην ^ ¹ 1: .. -. '-. "- ... ... 'I Α ζ² Ο Ν Ν</td><td> 352.00</td>

256 F

<img file="MX349718B_D0404.tif" />

<td> 1141</td><td>ΧθΟ-Ο-A CA ^ NN * - ' k ^ -NH</td><td> 563.10</td>

<td> 1142</td><td>/ = to '--NH \ —Nh₂OR</td><td> 419.00</td>

<td> 1143</td><td>H₂N '|² || '· Αθ; -Π ONN &lt; OR-' —NH ~ or h₃c</td><td> 418.10</td>

<td> 1144</td><td>h₂n '' 'a _ / “or ..... 1, L 'or 7 ONN -----^H or- —Nh₂</td><td> 376.20</td>

<td> 1148</td><td>HN—_Ί7 1 OR - Ϊ. I ... '-o, ·· -' 'N - ^ 0--0 ^ / \? I f 1, Τ-so ONN --- HN T 1 NH</td><td> 535.10</td>

<td> 1149</td><td>H₂N r N or - o ° ¿H a .. oL · - \, / - r ° ONN - HN T Ί NH</td><td> 447.00</td>

<img file="MX349718B_D0405.tif" />

<img file="MX349718B_D0406.tif" />

257

IMSTITUTlι MEXICANO úl · la ¡'kOPIEDAD INDUSTRIAL

<td> 1150</td><td>z H zz J z,? | Z ^^^ Z&gt; k T 1J</td><td> 417.00</td>

<td> 1151</td><td>J NC-- '</td><td> 400.00</td>

<td> 1152</td><td>ch₃i Y ⁿ NH OO 11 ... hee:^H*^N Η H j II Y......' ONN =, O / \ II, or -&gt; - Á,&gt; - S .....- A '' '' HN &lt;NH</td><td> 734.40</td>

<td> 1153</td><td>NH 1. ........ h₂nnnyyo Η H 4 .. -T 'a .. ... a. HN S Ί X / ¿ch₃ONN</td><td> 447.10</td>

<td> 1154</td><td>ITEM . . . .. H₂NN - N |. Ί^{H H} H .1 _ or N 'τ-' - \ II NH ... J. - Y, Yj ..... ú .1 ONNO</td><td> 549.10</td>

<img file="MX349718B_D0407.tif" />

258

IMPI

I. MEXICAN INSTITUTE

DF THE INDUSTRIAL PROPERTY

<td> 1155</td><td>H HN \ .N_z. NH₂ OR oA ^ n ^ n ΓΊ</td><td> 366.00</td>

<td> 1156</td><td>Η, Ν. · ...² ν γ · ' '..J kw J. ° ^N H</td><td> 324.10</td>

<td> 1157</td><td>X / - '^z/ x ° / A rr s Or d z X</td><td> 573.00</td>

<td> 1158</td><td>HzN' — YA A ^ A — AA ΑΛρ-d / Άχ O— '(/ __ / \ ___ NH HjC-O</td><td> 581.00</td>

<td> 1159</td><td>NH . Λ H₂NN n J Αχ / '-, -' Ύχ. ^ - ----- Do not. / A .A ../ x / o '' ν N -^; P X. -- DO NOT , .' AN '/ / N - NH</td><td>NA</td>

259

<img file="MX349718B_D0408.tif" />

<td> 1160</td><td>H₂N ^ y ^ y ιΊΛ-Ω or ^ -n ^ n TO —N. OR_ Ry q</td><td> 601.00</td>

<td> 1161</td><td>h₂nn N,^{H H} . eleven . 'N, S^N H ' ~ '-A. '' --- io R ,-Do not / r ~~ o- ', ..... nh h₃Co</td><td> 680.00</td>

<td> 1162</td><td>NH l ... H₂N Ν Ν Γ .1^{H H} L 11 '-, / O Ν N '--- \^H p HN N—</td><td> 558.00</td>

<td> 1163</td><td>JT X HjN '^ N' ^^^ N '^&gt; &lt;^:&gt;&gt; i^{H H} L JL -A Py X 'yv ^^Ohο ^ ν ^ ν '-' ¡ NH₂</td><td> 503.20</td>

<td> 1164</td><td>NH O^{H H} AA —-Χ / = \ &lt;AA_w^ ^H nh₂</td><td> 503.20</td>

<img file="MX349718B_D0409.tif" />

260

IMPI

IbtfTITUTO MEXICANO Oí LA PRO? I £ üAP INDUSTRIAL

<td> 1165</td><td>X . Z '\ Or \ _ / J ..^rOR Y to go Z '' F 7 ^z-— or X .— (''&gt; X or &lt;) 'i) X'</td><td> 563.10</td>

<td> '1166</td><td>r H₂N N '^^x 'Ν' YXi ^{H H} [II rx 0</td><td> 558.00</td>

<td> 1167</td><td>NH 1 . ... H₂NN - Ν N __ '^/= \ O 'Ν H ⁷⁰ N CH₃h₃c</td><td> 503.20</td>

<td> 1168</td><td>HíN ^ VV rx rx F</td><td> 379.00</td>

<img file="MX349718B_D0410.tif" />

261

IMPI

INSTITUTO MLXICANO Ot THE INDUSTRIAL PROPERTY

<td> 1169</td><td>NH ΗΧ Ν N ¡· • ^ΧΤΎ'Μ- or ^N H 4 / or- '..... NH Λ — NH₂or</td><td> 512.20</td>

<td> 1170</td><td>I z 'r ^ -ZI xz&gt; = O IZ Π or: - = -\\ / 4 / \ XZ J Yes. 1 OR'</td><td> 490.20</td>

<td> 1171</td><td>J____^{H H} II 1 o ^ n ^ n 5 L / ^ X ° - o ¿- \ HO '</td><td> 621.30</td>

<img file="MX349718B_D0411.tif" />

262

IMPI

LNSTIMyxaKííxic ^ Mw

M LA «UVllSjAt&gt;

INOUCTMaXI

<td> 1172</td><td>NH TO .. ​​. . Η, Ν NN ri Η H | ] XX1 ° B —NH 1__1 \ ___ / or ^{s N}'° / ( \ F</td><td> 700.00</td>

<td> 1173</td><td>NH O 11 0 h₂nnn Y Η Η 1 II do H λλ ^? HN— (NH</td><td>NA</td>

<td> 1174</td><td>I heard O m OR p¹Z CM T</td><td> 573.00</td>

<img file="MX349718B_D0412.tif" />

<img file="MX349718B_D0413.tif" />

263

INSTITUTE Μ! ΧΙΓ-ΑΝΟ nt THE INDUSTRIAL RRGPKTY

<td> 1175</td><td>I Η, νΑ'ΧΑΑΑ HH 1 II AY u ΙΊ H the \ Y tá / ₍ TO * -^v N— &lt;NH HN A ^ /⁵¾. A&gt;</td><td> 762.00</td>

<td> 1176</td><td>NH^{H? N} h 'aA —NH IX &lt;i '- \ _n^ SN 0 Ν — N / ú ^:</td><td> 672.00</td>

<td> 1177</td><td>HN. N X&gt; —N /_or7 \ ΑίΑπ h₂n I j AA ___ xx ξ Ο ^ Ν ^ νΑ &amp; A \ I^-sX and \ / \ '-' N— &lt;NH il A ^^N</td><td> 695.10</td>

<img file="MX349718B_D0414.tif" />

<td> 1178</td><td> .¹ζ ^ ζτ ύ δ ρ τ ω = Ο / \ I</td><td> 681.20</td>

<td> 1179</td><td>ΝΗ_Η2ν ν 'ν^ζ' ϊ -Χ^-O Ν Ν Π &gt; / \ / ο— · .. νη₂</td><td> 489.20</td>

<td> 1180</td><td>ΝΗ Λ .......... Η₂Ν Ν Ν ι, ^{Η Η} 1 Á, 'Ζ. _ ζ =. 0 -^Ν j --ί&gt; —S— &lt;ΝΗ Λ -τΥ.- 'L / II ___ / 0 Ν pj 0</td><td> 563.10</td>

<td> 1181</td><td>Γ Η'Ν ΥΥΥΥ Ν — CH₃h₃c</td><td> 517.30</td>

265

<img file="MX349718B_D0415.tif" />

<td> 1182</td><td>Η₂Ν Γ | 1. Ί. ____ ---- ΝΗ -Y·· ' _Ν F, .. ............ \ / \ 1 .-. L ·^;—X ρ \ - · ' ° ^ν η - - or ^{yes Ν}ό ' ΟΗ</td><td> 599.00</td>

<td> 1183</td><td>Η, Ν '^ ν ^ Χΐ Υ Λ / -^ΝΗcAhArj ^ - / yr ο&gt;</td><td> 576.00</td>

<td> 1184</td><td>1 II / —ΝΗ / \ JL / Κ # \ / Ο ^ 'Ν ^^ Ν - \&gt; -' ΓΊ \ / ° = ®s — Ν Ο&gt; \ / -^νο2</td><td> 628.00</td>

<td> 1185</td><td>I Ζ λ ^ -Ζ ζζ ¹νύν ΤΖ two \ 9 r ιι α _ΧΑ · - yf '\ Ο ^ "\ / - Ζ ... ° i ':' ϊ i Fi - .. 'Ί) -4'^ΙΖ J ο Υ- Μ,</td><td> 727.00</td>

266 i jví pi ίζχ

MEXICAN INSTITUTE

DHAi'R &lt;'?&gt; F.DAn C ** - »* - &amp;; INDUSTRIAL 2?

<td> 1186</td><td>NH J h₂n NN i^H HI Y Ύ -P or 'Ν' n , —NH C \ ./, / or ^{s N}Λ ·. 0. N / \</td><td> 675.00</td>

<td> 1187</td><td>Η, Ν ^ ΧΧΐ L 1 and - NH / "X / X P JL, / —K / \ / o ^ n ^ nv / y_j or \ ⁰ / 0</td><td> 572.00</td>

<td> 1188</td><td>HN Λ. i- i - o --- Χγι / - \? I ..— e so 0-77 N v_z _HN1 'i^NH</td><td> 546.10</td>

<td> 1189</td><td>T H₂N θ o ^ n ^ -n Π</td><td> 475.10</td>

<img file="MX349718B_D0416.tif" />

267

IMPI

INSTITUTE .MEXICANO

BE LA FR &lt;4 · ΙΕΙ&gt; ΑΓ) industrial

<td> 1190</td><td>I to 2 IZ 7 ;; Λ / W »1. -</td><td> 711.20</td>

<td> 1191</td><td>NH l .. .... . H..NNN, i^{H H} II, _ '' n '' γ ..... / _____. ' ONN ' OR H, N&gt; - HN</td><td> 516.00</td>

<td> 1194</td><td>NH 0 [) j 40- ^, and-- ' H₂N</td><td> 677.20</td>

<td> 1195</td><td>NH O h₂n υΛΛ_κs N— &lt;NH nc —</td><td> 659.30 __</td>

268

Τ Μ Ρ 7 ^Α VAT A Α αα

Mexican INSTITUTE R

OF THE PROPERTY

INDUSTRIAL

<td> 1196</td><td>z N z &gt; -ϊ zz¹uurv '।</td><td> 730.20</td>

<td> 1199</td><td>r^{H H} Γ II Ac / y OR '—NH</td><td> 528.00</td>

<td> 1200</td><td>H₂N '' 'and -' 'and N /⁼\ 1. Ay “W ONN ( Π '. \ N— NH</td><td> 429.00</td>

<td> 1201</td><td>NH h₂n —- &lt;^hn^ 'J T ii O '' N '^' N 'H —- '^N / &gt;. / N-, A- · ~ sr \ ' _1LJ \ _ / ó 'o ^NH</td><td> 715.40</td>

269

<img file="MX349718B_D0417.tif" />

<td> 1202</td><td>r I^H2N h /⁼\ cr '- \^H Z N — CH₃J ^Jh₃c</td><td> 531.40</td>

<td> 1203</td><td>NH | i H₂N ν N i '·, Η Η | || '' N 'X- ·'^{7 7} \ J .1 - - ⁷. ONN - 9 NC ⁷</td><td> 499.00</td>

<td> 1204</td><td>NH I. .. .... .. H₂N Ν 'Ν V-⁵' Η H:⁷ 'T =^_ °.....^N »" Op N h₃c -_λ</td><td> 607.30</td>

<td> 1205</td><td>NH O Jl ... ü _Λ ... H₂NN 'N' Ύ⁷ You^{H H} L 1 'í.' ' _N J 1 L. 'T OR⁷ Ν N __ or '·. . 1 -O . · S '/ - „ N NH F₃c _λs — z&gt;</td><td> 782.30</td>

<img file="MX349718B_D0418.tif" />

270

INSTITUTO MEXICANO DF Ι Λ INDUSTRIAL PROPERTY

<td> 1206</td><td>_ZNH η, ν ^ ζζ ξ h &lt;.o ΊΛ&gt; "&lt;/" T '----' N'H &lt;&gt; &amp;</td><td> 688.40</td>

<td> 1207</td><td>_YNH H₂N - Z / oXXX Ο / '---' / NH O '—Ν_χ'ch₃</td><td> 730.30</td>

<td> 1208</td><td> , ^Ohx - Y_K1- /. - or 1 A- '- \? ° OR^z Ν N '---- hn .-. or</td><td> 466.00</td>

<td> 1209</td><td>CH, O - HO / N '' H -X r you? - ......., - s — NH 'n ______¹ ii \ TO . - θ .-— \ ° - Ν N, _;- NH</td><td> 572.10</td>

271

<img file="MX349718B_D0419.tif" />

<td></td><td> 1210</td><td>Τ Η₂Ν '^ Ν^{/ Χ}^^ Ν '^' Η Η</td><td>XI _</td><td></td><td> 423.10</td>

<td></td><td></td><td></td><td>Ν</td><td>^ ΝΗ</td><td></td>

<td> 5</td><td> 1211</td><td>X^{Η Η} L</td><td>Χι</td><td></td><td> 465.20</td>

<td></td><td></td><td></td><td>Ο ^ Ν ^ Ν</td><td>'—Ν ^ = ΝΗ Η₂Ν</td><td></td>

<td> 10</td><td> 1214</td><td>ΝΗ II</td><td></td><td></td><td> 698.00</td>

<td></td><td></td><td>. 7 ... .... Η, Ν Ν 'Ν Η Η</td><td>'ΤΊ Υ I Ο Ν</td><td>_Νί Η</td><td></td>

<td></td><td></td><td rowspan="2">ί&gt; -and-</td><td>__, .— ΝΗ</td><td></td><td></td>

<td></td><td></td><td>γ X \ /</td><td></td><td></td>

<td> 15</td><td></td><td></td><td>_ηΥ — Ν ° \\, 0 ί</td><td></td><td></td>

<td></td><td></td><td></td><td>¡Í</td><td>ΟΗ</td><td></td>

<td></td><td> 1215</td><td></td><td> _______&lt;—</td><td>ΜΗ</td><td> 613.00</td>

<td> 20</td><td></td><td> '^Ν XX c / V £</td><td>• X ______ / \ ( ΎΤ and--</td><td> /</td><td></td>

<td></td><td></td><td></td><td>O-VY</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> ¡1 /’</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>och₃</td><td></td>

<img file="MX349718B_D0420.tif" />

272

IMPI ιν, -πτιγγο Mexican

DF IA rRQPfFOAD

INDUSTRIAL

<td> 1216</td><td>H₂N '·' N Ί ·^&gt;;· ' . ^h eleven . r τχ ii ONN --- &lt;^H or ) / - NH . H₂N</td><td> 474.00</td>

<td> 1217</td><td>Z z H IZ zz á ^zY? ZZ ώ γ a / λχ zz</td><td> 516.00</td>

<td> 1218</td><td>JT____^{H H} II 1 xm or Hey </td><td> 544.10</td>

<td> 1219</td><td>NH H₂N-. , 1 L f O 'Ν N' ΓΊ -i "X^or - --N— NH N-_T^z 'ñ N</td><td> 699.30</td>

*“***** &gt;^·^^*^

<img file="MX349718B_D0421.tif" />

<td> 1220</td><td>I ω ζ 6 aA / v »\ Σ * ννν » 1</td><td> 657.30</td>

<td> 1221</td><td>ΝΗ η₂ν --- / ^ Χ Αγγ ΝΗ h₃c</td><td> 503.20</td>

<td> 1222</td><td>ΝΗ η₂ν-_λΗΝ ^ · '....... ^Ν ; Γ γ ON Ν .. =. ° Ο .—_s.__. - Ν ΝΗ Ν—., -^s ο Ο</td><td> 765.30</td>

<td> 1223</td><td>. ° ΝΗ ... J-. or '! | αΧγ -ΥΓ Γ.γ</td><td> 563.10</td>

274

<img file="MX349718B_D0422.tif" />

<td> 1224</td><td>H_:N | .--- NH^l4so- 'N' ____ /) 1 -4 '--- \ i \ 7 0 N 1 '\ oV or / NH OR- ch₃</td><td> 564.00</td>

<td> 1225</td><td>y — NH Ροτ-q P ^H nks-N hn_x ZN</td><td> 587.00</td>

<td> 1226</td><td>nv \ ¿ ^ZI 5 ) - (4th V \ To'o. , Or 'o' WT l 4. .U / = {b ' (&gt; 44 4 «-⁰YI ΖΈ ú,. x ^ZI2 = ^ -. z CM X _____</td><td> 712.00</td>

275

<img file="MX349718B_D0423.tif" />

<td> 1227</td><td>ΝΗ I χ&gt; Ο Ν Ν __ ..— ΝΗ ° Ά \ ⁰Ν-.</td><td> 671.00</td>

<td> 1228</td><td>ΙΓ_ β^H¡ ϊ ^ 'Ιη'Χ ^ Ίι ^ΝΗ2'-' ΗΝ— &lt;ΝΗ</td><td> 607.20</td>

<td> 1229</td><td>X / —ζ y ^ zx λ ^ ζ ζχ ζχ ζ ζ (Μ X</td><td> 409.10</td>

<td> 1230</td><td>ΝΗ 1 . . . . Η₂Ν Ν ⁷ Ν Ύ hee ^{Η Η} L 1.⁷’-'⁷'' Ν '' Y '' '., ___ /¹ μ .Ν. . ΝΗ Ο Ν Ν η₂ν</td><td> 451.00</td>

276

<img file="MX349718B_D0424.tif" />

<td> 1231</td><td>NH^H*^N N ñ ^NO Ν N / --- · .. HN OH Xo / / \\ \ ^z</td><td> 517.10</td>

<td> 1232</td><td>° Ν N —f --N HN '</td><td> 415.00</td>

<td> 1233</td><td>ZZH ZZ zz 3 w ^IZ\ X cw</td><td> 514.00</td>

<td> 1239</td><td>O ^ N ^ N</td><td> 541.10</td>

<td> 1240</td><td>r 9 Ο = φ = Ο e ZZ ZZ H z «M z</td><td> 515.30</td>

277 «I;

<td> 1241</td><td>Η Ν, j i'oo ......... .eleven .. Η, Ν 'Ν,^Η 1. II. .. .eleven. Α- ° ^Ν..... Η Ο _ ί. ·_{; s} Ο ..... ~ ^: 'ΗΝ— &lt;ΝΗ</td><td> 663.10</td>

<td> 1242</td><td>Χ^Η _ Η, Ν Η Η [] [ οΑΑ) ιΑγ '—s ΗΝ— &lt;ΝΗ</td><td> 579.10</td>

<td> 1243</td><td>ΝΗ H_!N '^TO'N'^XX^ n^zXX Η Η 1 || χΧΗ Ύ Ρ ° / θ / ΝΗ ch₃</td><td> 663.00</td>

<td> 1245</td><td>ΝΗ and _,. ....... Η, Ν Ν 'Ν।^{Η Η} L. 1 ... .νη₂Λ - · ί. 1 Ο Ν Ν ° ΗΟ</td><td> 455.10</td>

<img file="MX349718B_D0425.tif" />

278

IMPI

INSTITUTO MEXICANO L&gt; fe LA INDUSTRIAL PROPERTY

<td> 1246</td><td>I you z IZ á^zor 0 z J% O-&gt; * z I</td><td> 413.20</td>

<td> 1247</td><td>W^H «I? H, N ² Η 1 H Ο '^ Ν ^' ^ 'Ν' r .------. OR HN— &lt;NH</td><td> 608.10</td>

<td> 1248</td><td>ΗτΝ '^ Ο ^ Χΐ Oo 0. oYY MM_or-r \ O) Ν — N h₂n--</td><td> 588.00</td>

<td> 1249</td><td>H₂N ·, | 1 . II --- NH 'N ___. \ \ or Ν N&gt; - OR ^YNOr. ) '= or h₂n</td><td> 550.00</td>

<td> 1250</td><td>NH Η, Ν'Ά^{H H} 1 JL JCXcXi^N H , ---- OR § YY II V_Z - 'O / = \ _ HN— &lt;and — och₃</td><td> 643.00</td>

<img file="MX349718B_D0426.tif" />

279

IMPI ιΚτγπ. ' ΤΟ me «Cano LA?» OP | £ DAE&gt; ENDUSTMAL

<td></td><td></td><td> -------------------------------------------------------------.------------------------------------------ |</td><td rowspan="2"> 558.20</td>

<td> 5</td><td> 1251</td><td>- NH .eleven ... .... ...^H2N í¡ H t 1 ... I _N T or N and OR II s— ξ; II \ HN —NH</td>

<td></td><td></td><td></td><td rowspan="2"> 596.00</td>

<td> 10</td><td> 1252</td><td>T Ϊ H₂NN - N | θ^N ν A- OR ^N H _____ OR X. λ — S — Ν &lt;/^Z 'LY Ü ^H NH</td>

<td> 15</td><td> 1253</td><td>^H2Np ^ o or Pb LA or / \ __ ii _ 1 / if # s = o cY ^ NN '-' ^ΗΝ\ / \ X / NH</td><td> 523.10</td>

<td> 20</td><td> 1254</td><td>I 9 O = &lt;n = O X ^ zr t M YO 1</td><td> 528.00</td>

<img file="MX349718B_D0427.tif" />

<img file="MX349718B_D0428.tif" />

280

INSTITUTO MrXICANO O · LA TRONhOAD INDUSTRIAL

<td> 1255</td><td>NH O Λ .... ... L .7. Η, Ν Ν Ν ι ή² Η H | | ..... ΐ I '&lt;&gt; ° H ~ O \ \ nh₂</td><td> 503.10</td>

<td> 1256</td><td>V^H ? HjN '^ N' ^^^ 'N' ^ Y ^ h H ^H | l 1 / \ '—N^H ) = NH h₂n</td><td> 479.10</td>

<td> 1257</td><td>Z \ I rr ZXl Y¹zr ΖΣ z X</td><td> 437.10</td>

<td> 1258</td><td>I if Q and z I</td><td> 525.10</td>

<td> 1259</td><td>H₂N N '^ - N' ^ r = ^ Y₁^{H H} LX. ξ O ^ N ^ N P —YesY — N ° \\ \ X h₂n</td><td> 649.00</td>

281

<img file="MX349718B_D0429.tif" />

<td> 1260</td><td>r? Ζ Η χζ J Ο = ω = ο / ο X Η φ ζ ο</td><td> 657.00</td>

<td> 1261</td><td>ΝΗ Ο Η₂Ν '' ^ Ν '' '' - Η Η Γ | Ι π t / = \? - θ —X / —X ΗΝ— (ΝΗ</td><td> 634.00</td>

<td> 1262</td><td>ΝΗ .1 ... ... ,. .. Η, Ν Ν Ν Γ³'] Η Η | [ 'X-' ν ·, JX '· / Ο ^Ν Η ___ ΝΗ '&gt;' Ζ // 1 / Ó / Ν - Ν Η₂Ν i</td><td> 687.00</td>

<td> 1263</td><td>Γ. .^FΗ, Ν Ν '- Ν Ί -' ί | Η Η 1 Ο- Ν '-Ν -θ &gt; ΝΗ_?</td><td> 507.00</td>

<img file="MX349718B_D0430.tif" />

282

IMPI

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<td> 1264</td><td>NH O IJ. ...... li. H₂NN '' 'N' 'tA- 0-1^H η κ i | .1. .1 T O 'Ν' N . -----, O. 5 HO -χ. ·. . &lt;- S '-. '- hn&gt; —NH</td><td> 592.50</td>

<td> 1265</td><td>H₂N^XAA^X|| To AM O ^ N ^^⁰ 'HN— / NH</td><td> 580.30</td>

<td> 1266</td><td> . ...... h₂nnn aa a^{H H} LL. _{&gt; N}h₂~ JTX . O Ν N 0 HO</td><td> 455.10</td>

<td> 1267</td><td>NH . TO. ... ... ... H₂N ν N T- 7^{H H} U Jl .... - ^ NH₂- Ν .'τ '. . r λ Λ ....... b 1 Ο Ν Ν 0 S Η | HO</td><td> 455.10</td>

<td> 1268</td><td>ΝΗ O JL. . eleven . h₂n N Ν Ύ 'X^{H H} 11 Λ. ^XN^x 'V' i £&gt; r OR' ^N H - o S / \ II H. / i— SN- NH '\\ / II. - 0</td><td> 564.40</td>

<img file="MX349718B_D0431.tif" />

283

MEXICAN INSTITUTE

DI THE INDUSTRIAL PROPERTY

<td> 1272</td><td>NH OCH₃Η Η 1 | l Γ1 -KY-h'-Q</td><td> 608.60</td>

<td> 1273</td><td>NH OCH₃Η, Ν 'N' N, - ',,² Η H | || ^N Ί ....... + or ^N H &gt; '' ' OR nh₂</td><td> 519.30</td>

<td> 1274</td><td>NH O^{H H} [ eleven —XSO ^ N ^ N ^&gt; 4 ^ o HN— € ch₃</td><td> 593.00</td>

<td> 1275</td><td>NH H₂NN ^ X ^ Xi^{H H} l 1 -k3-h &lt;V ^ Z ¿\ -₀HN — f 5</td><td> 621.00</td>

<img file="MX349718B_D0432.tif" />

<td> 1276</td><td>NH O - = ....... JL 44. h₂nn - N y- χ . I XX . ONN , = - θ e ---_χ NH hn (;</td><td> 632.00</td>

<td> 1277</td><td>NH H ^H l 1 o ^ n ^ n? M - ^ X hn— ch₃</td><td> 579.00</td>

<td> 1278</td><td>I ro z /^-yz&gt; y Ο = ω = Ο Ó X</td><td> 469.00</td>

<td> 1279</td><td>jMH CH₃^h= ....... «'' -y Y n ΪΓ 'k ~ O Ν N --- OR ----. s / - '1 / \ -5—4 l) - s — N \.&gt; ? V 7 1 Η \ .Z, or —NH</td><td> 592.00</td>

<img file="MX349718B_D0433.tif" />

285

IMPI

INSTITUTO MEXICANO DE LA PIválEI AI 'INDUSTRIAL

<td> 1280</td><td>NH CH₃^{H H} L JL AÍYl n NH,</td><td> 503.00</td>

<td> 1281</td><td>NH O J_; ........ I. ... Η, Ν N '' 'NA'⁷⁷^{H H} 1 · 1 J Y- O Ν N 0 / = II H i '\ AN CHj^_&gt;⁷. \,) - N "x. ' ^H h₃c ch₃</td><td> 558.70</td>

<td> 1282</td><td>h₂n - _NH =⁷. __J \ . II ° - . ⁷⁷- 'Ν γτ __ / ÍfA,^NHJ, .L.⁷- or - O Ν 'N Π</td><td> 482.80</td>

<td> 1284</td><td>NH or 11 '11 h₂n Η H 1 || aO3H- Π , ---- VO HN — ζ&gt;</td><td> 635.00</td>

<img file="MX349718B_D0434.tif" />

286

IMPI

MEXICAN INSTITUTE

FROM ΙΑ ΕΧυΐΊΕ.ΠΑΒ

INDUSTRIAL

<td> 1285</td><td>Y. i¹ zx f 1 . Ή Ύ ¡I / τ. 'yj / = &lt;or 1 / ο-ω-ο 0/1 &lt;I 1 X j 1 / ( ZI I / z = K z (M T</td><td> 620.00</td>

<td> 1286</td><td>NH H₂N., YY HN- yi: t .... '..... Τ Τ A O Ν N . . 0 .Y \ __ ll_ 'Y 1 1^— N ... i X Ί F Λ ^NH</td><td> 680.10</td>

<td> 1287</td><td>0 TO ,...... . _ or H₂NN - N _:F0 Ν N - HN. . NH</td><td> 501.90</td>

<td> 1288</td><td>NH O Λ A, and .y. . h₂ⁿ n N - j O Ν N Π -or i / - \ II 31 s or HN .x -, _ 'N ^ H</td><td> 544.10</td>

<img file="MX349718B_D0435.tif" />

287

IMPI ^

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<td> 1289</td><td>Η Μ HoN N / -x _ r 'ry TM-^NH or _{or N} N ' Π &gt; —X 9 0Λ -so '^k HN T Ί 0 NH</td><td> 531.10</td>

<td> 1290</td><td>1 JVW SP f or / 'l' ZI H z OJ I</td><td> 570.60</td>

<td> 1292</td><td>I z 1 v / vw »X —__ 4 7 _ /^z-{J ! -; / "X &lt;1 ZNI</td><td> 606.00</td>

<td> 1293</td><td>NH h₂n^/^ 'n ^ ~ ^^' n ^ X *^yes:X₁Η Η 1 | l H K&gt; h ^ / -NH^HN \ /</td><td> 620.00</td>

<img file="MX349718B_D0436.tif" />

<img file="MX349718B_D0437.tif" />

288

INSTITUTO MEXICANO nt INDUSTRIAL PROPERTY

<td> 1298</td><td> 0 ....... - 0 ^{two H} .ii .M \ / H- ° O Ν H HN .. j ^Z^XN H</td><td> 502.30</td>

<td> 1299</td><td>NH 0 L .... IJ .... ... ..² H ^H | . γ- 0 Ν N ' H ——. or &gt;. '' 1 11 i \ · .—^{S 0}HN „... [JN H</td><td> 544.30</td>

<td> 1300</td><td>I ro z IZ «x / iLv» / XIZ /&gt; rr Η Ó '---' / v ^ Ar</td><td> 573.00</td>

<td> 1301</td><td>I ro Z^IZ\ X ° ^ ι z J — V o— * T re</td><td> 355.10</td>

289

<img file="MX349718B_D0438.tif" />

<td> 1306</td><td>N^H cf₃Η₂Ν^Ζ^ Ν^ΖΧ^Λ'Ν^ΖΧτΑ η ^Η 1 II Α Μ_r / —7 ο ΑΧ LkO Π Α / \ '---' ΗΝ γ) '—ΝΗ</td><td> 646.37</td>

<td> 1307</td><td>cf₃TO Αλ '---' ΗΝΙ · /) '—ΝΗ</td><td> 604.10</td>

<td> 1309</td><td>and CH₃η₂ν Ν Ν Χ'ρ Ο Ν Ν ' Π __ 0 8 IUO . ,&gt; - yes.^Ρ '-' 'ΗΝ * -) ΝΗ</td><td> 592.00</td>

<td> 1310</td><td>JA „ ΑΧ + οχ \ ^ ΝΗ</td><td> 579.00</td>

<img file="MX349718B_D0439.tif" />

290

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<td> 1316</td><td>NH H₂N · - ^h π ι II / \ nh₂</td><td> 491.1</td>

<td> 1324</td><td>I you z zz Xr _I2' „Ó and / yr</td><td> 590.2</td>

<td> 1325</td><td>jr Η H OH. A X&gt; - 5 / ^ X l! &lt;O ΊΆ X x / - \ '----' HNI »&lt;2 NH</td><td> 594.3</td>

<td> 1326</td><td>TO^H TO h₂n Ν ^ Ν ^ γχ ACQi- ---- or &amp; Ύ ° ~ X x _z-i Í '---' ΗΝ · - &lt; \ _- NH</td><td> 578.4</td>

<img file="MX349718B_D0440.tif" />

291

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<td> 1327</td><td>NH H₂N 'N' '' N ·&gt;^{H H} THE .. 'N ..... vl. 7 J 1 -X ~ O Ν N ^sΓΊ 4 ___/ ¹or— H₃c -. ch₃^nh*</td><td> 517.2</td>

<td> 1328</td><td>N^H OCH₃Λ. ... ... I. H₂NN n,^h h 4 x ~ Jf T&gt; h _ ^{0 N} H or-_xH₃C '- .. ch₃ nh₂</td><td> 547.5</td>

<td> 1329</td><td>NH Jl. ...... H₂NN '- N r' ^- or Η H -.TO .eleven / \ / O Ν N —NH M</td><td> 425.8</td>

<td> 1330</td><td>NH^H*^N Ή ή Γ1 ^ T'T^:&gt;4- O- Ν N ' , ---- or&gt; .. '¡1 -2- :, —s— ·. './ il \ Or -. / -_NHHN— J</td><td> 606</td>

292

<img file="MX349718B_D0441.tif" />

<td> 1334</td><td>ΝΗ ΗχΧ - ^ - ^ ν ΑΜ ^{Η η} ι I / Ά I Α / 7 / οΜ ν Μ^Η ΟΗ</td><td> 432.1</td>

<td> 1335</td><td>ΝΗ Λ Η, Ν Ι '^^' νΥΥ Η Η Γ 0 Τγο^Η 0 = ΝΗ 'Η₂Ν</td><td> 466.8</td>

<td> 1336</td><td>ΝΗ 1 Η₂Ν 'Ν -' ν '^Ζ 'γ η ^Η L Η Ν 'q^c? Μ ⁵Μ Τ '\ ° Υ h₃c νη₂</td><td> 503.0</td>

<td> 1342</td><td>η₂ν ν ^ - ^ ν Ίτ ιΊ² Η Η Γ || 7γ Π ς / ^ Ζ^ΝΗ2S \ 1 ⁰ °^s'X'nh₂</td><td> 512.4</td>

<img file="MX349718B_D0442.tif" />

• ΝΓΠΤΌΤΟ MEXICAN • Ε LA rxOMSOAD

INDUSTRIAL

293

<td> 1343</td><td>H₂NN ⁴ N 'Ύ cnn Π 'í¹ // = -., \\ / 7 b, &lt;? ΊΟΗ nh₂</td><td> 505.8</td>

<td> 1344</td><td>NH or ^CHsh₂n 'n₌ ° ^N B k _ / &lt;/ \ p —Ch₃/ nh₂</td><td> 533.6</td>

<td> 1349</td><td> |^^H ocf₃H₂N n N A k 'T d-'N 'N xX '^:or ( '1 IOH nh₂</td><td> 535.3</td>

<img file="MX349718B_D0443.tif" />

294

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

<img file="MX349718B_D0444.tif" />

<img file="MX349718B_D0445.tif" />

295

IMPIí ^

INSTITUTO MEXICANO DF LA PROPERTY

INDUSTRIAL

<td> 1359</td><td>. I re z . xz 1 iz '¹X</td><td> 502.8</td>

<td> 1360</td><td>NH eleven H₂N Ν N XX 0 ' ^N H OR Aoh nh₂</td><td> 505.8</td>

<td> 1361</td><td>NH _FII i ^h'ⁿ X ...... n '' N s 0 Ν N ...... X} p \ CH₃X ch₃nh₂</td><td> 535.4</td>

<img file="MX349718B_D0446.tif" />

<img file="MX349718B_D0447.tif" />

296

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<td> 1365</td><td>NH OCH, ΐ 1 i ^Jii. ... 1 H₂NN - Ν Ί &lt;&gt; 0^{H H} lu .1 - i / Y- O Ν 'N Π p MOH nh₂</td><td> 535.1</td>

<td> 1366</td><td>II * Ί^/%ΎΥΐι X ΓΊ p Υ'ΊΟΗ nh₂</td><td> 523.1</td>

<td> 1367</td><td>1 ..ΛΓι / ιΛ, ύ¹í '' z / - - &lt;O n U. / \ x W // o. ....., Z rr zx X,¹&gt; /. zx X / z ΛΙ X</td><td> 525.00</td>

297

<img file="MX349718B_D0448.tif" />

<td> 1371</td><td>I Μ Η ζζ ΛΛ / νν ΖΖ_ο 3 1</td><td> 535.4</td>

<td> 1372</td><td>X Η₂Ν '^' Ν '^^^_Ν-^χΥγίχ_ιΗ ^Η 1 II θΑ Α ^?π ^ • IIF νη₂</td><td> 507.00</td>

<td> 1373</td><td>NH or ^CH31- -γ γ. Λ .^Η2Ν ñ ~ Η I ι] -γ 'ν'Χυ. ρ Α X&gt; τ Ν 'Ν π -THE'\ ? \\ // Ο ) iiF νη₂</td><td> 536.9</td>

<img file="MX349718B_D0449.tif" />

298

IMPI

MEXICAN INSTITUTE

I HEARD THE PRO HE DAD INDUSTRIAL

<img file="MX349718B_D0450.tif" />

<img file="MX349718B_D0451.tif" />

299

IMPI

MEXICAN INSTITUTE

OI THE PROPERTY 'NDUSTtlAL

<td> 1381</td><td>Γ h ^H | l 1 C&gt; nh₂</td><td> 496.3</td>

<td> 1390</td><td>NH H₂NN Ν^H H 2 |] ''^Z''? λ X. r O 'Ν N Π | ..^z- \ ¿\? I '' p NH_Z</td><td> 507.3</td>

<td> 1391</td><td>I M z —z / I TZ \ 1 \ ^ rcr \ f / ....... OF Z 'Y o, 7—_λ n ^C-Y ° O) ---^/ T \\ / ω '&gt;' Ύ X χ. ί '</td><td>N / A</td>

<img file="MX349718B_D0452.tif" />

300

I Μ ρ Τ 1 AVA 11 Λ

INSTITUTO MEXICANO L! LA MOHEDA * 'INDUSTRIAL

<td> 1392</td><td>I ζ&gt; í IZ 1 \ 'vyw' and ή '1 i</td><td> 455.3</td>

<td> 1393</td><td>T z IZ ^ i ^IZΛΑΛΑ \ what⁷to / \ 1</td><td> 455.3</td>

<td> 1397</td><td>H₂N,._t NH and q HN. -. NH I ..... X ih₂n „..... UJ i NH Η TO ^N , x --- &lt;O j ¿A--./</td><td> 704.2</td>

<td> 1398</td><td>^NH ... h₂n 'nn, '' ν 'ΎΎ j, j .1 -i- . O 'Ν N NH NH</td><td> 438.00</td>

<img file="MX349718B_D0453.tif" />

301

IMPI

INSTITUTO MBXICAN ·, DI LA PaOPI £ DA5 industrial

<td> 1399</td><td>NH O h₂n ν ν ΎΆ &lt;L 7 ν Ί _ O- Ν N. p '- \ ·. 9 v ·, P ____ / OR / &gt; OH nh₂</td><td> 519.1</td>

<td> 1400</td><td>NH JJ - - H₂NN 'N | Η Η ί | [ '1 Σ n O' NN í&gt; ....... 7. /; 0 / ;&gt; och₃&lt; NH₂</td><td> 519.7</td>

<td> 1404</td><td>. I z ) z . · 'I IZ . OX zo / Z -n -n A \ 7 or. W &lt;\ / —Z z? '7' / ! \ ΙΖ i</td><td> 525.00</td>

<img file="MX349718B_D0454.tif" />

302

1405

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

505.2

1406

1408

<img file="MX349718B_D0455.tif" />

<img file="MX349718B_D0456.tif" />

<img file="MX349718B_D0457.tif" />

508.3

452.00

303

<img file="MX349718B_D0458.tif" />

<td> 1410</td><td>NH n. .... ..... .^h₂N ν Ν 1 || '..... ΎΧ.4 O Ν N M _L /^{= X}&lt;4. d OR h₃c. ,^H^^c nh₂</td><td> 517.3</td>

<td> 1411</td><td>r. .. ... h₂n H hj ! .i N '·. . ._Q-d .. -d. Η_r _ OH ! ^H / or V ^N NH₂</td><td> 498.4</td>

<td> 1412</td><td>NH^{H H} 1 J _ - \ &amp; 1 1 z? ΓΊ r / ^ = \, P g / \ __ / «HN — Σ / ΝΗ</td><td> 514.8</td>

<td> 1413</td><td>NH h₂n 0— 'H' O _. 'XT ^ t- O- Ν N '^τΑ '·, d P nh₂</td><td> 514.4</td>

<img file="MX349718B_D0459.tif" />

304

ΙΜΡ.Ι

INSTITUTE MbXI * .AN &lt;&gt; D! INDUSTRIAL PROPERTY

<td> 1414</td><td>X H₂N o ^ n ^ n Π "KZ ^ PH₃C — ¿ nh₂</td><td> 503.2</td>

<td> 1415</td><td>Z W z zz $} 0 = ^ = 0 X 'j ^lzx&gt; ΠΛΑΤ 1</td><td> 618.1</td>

<td> 1416</td><td>NH . .......- II. . . ... .... Η₂Ν NTN Ϋ, 1 Η&gt; H OH Λ .. - NV · \ Á ..X .J ..... 'T ~ ON ü Γ1 . = or ί \ IH. Ύ&gt;,? - s — N— NH 'II ... or</td><td> 566.3</td>

<td> 1417</td><td>NH 1 .. .... .... ... h₂n N ynyy OH X ¹ . to. .. , 1 .1 x ~ ONN NH s = \ o _x II. SNN ^nh2 ¿ . -</td><td> 608.6</td>

<img file="MX349718B_D0460.tif" />

305

IMPI

MEXICAN INSTITUTE

OF THE industrial PROPERTY

<td> 1418</td><td>r ... h₂nnn '' γ Η Η 1 i [ ' ^N γχ. γ or ν N^¿b Y 'Wildebeest</td><td> 501.00</td>

<td> 1422</td><td>NH H₂N '^ N' ^^V^^ N '^&gt; &lt;^₁Η H [| I A k H₂N</td><td> 496.4</td>

<td> 1423</td><td>NH Ll,. h₂nn N _r Y ...... O Ν N 3 / - i OR i NH</td><td> 515.00</td>

<td> 1428</td><td>I or 0 ™ 7 I ur^ZI z I</td><td> 420.00</td>

306

<img file="MX349718B_D0461.tif" />

<td> 1431</td><td>ΝΗ ^{Η Η} | Ι 1 αΟοη (ΑνΑ cf₃-Ια k - &lt;; νη '\ _ / Η ΧΖ</td><td> 568.2</td>

<td> 1432</td><td>ΝΗ 1 ...... ... ..... Η, Ν Ν Ν 7 | 1 Η Η | Ι. 1. '1 Σ' Μ- Ο Ν Ν CF₃ ΝΗ X ^{Ν Ν} ΝΗ 'λ ___ / Η ΝΗ₂</td><td> 610.1</td>

<td> 1433</td><td>Γ 1 η η Η 1_οχ &lt;χ νη₂</td><td> 501.1</td>

<td> 1434</td><td>ΝΗ Η, Ν- ^ Ν - ^ ---^Η Η I || xO&gt; l ΓΙ ^ ςς νη₂</td><td> 529.0</td>

307

<img file="MX349718B_D0462.tif" />

<td> 1435</td><td>η₂ν — ΆΡ Ο ^ νΑν Ρ νη₂</td><td> 408.00</td>

<td> 1436</td><td>^Η ο TO^F/F νη₂</td><td> 426.00</td>

<td> 1437</td><td>ΝΗ .1. ...,. . .. Η₂Ν Ν 'Ν ΐι X² Η Η || | ^Ν ι Ο Ν Ν&gt; Π . 4 ...... Ί ' '' ..- Ν .... '- νη₂</td><td> 480.3</td>

<td> 1438</td><td>γ 'ζι π ό 'ζ ζχ_νΟ λ ΐ '7 \ ν '/ ^{C ΖΙ}^ζι ..X / 1 \ ΖΙ I / Ζ— ζ - IN I</td><td> 515.3</td>

308

<img file="MX349718B_D0463.tif" />

<td> 1439</td><td>^{H H} 1 II o- ^ n N n J h₃c * ^ nh₂</td><td> 503.2</td>

<td> 1440</td><td>JT _ _^{H H} 1 LL Xkk 4 ^ 'or H ₃O or P nh₂</td><td> 503.2</td>

<td> 1442</td><td>NH II. ...... h₂nnn%² Η H || .....? i .....&gt; l ° ^N H . Γ³ &gt; N— NH y- h -</td><td> 505.8</td>

<td> 1443</td><td>^Η2Ν⁴Γ-'θ IPrW ~&gt; NNY / : | F nh₂</td><td> 408.00</td>

<img file="MX349718B_D0464.tif" />

IMPI

309

Mexican Institute of Industrial Property

<td> 1444</td><td>ΠΡΡΡ ° ^N H - \ p - ^ OCH, ñh₂</td><td> 419.5</td>

<td> 1446</td><td>NH. Λ. . . . Η, Ν Ν Ν Ύ 'i Η H | 'V O Ν N ' / h₂n</td><td> 473.5</td>

<td> 1447</td><td>1 0 - zz z N I</td><td> 543.6</td>

<td> 1448</td><td>HN H Κχ \ - ^^ nh₂</td><td> 466.2</td>

310

<img file="MX349718B_D0465.tif" />

491.5

1452

1453

<img file="MX349718B_D0466.tif" />

<img file="MX349718B_D0467.tif" />

<img file="MX349718B_D0468.tif" />

531.00

518.7

<img file="MX349718B_D0469.tif" />

<img file="MX349718B_D0470.tif" />

311

VrTiCA INSTITUTE^: J &lt;LA .RGHEDAI '»&lt;:&gt; USTR1AL

<td></td><td> 1455</td><td colspan="5">NH</td><td> 587.00</td>

<td></td><td></td><td>h₂nn H</td><td>NH</td><td></td><td> '1</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>N</td><td>'V' '' 1</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>Ó N</td><td>NH</td><td></td>

<td> 5</td><td></td><td></td><td> '/____</td><td> 6</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>—Cf₃</td><td></td><td></td>

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

<td></td><td> 1456</td><td>HN</td><td></td><td></td><td></td><td></td><td> 482.1</td>

<td></td><td></td><td>H₂N^Z^ 'h</td><td>H</td><td>r⁵^</td><td>j</td><td></td><td></td>

<td> 10</td><td></td><td></td><td></td><td></td><td>'^' N '^⁵</td><td>^^^ N</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>OR'^!’^S^ 'N^í</td><td>H</td><td></td>

<td></td><td></td><td></td><td>_c_ / 1</td><td>Oh</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>^s V — N_s</td><td></td><td>^ nh₂</td><td></td><td></td>

<td></td><td> 1457</td><td>HN</td><td></td><td></td><td></td><td></td><td> 508.2</td>

<td></td><td></td><td>N H₂N h</td><td>NH</td><td>'r'^s:'</td><td> ¡1</td><td></td><td></td>

<td> 15</td><td></td><td></td><td></td><td></td><td>N _ Λ ON</td><td>X 11 N 'H</td><td></td>

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

<td></td><td></td><td></td><td> —?—1</td><td rowspan="2">! N</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>X NH</td><td></td><td></td>

<td></td><td> 1458</td><td></td><td></td><td></td><td></td><td></td><td> 533.7</td>

<td> 20</td><td></td><td>NH JL h₂nn H</td><td> N H</td><td></td><td>1. . 1 'N</td><td>Χ ~ Ήa</td><td></td>

<td></td><td></td><td></td><td>-........- - Λ</td><td>or</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>&gt; ..... Q</td><td></td><td></td><td></td>

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

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

<img file="MX349718B_D0471.tif" />

312

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<td> 5</td><td> 1459</td><td>NH h₂n ^ Xxy - or iC / - | -ⁿ0&gt;—^NHj'-' or</td><td> 549.7</td>

<td> 10</td><td> 1460</td><td>NH 1 ... ... . ...^HN N - Ν ₍ I^{N r} _Y O Ν N 5 i, Or me - NH₂</td><td> 537.1</td>

<td> 15</td><td> 1461</td><td>NH. ......... ... H Ή 1 Ί ..... “X4 O ^N H cf₃ _. ; N—. NH XH _</td><td> 534.7</td>

<td> 20</td><td> 1462</td><td>J .. or¹l&gt; ir 1^z ° i⁰ 1 X Γ j &lt;T νΠ-Λ '' ZX / ZX X / z ---</td><td> 550.7</td>

Tt Mi MI-H.JU ..

313

IMPI

INSTITUTO MEXICANO OF LA FROHEDAD industrial

<img file="MX349718B_D0472.tif" />

<img file="MX349718B_D0473.tif" />

<td>2000th</td><td>HN Η, Ν H ^H LJ JT'U O ΊΧ N / H A Λ.-Α</td><td> 485.10</td>

<td>2001a</td><td>TO^Hh_sn^xxn '^zxx^xnAA h ^H 1 II ^ OCM- An o ^ n ^ n p \&gt; IF nh₂</td><td> 584.40</td>

<td>2002a</td><td></td><td> 661.30</td>

<img file="MX349718B_D0474.tif" />

<img file="MX349718B_D0475.tif" />

315

IMPI

INSTITUTO MEXICANO DI LA PROriíDAD

INDUSTRIAL

<td></td><td>,!F Π₂Ν N - n / -Xk &lt;&gt; ° Ν N - N --- ' O ....... hF / \ nh₂</td><td></td>

<td>2006a</td><td>Jj ^ H Η, Ν- ^ Ν 'TAíA^{H H} [eleven uOA cAt / A __ cf₂h W^h</td><td> 592.60</td>

<td>2007a</td><td>Κ ^ Α ^^ ΆΑ ^ Α^{H H} | l 1 oOA ° ^N H O '--- \ nh₂</td><td> 538.1</td>

<td>2008a</td><td>HN h₂n H ^h And 1 .T YjH- ON to ⁵-IX Ί S^h3 'nh₂</td><td> 480.20</td>

<td>2009a</td><td></td><td> 571.12</td>

316

<img file="MX349718B_D0476.tif" />

<img file="MX349718B_D0477.tif" />

<img file="MX349718B_D0478.tif" />

2012a

593.00

<img file="MX349718B_D0479.tif" />

317

IMPI

MEXICAN INSTITUTE

DI THE INDUSTRIAL PROPERTY

<td></td><td>OR^H*^N Η Π 'γγ N Ύ - &lt;\ Z fí -AJ. --Y O ° ^N to / - 'nh₂? \ \ /, ' me ( .......... &lt; nh₂</td><td></td>

<td>2013a</td><td>T .....-....... =^HjN H ñ [1; | , ...... YT i&gt; 1 &lt;&gt; ONN N-- 4-0 or (y., uF / nh₂</td><td> 592.30</td>

<td>2014a</td><td>NH O IL. . U 4 h₂n 'NN γ r 'T ^&gt; ........ \ Ο NN CF₃"OO 'N— NH</td><td> 582.80</td>

<td>2015a</td><td>Η, Ν ^ N ΊΓ^{H H} II 1^π H __ cf₃ NH _L_Z \ -_N—/^_nP ^ nh₂&gt; \ ZHX / ²</td><td> 624.30</td>

<td>2016a</td><td></td><td> 480.30</td>

<img file="MX349718B_D0480.tif" />

318

IMPU

INSTITUTO MEXICANO Dt LA RRGriEDAD INDUSTRIAL

<td></td><td>HN H₂NH h K i] Xp o- Ν N -IPP ch., ^N NH₂</td><td></td>

<td>2017a</td><td>IN z You IZ zz pz \ zz \</td><td> 482.9</td>

<td>2018a</td><td>NH J1 ........ ..... .... .....^h2ⁿ NN j, X Η H ' O Ν N '—N^H. / ς NH X CH₃</td><td> 508.3</td>

<td>2019a</td><td>NH .A and Y h₂n _n ν γ and H Η [I X- JyZ \ / O Ν NN^H &gt; / NH NH₂</td><td> 509.0</td>

<td>2020a</td><td>r .. .......^H2^N N 'N | ¡', Η H || XX&gt; ...... x? O Ν N e—_NΠ \ &lt; HN ~ X nh₂</td><td> 507.4</td>

319

<img file="MX349718B_D0481.tif" />

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

<td>2021a</td><td>I rsj z IZ IZ \) ai? zi] 0</td><td> 522.1</td>

<td>2022a</td><td>NH h ....... ·. ..^H2^N ν Ν i, ^{H H} ί 1 - and 'Γ ^&lt;zO Ν N 'N^H / HN-k N</td><td> 502.9</td>

<td>2023a</td><td>NH eleven ... .... ... .. H₂NNNXX² Η H [[ N 'X ..... c eleven - , ____, ON ..... N ' r / \ ΓΊ - z. z ) —CF₃HN X &lt;/ NH</td><td>600.40 [M + Na 23]</td>

<td>2024a</td><td>NH 1 ... .... ... .... H₂N nn 'Ϊ X . . -X °^N H —CF₃HN ? ? N h₂n ^nh</td><td> 610.10</td>

<img file="MX349718B_D0482.tif" />

320

IMPI

MEXICAN INSTITUTE

OF THE INDUSTRIAL EROHEUAO

<img file="MX349718B_D0483.tif" />

<img file="MX349718B_D0484.tif" />

321

IMPI

INSTITUTE m.xican. .

OF INDUSTRIAL PROPERTY

<img file="MX349718B_D0485.tif" />

<img file="MX349718B_D0486.tif" />

2031a

628.00

322

<img file="MX349718B_D0487.tif" />

<img file="MX349718B_D0488.tif" />

2032a

2033a

592.50

<img file="MX349718B_D0489.tif" />

578.00

<img file="MX349718B_D0490.tif" />

2034a

569.10

<img file="MX349718B_D0491.tif" />

323

IMPI

INSTITUTO MEXICANO OE LA PROPERTY

INDUSTRIAL

<img file="MX349718B_D0492.tif" />

2035a

<img file="MX349718B_D0493.tif" />

609.50

2036a

551.4

<img file="MX349718B_D0494.tif" />

2037a

614.3

<img file="MX349718B_D0495.tif" />

324

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX349718B_D0496.tif" />

<img file="MX349718B_D0497.tif" />

<img file="MX349718B_D0498.tif" />

325

IMPI

INSTITUTO MFJUCAN »► Dt LA PROPIEÜAU INDUSTRIAL

<td></td><td>I M z. 2-0 A. /^r 7</td><td></td>

<td>2042a</td><td>HA Η, Ν TO NH / ch₃</td><td> 480.0</td>

<td>2043a</td><td>NH A, ^ ____ H₂N ν N '&gt;&gt; 1^{H H} 1 11 χΎ? γ- TO ^x—N ') ( \ or / &lt; ) HÓ</td><td> 511.0</td>

<td>2044a</td><td></td><td> 550.0</td>

<img file="MX349718B_D0499.tif" />

327

<img file="MX349718B_D0500.tif" />

.NDUSTRIA'-

<td></td><td>Z z zz TZ ₂^ &lt;Xl₀ p</td><td></td>

<td>2048a</td><td>or . IJ ...... 1.1_H2n- O Ν N __P ^^CF- &gt; / \ / nh₂</td><td> 585.6</td>

<td>2049a</td><td>NH eleven .._H2N N Ν γ ^.₍^NO Ν N ΓΊ ch₃/ ^ / -.......- s ..... or / Y........ &lt; nh₂</td><td> 568.2</td>

<td>2050a</td><td></td><td> 537.6</td>

328

<td></td><td> 1? ^Hto^N N - N yy OR _N N / OH Y or 7 ......... &lt;' nh₂</td><td></td>

<td>2051a</td><td>r. . Η, Ν ν - Ν and. OR _N N₇—Nh₂me / .......... \ nh₂</td><td> 535.7</td>

<td>2052a</td><td>I z zz zz 4- o 0 £ X ^{f A} Yq&gt; Λ / ν</td><td> 621.3</td>

<td>2053a</td><td></td><td> 531.0</td>

329 ί ΜΡΙ. Α

ΝΫΠΤυΤΟ 'uXICaNL;

γ »· ¡A 'fc.' *** ® INDUSTRIAL PROPERTY

<td></td><td>Η ^ '^ ΐΓ ^' ^ Χ γΧγ^{H H} u 1 0γΟ Oh "KZz nh₂</td><td></td>

<td>2054a</td><td>NH or . ... ^ ... .... Η, Ν NNYY Η H | 1 O Ν N OR^X s -cf₃'______ / \ / ς &lt;nh₂</td><td> 603.0</td>

<td>2055a</td><td>X .......................... H₂NNNY '&lt;1² Η Η] 1 '- ^' '' '- Ν^ΖΧγΥ ₃J. 0 '7X O 'n' n Π 0 O — S — CF3 -TO &lt; nh₂</td><td> 619.0</td>

<td>2056a</td><td></td><td> 388.6</td>

330

<img file="MX349718B_D0501.tif" />

<td></td><td>or 77^{They have} 1 71 ON / \ h₂n</td><td></td>

<td>2057a</td><td>H.N'XjX / = \ J4 Á / W o ^ n ^ n \ -Ύ h₂n</td><td> 374.6</td>

<td>2058a</td><td>NH H₂N '^' N '' ^^ 'N ^ VX Η H || ] cr ^ N ^^ y ri __PCF₃^ 'O H, N</td><td> 557.1</td>

<td>2059a</td><td>I M z H IZ IZ w / = ( J \ n&gt; 0 0 ή Z_v to</td><td> 622.1</td>

<td>2060a</td><td></td><td> 488.3</td>

<img file="MX349718B_D0502.tif" />

332

<img file="MX349718B_D0503.tif" />

INSTITUTO MEXICAN &lt;'□ FM ίΈΟΙΤΟΑΐ' INDUSTRIAL

<img file="MX349718B_D0504.tif" />

<td>2065a</td><td>NH H_2N N 'NJ already / ? Ύ N ^ OH - ^ £) &gt; \ ( nh₂</td><td> 517.3</td>

<td>2066a</td><td></td><td> 533.2</td>

<img file="MX349718B_D0505.tif" />

<img file="MX349718B_D0506.tif" />

<img file="MX349718B_D0507.tif" />

334

INSTI'H / I'u •. • X'Cáí * · PF LA iif.CW.DAD iNDUrTRIAL

<td></td><td>NH JL ... ... ... Η, Ν 'N' N 00 Y H. H || | r XX- ° ^N H I Vnh₂X / / \ nh₂</td><td></td>

<td>2070a</td><td>r____ ^{H H} | l 1 oXX , ocf₃~ K ~ / HN nh₂</td><td> 572.3</td>

<td>2071a</td><td>r ____^{H H} l 1 cAn ^ N NH_to</td><td> 505.3</td>

<td>2072a</td><td></td><td> 571.3</td>

<img file="MX349718B_D0508.tif" />

<img file="MX349718B_D0509.tif" />

335

INSTITUTO MVXICAS »DE LA PROHIEDA.» INDUSTRIAL

<td></td><td>z h¿l z s IZ IZ T 0 O 1</td><td></td>

<td>2073a</td><td>T M z ZZ ZZ X Ψ O</td><td> 521.3</td>

<td>2074a</td><td>NH Λ .... ... .. ... Η, Ν Ν 'Ν A^{Η Η} 1 X. .... J ΤΥζ Ο ^Ν Η eighth₂) &lt; ) / \ νη₂</td><td> 553.3</td>

<td>2075a</td><td></td><td> 555.1</td>

<img file="MX349718B_D0510.tif" />

<td></td><td>(· / ZI U- AV £ , A- - A z HQ or A () T ZI / / / ZI I / Z = X z CM I</td><td></td>

<td>2076a</td><td>0. «. Γ F or ° r AXA. z C&gt; ¡I। AA r --- &lt;0 1 ' / X \ / \ - / / ZI \ / '\ ZI I / Z CM I</td><td> 605.1</td>

<td>2077a</td><td>I M z A IZ i TI II ς '&gt; IZ / X or 0 io 1— '' ω? 1 / \^{w IZ}\ P</td><td> 589.1</td>

<td>2078a</td><td></td><td> 639.1</td>

<img file="MX349718B_D0511.tif" />

337

IMPI ^

INSTITUTO MEXICANODE LA rxOPl £ JAi&gt; INDUSTRIAL

<img file="MX349718B_D0512.tif" />

<td>2081a</td><td></td><td> 639.2</td>

338

MEXICAN INSTITUTE

OF THE rFOPIttAD

INDUSTRIAL Ώί

<td></td><td>NH CF₃A ... A ... H₂N Η H || ] X ίϊ A ~ ° Ν N ocf₃.— - &lt; C / \ ^ AA / \) &lt;. nh₂</td><td></td>

<td>2082a</td><td>NH CF₃² Η H || qA-n '' n ocf₃NH HN = (nh₂</td><td> 681.1</td>

<td>2083a</td><td>. NH TO,,-.. ...² H «1 1 n O Ν N ' / —Sch₃? &gt; / ÑH₂</td><td> 547.1</td>

<td>2084a</td><td></td><td> 512.1</td>

<img file="MX349718B_D0513.tif" />

339

IΜ ΡI

INSTITUTE MrX'CANV ·

Ι.Α INDUSTRIAL PROPERTY

<td></td><td>Γ Y Y ..... YY -^N N - NJ '' 7 N I, 1 O Ν N N / \. / \ nh₂</td><td></td>

<td>2085a</td><td>NH 1 ... ... .... ... H₂NN - N _;| &lt;| . .1 J. / '“T ON £ j F '. X \ Ph₂</td><td> 505.1</td>

<td>2086a</td><td>r ............. ..... .... H₂NN - NYY² Η H || . [ A p ^ 'A (T ^ N ^' N n CF, X 'X \ &gt; - 'CH₃&lt;nh₂</td><td> 569.1</td>

<td>2087a</td><td></td><td> 537.1</td>

<img file="MX349718B_D0514.tif" />

340

IΜ ΡI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

<img file="MX349718B_D0515.tif" />

<img file="MX349718B_D0516.tif" />

341

<img file="MX349718B_D0517.tif" />

<img file="MX349718B_D0518.tif" />

<td>2092a</td><td>1 r. 0⁰ZI ZI z I</td><td> 566.1</td>

<td>2093a</td><td></td><td> 521.1</td>

<img file="MX349718B_D0519.tif" />

342

Í T / 7 Tt ·. 17 ii iy&gt; 1 L do

INSTITUTE v.rxiCAN-) Dt LA PROHPDAD INDUSTRIAL

<td></td><td>I M z zz zz O or V To</td><td></td>

<td>2094a</td><td>NH Η, Ν ^ Ν ^^^ νΟιΟ H ^H [eleven O ^ N ^ N ° P — NH and 1 ^ - nh NH₂</td><td> 621.1</td>

<td>2095a</td><td>NH CHF₂H₂N '^X^ N^/^^x^^ 'N^Xgf^XOR² Η H || 1 O ^ N ^ N ocf₃Y nh₂</td><td> 621.2</td>

<td>2096a</td><td></td><td> 574.1</td>

343

<img file="MX349718B_D0520.tif" />

<img file="MX349718B_D0521.tif" />

In other embodiments, the compounds of the present invention do not encompass a compound having the structure:

<img file="MX349718B_D0522.tif" />

The compounds of the present invention can be

344

<img file="MX349718B_D0523.tif" />

done using synthesis techniques by those skilled in the art.

well known chemicals

EXAMPLES

Example 1 - Synthesis of compound 682

BocHN NH₂

<img file="MX349718B_D0524.tif" />

i: Et₃N ii: Boc₂OR

<img file="MX349718B_D0525.tif" />

Br {3 - [(4-Bromo-benzyl) -tert-butoxycarbonyl-amino] -propyl} carbamic acid tert-butyl ester: A solution of 1-bromo4-bromomethyl-benzene (17.79 g, 71.17 mmol) in toluene (50 mL) was added dropwise to a mixture of 3-amino-propyl) carbamic acid tert-butyl ester (16.1 g, 92.51 mmol), triethylamine (29.6 mL, 213.5 mmol) in toluene (200 mL) over 30 min. at 80 ° C. The resulting mixture was heated to 80 ° C for a further 2 h before cooling to 0 ° C. Di-tert-butyl pyrocarbonate (23.5 g, 107.80 mmol) was added at 0 ° C. After 2 h, the mixture was warmed to room temperature and stirred overnight, diluted with EtOAc (500 mL) and washed with water (300 mL), brine (300 mL). The organic solution was concentrated and purified by flash chromatography (10% - 25% EtOAc in heptane) to give the desired product (16.15 g, 51%) as a colorless oil.¹NMR '' RIwtwi Μ i

3. 4. 5 (300 MHz, CDC1₃): 57.44 (d, J =

5.16 (br.s, 0.5H), 4.62 (br.s, (m, 2H), 3.10 (m, 2H), 1.65 (m,

BocHN

Boc

<img file="MX349718B_D0526.tif" />

<img file="MX349718B_D0527.tif" />

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

<img file="MX349718B_D0528.tif" />

8.4 Hz, 2H), 7.01 (br, 2H), 0.5H), 4.34 (br, 2H), 3.40 2H), 1.43 (br.br.s, 18H).

<img file="MX349718B_D0529.tif" />

(3-tert-Butoxycarbonylamino-propyl) - (4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) -benzyl] -carbamic acid tertbutyl ester: A mixture of {3 - [(4-bromo-benzyl) -tert-butoxycarbonyl-amino] -propyl} -carbamic acid tert-butyl ester (16.15 g, 36.46 mmol), bispinacolate boronate (10.20, 40.11 mmol), KOAc (10.72 g, 109.38 mmol), Pd (PPh₃)₄ (0) (2.03 g, 1.82 mmol) and DMF (80 mL) was heated at 80 ° C for 16 h under argon atmosphere. The reaction mixture was diluted with EtOAc (500 mL), washed with water (300 mL) and brine (300 mL). The organic solution was concentrated and purified by flash chromatography (10% - 30% EtOAc in heptane) to give the desired product (14.15 g, 80%) as a colorless oil.¹NMR (300 MHz, CDC1₃): 5 7.76 (d, &lt;7 = 8.1 Hz, 2H), 7.01 (br.s, 2H), 5.16 (br.s, 0.5 H), 4.62 (br.s, 0.5 H), 4.40 (br, 2H ), 3.28 (m, 2H), 3.08 (m, 2H), 1.50 (m, 2H), 1.43 (br.s, 18H), 1.34 (s, 12H).

<img file="MX349718B_D0530.tif" />

346

IMPIA l / ty * PuontK.w

<img file="MX349718B_D0531.tif" />

<img file="MX349718B_D0532.tif" />

2- (4- ([tert-Butoxycarbonyl- (3-tert-butoxycarbonylaminopropyl) -amino] -methyl} -phenyl) -3-methoxy-acrylic acid methyl ester: A mixture of (3-tert-butoxycarbonylamino-propyl ΙΕ 4 - (4, 4, 5, 5-tetramethyl- [1,2,3] dioxaborolan-2-yl) -benzyl] carbamic acid tert-butyl ester (6.00g, 12.25 mmol), 2-iodo-3-methoxy-acrylic acid methyl ester (4.45 g, 18.38 mmol), K3PO4 (7.79.g, 36.75 mmol), Pd (PPh₃)₄ (0) (0.68 g,

0.61 mmol), dioxane (60 mL) and water (12 mL) were degassed and heated at 80 ° C for 20 h under argon atmosphere. The reaction mixture was diluted with EtOAc (500 mL), washed with water (300 mL) and brine (300 mL). The organic solution was concentrated and purified by flash chromatography (0% -30% EtOAc in heptane) to give the desired product (5.35 g, 91%) as a brown oil.¹NMR (300 MHz, CDC1₃): δ 7.56 (s, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.20 (br.d, 2H), 5.20 (br.s, 0.5 H), 4.62 (br.s, 0.5 H) , 4.39 (br, 2H), 3.86 (s, 3H), 3.74 (s, 3H), 3.27 (m, 2H), 3.08 (m, 2H), 1.62 (m, 2H), 1.50 (br.d, 9H ), 1.43 (s, 9H). LCMS (IE) m / z: 501 (M + Na⁺) .

<img file="MX349718B_D0533.tif" />

347

IMPIAS

MEXICAN INSTITUTE

DE IA PROPERTY P'ea ^ i'.FJ INDUSTRIAL V », - V» (3— {tert-Butoxycarbonyl- [4- (7-oxo-l, 7-dihydro-imidazo [1,2a] pyrimidin-6- yl) -benzyl] -amino} -propyl) -carbamic acid tert-butyl ester: For a mixture 2 (-4 {[tertButoxycarbonyl- (3-tert-butoxycarbonylamino-propyl) -amino] methyl} -phenyl) -3- methoxy-acrylic acid methyl ester (97 mg, 0.2 mmol), 1 W-imidazol-2-ylamine sulfate (29 mg, 0.223 mmol) and ethanol (10 mL) a solution of sodium methoxide (0.5 mL, 0.5 M in methanol, 0.25 mmol.). The resulting mixture was refluxed for 18 hours, added 0.5 mL of sodium methoxide (0.5 M in methanol, 0.5 mmol) and continued to reflux for 20 hours. The reaction was concentrated and diluted with EtOAc (30 mL) and washed with water (20 mL), brine (20 mL). The EtOAc solution was concentrated. The crude product was purified by flash chromatography (10% methanol in dichloromethane) to give the desired product (48mg, 48%) as a white solid.¹NMR (300 MHz, CD₃OD): δ 8.40 (s, 1H), 7.59 (br.s, 2H), 7.29 (m, 4H), 4.46 (s, 2H), 3.23 (m, 2H), 3.02 (m, 2H), 1.68 ( m, 2H), 1.52 (br.d, 9H), 1.42 (s, 9H). LCMS (IE) m / z: 498.1 (M + H⁺) .

<img file="MX349718B_D0534.tif" />

<img file="MX349718B_D0535.tif" />

348

<img file="MX349718B_D0536.tif" />

6- {4 - [(3-amino-propylamino) -methyl] -phenyl) -lH-imidazo [1,2-a] pyrimidin-7-a hydrochloride salt (hydrochloride salt of compound 563): {(3 - {tert-Butoxycarbonyl- [4- (7-o xo-1,7-dihydro-imidazo [1,2-a] pyrimidin-6-yl) -benzyl] -amino} propyl) -carbamic acid tert-butyl ester (48 mg, 0.097 mmol) was dissolved in CH₂C1₂ (5 mL), TFA (1 mL) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated and 3 mL of 0.6 N HC1 and 2 mL of acetonitrile and stirred for 0.5 h, concentrated at ca. 3 mL and lyophilized to give the title compound (35 mg, 100%). . YMR (300 MHz, CD₃OD): δ 8.90 (s, 1H), 7.79 (s, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.67 (s, 1H), 4.33 (s, 2H), 3.23 (t, J = 8.1 Hz, 2H), 3.06 (t, J = 7.5 Hz, 2H), 2.15 (m, 2H). LCMS (El) m / z: 297.1 (M + H⁺) .

<img file="MX349718B_D0537.tif" />

N- {3- [4- (7-Oxo-l, 7-dihydro-imidazo [1,2-a] pyrimidin-6-yl) benzylamino] -propyl} -guanidine hydrochloride salt (salt

<img file="MX349718B_D0538.tif" />

349

IΜ ΡI

IHSn, υτο «LAY

Di LA IWHIDad industrial hydrochloride of compound 564): To a mixture of compound 563 (26 mg, 0.07 mmol), Hunig's base (90 mg, 0.70 mmol) and DMF (10 mL) was added N, N-bis-Boc- 1 -guanylpyrazole (22 mg, 0.07 mmol). The reaction mixture was stirred at room temperature overnight and diluted with water (30 mL), extracted with EtOAc (50 mL x 3). The organic solution was concentrated and purified by PTLC (2N NH3 in methanol / CH₂C1₂, 1: 4) to give the guandilated product as a white solid (30 mg, 80%) that was dissolved in 3 mL of CH₂C1₂ and 1 mL of TFA was added. The resulting mixture was stirred overnight and 3 mL of 0.6 N HC1 and 2 mL of acetonitrile was concentrated and stirred for 0.5 h, concentrated at ca. 3 mL and lyophilized to give the title compound (20 mg, 100%).^XNMR (300 MHz, D2O): δ 8.41 (s, 1H), 7.60 (d, J =

8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 2.1 Hz,

1H), 7.35 (d, J = 2.1 Hz, 1H), 4.27 (s, 2H), 3.25 (t, J = 6.9 Hz, 2H), 3.12 (m, 2H), 1.96 (m, 2H). LCMS (IE) m / z: 339.7 (M + H +).

<img file="MX349718B_D0539.tif" />

N— (3 - {(4-Amino-butyl) - [4- (7-oxo-1,7-dihydro-imidazo [1,2

a] pyrimidin-6-yl) -benzyl] -amino} -propyl) -guanidine salt

<img file="MX349718B_D0540.tif" />

350 hydrochloride (hydrochloruzo salt of compound 616): To a mixture of compound 563 (26 mg, 0.07 imol), Hunig's base (90 mg, 0.70 mmol) and DMF (10 mL) was added N, N-bis-Boc- 1 guanylpyrazole (22 mg, 0.07 mmol). The reaction mixture was stirred at room temperature overnight and diluted with water (30 mL), extracted with EtOAc (50 mL x 3). The organic solution was concentrated and purified by PTLC (2N NH₃ in methanol / CH₂C12, 1: 4) to give the guandylated product as a white solid (30mg, 80%).

A mixture of the guandilated compound (27 mg, 0.05 mmol), (3-oxo-propyl) -carbamic tert-butyl ester (9 mg, 0.05 mmol), acetic acid (6 mg, 0.1 mmol) and CH2CI2 (5 mL) was stirred for 30 min at room temperature before sodium cyanoborohydride (13 mg, 0.2 mmol). The resulting mixture was stirred overnight, diluted with CH₂C1₂(15 mL), washed with saturated sodium bicarbonate solution. The CH solution₂C1₂ concentrated and purified by PTLC (2N NH₃ in methanol / CH₂C12, 1: 9) to give the desired tertiary amine as a white solid (13mg, 37%).

The tertiary amine product (13 mg, 0.0187 mmol) was dissolved in 3 mL of CH₂C1₂ and 1 mL of TFA was added. The resulting mixture was stirred overnight and 3 mL of 0.6 N HC1 and 2 mL of acetonitrile was concentrated and stirred for 0.5 h, concentrated at ca. 3 mL and lyophilized to give the title compound (9.4 mg, 100%).¹NMR

351

<img file="MX349718B_D0541.tif" />

(300 MHz, CD₃OD): δ 8.99 (s, 1H), 7.86 (d, J = 2.1 Hz, 1H), 7.81 (br.s, 4H), 7.74 (d, J = 2.1 Hz, 1H), 4.55 (s, 2H) , 3.36 (m, 6H), 3.05 (m, 2H), 2.22 (m, 2H), 2.09 (m, 2H). LCMS (IE) m / z: 396.9 (M + H⁺) .

<img file="MX349718B_D0542.tif" />

<img file="MX349718B_D0543.tif" />

{4- [2— (4-Bromo-phenyl) -7-oxo-l, 7-dihydro-imidazo [1,2— a] pyrimidin-6-yl] -benzyl} - (3-tert-butoxycarbonilanu.nopropyl ) -carbamic acid tert-butyl ester: For a mixture of 2— (4 - {[tert-Butoxycarbonyl- (3-tert-butoxycarbonylaminopropyl) -amino] -methyl} -phenyl) -3-methoxy-acrylic acid methyl ester ( 5.70 g, 11.92 mmol), 5- (4-bromo-phenyl) - 1 / i-imidazol2-ylamine (2.84 g, 11.92 mmol) and ethanol (60 mL) a solution of sodium methoxide (12 mL, 0.5 M in methanol, 6 mmol). The resulting mixture was refluxed for 18 hours, added 12 mL of sodium methoxide (0.5 M in methanol, 6 mmol) and continued to reflux for 20 hours. The reaction was concentrated and diluted with EtOAc (300 mL) and washed with water (200 mL), brine (200 mL). The EtOAc solution was concentrated. The crude product was purified by flash chromatography (0% - 8% methanol

<img file="MX349718B_D0544.tif" />

352

IMPI l&gt; f LA ΡΡ.ΟΗΓΠαγ&gt;

in dichloromethane) to give the desired product (4.05 g,

52%) as a brown solid. ¹NMR (300 MHz, CDC1₃): δ 7.96 (s, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.54 (m, 2H), 7.35 (s, 1H), 7.27 (d, J = 8.1 Hz, 2H), 5.25 ( br.s, 0.5H), 4.70 (br.s, 0.5H), 4.44 (s, 2H), 3.29 (m, 2H), 3.11 (m, 2H), 1.67 (m, 2H), 1.52 ( br.d, 9H), 1.44 (s, 9H). LCMS (IE) m / z: 654 (M + H⁺) .

<img file="MX349718B_D0545.tif" />

6— {4 - [(3-Amino-propylamino) -methyl] -phenyl} -2- (4-bromophenyl) -lH-imidazo [1,2-a] pyrimidin-7-one hydrochloride salt (hydrochloride salt of compound 617): {4- [2- (4-Bromo-phenyl) -7-oxo-l, 7-dihydro-imidazo [1,2-a] pyrimidin-6-yl] benzyl} - (3-tert- butoxycarbonylamino-propyl) hydrochloride salt (hydrochloride salt of compound 617): tert-butyl ester acid (100 mg, 0.153 mmol) was dissolved in CH2CI2 (5 mL), TFA (1 mL) and stirred at room temperature for 2 h . The reaction mixture was concentrated and 3 mL of 0.6 N HC1 and 2 mL of acetonitrile and stirred for 0.5 h, concentrated at ca. 3 mL and lyophilized to give the title compound (80 mg, 100%).¹NMR (300 MHz, CD3OD): δ 8.99 (s, 1H), 8.24 (s, 1H), 7.75 (m, 8H), 4.30 (s, 2H), 3.32 (t,

J = 8.1 Hz, 2H), 3.09 (t, J = 7.5 Hz, 2H), 2.17 (m, 2H). LCMS

<img file="MX349718B_D0546.tif" />

IMPI

MEXICAN INSTITUTE

OS THE INDUSTRIAL MOHEDAL

353 (ΙΕ) m / z: 454 (Μ + Η⁺) .

<img file="MX349718B_D0547.tif" />

4- [6- (4 - {[tert-Butoxycarbonyl- (3-tert-butoxycarbonylaminopropyl) -amino] -methyl} -phenyl) -7-oxo-1,7-dihydro-imidazo [1,2-a] pyrimidine -2-yl] -benzoic acid 2,5-dioxo-pyrrolidin-l-yl ester: A mixture of {4 - [- (4-bromo-phenyl) -7-oxo-1,7-dihydro-imidazole [1,2 -a [pyrimidin-6-yl] -benzyl} - (3-tert-butoxycarbonylamino-propyl) -carbamic acid tert-butyl ester (1.50 g, 2.3 mmol), hydroxysuccylimide (0.40 g, 3.45 mmol), 9,9-dimethyl- 4,5-bis (diphenylphosphino) xanthan (67 mg,

0.115 mmol), palladium acetate (26 mg, 0.115 mmol), triethylamine (700 mg, 6.9 mmol) and DMSO (3 mL) in a sealed tube was degassed and filled with carbon monoxide (20 psi). The reaction mixture was heated at 80 ° C for 16 h. After cooling to room temperature, the mixture

354

<img file="MX349718B_D0548.tif" />

* · ** ^ - * - r ·¹· Ι i, «• —.Ta — ι&gt;

reaction was diluted with water (30 mL), extracted with

CH2CI2 (50 mL x 3). The CH2CI2 solution was concentrated and purified by chromatography (0-10% methanol in CH₂C1₂) to give activated ester as a brown solid (1.0 g, 61%). ^XNMR (300 MHz, CDCI3): δ 8.14 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.4 Hz, 2H), 7.96 (s, lH), - 7.64 (d, J = 9.1 Hz, 2H), 5.59 (s, 1H), 7.45 (d, J = 9.1 Hz, 2H), 5.25 (br.s, 0.5 H), 4.69 (br.s, 0.5 H), 4.45 (s, 2H), 3.29 (m, 2H), 3.11 (m, 2H),

2.92 (s, 4H), 1.67 (m, 2H), 1.52 (br.d, 9H), 1.44 (s, 9H).

LCMS (IE) m / z: 715 (M + H⁺) .

<img file="MX349718B_D0549.tif" />

6— {4 - [(3-Amino-propylamino) -methyl] -phenyl} -2- [4- (piperazine-1-carbonyl) -phenyl] -lH-imidazo [1,2-a] pyrimidin-7-a salt hydrochloride (hydrochloride salt of 682): A mixture of 4 [6-4 {- {[tert-butoxycarbonyl- (3-tert-butoxycarbonylaminopropyl) -amino] -methyl} -phenyl) -7-oxo-l, 7 -dihydroimidazol [1,2-a] pyrimidin-2-yl] -benzoic acid 2,5-dioxopyrrolidin-l-yl ester, 1-boc-priperazine (229 mg, 1.23 *

355 mmol) and CH₂C1₂ (5 mL) was stirred at room temperature overnight, concentrated and purified by chromatography (0-10% methanol in CH₂C1₂) to give the desired amide as a white solid (330 mg, 76%), ¹NMR (300 MHz, CDCI3); δ 8.03 5 (s, 1H), 7.85 (d, J = 13.8 Hz, 2H), 7.55 (d, J = 8.4 Hz,

2H), 7.43 (d, J = 8.4 Hz, 2H), 7.42 (s, 1H), 7.26 (d, J =

13.8 Hz, 2H), 5.35 (br.s, 0.5H), 4.95 (br.s, 0.5H), 4.44 (s, 2H), 3.70 (m, 2H), 3.44 (m, 6H), 3.20 (m, 2H), 3.10 (m,

2H), 1.67 (m, 2H), 1.52 (br.d, 9H), 1.48 (s, 9H) 1. 44 (s,

9H). LCMS (IE) m / z: 786 (M + H⁺). The amide product (330 mg) was dissolved in CH₂C1₂ (5 mL), TEA (1 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated and 4 mL of 0.6 N HCl and 4 mL of acetonitrile and stirred for 0.5 h, concentrated at ca. 5 mL and lyophilized to give the title compound (250 mg, 100%).¹NMR (300 MHz, CD3OD): δ 9.02 (s, 1H), 8.34 (s, 1H), 7.98 (d,

J = 8.4 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.1 Hz,

2H), 7.71 (d, J = 8.1 Hz, 2H), 4.35 (s, 2H), 3.90 (br.s,

4H), 3.34 (m, 2H), 3.25 (t, J = 7.5 Hz, 2H), 3.12 (t, J =

7.8 Hz, 2H), 2.17 (m, 2H). LCMS (IE) m / z: 486.1 (M + H)⁺.

Example 2 - Synthesis of Pyrrolocytosines

<img file="MX349718B_D0550.tif" />

356 .20

ΙΜ ΡΙ

Mexican Institute of Industrial Property

<img file="MX349718B_D0551.tif" />

<img file="MX349718B_D0552.tif" />

<img file="MX349718B_D0553.tif" />

<img file="MX349718B_D0554.tif" />

<img file="MX349718B_D0555.tif" />

Synthesis of compound 3:

Compound 2 (65.0 g, 373 mmol) was dissolved in ethanol (150 mL). The flask was purged with argon. Compound 25 1 (55.93 g, 373 mmol) was then added and the mixture

357 • "Λ" · * · was stirred at room temperature for 2 h. The reaction solution was then added via an addition funnel, over 20 minutes, to a suspension of NaBH₄(14.18 g, 373 mmol) in toluene (150 mL), at 0 ° C. The ice bath was removed, and the resulting mixture was stirred at room temperature for 3 h. IN HC1 (750 mL) was added to the solution, and the mixture was stirred at room temperature for 30 min. K2CO3 (205.9 g, 1.49 moles), Boc₂0 (81.41 g, 373 mmol) and THE (200 mL) were added to the solution, and it was stirred at room temperature for 23 h. Reaction solution was partitioned between EtOAc and brine / H₂O. The aqueous layer was washed with EtOAc (2 x 300 mL). The combined organic layers were washed with brine (500 mL); dried over Na2SO4; filtered and concentrated. The crude product was purified by Combi flash chromatography, in 3 portions, giving the product as a white solid (119.43 g, 78%); MRNA (300 MHz, CDCI3) δ 1.43 (bs, 18H), 1.63 (m, 2H), 2.95-3.30 (m, 4H), 4.45 (m, 2H), 5.93 (bs, 1H), 7.22 (bs, 1H ), 7.34 (bs, 1H), 7.78 (d: 8Hz, 1H), 8.19 (d: 8Hz, 1H).

Synthesis of compound 5:

For a mixture of compound 3 (42.28 g, 103.5 mmol) and compound 4 (24.54 g, 103.5 mmol) MeOH was added

358

<img file="MX349718B_D0556.tif" />

INSTITUTO MWUCani&gt; OT LA PROFltDAI INDUSTRIAL (3 L) y H₂0 (750 mL). The mixture was vigorously stirred in open air, at room temperature, for 30 min. Cu (OAc)₂»H₂O (20.67g, 103.5mmol) was then added, followed by TMEDA (18.63mL, 124.3mmol). The solution was stirred open in air, at room temperature, for 5 h.

After completion of the reaction, the solution was concentrated to 0.7 L, and then partitioned between CH₂C1₂ (700 mL) and 20% ΝΗ₄ΟΗ / Η₂Ο saturated with NH₄C1 (500 mL). The aqueous layer was washed with CH₂C1₂ (500 mL, 200 mL). The combined organic layers were dried over MgSO₄, filtered and concentrated. The crude product was purified by Combi flash chromatography: A: CH₂C1₂ B: 15: 1 CH₂C1₂/ 2N NH₃/ MeOH, 0-100% B for 85 min. (Two columns 330g). This gave the product as a white solid (35.52 g, 58%);

LCMS (ESI): m / e 600 (M + H)⁺.

Synthesis of compound 6:

Compound 5 (10.0 g, 16.68 mmol) was dissolved in THE (40 mL). The flask was purged with argon. Pyridine (40 mL) was then added, followed by BzCl (3.10 mL, 26.69 mmol). The solution was stirred at room temperature under argon atmosphere for 3 hours. MeOH (4 mL) was added, the mixture was stirred at room temperature for 10 min, and then partitioned between EtOAc (200 mL),

<img file="MX349718B_D0557.tif" />

IMPI • '' fT'niTu MEXICAN Λ tA PROPERTY INOUSTXfAl mL). The aqueous layer is

The

359 heptane (100 mL), and 5% KHCO₃/ H₂O (200 washed with EtOAc (100 mL, 50 mL).

combined were washed with 5% KHCO₃/ H₂O (300 mL); dried over Na₂SO4, · filtered and concentrated. The crude product was purified by Combi flash chromatography: 0-100% EtOAc / heptane, more than 55 min. (330 g column). The product was obtained as an off-white powder (9.81 g, 84%); LCMS (ESI): m / e 704 (M + H)⁺.

Synthesis of compound 8:

3,5-Dibromobenzoic Acid 7 (3.35 g, 11.97 mmol) was dissolved in DMF (30 mL). TBTU (5.38 g, 16.76 mmol) and the solution was stirred under argon, at 22 ° C, for 5 min. Diisopropylethylamine (4.95 mL, 29.92 mmol) was added, followed immediately by thiapiperazine S, S-dioxide (2.26 g, 16.76 mmol ·). The mixture was stirred at 22 ° C for 24 h, and then partitioned between EtOAc (200 mL) and 3% ΚΗΟΟ₃/ Η₂Ο (300 mL). The organic phase was washed with H₂0 (200 mL), and then with brine (100 mL), dried over Na₂SC&gt; 4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (200 g) using 3% (2.5 M NH₃/ MeOH) / CH₂C1₂. This gave compound 8 (1.72 g, 36%) as a solid;¹H-NMR (300 MHz, DMSO-d6) δ 3.10 to 3.30 (m, 4H), 3.64 (m, 2H), 3.98 (m, 2H), 7.75 (d: 2.0 Hz,

<img file="MX349718B_D0558.tif" />

360

IMPI wjTnim- Mexican ce la raonsDAn INCUSTKIA !.

2Η), 7.97 (t: 2.0Hz, 1H).

Synthesis of co-question 9:

Compound 8 (1.72 g, 4.33 mmol), N-Bocpiperazine (931 mg, 5.0 mmol), K₂CO₃ (1.26 g, 9.1 mmol), Cul (83 mg, 0.43 mmol), and proline L- (100 mg, 0.87 mmol) were suspended in dimethylsulfoxide (15 mL). The mixture was purged with argon, and then stirred under argon at 85 ° C, for 20 h. After cooling to room temperature, the mixture was partitioned between water (150 mL) and ethyl acetate (200 mL), the organic phase was washed with water (100 mL), dried over Na₂SW₄, and concentrated. The crude product was purified by flash chromatography on silica gel (200 g) using 2% (2.5 M NH₃/ MeOH) / CH₂C1₂. This gave compound 9 (0.65 g; 30%) as a solid;¹H-NMR (300 MHz, DMSO-d6) δ 1.42 (s, 9H), 3.12 - 3.28 (m, 8H), 3.44 (m, 4H), 3.64 (m, 2H), 4.00 (m, 2H), 7.02 (bs, 2H), 7.17 (bs, 1H).

Synthesis of compound 10:

Compound 9 (0.63 g, 1.25 mmol) was dissolved in

THF (10 mL). The solution was placed in a pressure vessel, purged with argon, and then Cul (60 mg, 0.313 mmol), Pd (PPh₃)₄ (145 mg, 0.125 mmol), Et₃N (1.40 mL, · * '-. 1 I—— mmol), and acetylene trimethylsilyl (0.3

The container was sealed, and the mixture was stirred at 45-50 ° C. After 3 h, the mixture was diluted with EtOAc (30 mL), concentrated, and then purified by chromatography on silica gel (120 g) using 70% EtOAc - 30% heptane. This gave a semisolid (1.2 g) that was dissolved in MeOH (70 mL). The solution was purged with argon, K₂CO₃ (1.0 g) was added, and the mixture was stirred under argon, at 45 ° C, for 30 min. The mixture was filtered, concentrated and purified by flash chromatography on silica gel (120 g) using ethyl acetate 75% - 25% heptane. This gave compound 10 (0.425 g, 76%) as a solid, white foam; LCMS (ESI): m / e 448 (M + H)⁺.

<td>362 BocHN Άχ-Α- _N^Boc LX। ίΓ + o '^ n' ^ nh 5 ₆ Bz BocH Ν _N AAN. Boc IN - αΎΥα¹⁰ Λα / Cr Ν Ν eleven ^Hυ¹⁵ Η₂Ν^χΧνχ-^χΧΧΝ^χΧΥ &lt;^{# ί}Υ]^H L 1 O ^ N ^ NH 12A: x 4 TFA 12B: x 4 HCI 20 nh " H ₂ Ν · Χ Ν ΆΑ n^{H H} l 1 x 4 HCI XX- o ^ n ^ n 13 ^H 25</td><td>IMPI INITITUTE MtXICAN * · tU LA MOHEDAL »INDUSTRIAL aA Ck / TY 10 Boc V / \ X / - ('- ° or '—N \ Boc / \ ^ o / \ X —Z '- / ° 'or '—NH ° w / \ ^ o .— (\ - / 0 or '—NH</td>

<img file="MX349718B_D0559.tif" />

363

IMPI ΐΝ, Mexican τιτυτα

OR THE »« OMTO * U INDUSTRIAL

Synthesis of compound 11:

Compound 6 (669 mg, 0.95 mmol) and compound 10 (425 mg, 0.95 mmol) were placed in a pressure vessel, and anhydrous DMF (15 mL) were added. The solution was purged with argon and then Cul (46 mg, 0.24 mmol), Pd (PPh₃)₄ (110 mg, 0.095 mmol), and Et₃N (1.06 mL, 7.6 mmol) were added, the container was sealed, and the mixture was stirred at 22 ° C, for 15 min. Subsequently, the temperature was increased to 80-85 ° C, and the mixture was stirred for 14 h. It was cooled to room temperature, MeOH (10 mL) was added, the container was sealed, and the mixture was stirred at 90 ° C for 3 h. After cooling to room temperature, the mixture was partitioned between sat. KH₂PO₄/ H₂O (250 mL) and ethyl acetate (200 mL), the organic phase was washed with brine (150 mL), dried over Na₂SW₄, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (150 g) using 5% (2.5 M

NH₃/ MeOH) / CH₂C1₂. This gave compound 11 (490 mg; 56%) as a yellow solid; LCMS (ESI): m / e 920 (M + H)⁺.

Synthesis of compounds 12A and 12B:

Compound 11 (490 mg, 0.533 mmol) dissolved

364

<img file="MX349718B_D0560.tif" />

in CH2Cl2 (20 mL), trifluoroacetic acid (20 mL) was added, and the mixture was stirred at 22 ° C for 40 min. CH₂C1₂ (30 mL) was added, and the mixture was concentrated in vacuo to a viscous oil. Water (3 mL) and EtOH (70 mL) were added, the mixture was concentrated to provide crude 12A compounds as a solid residue. This residue was dissolved in [(10% MeOH-90% H₂O) 0.15% TFA] (40 mL). An aliquot (10 mL) was injected onto a 41.4 mm Dynamax column, HPLC unit C-18 prep (guard + column), which was eluted with a 10% - 55% solvent gradient (MeOH / H₂O + 0.15% TFA), for 40 min. The pure fractions were combined and concentrated with EtOH, to dryness. This sample was treated with IN HC1 / H₂O (5 mL) and EtOH (70 mL), and concentrated. This operation was repeated; the solid thus obtained was lyophilized from H₂O-MeCN (4: 1), yielding compound 12B (78 mg) as a yellow powder; LCMS (ESI): m / e 619 (M + H)⁺.

Synthesis of compound 13:

A solution of compounds 12A in the solvent mixture [(10% MeOH-90% H₂O) 0.15% TFA], described above, (30 mL, 0.40 mmol), was concentrated with EtOH, to a viscous oil. This sample was dissolved in a mixture of DMF (10 mL) and diisopropylethylamine (0.53 mL,

3.20 mmol). Ν, N'-bis-Boc-1-guanylpyrazole (149 mg, 0.48 mmol), and the mixture was stirred at 22 ° C, for 15 h. EtOH (80 mL) was added, and the mixture was concentrated in vacuo (&lt;1 mm Hg, 45 ° C) to a viscous oil, which was dissolved in a mixture of CH2Cl2 (25 mL) and trifluoroacetic acid (30 mL) . The mixture was stirred at 22 ° C, for 2 h, and then CH₂C1₂ (70 mL) was added, the solution was concentrated, the residue was dissolved in MeOH (30 mL) and treated with Amberslyst A26 (OH) resin (10 g). The mixture was stirred for 1h, filtered, and the filtrate was concentrated to a semisolid. This sample was purified by preparative HPLC: Dynamax 41.4 mm, C18 preparative HPLC unit (column guard +), which was eluted with a solvent gradient of 10% - 55% (MeOH / H₂Or + 0.15% TEA), more than 40 min. The pure fractions were combined and concentrated with EtOH, to dryness. This sample was treated with 1 N / H HCl₂O (5 mL) and EtOH (70 mL), and concentrated. This operation was repeated; the solid thus obtained was lyophilized from H2O-MeCN (4: 1), yielding compound 13 (122 mg) as a yellow powder; LCMS (ESI): m / e 661 (M + H)⁺.

Example 3: Synthesis of compounds 2009a (series a) and 2029a (series b)

<img file="MX349718B_D0561.tif" />

Synthesis of 2a and 2b:

A mixture of phosphonium salt 12 (5.24 g, 9.88 mmol), la (or Ib) (2.65 g, 9.88 mmol), K₂CO₃ (1.36 g, 9.88 mmol), and 18-crown-6 (catalytic amount) in toluene (50 mL) was refluxed under argon overnight. Upon completion, the mixture was cooled to room temperature and water was added. The aqueous layer was extracted with ethyl acetate (3 x 75 mL) and the combined organic extracts were dried over Na₂SW₄ and then concentrated. The residue was purified by silica gel chromatography (2: 1 heptane / ethyl acetate). Compound 2a was cleanly isolated as a mixture of E and Z isomers (3.78 g, 87% yield).

Synthesis of 3a and 3b:

To a flask containing phthalimide

2a (3.78 g,

367

<img file="MX349718B_D0562.tif" />

iNSTIT'lTJ MtXICANL;

ÍV INDUSTRIAL MOBILITY

8.58 mmol) (or 2b) in ethyl acetate was added 10% Pd / C (0.7-6 g, 20% w / w). The flask was evacuated and filled with hydrogen through a balloon assembly. Stirring at room temperature was continued for 45 minutes at which time the contents were purged with argon. After filtering the mixture through celite, solvent was evaporated to provide the desired product 3a in quantitative yield (3.77 g).

Synthesis of 4a and 4b:

In a screw cap pressure tube, 3a (3.70 g, 8.37 mmm or 1) (or 3b) was dissolved in anhydrous ethanol. Hydrazine monohydrate (1.62 mL, 33.5 mmol) was added to the solution and heat was applied at 65 ° C for 8 h. After cooling to room temperature, the suspension was filtered to remove the white solid by-product and the resulting solution was concentrated to dryness. Water was added and the aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with water and brine and dried over NaSO₄. Evaporation of the solvent provided a clear, colorless oil (2.32 g, 89% yield) which was redissolved in dichloromethane (75 mL) and treated at 0 ° C with benzyl chloroformate (1.27 mL,

8.94 mmol) and triethylamine (2.07 mL, 14.9

<img file="MX349718B_D0563.tif" />

368

I Μ ΡI instituio • uxicano? T tA ÍRCI'IEDAP industrial mmol). After 1 hr of stirring, water was added and the organic layer was collected, dried over NaSO₄, Y. concentrated. Purification of the crude residue by silica gel chromatography (2: 1 heptane / ethyl acetate) supplied 4a as a viscous oil. (3.06 g, 92% yield)

Synthesis of 5a and 5b:

Compound 5a (and 5b) was prepared through the same two-step Sonogashira-deprotection sequence used for the synthesis of alkyne 10. From 1.5 g 4a, the product was obtained in 53% yield (0.69 g) .

369

<img file="MX349718B_D0564.tif" />

<img file="MX349718B_D0565.tif" />

<img file="MX349718B_D0566.tif" />

5b R = CF,

<img file="MX349718B_D0567.tif" />

Synthesis of 7a and 7b:

<img file="MX349718B_D0568.tif" />

370

IMPI

INSTITUTO MkXICANl,