Substituted nucleosides, nucleotides and analogs thereof.

(54) Title: SUBSTITUTED NUCLEOSIDS, NUCLEOTIDES AND ANALOGS THEREOF. (54) Title: SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF.

(57) Summary

The present invention relates to nucleosides, nucleotides, and analogs thereof, pharmaceutical compositions including one or more nucleosides, nucleotides, and analogs thereof, and methods of synthesizing them. There are also disclosed herein methods of ameliorating and / or treating a disease and / or condition -including infection caused by a paramyxovirus and / or an orthomyxovirus- with a nucleoside, nucleotide, and analog thereof. .

(57) Abstract

Disclosed herein are nucleosides, nucleoids and analogs thereof, pharmaceutical compositions that inelude one or more of nucleosides, nucleoids and analogs thereof, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and / or treating a disease and / or a condition, including an infection from a paramyxovirus and / or an orthomyxovirus, with a nucleoside, a nucleoid and an analog thereof.

yes

IMPIC, 1

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PATENT TITLE No. 356509

Owner (s): ALIOS BIOPHARMA INC.

Address: 26 (1 E. Grand Avenue. 2nd Floor, South San Francisco, California, 94080, USA

D nomination: SUBSTITUTED NUCLEOSIDS, NUCLEOTIDES AND THE LIKE.

Classification: CIP: C07H19 / 00; A61K31 / 506; A61K31 / 522; A61K31 / 675; A61K31 / 708;

A61K31 / 4184; Α61Κ31 / 4Ϊ92; A61K31 / 7068; A61K31 / 7072; A61P31 / 14; C07D471 / 04; C07D473 / 34; C07H19 / 06; C07H19 / 14; C07H19 / 16; C12N9 / 99 CPC: C07M19 / 0Ü; A61K45 / 06; C07D4Q5 / Q4; C07D405 / 14; C07D473 / 18;

C07D473 / 34; C07D487 / O4; C07D493 / 04; C07H19 / 06; C07H19 / 10;

C07H19 / 12; CO7H10 / 14; CO7H10Z16; C07H19 / 20; C07H19 / 207; C12N9 / 127; C12Y207 / 07048

Inventor (s)

LEONID 8EKSELMAN; GMANGYI WANG; DAVID BERNARD SMITH; JEROME DEVAL: MARtJA PRHAVC

SOLI

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Number:

MX / a / 2014/007480 i »of International Presentation:

from Diftiembrécfe 2012

PmORfMD

Country:

US

US

<img file="MX356509B_D0003.tif" />

Date:

December 2011 March 2012

Number:

61/579,560

61/613,836

Validity: Twenty years

Expiration date: December 20, 2032 Issue date: May 30, 201.8

The reference patent is granted with all articles!⁰, 2nd fraction of the useful fraction, and 59 of the Industrial Property Law.

In accordance with article 23 of the Law on: Industrial Property, this patent has a non-extendable term of twenty years, counted from the date of filing of the intemational application and subject to the payment of the fee to keep the rights in force.

Whoever subscribes to this title does so based on the provisions of articles β * fraóóionesHI> 7'bis 2 of the Industrial Property Law (Official Gazette of the Federation (DOF) 06/27/1991, amended on 02 / 0β / Ίβ9 <, 25/10/1996, 12/26/1997, 05/17/1999, 01/26/2004, 06/16/2005, 01/25/2006, 06/05/2009, 06/01/2010, 06/18/2010, 06/28/2010, 01/27/2012 and 04/09/2012), articles 1 «, 3rd fraction V Subsection a), 4th and 12th fractions I and III of the Regulation of the Mexican Institute of Industrial Property (O'OF. 14/12/1999, rWlli ^ of «I 07/01/2002, 07/15/2004, 07/28/2004 2004 and 7/09/2007); Articles 1, 3, 4, 5, section V, Section a), 16 sections I and III and 30 dafeEsteV⁰ OrgántógíégMestltuto Mexicano de la Propiedad Industrial (DOF 27/12/1999, amended on 10/10/2002, 07/29/2004, 08/04/2004 and 09/13/2007); 5 'subsection a) of the Delegating Agreement faculties in the Deputy Directors General, Coordinator, Divisional Directors, Head of the 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 letter 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 III, 2 fraction V, 26 BIS and 26 TER of the Agreement establishing the guidelines for the use of the Electronic Payment and Services Portal (PASE) of the Mexican Institute of Industrial Property, in the procedures indicated.

THE DIVISIONAL DIRECTOR OF PATENTS

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NAHANNY CANAL REYES

Original string:

NAHANNY MARISOL CANAL REYES | 00001000000403252793 | Tributary Administration Service | 1695 || MX / 2018/46460 | MX / a / 2014/007480 | Patent title PCT | 1223 | GAGV | Pág (s) | wOJTCyhWI3aXyt + 8EqsccUMIyP

Digital stamp:

NMkAvCR + PI + AEaosGv9ZYohGP8X4pal4cf9zD + cxxRAtiV9ai7Mgf / EEoPEKT0qY / Huc5nYIJIc4up3kbD + IF6BTfT

SE7ctJxRuq3CkxhkYkqncWfl / 8sfA9K9Gue6Ca8VfckCmudR7 / klYQd5fA + rb7rPLdUpHUaQGIDVg / JSBiceHkBSZe + s59W> 7udB7bS16 / bmqe + 21Cb2PnjKGcul8WQy6C4kHYhGK9S4qydNeK7ezl7zmgYpuf02JhN0jFb829PtAja5L + / d nqTBfgksUojcC8Hu + E + WphkidnJdqLI5A4M6x115k9N2 / mEtgF2xlMblXrxmoAC2dQ9¡UJQ ==

Arenal No, 550, Pise ' ^{* 1} ,>>, ί pan, Xochimilco, 16020,, j, i '- ¹ vv ¡t go «. nnpi

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MX / 2018/46460

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SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS

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BACKGROUND

Countryside

The present application relates to the fields of chemistry, biochemistry and medicine. More particularly, nucleosides, nucleotides and analogs thereof, pharmaceutical compositions including one or more nucleosides, nucleotides and analogues thereof, and methods for synthesizing all of them are described herein. Also disclosed herein are methods for ameliorating and / or treating a viral infection caused by a paramyxovirus and / or an orthomyxovirus with one or more nucleosides, nucleotides, and analogs thereof.

Viral respiratory infections, including viral upper and lower respiratory tract infections, infect millions of people each year and is the leading cause of death. Viral upper respiratory tract infections involve the nose, sinuses, pharynx and / or larynx. Viral lower respiratory tract infections affect the respiratory system below the vocal cords, including the trachea, primary bronchi, and lungs.

ÍVtí í

MEXICAN INSTITUTE Df THE PROPERTY

INDUSTRIAL

<img file="MX356509B_D0008.tif" />

Nucleoside analogs are a class of compounds that have been shown to exert antiviral activity both in vitro and in vivo and have therefore been the subject of extensive research for the treatment of viral infections. Nucleoside analogues are generally therapeutically inactive compounds that are converted by the host or viral enzymes to their respective active antimetabolites, which, in turn, can inhibit polymerases that are involved in viral or cellular proliferation. Activation occurs by a variety of mechanisms, such as the addition of one or more phosphate groups and, or in combination with, other metabolic processes.

SUMMARY

Some embodiments disclosed herein refer to a compound of Formula (I), Formula (II) and / or Formula (III) or a pharmaceutically acceptable salt of the foregoing.

Certain embodiments presented herein relate to methods of ameliorating and / or treating a paramyxovirus viral infection which may include administering to a subject suffering from paramyxovirus viral infection, an effective amount of one or more compounds of Formula (I) ,

-.2 a !. _s_;

MEXICAN INSTINCT m THE PROPERTY

INDUSTRIAL

<img file="MX356509B_D0009.tif" />

of Formula (II) and / or of Formula (III), or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition including one or more compounds of Formula (I), of Formula (II) and / or of Formula (III), or a pharmaceutically acceptable salt of the foregoing. Other embodiments described herein relate to the use of one or more compounds of Formula (I), Formula (II) and / or Formula (III), or a pharmaceutically acceptable salt of the foregoing , in the manufacture of a medicine to improve and / or treat a viral paramyxovirus infection. Other embodiments more described herein refer to compounds of Formula (I), Formula (II) and / or Formula (III), or a pharmaceutically acceptable salt of the foregoing, which can be used to improve and / or treat a viral paramyxovirus infection. Still further embodiments described herein relate to methods of ameliorating and / or treating a viral paramyxovirus infection which may include contacting a paramyxovirus infected cell with an effective amount of one or more compounds of the Formula (I), of Formula (II) and / or of Formula (III), or a pharmaceutically acceptable salt of the foregoing, or a

<img file="MX356509B_D0010.tif" />

pharmaceutical composition including one or more compounds of Formula (I), Formula (II) and / or Formula (III), or a pharmaceutically acceptable salt of the foregoing.

Certain embodiments disclosed herein refer to methods of inhibiting replication of a paramyxovirus, which may include contacting a paramyxovirus infected cell with an effective amount of one or more compounds of Formula (I), of Formula (II) and / or of Formula (III), or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition including one or more compounds of Formula (I), of Formula (II) and / or of Formula (III), or a pharmaceutically acceptable salt of the foregoing. For example, viral paramyxovirus infection can be caused by a henipavirus, a morbillivirus, a respirovirus, a rubulavirus, a pneumovirus (including a respiratory syncytial virus infection), a metapneumovirus, hendravirus, Nipah virus, measles, Sendai virus, mumps , a human parainfluenza virus (HPIV-1, HPIV-2, HPIV-3 and HPIV-4) and / or a metapneumovirus.

Certain embodiments disclosed in this document refer to methods of ameliorating and / or treating an orthomyxovirus viral infection, which may include

<img file="MX356509B_D0011.tif" />

<img file="MX356509B_D0012.tif" />

mexicanoπτυτο Mexican CE VA INDUSTRIAL PROPERTY administer to a subject suffering from viral orthomyxovirus infection an effective amount of one or more compounds of Formula (I), Formula (II) and / or Formula (III), or a salt pharmaceutically acceptable from the foregoing, or a pharmaceutical composition including one or more compounds of Formula (I), Formula (II) and / or Formula (III), or a pharmaceutically acceptable salt of the foregoing. Other embodiments described herein relate to the use of one or more compounds of Formula (I), Formula (II) and / or Formula (III), or a pharmaceutically acceptable salt of the foregoing , in the manufacture of a medicine to improve and / or treat an orthomyxovirus viral infection. Other embodiments more described herein refer to compounds of Formula (I), Formula (II) and / or Formula (III), or a pharmaceutically acceptable salt of the foregoing, which can be used to improve and / or treat a viral infection by orthomyxovirus. Still further embodiments described herein relate to methods of ameliorating and / or treating an orthomyxovirus viral infection, which may include contacting an orthomyxovirus infected cell with an effective amount of one or more compounds of the Formula (I),

<img file="MX356509B_D0013.tif" />

IMPI ^{, HS} 1 MEXICAN ROUTE OF INDUSTRIAL PROPERTY of Formula (II) and / or Formula (III), or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition including one or more compounds of Formula (I ), of Formula (II) and / or of Formula (III), or a pharmaceutically acceptable salt of the foregoing.

Certain embodiments disclosed herein refer to methods of inhibiting the replication of an orthomyxovirus, which may include contacting a cellular infection with the orthomyxovirus with an effective amount of one or more compounds of Formula (I), of Formula (II) and / or of Formula (III), or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition including one or more compounds of Formula (I), of Formula (II) and / or of Formula (III), or a pharmaceutically acceptable salt of the foregoing. For example, the orthomyxovirus viral infection may be a viral influenza infection (such as influenza A, B, and / or

C).

Certain embodiments disclosed herein refer to methods of ameliorating and / or treating a viral paramyxovirus infection and / or a viral orthomyxovirus infection, which may include administering to a subject suffering from the viral infection an effective amount of a '--τ—

<img file="MX356509B_D0014.tif" />

^{, NST}”7th Mexican DE LA PRCPWDAÜ INDUSTRIAL compound described herein or a pharmaceutically acceptable salt thereof (eg, one or more compounds of formulas (I), (II) and / or (III), or a pharmaceutically acceptable salt of the foregoing), or a pharmaceutical composition including one or more compounds described herein, in combination with one or more agents described herein. Certain embodiments disclosed herein relate to methods of ameliorating and / or treating a viral paramyxovirus infection and / or a viral orthomyxovirus infection, which may include contacting a cell infected with the virus with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (eg, one or more compounds of the formula (I), (II) and / or (III), or a pharmaceutically acceptable salt of the above), or a pharmaceutical composition that includes one or more compounds described herein, in combination with one or more agents described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows exemplary RSV agents.

DETAILED DESCRIPTION

The family Paramyxoviridae is a family of viruses of

Single-stranded RNA. There are several genres of the family

<img file="MX356509B_D0015.tif" />

JL A

MEXICAN INSTITUTE (2 «“ ^ OF THE INDUSTRIAL PEOPLE paramyxoviridae, including the henipavirus, the

------- ·· - -. ·. ... go morbillivirus, respirovirus, rubulavirus, pneumovirus, and metapneumovirus. These viruses can be transmitted from person to person, by direct or close contact with tiny contaminated breath drops or fomites. Henipavirus species include hendravirus and Nipah virus. One species of morbillivirus is measles.

Respirovirus species include Sendai virus and human parainfluenza viruses 1 and 3; and rubulavirus species include the mumps virus and human parainfluenza viruses 2 and 4. One species of metapneumovirus is the human metapneumovirus.

Human respiratory syncytial virus (RSV), a kind of pneumovirus, can cause respiratory infections, and can be associated with bronchiolitis and pneumonia. Symptoms of a RSV infection include cough, sneezing, runny nose, fever, loss of appetite, and wheezing. RSV is the most common cause of bronchiolitis and pneumonia in children under one year of age in the world and can cause tracheobronchitis in older children and adults. In the United States, between 75,000 and 125,000 infants are hospitalized each year with RSV. Among adults over 65 years of age, an estimate of 14,000

IMPI

<img file="MX356509B_D0016.tif" />

Deaths and 177,000 hospitalizations have been attributed to RSV.

Currently, therapeutic options for people infected with RSV are limited. Antibiotics, which are normally prescribed to treat bacterial infections and over-the-counter medications, are not effective in treating RSV and may serve only to alleviate some of the symptoms. In severe cases, nebulizations with a bronchodilator, such as albuterol, may be prescribed to relieve some of the symptoms, such as wheezing. For the treatment of RSV, the following medications have been approved: RespiGram® (RSV-IGIV, Medlmmune, approved for children up to 24 months of age and at high risk), Synagis® (palivizumab, Medlmmune, approved for children up to 24 months old and at high risk) and Virzole® (ribavirin spray, ICN pharmaceuticals).

Symptoms of measles include: fever, cough, runny nose, red eyes and a generalized rash. Some individuals with measles can get pneumonia, ear infections, and bronchitis. Mumps leads to inflammation of the salivary glands. Mumps symptoms include: fever, loss of appetite, and fatigue. Often individuals are immunized against

IMPI

<img file="MX356509B_D0017.tif" />

measles and mumps, with a triple MMR vaccine (measles, mumps, and rubella, measles, mumps, and rubella). The human parainfluenza virus includes four serotypes and can cause upper and lower respiratory tract infections. Human parainfluenza virus 1 (HPIV-1) can be associated with croup; Human parainfluenza virus 3 (HPIV-3) can be associated with bronchiolitis and pneumonia. According to the Centers for Disease Control and Prevention (CDC, Centers of Disease

Control and Prevention), there are no vaccines to combat the human parainfluenza virus.

Influenza is a single-stranded RNA virus and a member of the Ortomixoviridae family. Today there are three species of influenza: influenza A, influenza B, and influenza C. Influenza A has been further classified, according to viral surface proteins, into hemagglutinin (H or HA) and neuramididase (N) . There are approximately 16 ant antigens (H1 to H16) and 9 N antigens (NI to N9). Influenza A includes several subtypes, including the following:

H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8,

H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H9N2, H10N7. As with RSV, influenza viruses can be transmitted from one person to another through direct contact with

<img file="MX356509B_D0018.tif" />

<img file="MX356509B_D0019.tif" />

secretions infected and / or with contaminated surfaces ^^ A ^ o ^ g ^ j. Complications arising from a viral influenza infection include: pneumonia, bronchitis, dehydration, and sinus and ear infections. Medications currently approved by the FDA against influenza infection include: amantadine, rimantadine, Relenza® (zanamivir, GlaxoSmithKline), and Tamiflu® (oseltamivir, Genentech).

Definitions

Unless otherwise defined, all scientific and technical terms used herein have the same meaning as is commonly understood by an expert with common knowledge in the art. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entirety, unless otherwise indicated. In the event that there is a plurality of definitions for a term mentioned in this document, those of this section will prevail unless otherwise indicated.

As used herein, any group R, such as, without limitation, R^1A, R^2A, R^3A, R^4A, R^5A, R^6A(R^7A, R^8A, r9a _rioa R^11a R^12a R^13A R^{14 TO} R^15A R^16a R^17A R¹⁸ R^19th R^{20 A}

ΙΜΡΪ

<td>r^21A,</td><td>_r22A</td><td>R^23A,</td><td>r^24At</td><td>r^25A,</td><td>_R2SA _r27a</td><td>_r28A</td><td colspan="2">INSTITUTE^1N'Muña® * ®_d29A r, 30A &lt;Νβ ^ ϊΧ^{, ΑΙ}_D32T— , K, κ, K i X- i</td>

<td>r^33A,</td><td>r^34A,</td><td>r^35A,</td><td>r^36A,</td><td>r^37A,</td><td>_r38A, _r1 B,</td><td>R^2b,</td><td>R^3B,</td><td></td>

<td>r^8b,</td><td>r^9B,</td><td>r^10B,</td><td>r^11b,</td><td>r^12B,</td><td>_r13B, _r14B ^</td><td>R^{1 C},</td><td>r^{2 C},</td><td>r^3C, r^4C, r^5C, r^6C,</td>

<td>r^7C,</td><td>r^8C,</td><td>r^9C,</td><td>_R10C,</td><td>R^11C,</td><td>_r12C _r13C</td><td>R^14C,</td><td>rISC</td><td>r^16C, r^17C, r^18C,</td>

<td>r^19C,</td><td>_r20C</td><td>. r^21C</td><td>_r22C</td><td>and R</td><td colspan="2">•And p represent</td><td colspan="2">substituents that</td>

can bind to the indicated atom. An R group can be substituted or unsubstituted. If two R groups are described as taken together, the R groups and the atoms to which they are attached can form a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocycle. For example, without limitation, if R^to and R^b from a NR group^to R^b indicated as taken together it means that they are covalently linked together to form a ring:

Furthermore, if two R groups are described as taken in conjunction with the atom (s) to which they are attached to form a ring as an alternative, the R groups are not limited to the variables or substituents defined above.

Each time a group is described as optionally substituted, that group may be unsubstituted or substituted with one or more of the indicated substituents. The same way,

1Μ ±I ± τ, τυτθ MEMCAWC alkenyl, alkynyl, cycloalkynyl, aryl, (KJT1TUTO when a group is described as being substituted, if in effect substituted, p, 1 -q loa. * Substituents may be selected from one or more of the indicated substituents. If no substituents are indicated, it means that the optionally substituted or substituted group indicated may be substituted with one or more groups, which are individually and independently selected from alkyl, cycloalkyl, cycloalkenyl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl ) alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, Otiocarbamyl, N-thiocarbamyl, C-amido, N-amido, Ssulfonamido, N-sulfonamido, C-carboxy, C-carboxy protected,

O-carboxy, isocyanate, thiocyanate, isothiocyanate, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a disubstituted amino group and protected derivatives thereof.

As used herein, C_to a Cb where a and b are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group or the

<img file="MX356509B_D0020.tif" />

ΙΜΡΪ

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, cycloalquinyl, aryl, heteroaryl or heteroalicyclyl group. That is, the alkyl, alkenyl, alkynyl, cycloalkyl ring, cycloalkenyl ring, cycloalkynyl ring, aryl ring, heteroaryl ring, or heteroalicyclyl ring may contain from a to b, inclusive, carbon atoms. Thus, for example, an alkyl group C₃ a C₄ refers to all alkyl groups having 1 to 4 carbons, i.e. CH₃-, CH₃CH₂-, CH₃CH₂CH₂-, (CH₃)₂CH-, CH₃CH₂CH₂CH₂-, CH₃CH₂CH (CH₃) - and (CH₃)₃C-. If a and b are not designated with respect to an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group, the widest range indicated in these definitions should be assumed.

As used herein, "alkyl" refers to a straight or branched hydrocarbon chain comprising a fully saturated hydrocarbon group (without double or triple bonds). The alkyl group can have from 1 to 20 carbon atoms (whenever it is mentioned there, a numerical range such as 1 to 20 refers to each integer in the given range; for example, 1 to 20 carbon atoms means that the alkyl group may consist of

IMPI

<img file="MX356509B_D0021.tif" />

carbon atom, 2 carbon atoms, 3 carbon atoms etc., up to and including 20 carbon atoms, although the present definition also covers the appearance of the term alkyl in which no numerical range is designated). The alkyl group can also be a medium-sized alkyl, having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl, having 1 to 6 carbon atoms. The alkyl group of the compounds can be designated as Ci-C alkyl₄ or with similar names. By way of example only, Ci-C alkyl₄ indicates that there are one to four carbon atoms in the alkyl chain, that is, the alkyl chain is selected from: methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl . Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. The alkyl group can be substituted or unsubstituted.

As used herein, alkenyl refers to an alkyl group containing, in the straight or branched hydrocarbon chain, one or more double bonds. An alkenyl group can be unsubstituted or substituted.

As used herein, "alkynyl" refers to an alkyl group that contains, in the hydrocarbon chain

<img file="MX356509B_D0022.tif" />

ΪΜΡΙ straight or branched one or more triple bonds. An alkynyl group may be unsubstituted or substituted.

As used herein, cycloalkyl refers to a monoo multi-cyclic (no double or triple bond) fully saturated (no double or triple bond) hydrocarbon ring system. When it is made up of two or more rings, the rings can be joined together by fusion. Cycloalkyl groups can contain from 3 to 10 atoms in the ring or from 3 to 8 atoms in the ring or rings. A cycloalkyl group can be unsubstituted or substituted. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

As used herein, cycloalkenyl refers to a mono- or multi-cyclic hydrocarbon ring system, containing one or more double bonds in at least one ring; however, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system in all rings (otherwise, the group would be aryl, as defined herein). When made up of two or more rings, the rings can be fused together. A cycloalkenyl group can be unsubstituted or substituted.

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MEXICAN INSTITUTE

OE LA ^{ΡΒ &lt;}1 * ΓΛ ^ "₁'Υ? -

As used herein, cycloalkWin.iT.o refers to a multi-cyclic or multi-cyclic L) LirCT? Trione - "'*'" hydroeai ring system containing one or more triple bonds on at least one ring. If there is more than one triple bond, the triple bonds cannot form a fully delocalized pi-electron system in all rings. When it is made up of two or more rings, the rings can be joined together by fusion. A cycloalkynyl group can be unsubstituted or substituted.

As used herein, aryl refers to a carbocyclic (all carbon), mono-cyclic, or multi-cyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a system of totally delocalized pielectrons in all rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be an aryl group C₆-Ci₄, an aryl group C₆-Ci₀ or an aryl group C₆. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. An aryl group can be substituted or unsubstituted.

As used herein, heteroaryl refers to a mono- or multi-cyclic aromatic ring system (a

<img file="MX356509B_D0023.tif" />

<img file="MX356509B_D0024.tif" />

IMPI

INSTITUTO MEXICANO DE LA FROPUOAt) INDUSTRIAL ring system with totally delocalized pi-electron system), which contains (n) one or more heteroatoms, that is, an element other than carbon, including, in a non-exhaustive way, nitrogen, oxygen and sulfur. The number of atoms in the ring or rings of a heteroaryl group can vary. For example, the heteroaryl group may contain from 4 to 14 atoms in the ring or rings, 5 to 10 atoms in the ring or rings, or 5 to atoms in the ring or rings. Also, the term heteroaryl includes a fused ring system, where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1.2.3-oxadiazole,

1,2,4-oxadiazole, thiazole, 1.2.3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. A heteroaryl group can be substituted or unsubstituted.

As used herein heterocyclyl or

ΙΜΡΪ

<img file="MX356509B_D0025.tif" />

Heteroalicyclyl refers to a ring system of three, four, five, six, seven, eight, nine, ten and up to 18 members, monocyclic, bicyclic and tricyclic, where carbon atoms together with 1 to 5 heteroatoms constitute said ring systems. An heterocycle may optionally contain one or more unsaturated bonds, positioned such that, however, there is not a fully delocalized pi-electron system in all rings. The heteroatom or atoms are elements other than carbon, which include, but are not limited to, oxygen, sulfur and nitrogen. A heterocycle may also contain one or more carbonyl or thiocarbonyl functionalities, to make the definition include oxo systems and thio systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When they are made up of two or more rings, the rings can be fused together. On the other hand, any nitrogen present in a heteroalicyclic can be quaternized. Heterocyclyl or heteroalicyclic groups can be unsubstituted or substituted. Examples of such heterocyclyl or heteroalicyclyl groups include, but are not limited to, 1.3-dioxin, 1.3-dioxane, 1,4-dioxane, 1.2-dioxolane, 1.3-dioxolane, 1,4-dioxolane, 1.3-oxathian, 1,420

<img file="MX356509B_D0026.tif" />

oxatiine, 1,3-oxathiolane, 1,3-dithiol, 1,3-dithiolane, 1,4 oxathian, tetrahydro-l, 4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1.3.5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidin-N-oxide, piperidine, piperazine, pyrrolidine, piperazine, pyrrolidine piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone and its analogues with benzo fusion (for example, benzimidazolidinone, tetrahydroquinoline, and 3,4-methylenedioxyphenyl).

As used herein, aralkyl and aryl (alkyl) refer to an aryl group attached, as a substituent, by a lower alkylene group. The lower alkylene group and the aryl group of an aralkyl can be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3phenylalkyl, and naphthylalkyl.

As used herein, heteroaralkyl and heteroaryl (alkyl) refers to a heteroaryl group

<img file="MX356509B_D0027.tif" />

connected, as a substituent, by a lower alkylene group. The heteroaryl and lower alkylene group of the heteroaralkyl can be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, imidazolylalkyl and their analogs with benzo fusion.

A (heteroalicyclyl) alkyl and (heterocyclyl) alkyl refer to a heterocyclic or heteroalicyclic group connected, as a substituent, by a lower alkylene group. The heterocyclyl and lower alkylene of a (heteroalicyclyl) alkyl can be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl) methyl, (piperidin-4yl) ethyl, (piperidin-4-yl) propyl, (tetrahydro-2H-thiopyran-4yl) methyl and (1.3- thiazinan-4-yl) methyl.

Lower alkylene groups are CH linking groups₂- straight-chain, which form bonds to connect molecular fragments through their terminal carbon atoms. Examples include, but are not limited to, methylene - (- CH₂-), ethylene- (-CH₂CH₂-), propylene- (-CH₂CH₂CH₂-) and butylene - (- CH₂CH₂CH₂CH₂-). A lower alkylene group can be substituted by replacing one or more hydrogens from the group

<img file="MX356509B_D0028.tif" />

lower alkylene with one or more substituents mentioned under the definition of substituted.

As used herein, "alkoxy" refers to the formula -0R, in which R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a cyclialquinyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl or (heteroalicyclyl) alkyl, as defined herein. A non-limiting list of alkoxies are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy can be substituted or unsubstituted.

As used herein, acyl refers to a hydrogen, alkyl, alkenyl, alkynyl, or aryl connected, as substituents, by a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acrylic. An acyl can be substituted or unsubstituted.

As used herein, "hydroxyalkyl" refers to an alkyl group in which one or more of the hydrogen atoms is replaced by a hydroxy group. Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2hydroxypropyl, and 2,2-dihydroxyethyl. A hydroxyalkyl can

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<img file="MX356509B_D0030.tif" />

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL be replaced or unsubstituted. - '

As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (eg, mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, l-chloro-2fluoromethyl and 2-fluoroisobutyl. A haloalkyl can be substituted or unsubstituted.

As used herein, haloalkoxy refers to an alkoxy group, in which one or more of the hydrogen atoms are replaced by a halogen (eg, mono-haloalkoxy, di-haloalkoxy, and tri-haloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, l-chloro-2fluoromethoxy and 2-fluoroisobutoxy. A haloalkoxy can be substituted or unsubstituted.

As used herein, arylthio refer to

RS-, where R is an aryl, such as, but not limited to, phenyl. An arylthio can be substituted or unsubstituted.

A sulfenyl group refers to a group -SR in which R can be a hydrogen, alkyl, alkenyl, alkynyl,

<img file="MX356509B_D0031.tif" />

cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl or (heteroalicyclyl) alkyl. A sulfenyl can be substituted or unsubstituted.

A sulfinyl group refers to a group -S (= O) -R, in which R can be as defined with respect to sulfenyl. A sulfinyl can be substituted or unsubstituted.

A sulfonyl group refers to a SO group₂R, in which R may be as defined with respect to sulfenyl. A sulfonyl can be substituted or unsubstituted.

An O-carboxy group refers to a RC (= O) O- group_Zwherein R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl or (heteroalicyclyl) alkyl, as defined herein. An O-carboxy can be substituted or unsubstituted.

The terms ester and C-carboxy refer to a group -C (= O) OR, in which R can be as defined with respect to O-carboxy. An ester and a C-carboxy can be substituted or unsubstituted.

<img file="MX356509B_D0032.tif" />

A thiocarbonyl group refers to a group in which R can be as defined with respect to Ocarboxy. A thiocarbonyl can be substituted or unsubstituted.

A trihalomethanesulfonyl group refers to a group X₃CSO₂-, in which each X is a halogen.

A trihalomethanesulfonamido group refers to a group X₃CS (O) ₂N (R_TO), in which each X is a halogen and an R_TO hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl or (heteroalicyclyl) alkyl.

The term amino, as used herein, refers to a group -NH₂.

As used herein, the term "hydroxy" refers to an -OH group.

A cyano group refers to a -CN group.

The term azido as used herein refers to a group -N₃.

An isocyanate group refers to a -NCO group.

A thiocyanate group refers to a group -CNS.

An isothiocyanate group refers to a -NCS group.

A mercapto group refers to a -SH group.

IMPIOUS*

<img file="MX356509B_D0033.tif" />

INDUSTRIAL

A carbonyl group refers to a group C = 0.

An S-sulfonamido group refers to a SO group₂N (R_toR_b), in which R_TO and R_B they can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalicyclyl, aralkyl, (heteroalicyclyl) alkyl. An S-sulfonamido can be substituted or unsubstituted.

aryl, heteroaryl, (heteroaryl) alkyl or to a group can be,

An N-sulfonamido group refers

RSO₂N (R_TO) in which R and R_TO independently, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl or (heteroalicyclyl) alkyl. An N-sulfonamido can be substituted or unsubstituted.

An O-carbamyl group refers to a group OC (= 0) N (R_toR_b), in which R_TO and R_B they can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl or (heteroalicyclyl) alkyl. An O-carbamyl can be substituted or unsubstituted.

A group

N-carbamyl refers to a group

<img file="MX356509B_D0034.tif" />

Mexicano Mexican institute OF INDUSTRIAL PROPERTY

ROC (= 0) N (R_TO) -, in which R and R_TO they can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl or (heteroalicyclyl) alkyl. An N-carbamyl can be substituted or unsubstituted.

An O-thiocarbamyl group refers to an OC (= S) -N (R_toRb) θη which R_TO and Rb can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl or (heteroalicyclyl) alkyl. An O-thiocarbamyl can be substituted or unsubstituted.

An N-thiocarbamyl group refers to a ROC (= S) N (R_TO) -, in which R and R_TO they can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl or (heteroalicyclyl) alkyl. An N-thiocarbamyl can be substituted or unsubstituted.

A C-amido group refers to a group -C (= 0) N (R_toRb), in which R_to and Rb can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

<img file="MX356509B_D0035.tif" />

MEXICAN INSTITUTE, hetenffeai ^ Sjfil &amp;

cycloalkynyl, aryl, heteroaryl, aralkyl, (heteroaryl) alkyl or fbptprna 1 -i ri el; i] _) to 1 gni3-q-ifaC-amido may be substituted or unsubstituted.

An N-amido group refers to a RC group (= 0) N (R_TO) -, in which R and R_TO they can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl or (heteroalicyclyl) alkyl. An N-amido can be substituted or unsubstituted.

The term halogen or halogen atom as used herein, refers to any of the radio stable atoms in column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.

When the substituent numbers are not specified (eg, haloalkyl), there may be one or more substituents present. For example, haloalkyl can include one or more of the same or different halogens. By way of another example, Ci-C alkoxyphenyl₃ it may include one or more of the same or different alkoxy groups containing one, two or three atoms.

As used herein, abbreviations for any protecting groups, amino acids, and other compounds, unless otherwise noted, are consistent with their

IMPI inSTitwo μεχκανο

M THE INFTUMIAL ITEM

<img file="MX356509B_D0036.tif" />

common use, recognized abbreviations or the IUPAC-IUB Commission on Biochemical Nomenclature (see, Biochem.

11:942-944 (1972)).

The term nucleoside is used herein in its common sense, as understood by those skilled in the art, and refers to an integrated compound, by an optionally substituted pentose moiety or modified pentose moiety attached to a heterocyclic base or tautomer of the itself, via an N-glycosidic bond, such as linked by position 9 of a purine base or position 1 of a pyrimidine base. Examples include, but are not limited to, a ribonucleoside comprising a ribose fraction and a deoxyribonucleoside, comprising a deoxyribose fraction. A modified pentose fraction is a pentose fraction, in which an oxygen atom has been replaced by a carbon and / or a carbon has been replaced by a sulfur or an oxygen atom. A nucleoside is a monomer that can have a substituted base and / or a sugar moiety. On the other hand, it is possible to incorporate a nucleoside into a larger DNA and / or RNA polymers and oligomers. In certain instances, the nucleoside can be a nucleoside analog drug.

The term nucleotide is used herein in its

<img file="MX356509B_D0037.tif" />

<img file="MX356509B_D0038.tif" />

INSTITUTO MEXICANO DE LA PUOITEDAl) INDUSTRIAL, in the ordinary sense, as understood by those skilled in the art, and refers to a nucleoside that has a phosphate ester attached to the pentose fraction, for example, in the 5 'position.

As used herein, the term "heterocyclic base" refers to an optionally substituted nitrogen containing heterocyclyl that can be attached to an optionally substituted pentose moiety or modified pentose moiety. In certain embodiments, the heterocyclic base can be selected from an optionally substituted purine base, an optionally substituted pyrimidine base, and an optionally substituted triazole base (eg, 1,2,4-triazole). The phrase "purine base" is used herein in its ordinary sense, as understood by those skilled in the art, and includes its tautomers. Similarly, the term pyrimidine base is used herein in its ordinary sense, as understood by those skilled in the art, and includes its tautomers. A non-limiting list of optionally substituted purine bases includes purine, adenine, guanine, hypoxanthine, xanthine, alloxanthin, 7-alkylguanine (eg, 7-methylguanine), theobromine, caffeine, uric acid, and isoguanin. Examples of pyrimidine bases include,

IMPI

MEXICAN INSTITUTE. . . DS LA ttpriEDAD although not exhaustively, cytosine, thymine, uraoaqL · © '}¹*¹

<img file="MX356509B_D0039.tif" />

dihydrouracil and 5-alkylcytosine (eg omplo, —-- 5- = methylcytosine). An example of an optionally substituted triazole base is 1,2,4-triazol-3-carboxamide. Other non-limiting examples of heterocyclic bases include diaminopurine, 8-oxo-N⁶-alkyladenine (eg 8-oxo-N⁶methyladenine), deazaadenine,

N⁶, N⁶-ethane-2.67-deazaxanthin, 7-deazaguanine,

N⁴, N⁴-ethacytosine, diaminopurine, 5-halouracil (for example, 5-fluorouracil and

5-bromouracil), pseudoisocytosine, isocytosine, isoguanine, and other heterocyclic bases that are described in U.S. Patent Documents 5,432,272 and

7,125,855, which are incorporated herein by reference for the limited purpose of disclosing additional heterocyclic bases. In certain embodiments, a heterocyclic base can be optionally substituted with an amine or one or more enol protecting groups.

The phrase "N-linked amino acid" refers to an amino acid that is linked to the indicated moiety by a main chain or mono-substituted amino group.

When the amino acid is linked to an amino acid linked to -N-, one of the hydrogens that are part of the main chain amino or mono-substituted amino group is not present and

IMPI

IN;. 'TIT &lt;ITO MEXICANO Oí LA LA ί'ΜΟ.'ΊΕΕιζΟ wrxiSTRUi.

the amino acid is linked by nitrogen. N-linked amino acids' can be substituted or unsubstituted.

The phrase "N-linked amino acid ester derivative" refers to an amino acid in which a main chain carboxylic acid group has been converted to an ester group. In certain embodiments, the ester group has a formula selected from: alkyl-OC (= 0) -, cycloalkyl-0-C (= 0) -, aryl-OC (= 0) - and aryl (alkyl) -0-C (= 0) -. A non-limiting list of ester groups includes substituted and unsubstituted versions of the following: methyl-OC (= 0) -, ethyl-OC (= 0) -, n-propyl-OC (= 0) -, isopropyl-OC (= 0) -, n-butyl-OC (= 0) -, isobutyl-OC (= O) -, tert-butyl-OC (= 0) -, neopentyl-OC (= 0) -, cyclopropyl-OC (= 0 ) -, cyclobutyl-OC (= 0) -, cyclopentyl-OC (= 0) -, cyclohexyl-0-C (= 0) -, phenyl-0-C (= 0) -, benzyl-OC (= 0) and naphthyl-OC (= 0) -. -N-linked amino acid ester derivatives can be substituted or unsubstituted.

The phrase "-0- linked amino acid" refers to an amino acid that is linked to the moiety indicated by the hydroxy of its main chain carboxylic acid group.

When the amino acid is linked to an amino acid linked to -O-, the hydrogen that is part of the hydroxy in its main chain carboxylic acid group is not present and the amino acid is linked via oxygen. Amino acids

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<img file="MX356509B_D0041.tif" />

IMIIIUTO MEXICANO DE UA MtOFlEDAO IM5USTRIAL joined to O may be substituted or unsubstituted.

As used herein, the term "amino acid" refers to any amino acid (both conventional and unconventional amino acids), including, but not limited to, α-amino acids, β-amino acids, γ-amino acids, and δ-amino acids. Examples of suitable amino acids include, but are not limited to: alanine, asparagine, aspartate, cistern, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. . Additional examples of suitable amino acids include, but are not limited to, ornithine, hypusin, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta-alanine, alphaethyl-glycine, alpha-propyl-glycine, and norleucine.

The terms phosphorothioate and phosphothioate refer to? ' s S = P — o — § to a compound of the general formula?^H >

S = P — o — ξ I &lt;

protonated (eg, O

SH

I so = p — o—?

I ^ξ

).

tautomers (such as

OH 'your ways?^H s = p — oOH sus

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As used herein, the term phosphate is

<td>employs in</td><td>its</td><td colspan="2">ordinary sense as they understand it</td><td>the</td>

<td>experts in</td><td>the</td><td>technique and includes its forms</td><td>protonated</td><td>(by</td>

<td></td><td>Oh I</td><td>Oh T</td><td></td><td></td>

<td> 0-</td><td>one = p- one</td><td>-o — j 0 = P — o— | one</td><td></td><td></td>

<td>example,</td><td> 1 0’</td><td>and OH). According</td><td>it is used in</td><td>the</td>

<td>Present,</td><td>the</td><td>monophosphate terms,</td><td>diphosphate</td><td>and</td>

<td>triphosphate</td><td>in</td><td>its ordinary meaning, according to</td><td>they get it</td><td>the</td>

skilled in the art and include protonated forms.

The phrases protecting group and protecting groups, as used herein, refer to any atom or group of atoms that is added to a molecule, to prevent existing groups in the molecule from undergoing unwanted chemical reactions. Examples of protecting group fractions are described in TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3.

Ed. John Wiley &amp; Sons, 1999 and in JFW McOmie, Protective

Groups in Organic Chemistry Plenum Press, 1973, both incorporated herein by reference, for the limited purpose of disclosing suitable protecting groups. The protecting group fraction can be selected such that they are stable under certain reaction conditions and that they can be easily removed in a convenient step, using the methodology known in the art. Not a list

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MEXICAN INSTITUTE K *

Di LA TKOFIÍDAP iNnnsTSiAi limiting protecting groups include benzyl; substituted benzyl; alkylcarbonyls and alkoxycarbonyls (eg isobutyryl);

t-butoxycarbonyl (BOC), acetyl or arylalkylcarbonyl and arylalkoxycarbonyl (eg benzyloxycarbonyl); substituted methyl ether (eg, methoxy-methyl ether); substituted ethyl ether; a substituted benzyl ether; tetrahydropyranyl ether; silyls trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, tri-iso (eg, triisopropylsilyl, propylsilyloxymethyl, [2- (trimethylsilyl) ethoxy] methyl or tbutyldiphenylsilyl); esters (eg, benzoate ester); carbonates (eg methoxymethylcarbonate); sulfonates (eg tosylate or mesylate); acyclic ketal (eg, dimethyl acetal), - cyclic ketals (eg, 1,3-dioxane, 1,3-dioxolanes and those described herein); acyclic acetal; cyclic acetal (eg, those described herein); acyclic hemiacetal; cyclic hemiacetal; cyclic dithiocetals (eg, 1,3-dithian or 1,3-dithiolane); orthoesters (eg, those described herein) and triarylmethyl groups (eg, trityl;

monomethoxytrityl (MMTr); 4.4'-dimethoxytrityl (DMTr);

4.4 ', 4-trimethoxytryl (TMTr) and those described herein).

IMPIOS

MEXICAN INSTITUTE

PE PROPERTY ¿5¡

INDUSTRIAL ^ A ~ T

The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not negate the biological activity and properties of the compound. In certain embodiments, the salt is an acidic addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids, such as hydrochloric acid (eg hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid, such as aliphatic, or aromatic carboxylic, or sulfonic acids, for example, formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic acid. , ethanesulfonic, ptoluenesulfonic, salicylic or naphthalenesulfonic. Pharmaceutical salts can also be obtained by reacting a compound with a base, to form a salt, such as an ammonium salt, an alkali metal salt, such as a sodium salt or a potassium salt, an alkaline earth metal salt , such as a calcium salt or a magnesium salt, an organic base salt, such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl). »

IMPI methylamine alkylamine cyclohexylamine

ΙΗίΤΠυΤΟ MEXICANO Dt THE PROPERTY

INDUSTRIAL

<img file="MX356509B_D0044.tif" />

triethanolamine, ethylenediamine and salts with amino acids, such as arginine and lysine.

The terms and phrases used in this application and variations thereof, especially in the appended claims, unless expressly stated otherwise, are to be construed as open, as opposed to limiting. As examples of the foregoing, the phrase 'including / n' should be interpreted as 'including / n without limitation', 'including, but not limited to' or the like; the term 'comprising / n' as used herein is a synonym for 'including / n', 'containing / n' or 'characterized by' and is inclusive or open-ended and does not exclude additional elements, not explicitly mentioned or method steps; the term 'having / n' should be interpreted as 'having / n at least'; the term 'includes / n' should be interpreted as 'includes / n although not exhaustively'; the term 'example' is used to provide exemplary instances of the item under discussion, not an exhaustive or limiting list thereof; and the use of terms such as 'preferably', 'preferred / s', 'desired / s' or 'desirable / s' and words of a similar meaning should not be construed as implying that certain characteristics

<img file="MX356509B_D0045.tif" />

they are critical, essential or even structure or function of the invention, but instead merely merely highlight alternative or additional features that may or may not be used in a particular embodiment. Furthermore, the term comprising / n should be understood as, synonymous with the phrases that have / n at least or that include / n at least. When used in the context of a process, the term "comprising" means that the process includes at least the named steps, but may include additional steps. When used in the context of a compound, composition, or device, the phrase "comprising" means that the compound, composition, or device includes at least the aforementioned features or components, although they may also include additional features or components. Similarly, a group of elements joined with the conjunction 'and' should not be interpreted as a requirement that each and every element must be present in the groups, but is 'and / or', unless indicated expressly otherwise. Similarly, a group of elements united with the conjunction Ό 'should not be interpreted as a requirement of mutual exclusivity within that group, but should be interpreted as' and / or', unless stipulated

<img file="MX356509B_D0046.tif" />

expressly the opposite.

Regarding the use of substantially

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In the plural and / or singular mentioned herein, experts in this area can translate from plural to singular and / or from singular to plural as appropriate in context and / or application. The various singular / plural permutations may be expressly stated in this document for clarity. The indefinite article a / a or ones does not exclude plurality. A single processor or other unit can fulfill the functions of various elements mentioned in the claims. The mere fact that certain measures are cited in mutually different dependent claims does not indicate that a combination of these measures cannot be used if it is advantageous. Any reference signs in the claims should not be construed as limiting the scope.

It is understood that, in any compound described herein that has one or more chiral centers, if the absolute stereochemistry is not expressly indicated, then each center may be independently of the R-configuration or the S-configuration or a mixture of both. Thus, the compounds provided herein can be

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<img file="MX356509B_D0048.tif" />

enantiomerically pure, enantiomerically enriched, a racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. Furthermore, it is understood that, in any compound described herein that has one or more double bonds that generate geometric isomers that can be defined as E or Z, each double bond can be, independently,

E or Z a mixture of both.

Similarly, it should be understood that, in any disclosed compound, all tautomeric forms are also to be included. For example, it is understood that all tautomers of a phosphate group and a phosphorothioate group must be included. Examples of tautomers of a phosphorothioate include the following:

OR

S — P — o I o

S = P — oyyo

II

HS — P — Q i V

Oh

Oh

S = P — O ¹ V

Oh

Likewise, all heterocyclic base tautomers known in the art are included, which includes natural and non-natural purine base and pyrimidine base tautomers.

It should be understood that when the compounds disclosed herein have unsatisfied valences, the valences

<img file="MX356509B_D0049.tif" />

INSTITUTO MEXICANO DE ΙΑ PKOPIEOA0 INDUSTRIAL must be supplemented with hydrogens or isotopes thereof, for example, hydrogen-1 (protium) and hydrogen-2 (deuterium).

It is understood that the compounds described herein can be isotopically labeled. Substitution with isotopes such as deuterium may offer certain therapeutic advantages resulting from increased metabolic stability, such as, for example, requirements for a longer in-vivo half-life or reduced dosage.

Each chemical element as represented in a compound structure can include any isotope of said element. For example, in a compound structure, a hydrogen atom can be specifically disclosed or it can be understood that it is present in the compound. At any position in the compound where a hydrogen atom may be present, the hydrogen atom can be any hydrogen isotope, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, the reference here to a compound encompasses all potential isotopic forms, unless the context clearly dictates otherwise.

The methods and combinations described herein are understood to include crystalline forms (also known as polymorphs, which include the different arrangements

<img file="MX356509B_D0050.tif" />

of crystalline packings of the same elemental composition of a compound), amorphous phases, salts, solvates and hydrates. In certain embodiments, the compounds described herein are presented in solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, or the like. In other embodiments, the compounds described herein are presented in an unsolvated form. Solvates contain stoichiometric or non-stoichiometric amounts of a solvent and can be formed during the crystallization process with pharmaceutically acceptable solvents, such as water, ethanol, or the like. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is alcohol. Furthermore, the compounds provided herein can be presented in both solvated and unsolvated forms. In general, solvated forms are considered equivalent to non-solvated forms for the purposes of the compounds and methods provided herein.

When a range of values ​​is provided, it is understood that the upper and lower limits and each value comprised between them, between the upper and lower limits of the range are included within the embodiments.

<img file="MX356509B_D0051.tif" />

Κ 1

MEXICAN INSTITUTE

OF THE PROPERTY Cfca »-; INDUSTRIAL

Compounds

Certain embodiments disclosed herein refer to a compound selected from the

Formula (I), Formula (II) and Formula (III), or a pharmaceutically acceptable salt of the above:

<img file="MX356509B_D0052.tif" />

in which: B^1A, B^{1 B} and B^{1 C} they can be, independently, an optionally substituted heterocyclic base or a heterocyclic base optionally substituted with a protected amino group; R^1A can be selected from hydrogen, an acyl

Or p1A^8AC> 7A

<td>with</td><td>link</td>

<td>r</td><td>^ 3A II</td>

<td>p— |</td><td>r^1qa-p—: |</td>

<td> 1 ’ _d9A</td><td>11A</td>

_r6A_or-p optionally substituted,

OR '

<img file="MX356509B_D0053.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL MOPIDITY) of Formula (I) is a when the dotted line (--single link, R^2A can be CH₂ and R^3A it can be O (oxygen); when the dotted line (------) of Formula (I) is absent, R can be selected from an alkyl C! -₆optionally substituted, an alkenyl C₂-6 substituted, a C-alkynyl₂-₆ optionally substituted, a cycloalkyl C₃_₆optionally substituted, a -O-Ci-alkyl₆ optionally substituted, a -O-alkenyl C₃_₆ optionally substituted, a -O- alkynyl C₃-₆ optionally substituted and cyano and R^3A can be selected from OH, -OC (= O) r^to and an optionally substituted O-linked amino acid; R^{1 B} can be selected from O ',

<img file="MX356509B_D0054.tif" />

Wx

9B ⁰

2B> 10B an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; R^{1 C} and R^{2 C} can be independently selected from 0, OH or an alkoxy Ci> 11C

<img file="MX356509B_D0055.tif" />

optionally substituted;

<img file="MX356509B_D0056.tif" />

d12C d13C θ

A I.

^r xr ^ z^{1 C} r^14C

<img file="MX356509B_D0057.tif" />

an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; or R^{1 C} can r16Cq — p_o - p — o

OR

17C

I

OR

18C and R^{2 C} it can be 0 'or OH; R^2B and R can be independently selected from an alkyl 0_χ.

₆ optionally substituted, an alkenyl C₂-6 optionally substituted, a C-alkynyl₂.₆ optionally substituted, an optionally substituted -0 Cx-6-alkyl, a -O-alkenyl C₃.₆ optionally substituted, an -O-alkynyl Ο₃._ε optionally substituted, a cycloalkyl C₃.₆ optionally substituted and cyano; R^4C can be selected from OH, -OC (= O) r "^c and an optionally substituted O-linked amino acid; R^4A, R^3B and R^5C they can be, independently, a halogen; R^5A, R^4B and R^6Cthey can be independently hydrogen or halogen; R^6A, R^7Aand R^8A can independently be selected to be absent or hydrogen, an alkyl Ci-₂₄ optionally substituted, an alkenyl C₂.₂₄ optionally substituted, a C-alkynyl₂.₂₄ optionally substituted, a cycloalkyl C₃-₆ to be

Optionally substituted 3C, a C cycloalkenyl₃.₆ optionally

INSTITUTO MEliCA ^ O substituted, an optionally substituted aryl, an 'optionally substituted heteroaryl, an aryl (optionally substituted alkyl, a * - (CR^15AR^16A) optionally substituted p-0-Ci-24 alkyl, a * - (CR^17AR¹⁸) q-0-C1-24 alkenyl optionally

<img file="MX356509B_D0058.tif" />

R^12AO — P0R^13A

0 — by^{14 TO}

R^6th it can or can be hydrogen;

or R^6A and R^7A can and R^7A may be absent taken together to form a fraction selected from

<img file="MX356509B_D0059.tif" />

optionally substituted, in substituted and a where the oxygens

<img file="MX356509B_D0060.tif" />

optionally _r6th _yr7a, _θ1 phosphorus and the fraction form a ring system of six to

<img file="MX356509B_D0061.tif" />

lNSTTnn »M ^ CAMO Dt LA PROMBAD

HD'JSTRIAL ten members;

R^9a can be selected independently -; - «i'tre ^ Síi ^ aTqüTTo^-

Optionally substituted Ci-24, a C-alkenyl₂-₂₄ optionally substituted, a C-alkynyl₂.₂₄ optionally substituted, a cycloalkyl C₃.₆ optionally substituted, a cycloalkenyl C₃-6 optionally substituted, NR^30AR^31A, optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; R^10A and R^11Athey may, independently, be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; R^12A, R^13A and R^{14 TO} they can, independently, be absent or hydrogen; each R^15A, each R^16a, each R^17A and each R¹⁸ they can be, independently, hydrogen, a Ci-alkyl.₂₄ optionally substituted or alkoxy;

r19A r^{20 a} R^22a R^23A R^5B R^6b R^8b R^9b R^9C R^10C R^12C and R^13C can independently be selected from hydrogen, an alkyl Ci-₂₄ optionally substituted and an optionally substituted aryl; R^21A, R^24A, R^7B, R^10B, R^11C and R^14C can independently be selected from hydrogen, an alkyl Ci-₂₄ optionally substituted, an optionally substituted aryl, a -O-Ci-alkyl₂₄ optionally substituted and an optionally substituted -0-aryl; R^25A, R^29A, R^11B and R^15C can be independently selected from hydrogen, an optionally substituted C1-24 alkyl and an aryl

IMPI

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<img file="MX356509B_D0062.tif" />

optionally substituted; R^16C, R^17C and R^18C they can, independently, be absent or hydrogen; R^26A and R^27Athey can be, independently, -CsN or an optionally substituted substituent selected from organylcarbonyl C₂-8, alkoxycarbonyl C₂.₈ and organylaminocarbonyl C₂-8; R^28Acan be selected from hydrogen, an alkyl Ci_₂₄optionally substituted, an alkenyl C₂_₂₄ optionally substituted, a C-alkynyl₂-₂₄ optionally substituted, a cycloalkyl C₃.₆ optionally substituted and a cycloalkenyl C₃-6 optionally substituted; R^30A and R^31A can independently be selected from hydrogen, an alkyl C! -₂₄ optionally substituted, an alkenyl C₂_₂₄ optionally substituted, a C-alkynyl₂.₂₄ optionally substituted, a cycloalkyl C₃.₆ optionally substituted and a cycloalkenyl

C₃-6 optionally substituted; For Formula (III), ------ can be a single bond or a double bond; when ------ is a single link, each R^7C and each R^8C they can be independently hydrogen or halogen; and when ------- is a double bond, each R^7C is absent and every R^8C it can be independently hydrogen or halogen; r^to and R ”^c can independently be a C-alkyl₃-₂₄ optionally substituted, m and n can be, independently, 0 or 1; py

IMPIO ^ q can be selected, independently, between and 'ⁱ* ^ 7— can be 1 or 2; Z^1A, Z^2A, Z^3A, Z^4A, Z^{1 B}, Z^2B and z>^{1 B} they can ..... be / independently, O or S; and with the proviso that when the dotted line (------) of Formula (I) is absent;

₇2A

R^8AO-P-s

R^1A let s9A in which R^8A be an unsubstituted Οχ-4-alkyl or phenyl, optionally para-substituted with a halogen or methyl and R^9Abe methyl ester, ethyl ester, isopropyl ester, n-butyl ester, benzyl ester or phenyl ester of an amino acid selected from glycine, alanine, valine, leucine, phenylalanine, tryptophan, methionine and proline; R^3A let OH; R^4Abe fluoro; R^5A be it fluoro or hydrogen; and B^1A be an unsubstituted uracil; then R^2A can't be -OCH₃; with the proviso that when the dotted line () of the

<td>Formula</td><td>(I) is absent</td><td>; R^1A let H;</td><td>r^3A</td><td>let OH; R^4A</td><td>be</td>

<td>fluoro;</td><td>R^5th be fluoro; and</td><td colspan="4">B^1A be an unsubstituted cytosine;</td>

<td>so</td><td>R^2nd can not be</td><td>alenyl; with</td><td>the</td><td>condition of</td><td>than</td>

<td colspan="2">when the dotted line</td><td>(------) of</td><td>the</td><td>Formula (I)</td><td>this</td>

<td>absent;</td><td>R^1A let H; R^3A</td><td>let OH; R^4A</td><td>be</td><td>fluoro; R^5A</td><td>be</td>

hydrogen; and B^1A be an unsubstituted thymine; then R^2A cannot be Ci-alkyl substituted with an N-amido optionally

1yes · ^ '

MEXICAN INSTITUTE -A

FROM THE PKOFtEOAD V ^ Rask · £ &amp;

fNDUSnMAA ^v^ hb _ w * substituted (for example, -NC (= O) CF₃); and with the condition that when the dotted line (------) of the Formula (t) 'is absent; R^1A let H; R^3A let OH; R^4A be fluoro; R^5A be fluoro; and B^1A be an unsubstituted cytosine; then R^2A it cannot be ethinyl.

In certain embodiments, the compound can be a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: B^1A an optionally substituted heterocyclic base may be an optionally substituted heterocyclic base with an amino group may be protected;

, 1A

<td>F.</td><td>_z2AII</td>

<td>R^6AO — p — ξ</td><td>R^8AO — P—;</td>

<td>or^7A</td><td>, R^9A</td>

<td colspan="2">when the line]</td>

<td>a link</td><td>simple, R^2nd</td>

select from hydrogen, _Z3A

R10A-P—

R^11A ;

; eada (------) of Formula (I) is

CH₂ and R^3A it is O (oxygen); when the dotted line (------) of Formula (I) is absent, R^2A can be selected from an alkyl Ci-₆ optionally substituted, an alkenyl C₂.₆ optionally substituted, a C-alkynyl₂_₆ optionally substituted, an optionally substituted -O-Cx-6-alkyl, a -O-C-alkenyl₃.₆ optionally substituted, un-O-alkynyl C₃.₆ optionally substituted and, 4A

5A cyano and R^3A is OH; R^4A it can be a halogen; R³* can be

<img file="MX356509B_D0063.tif" />

_ i ΐΝϊπηιτο Mexican CE THE INDUSTRIAL PROPERTY hydrogen or halogen; R^6A, R^7A and R^8A They can be independently selected, between being absent or hydrogen, an alkyl Ci-₂₄ optionally substituted, an alkenyl C₂.₂₄ optionally substituted, a C-alkynyl₂_₂₄ optionally substituted, a cycloalkyl C₃.₆ optionally substituted, a cycloalkenyl C₃.₆ optionally substituted, an optionally substituted aryl, an optionally substituted heteroaryl, an aryl (Ci- alkyl₆) optionally substituted, a * - (CR^15AR^16A) optionally substituted pO-Ci_24 alkyl, a * (CR^17AR¹⁸) optionally substituted gO-alkenyl Ci_24,

<img file="MX356509B_D0064.tif" />

r^12Ao — pOR

13A o — pOR

14 TO

-im and R^7A it can be absent or it can be hydrogen; or R^6A and R^7A can be taken together to form a fraction selected from a

<img file="MX356509B_D0065.tif" />

<img file="MX356509B_D0066.tif" />

substituted and optionally substituted, wherein the oxygens connected to R^6A and R^7A, phosphorus and fraction form a ring system of six to ten members;

R^9a can independently be selected from an alkyl Ci-₂₄ optionally substituted, an alkenyl C₂.₂₄ optionally substituted, a C-alkynyl₂.₂₄ optionally substituted, a cycloalkyl C₃.₆ optionally substituted, a cycloalkenyl C₃.₆ optionally substituted, NR^30AR^31A, optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; R^10A and R^11A they may, independently, be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; R^12a, R^13a and R^{14 TO} they can, independently, be absent or hydrogen; each R^15A, each R^16A, each R^17A and each R¹⁸ they can independently be hydrogen, an alkyl Ci₂₄ optionally substituted or alkoxy; R^19A, R^{20 A}, R^22A and R^23A can independently be selected from hydrogen, a

<img file="MX356509B_D0067.tif" />

alkyl C! -₂₄ optionally substituted optionally substituted; R^21A and R^24A they can be independently selected from hydrogen, an optionally substituted C; l-24 alkyl, an optionally substituted aryl, an optionally substituted -O-Ci-24 alkyl and an optionally substituted -O-aryl; R^25A and R^29A independently, hydrogen may be selected from an optionally substituted CI_24 alkyl and an optionally substituted aryl; R^26A and R^27A they can be, independently, -C = N or an optionally substituted substituent selected from organylcarbonyl C₂-₈, alkoxycarbonyl C₂.₈ and organylaminocarbonyl C₂.₈; R^28A can be selected from hydrogen, an alkyl Ci_₂₄ optionally substituted, an alkenyl C₂-24 optionally substituted, a C-alkynyl₂.₂₄optionally substituted, a cycloalkyl C₃_₆ optionally substituted and a cycloalkenyl C₃.₆ optionally substituted; R^30A and R^31A can independently be selected from hydrogen, an alkyl Ci_₂₄ optionally substituted, an alkenyl C₂-₂₄ optionally substituted, a C-alkynyl₂.₂₄optionally substituted, a cycloalkyl C₃.₆ optionally substituted and a cycloalkenyl C₃.₆ optionally substituted; m can be 0 or 1; p and q can be independently selected from 1, 2 and 3; r can be 1 or 2; Z^1A,

ΙΜΡΪ

<img file="MX356509B_D0068.tif" />

Z^2A, Z^3A and Z^4A they may independently be O or S. In certain embodiments, a compound of Formula (I) may have a structure such as that shown herein, provided that when the dotted line (---- -) of Formula (I) is absent;

R^8AO — P — ϊ

R^1A let R^9A in which R^8A be an alkyl Ci-₄ unsubstituted or phenyl, optionally, para-substituted with a halogen or methyl and R^9Abe methyl ester, ethyl ester, isopropyl ester, n-butyl ester, benzyl ester or phenyl ester of an amino acid selected from glycine, alanine, valine, leucine, phenylalanine, tryptophan, methionine and proline; R^3A let OH; R^4Abe fluoro; R^5A be it fluoro or hydrogen; and B^1A be an unsubstituted uracil; then R^2A can't be -OCH₃; with the proviso that when the dotted line (------) of the

Formula (I) is absent; R^1A let H; R^3A let OH; R^4A be fluoro; R^5A be fluoro; and B^1A be an unsubstituted cytosine;

<td>then R^2A cannot be alenyl; with</td><td>the</td><td>condition of</td><td>than</td>

<td>when the dotted line (------) of</td><td>the</td><td>Formula (I)</td><td>this</td>

<td>absent; R^1A let H; R^3A let OH; R^4A</td><td>be</td><td>fluoro; R^5A</td><td>be</td>

hydrogen; and B^1A be an unsubstituted thymine; then R^2A not

IMPI

<img file="MX356509B_D0069.tif" />

may be Ci-alkyl substituted with an N-amido; and with the condition that when the dotted line (------) of the

Formula (I) is absent; R^1A let H; R^3A let OH; R^4A be fluoro; R^5th be fluoro; and B^1A be an unsubstituted cytosine; then R^2A it cannot be ethinyl.

In certain embodiments, R^1A can be

0A Í r6A_what-by^7A .

In certain embodiments, R^6A and R^7A they can both be hydrogen. In other embodiments, R^6A and R^7Aboth may be absent. In more than other embodiments, at least one of R^6A or R^7A, may be absent. In more than other embodiments, at least one of R^6A or R^7A, it can be hydrogen. Those skilled in the art understand that when R^6A and / or R^7A are absent, the associated oxygen (s) will be negatively charged. For example, when R^6Ais absent, the oxygen associated with R^6A will have a load

<td>negative.</td><td>In</td><td>certain</td><td>shapes</td><td>of</td>

<td>(oxygen)</td><td>. In</td><td>. others</td><td>shapes</td><td>of</td>

<td>(sulfur).</td><td>In</td><td>certain</td><td>shapes</td><td>of</td>

realization, Z^1A can be O realization, Z^1A can be S realization, R^1A It can be a

1A monophosphate. In other embodiments, R can be a

IMPI

<img file="MX356509B_D0070.tif" />

monothiophosphate.

In certain embodiments, when R^1A is

<img file="MX356509B_D0071.tif" />

r^6Ao — p—:

<img file="MX356509B_D0072.tif" />

one of R^6A or R^7A, can be hydrogen and the other R^6A or R^7Ais selected from an alkyl Ci-₂₄ optionally substituted, an alkenyl C₂-24 optionally substituted, a C-alkynyl₂-₂4 optionally substituted, a cycloalkyl C₃.6 optionally substituted, a C cycloalkenyl₃.₆ optionally substituted, optionally substituted aryl, optionally substituted heteroaryl and aryl (C! -alkyl -₆) optionally substituted. In certain embodiments, one of R^6A or R^7Acan be hydrogen and the other R^6A or R^7A it may be an optionally substituted Ci-24 alkyl. In other embodiments, both R^6A like R^7A can be independently selected from an optionally substituted Ci-24 alkyl, a C-alkenyl₂.₂₄ optionally substituted, a C-alkynyl₂.₂4 optionally substituted, a cycloalkyl C₃-₆ optionally substituted, a cycloalkenyl C₃.₆ optionally substituted, optionally substituted aryl, optionally substituted heteroaryl and aryl (Ci- alkyl₆) optionally substituted. In certain embodiments, both R^6A how

<img file="MX356509B_D0073.tif" />

R^7A they may be an optionally substituted Ci-24 alkyl. In other embodiments, both R^6A like R^7A they can be a C2 alkenyl.₂₄ optionally substituted. In certain embodiments, R^SA and R^7A they may, independently, be an optionally substituted version of the following: myristoleyl, myristyl, palmitoleyl, palmityl, sapienyl, oleyl, elaidyl, vaccenyl, linoleyl, a-linolenyl, arachidonyl, eicosapentaenyl, erucil, docosahexaenyl, capryl, lapril, lapril, , arachidid, behenyl, lignoceril and cerotyl.

In certain embodiments, at least one of R^6A or R^7A can be * - (CR^15AR^16A) p-0-alkyl Ci_24. In other embodiments, R^6A and R^7A both can be * - (CR^15AR^16A) p-0-alkyl Ci-₂₄. In certain embodiments, each R^15A and each R^1SAthey are hydrogen. In other embodiments, at least one of R^15A or R^16A is an alkyl Ci-₂₄ optionally substituted. In certain embodiments, at least R^15A or R^16A it is alkoxy (eg benzoxy). In certain embodiments, p may be 1. In other embodiments, p may be 2. In still other embodiments, p may be.

In certain embodiments, at least one of R^eA or R^7A can be * - (CR^17AR¹⁸) _what-0-alkenyl C₂.₂₄. In other ways

IMPI

MtXIGANO INSTITUTE

<img file="MX356509B_D0074.tif" />

of realization, R^eA and R^7A both can be * - (CR^lffft¥ c ™ F_whatalkenyl C₂-24- In certain embodiments? each -t⁷* and each R¹⁸ they are hydrogen. In other embodiments, at least one of R^17A or¹⁸- is an alkyl Ci-₂₄ optionally substituted. In certain embodiments, q may be 1. In other embodiments, q may be 2. In still other embodiments, q may be 3. When at least one of R^6A or R^7A is * - (CR^15AR^ieA) pO-Ci-24 alkyl or * - (CR^17AR¹⁸) q-Oalkenyl C₂_₂₄, C1-24 alkyl can be selected from: capryl, capryl, lauryl, myristyl, palmityl, stearyl, arachidyl, behenyl, lignoceryl and cerotyl and alkenyl

C₂.₂₄ can be selected from myristoleyl, palmitoleyl, sapienyl, oleyl, elaidyl, vaccenyl, linoleyl, alinolenyl, arachidonyl, eicosapentaenyl, erucil and docosahexaenyl.

In certain embodiments, when R^1A is βΑ Π r^6Ao — p— $

OR^7A, at least one of R^6A or R^7A can be selected from

OR,

<img file="MX356509B_D0075.tif" />

; and the other

I

M t ZIGANO INSTITUTE OF THE FROPIOAD de R^6th or R^7A can be selected between being ausenE'é^T,’^IALI know

<img file="MX356509B_D0076.tif" />

hydrogen, an alkyl Ci-₂₄ optionally substitute, ...... üTT alkenyl C₂-24 optionally substituted, a C-alkynyl₂.₂4 optionally substituted, a cycloalkyl C₃.₆ optionally substituted, a cycloalkenyl C₃-6 optionally substituted, one optionally substituted aryl, one optionally substituted heteroaryl and one aryl (Ci- alkyl₆) optionally substituted.

In certain embodiments, at least one of R^6A and _r19A _R20A, 7A can be

<img file="MX356509B_D0077.tif" />

21A

22A d23A 0

<img file="MX356509B_D0078.tif" />

Ax? 4A r24A embodiments, both R^6A like R^7A

In certain they can be> 19A d20A

<img file="MX356509B_D0079.tif" />

p19A R20A

<img file="MX356509B_D0080.tif" />

21A

21A

O When one or both of R^6A and R^7A, are R^19A and R^{20 a} independently, hydrogen may be selected from an optionally substituted Ci-24 alkyl and an optionally substituted aryl; and R^21A may be selected from hydrogen, an optionally substituted Ci-24 alkyl, an optionally substituted aryl, an -O-Ci- alkyl₂₄ optionally substituted and an optionally substituted -O-aryl. In certain embodiments, R^19A and R^{20 A} they can be hydrogen. In other embodiments, by

<img file="MX356509B_D0081.tif" />

minus one of R^19A or R^{20 A},

IMPI Mexican iMTmzro DE LA PR * PIEDAC hbustmal may be an alkyl Ci-₂4 optionally substituted or optionally substituted aryl. In certain embodiments, R^21A it may be an optionally substituted C24 alkyl. In other embodiments, R^21A it can be an optionally substituted aryl. In still other embodiments, R^21A it may be an optionally substituted -O-Ci-24 alkyl or an optionally substituted -O-aryl.

In certain embodiments, both R^6A like R^7A_R22A _r23A OR> 24A can be r22A _r23A θ

When one or both of R^6A or R^7A, are

<img file="MX356509B_D0082.tif" />

p4A r^24A

22A and R '

23A can be independently selected from hydrogen, an alkyl Ci_₂₄optionally substituted and an optionally substituted aryl; R^24A can independently be selected from hydrogen, an alkyl Ci_₂₄ optionally substituted, an optionally substituted aryl, a -O-Ci_alkyl₂₄ optionally substituted and an optionally substituted -O-aryl; and Z^4A it can be, independently, O (oxygen) or S (sulfur). In certain embodiments, R^22A and R^23A they can be hydrogen. In other embodiments, at least one of R^22A and R^23A, can

IMPI

<img file="MX356509B_D0083.tif" />

be an alkyl Ci-₂₄ optionally substituted ti nn · ηγι1ιί optionally substituted. In certain embodiments,, 24A can be a C! -Alkyl.₂₄ optionally substituted. In other embodiments, R^24A it can be an optionally substituted aryl. In still other embodiments,, 24A can be a -O-alkyl Ci-₂₄ optionally substituted or a

Optionally substituted -0-aryl. In certain embodiments, Z^4A it can be O (oxygen). In other embodiments, Z^4A it can be S (sulfur). In certain embodiments, one or both of R^6A or R^7A, can be isopropylcarbonyloxymethyl. In certain embodiments, one or both of R^eA and R^7A, can be pivaloyloxymethyl.

In certain embodiments, both R^6A like R^7A , 7A are can be

<img file="MX356509B_D0084.tif" />

When one or both of R '

6A _r26a _yr2? Ap_EU(j_{in se}r, independently, -C = N or an optionally substituted substituent selected from organylcarbonyl C₂.₈, alkoxycarbonyl C₂_₈ and organylaminocarbonyl C₂_₈; R^28A can be selected from hydrogen, an alkyl Ci-₂₄ optionally

<img file="MX356509B_D0085.tif" />

substituted, an alkenyl C₂-₂4 optionally substituted, a

MIXICAN INSTITUTE »r £ ~~ DE LA MONEDAD V.'ia INDUSTRIAL '' A alkynyl C₂.₂₄ optionally substituted, a cycloalkyl C₃.₆optionally substituted and a cycloalkenyl C₃.₆optionally substituted; and r can be 1 or 2. In certain embodiments, R^26A can be -C ^ N and R^27A it may be an optionally substituted C2.8 alkoxycarbonyl, such as C (= O) OCH3. In other embodiments, R^2SA can be -ON and R^27A it can be a C2 organo-aminocarbonyl.₈ optionally substituted, for example -C (= 0) NHCH₂CH₃ and C (= 0) NHCH₂CH₂phenyl. In certain embodiments, both R^26A like R^27A they may be an optionally substituted C2.8 organylcarbonyl, such as -C (= O) CH3. In certain embodiments, both R^26A like R^27A they may be an optionally substituted Ci-8 alkoxycarbonyl, for example, -C (= 0) OCH₂CH₃ and C (= O) OCH₃. In certain embodiments, including those described in this paragraph, R^28A can be an alkyl Ci_ ₄ optionally substituted. In a certain embodiment, R^28A it can be methyl or tere-butyl. In certain embodiments, r can be 1. In other embodiments, r can be 2.

The examples of

<img file="MX356509B_D0086.tif" />

include, but are not

<img file="MX356509B_D0087.tif" />

<img file="MX356509B_D0088.tif" />

<img file="MX356509B_D0089.tif" />

In certain embodiments, R^6A and R^7A they can both be an optionally substituted aryl. In certain embodiments, at least one of R^eA and R^7A, can be an optionally substituted aryl. For example, both R^SA like R^7A

<img file="MX356509B_D0090.tif" />

they can be an optionally substituted phenyl or an optionally substituted naphthyl. When you are

IHDUSTRI *¹· Substituted can be substituted with 1, 2, 3 or more than 3 substituents. When more than two substituents are present, the substituents can be the same or different. In certain embodiments, when at least one of R^6A or R^7A, is a substituted phenyl, the substituted phenyl can be a substituted para-, ortho- or meta-phenyl.

In certain embodiments, R^6A and R^7A they can both be an optionally substituted aryl (Ci-S alkyl). In certain embodiments, at least one ofR^6A or R^7A, can be an optionally substituted aryl (Ci-6 alkyl). For example, both R^eA like R^7A they can be an optionally substituted benzyl. When substituted, the substituted benzyl group may be substituted with 1, 2, 3, or more than 3 substituents. When more than two substituents are present, the substituents can be the same or different. In certain embodiments, the aryl group of aryl (Ci- alkyl₆) can be a substituted para-, ortho- or meta-phenyl.

In certain embodiments, R^6A and R^7A They may be

<img file="MX356509B_D0091.tif" />

both of them

IMPI

OR

S ' ^XR^25A. In certain embodiments, by

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX356509B_D0092.tif" />

minus one of R^SA or R^7A, They may be

<img file="MX356509B_D0093.tif" />

OR

S ' ^xr^25A

In certain embodiments, R^25A it can be hydrogen. In other embodiments, R^25A can be an alkyl C_x optionally substituted. In still other embodiments,

25A can be an optionally substituted aryl. In certain embodiments, R^25A can be an alkyl Ci-₆eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tere-butyl, pentyl (straight-chain and branched) and hexyl (straight-chain and branched).

In certain embodiments, R^6A and R^7A can be both

<img file="MX356509B_D0094.tif" />

In certain embodiments, by

7A minus one of R^6A or R '^to, can be

<img file="MX356509B_D0095.tif" />

A. In certain embodiments, R^29A it can be hydrogen. In other embodiments, R^29A can be an alkyl Ci-₂4

<img file="MX356509B_D0096.tif" />

optionally substituted. In certain embodiments,, 2 9A can be a Ci_alkyl₄, such as methyl, ethyl, npropyl, iso-propyl, n-butyl, iso-butyl, and t-butyl. In still other embodiments, R^29A it can be an optionally substituted aryl, such as an optionally substituted phenyl or an optionally substituted naphthyl.

In certain embodiments,, 1A can be

R^6AO — P

R^12AO — BY^7A; r^6th can be

OR

13A

OR

II • or fj> OR

14 TO

J m. r^7A can, 12A

RÍ3A _{and R}14 TO _{they can} be absent or be hydrogen; R independently, be absent or be hydrogen; and m can be 0 or 1. In certain embodiments, m can be 0 and r-7a,_Ri2A _yri3a p_Ueden independently, be absent or be hydrogen. In other embodiments, m can be 1 and R^7A, R^12a, R^13A and R^{14 TO} they can independently be absent or hydrogen. Those skilled in the art understand that when m is 0, R^6A can be diphosphate, when Z^1A is oxygen, or an alpha-thiodiphosphate, when Z^1A it is sulfur. Similarly, those skilled in the art understand that when m is 1, R^6Amay be triphosphate, when Z^1A is oxygen, or an alphatiotriphosphate, when Z^1A it is sulfur.

In certain embodiments, R^eA and R^7A they can

<img file="MX356509B_D0097.tif" />

taken together to form an optionally

<img file="MX356509B_D0098.tif" />

, 1A substituted. For example, R^{i * * * * * * * * x} optionally substituted. When substituted, the ring can be substituted 1, 2, 3, or 3 or more times. When substituted with multiple substituents, the substituents can be the same or different. In certain ways

<img file="MX356509B_D0099.tif" />

i^1A es, the ring may be substituted with an optionally substituted aryl group and / or an optionally substituted heteroaryl. An example of a suitable heteroaryl is pyridinyl. In certain embodiments, R^6A and R^7A they can be taken together to form * o32A an optionally substituted, such as -, in which R^32A it can be an optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.

In certain embodiments, R^6A and R^7A they can

<img file="MX356509B_D0100.tif" />

taken together to form an optionally substituted one, where the oxygens connected to R^6A and R^7A, phosphorus and fraction form a ring system of six to

<img file="MX356509B_D0101.tif" />

In certain embodiments, R^eA and R^7A they can be the same. In certain embodiments, R^6A and R^7A they may be different.

In certain embodiments, Z^1A it may be oxygen. In other embodiments, Z^1A it may be sulfur.

In certain embodiments, R^1A can be

8A. A r^8AO — P—

R^9A . In certain embodiments, R^8A can

IMPI

<img file="MX356509B_D0102.tif" />

select between being absent or being hydrogen, a

Optionally substituted Ci-24, a C-alkenyl₂.₂₄ optionally substituted, a C-alkynyl₂.₂₄ optionally substituted, a cycloalkyl C₃.₆ optionally substituted and a cycloalkenyl

C₃-₆ optionally substituted;

and R^9A can independently be selected from an alkyl Ci-₂₄ optionally substituted, an alkenyl C₂.₂₄ optionally substituted, a C-alkynyl₂.₂₄ optionally substituted, a cycloalkyl C₃.₆optionally substituted and a cycloalkenyl C_{3 6} optionally substituted.

In certain embodiments, R^8A can be hydrogen and R^9A can be an alkyl Ci-₆ optionally substituted. Examples of Ci- alkyls₆ Suitable include methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, tere-butyl, pentyl (straight-chain and branched) and hexyl (straight-chain and branched). In other embodiments, R^8A can be hydrogen and R^9A can be NR^30AR^31A, in which R³⁰ and R³¹can independently be selected from hydrogen, an alkyl Ci_₂₄ optionally substituted, an alkenyl C₂-₂₄optionally substituted, a C-alkynyl₂-₂₄ optionally substituted, a cycloalkyl C₃.₆ optionally substituted and a cycloalkenyl C₃.₆ optionally substituted.

In certain embodiments, R^8A may be absent

IMPI

MEXICAN INSTITUTE OF ΙΛ PROPERTY or being hydrogen; and R^9A can be an amino acid c¿ ^^JS1e'nlacé * TT •

optionally substituted or an optionally substituted N-linkyl ester ester "T". In other embodiments, R^8A it can be an optionally substituted aryl; and R^9a it may be an optionally substituted N-link amino acid or an optionally substituted N-link amino acid ester derivative. In still other embodiments, R^8A it can be an optionally substituted heteroaryl; and R^9Ait may be an optionally substituted N-link amino acid or an optionally substituted N-link amino acid ester derivative. In certain embodiments, R^9a can be selected from alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, usine, methionine, phenylalanine, threonine, tryptophan, valine, and ester derivatives thereof. Examples of optionally substituted N-linked amino acid ester derivatives include optionally substituted versions of the following: alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester, and leucine isopropyl ester. In certain embodiments, R^9A can have the structure

<img file="MX356509B_D0103.tif" />

in which R^33A may be selected from hydrogen, an optionally substituted Ci-6 alkyl, an optionally substituted C3-S cycloalkyl, an optionally substituted aryl, an optionally substituted aryl (Ci-6 alkyl) and an optionally substituted haloalkyl; R^34A may be selected from hydrogen, an optionally substituted Ci-6 alkyl, a Ci_haloalkyl₆ optionally substituted, a cycloalkyl C₃-₆ optionally substituted, a C aryl₆ optionally substituted, a C aryl₁₀ optionally substituted and an aryl (Ci_alkyl₆) optionally substituted; and R^35A it can be hydrogen or an optionally substituted Ci_4 alkyl; or R^34A and R^35A they can be taken together to form a C3 cycloalkyl. ₆ optionally substituted.

When R^34A is substituted, R^34A it may be substituted with one or more substituents selected from: N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy and amino. In certain embodiments, R^34A it may be an unsubstituted Cx-6 alkyl, such as those described herein. In certain embodiments, R^34A it can be hydrogen. In other embodiments, R^34A can be

<img file="MX356509B_D0104.tif" />

methyl. In certain embodiments, R^33A it may be an optionally substituted 0χ-6 alkyl. Examples of optionally substituted Ci-6 alkyls include optionally substituted variants of the following: methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, tere-butyl, pentyl (straight-chain and branched) and hexyl (straight-chain and branched). In certain embodiments, R^33Ait can be methyl or isopropyl. In certain embodiments, R^33A it can be ethyl or neopentyl. In other embodiments, R^33A it can be a C3 cycloalkyl.₆optionally substituted. Examples of Cycloalkyl C₃Optionally substituted _6 includes optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In one embodiment, R^33Ait can be an optionally substituted cyclohexyl. In still other embodiments, R^33A it can be an optionally substituted aryl, such as phenyl and naphthyl. In still other embodiments, R^33A it may be an optionally substituted aryl (Ci6 alkyl). In certain embodiments, R^33A it can be an optionally substituted benzyl. In certain embodiments, R^33A it may be an optionally substituted Ci-6 haloalkyl, for example,

35A

CF₃. In certain embodiments, R 'can be

<img file="MX356509B_D0105.tif" />

<img file="MX356509B_D0106.tif" />

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL hydrogen. In other embodiments, R^35A it can be an optionally substituted Ci-4-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and terebutyl. In one embodiment, R^35A it may be methyl. In certain embodiments, R^34A and R^35A they can be taken together to form a C3 cycloalkyl.₆ optionally substituted. Examples of Cycloalkyl C₃.₆ optionally substituted include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. According to the groups selected for R^34A and R^35A, the carbon to which R^34A and R^35A they are linked can be a chiral center. In a certain embodiment, the carbon to which R^34A and R^35A are attached can be a chiral center (R). In other embodiments, the carbon to which R^34A and R^35Aare attached can be a chiral center (S).

In certain embodiments, when R^1A is

Z^2A

8A. I

R^8A0 — p—

I

R^9A , z^2A it can be O (oxygen). In other forms of Z^2A

R^8AO — P— realization, when R^1A is R^9A , Z^2A it can be S (sulfur).

<img file="MX356509B_D0107.tif" />

In certain embodiments,

2> 3A _Rioa-P— <

11A, 11A

In certain embodiments, R^10A and R¹¹* can both be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. In certain embodiments, R^10A and R^11A can be independently selected from alanine, asparagine, aspartate, cistern, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine and ester derivatives of the themselves. In certain embodiments, R^10A and R^11Athey may be an optionally substituted version of the following: alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester, and leucine isopropyl ester. In certain embodiments, R^10A and R^11A can independently have r36Aq r3^?A d38A

O HN - <> the structure *>, in which R^3eA may be selected from hydrogen, an optionally substituted Cx-6 alkyl, a C cycloalkyl₃.₆optionally substituted, an optionally substituted aryl,

XST1 MEXICAN PROPERTY TUTE

INDUSTRIAL

<img file="MX356509B_D0108.tif" />

an aryl (alkyl Ci-₆) optionally substituted and an optionally substituted haloalkyl; R^37A may be selected from hydrogen, an optionally substituted Ci-6 alkyl, an optionally substituted Ci.s haloalkyl, an optionally substituted C3.6 cycloalkyl, an optionally substituted C6 aryl, an optionally substituted Ci0 aryl, and an aryl (Ci-6 alkyl) optionally substituted; and R^38A it can be hydrogen or an optionally substituted Ci-4 alkyl; or R^37A and R^38A can be taken together to form a cycloalkyl C₃. _s optionally substituted.

When R^37A is substituted, R^37A it may be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy and amino. In certain embodiments, R^37A it may be an unsubstituted Ci_6alkyl, such as those described herein. In certain embodiments, R^37A it can be hydrogen. In other embodiments, R^37A it may be methyl. In certain embodiments, R^36A it may be an optionally substituted Ci-6 alkyl. Examples of optionally substituted Ci-6-alkyls include optionally substituted variants of the following: methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, tere-butyl,

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX356509B_D0109.tif" />

pentyl (straight-chain and branched) and hexyl (straight-chain and branched). In certain embodiments, R^36Ait can be methyl or isopropyl. In certain embodiments, R^36A it can be ethyl or neopentyl. In other embodiments, R^36A can be a cycloalkyl C₃-₆optionally substituted. Examples of Cycloalkyl C₃.₆ optionally substituted include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In one embodiment, R^36Ait can be an optionally substituted cyclohexyl. In still other embodiments, R^36A it can be an optionally substituted aryl, such as phenyl and naphthyl. In still other embodiments, R^3SA it may be an optionally substituted aryl (Ci6 alkyl). In certain embodiments, R^36A it can be an optionally substituted benzyl. In certain embodiments, R^36A may be an optionally substituted Ci-6 haloalkyl, eg CF₃. In certain embodiments, R^38A it can be hydrogen. In other embodiments, R^38A can be an alkyl Ci-₄ optionally substituted, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and terebutyl. In one embodiment, R^38A it may be methyl. In certain embodiments, R^37A and R^38A can be taken in

<img file="MX356509B_D0110.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY together to form a cycloalkyl C₃-₆ optionally substituted. Examples of Cycloalkyl C₃__s optionally substituted include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. According to the groups selected for R^37A and R^38A, the carbon to which R^37A and R^38A they are linked can be a chiral center. In a certain embodiment, the carbon to which R^37A and R^38A are attached can be a chiral center (R). In other embodiments, the carbon to which R^37A and R^38Aare attached can be a chiral center (S).

_r33Aq R34A r35A

Examples of suitable groups of _R36Aq r37A d38A

OR HN include the following:

r36A₀^ r37A ^_r38A _R33Aq ^ r34A r35A _r36Aq r37A _R38A \ S 'rx, r \ §

O HN — 2

O HN — 2 í

O HN — 2 r \

O HNH₃CO h₃ch

HN &lt;

HNh₃coh₃q. h

-Q

Or HNV

<img file="MX356509B_D0111.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX356509B_D0112.tif" />

<img file="MX356509B_D0113.tif" />

<img file="MX356509B_D0114.tif" />

<img file="MX356509B_D0115.tif" />

In certain embodiments, R^10Athe same. In certain embodiments, and R^11A can be r^10A and R^11A they may be different.

<img file="MX356509B_D0116.tif" />

In certain embodiments, Z^3A it can be \ S (oxygen). In other embodiments, Z^3A it can be S (sulfur).

In certain embodiments, R^1A it can be hydrogen. In certain embodiments, R^1A it can be an optionally substituted acyl. In other embodiments, R^1A can be -C (= O) R^39A, in which R^39A can be selected from a Ci-i alkyl₂ optionally substituted, an alkenyl C₂-i₂ optionally substituted, a C-alkynyl₂-i₂optionally substituted, a cycloalkyl C₃.₈ optionally substituted, a cycloalkenyl C₅.₈ optionally substituted, a C aryl₆.₁₀ optionally substituted, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an aryl (Ci- alkyl₆) optionally substituted, a heteroaryl (Ci alkyl._s) optionally substituted and a heterocyclyl (Ci- alkyl₆) optionally substituted. In certain embodiments, R^39A it may be a substituted Ci.12 alkyl. In other embodiments, R^39A it may be an unsubstituted Ci-i2 alkyl.

In still other embodiments, R^1A it may be an optionally substituted 0-linked amino acid. Examples of suitable O-linked amino acids include: alanine, asparagine, aspartate, cysteine, glutamate,

<img file="MX356509B_D0117.tif" />

Ψ ',' - ΐκνΤίΛ »»

OF THE PROPERTY . -. . . . . . iNDUSTBIAl. . '* S ^ Sr_2ÍT ·' glutamine, glycine, prolma, senna, tyrosma, arginine, histidine, isoleucine, leucine, lisiriaT mehioriiriá, 'phenylalanine, threonine, tryptophan and valine. Additional examples of suitable amino acids include, but are not limited to, ornithine, hypusin, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, betaalanine, alpha-ethyl-glycine, alpha-propyl-glycine, and norleucine.

In certain embodiments, the O-linked amino acid may have the structure ^ -O. R⁴⁰* .R^41A nh₂ in which R^40A may be selected from hydrogen, an optionally substituted C! -6 alkyl, an optionally substituted Cx-6 alkyl, an optionally substituted C3.6 cycloalkyl, an optionally substituted Ce aryl, an optionally substituted Cyr aryl and an aryl (Ci-6 alkyl) optionally substituted; and R^41A it can be hydrogen or an optionally substituted Ci_4 alkyl; or R^40A and R^41A can be taken together to form a cycloalkyl C₃_₆ optionally substituted. Those skilled in the art understand that when R^1st is an optionally substituted O-linked amino acid, the oxygen of R^1AO- of Formula (I) is part of the amino acid with

<img file="MX356509B_D0118.tif" />

OR optionally substituted link. For example, when R^1A is

<img file="MX356509B_D0119.tif" />

>

MU ² , the oxygen indicated with is the oxygen of R^1stO- of Formula (I).

When R^40A is substituted, R^40A it may be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy and amino. In certain embodiments, R^40A it may be an unsubstituted Ci-6 alkyl, such as those described herein. In certain embodiments, r^40a it can be hydrogen. In other embodiments, R^40A it may be methyl. In certain embodiments, R^41A it can be hydrogen. In other embodiments, R^41A it can be an optionally substituted Ci-4-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and terebutyl. In one embodiment, R^41A it may be methyl. According to the groups selected for R^40A and R^41A, the carbon to which R^40A and R^41A they are linked can be a chiral center. In a certain embodiment, the carbon to which R^40A and R^41A are attached can be a chiral center (R). In other embodiments, the carbon to which R^40A and R^41A

<img file="MX356509B_D0120.tif" />

<img file="MX356509B_D0121.tif" />

are linked can be a chiral center (S) $

-OR^40/\ .r^41A

<img file="MX356509B_D0122.tif" />

include the

<img file="MX356509B_D0123.tif" />

or nh₂

In certain embodiments, the dotted line (-----) can be a single link, R^2A can be CH₂ and R^3A it can be O (oxygen). When the dotted line (------) is a single link, R^2A is CH₂ and R^3A is O (oxygen), a 4-membered ring is formed including 4'-carbon and 3'-carbon of the pentose ring. In other embodiments, the dotted line (------) may be absent,

R^2A can be selected from an alkyl Ci-₆ optionally substituted, an alkenyl C₂.₆ optionally substituted, a C-alkynyl₂_₆ optionally substituted, an optionally substituted -O-Cx-6-alkyl, a -O-C-alkenyl₃.₆ optionally

<img file="MX356509B_D0124.tif" />

substituted, a -O- alkynyl C₃.₆ optionally substituted and cyano and R^3A can be selected from OH, -OC (= O) r "^to and an optionally substituted O-linked amino acid.

Several groups can join at the 4 'position of the pentose ring. In certain embodiments, R^2nd can be a Cx-alkyl₆ optionally substituted. Examples of Cx-alkyls₆ Suitable include methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, tere-butyl, pentyl (straight-chain and branched) and hexyl (straight-chain and branched). In certain embodiments, R^2Ait may be an unsubstituted Cx-6 alkyl. In other embodiments, R^2A it may be a substituted Cx-6 alkyl. For example, R^2A it may be a halogen-substituted Cx-6-alkyl, a hydroxy-substituted Cx-6-alkyl, an alkoxy-substituted Cx-6-alkyl, or a sulfenyl-substituted 0χ.ε-alkyl (eg, -Ci-6-S-alkyl-alkyl Cx-6). In other embodiments, R^2A it may be a Cx-6 haloalkyl. In other embodiments, R^2A it may be an optionally substituted C2-g alkenyl. In certain embodiments, R^2A it may be a C2 alkenyl.₆ replaced. In other embodiments, R^2A it may be an unsubstituted C2.6 alkenyl. For example, R^2A it can be ethenyl, propenyl or alenyl. In still other embodiments, R^2A can be a C2_ alkynyl₆ optionally substituted. In certain forms of rea ^ ffi ^^ fcion;

, 2A

<img file="MX356509B_D0125.tif" />

INSTITUTO MEXICANO DE LA PROPISDAD can be an alkynyl C₂-s substituted. In other ways of realization, R^2A it may be an unsubstituted C2-6 alkynyl. Suitable C2.6 alkynyls include ethynyl and propynyl. In still other embodiments, R^2A can be a C3_ cycloalkyl₆optionally substituted. In certain embodiments, R^2A it may be a substituted C3.6 cycloalkyl. In other embodiments, R^2A it can be a C3 cycloalkyl._sunsubstituted. A non-limiting list of cycloalkyls C₃_₆includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R^2A it may be an optionally substituted -O-Ci-S alkyl. In certain embodiments, R^2A it may be a substituted -O-Ci-6-alkyl. In other embodiments, R^2A it may be an unsubstituted -O-Ci-6 alkyl. Examples of suitable Ci-6 O-alkyl groups include methoxy, ethoxy, n-propoxy, iso-propoxy, nbutoxy, isobutoxy, tert-butoxy, pentoxy (straight-chain and branched) and hexoxy (straight-chain and branched) . In other embodiments, R^2A can be a -O-C3 alkenyl-_soptionally substituted. In certain embodiments, R^2A it may be a substituted -C3-6 -O-alkenyl. In other embodiments, R^2A can be a -O-alkenyl C2_₆unsubstituted. In still other embodiments, R^2A can

<img file="MX356509B_D0126.tif" />

be a -O- alkynyl C₃-₆ optionally substituted. In certain embodiments, R^2A it may be a substituted -O- C3.6 alkynyl. In other embodiments, R^2A it may be a C3-O-alkynyl.₆ unsubstituted. In still other embodiments, R^2A it can be cyano.

The groups attached at the 3'-position of the pentose ring may vary. In certain embodiments, including those in paragraph [0119], R^3A it can be OH. In other embodiments, including those in paragraph [0119], R^3A it may be an optionally substituted O-linked amino acid. Examples of suitable O-linked amino acids include alanine, asparagine, aspartate, cistern, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Additional examples of suitable amino acids include, but are not limited to, ornithine, hypusin, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, betaalanine, alpha-ethyl-glycine, alpha-propyl-glycine, and norleucine.

In certain embodiments, the O-linked amino acid may have the structure

4-0 R^42A\ r^43A nh₂

<img file="MX356509B_D0127.tif" />

in which R^42A can be selected from hydrogen, an alkyl Ci-₆ optionally substituted, a Ci- haloalkyl₆optionally substituted, a cycloalkyl C₃.₆ optionally substituted, a C aryl₆ optionally substituted, a Ci aryl₀ optionally substituted and an optionally substituted aryl (Ci-6 alkyl); and R^43A it can be hydrogen or an optionally substituted Ci-4 alkyl; or R^42A and R^43A they can be taken together to form a C3 cycloalkyl.₆ optionally substituted.

When R^42A is substituted, R^42A it may be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy and amino. In certain embodiments, R^42A it can be an unsubstituted alkyl, such as those described in

<td>Present.</td><td>In certain</td><td>shapes</td><td>of</td><td>realization,</td><td colspan="3">R^42a can be</td>

<td>hydrogen.</td><td>In others</td><td>shapes</td><td>of</td><td>realization,</td><td>R^42a</td><td>can</td><td>to be</td>

<td colspan="2">methyl. In certain</td><td>shapes</td><td>of</td><td>realization,</td><td>r^43A</td><td>can</td><td>to be</td>

hydrogen. In other embodiments, R^43A it can be a Cx alkyl.₄ optionally substituted, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and terebutyl. In one embodiment, R^43A it may be methyl. According to the groups selected for R^42A and R^43A, the

<img file="MX356509B_D0128.tif" />

carbon to which R^42A and R^43A they are linked can be a chiral center. In a certain embodiment, the carbon to which R^42A and R^43a are attached can be a chiral center (R). In other embodiments, the carbon to which R^42A and R^43Aare attached can be a chiral center (S).

R^42A\ r^43A

The examples of _ORR⁴²TO _R43A below:

NH₂

<img file="MX356509B_D0129.tif" />

Λ nh₂

OH> CH₃

NH₂

<img file="MX356509B_D0130.tif" />

suitable include the i> _ h

/

NH₂

NH₂

In still other embodiments, including those in paragraph [0119], R^3A can be -OC (= O) r ”^to, in which R^to it can be an optionally substituted Ci_24 alkyl. In certain embodiments, r "^to it may be a substituted Ci-8 alkyl. In other embodiments, r^to it can be an unsubstituted Ci-e alkyl. In still other embodiments, including those in paragraph [0119], R^3rd can be an -O- acyl

<img file="MX356509B_D0131.tif" />

ΙΓ ÁT ΤΠ) ΤΓ

<img file="MX356509B_D0132.tif" />

optionally substituted. In still other f ^ -rmag i-paI i? Ap-i, on, including those in paragraph [0119], R^3A can be -OC (= O) R^44A, in which R^44A may be selected from an optionally substituted Ci-i2 alkyl, an optionally substituted C2.i2 alkenyl, an optionally substituted C2.12 alkynyl, an optionally substituted C3.8 cycloalkyl, an optionally substituted C5-8 cycloalkenyl, an optionally substituted C6-io aryl , an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl (Ci_6 alkyl), an optionally substituted heteroaryl (Ci_6 alkyl) and an optionally substituted heterocyclyl (Ci_6 alkyl). In certain embodiments, R^44A it may be a substituted Ci-12 alkyl. In other embodiments, R^44A can be an alkyl Ci-₁₂ unsubstituted.

Various substituents may be present at the 2'-position of the pentose ring. In certain embodiments, R^5A it can be hydrogen. In other embodiments, R^5A it can be halogen, for example fluoro. In certain embodiments, R^4A it can be halogen, such as fluoro. In certain embodiments, R^5A can be hydrogen and R^4A it may be halogen. In other embodiments, R^4A and R^5A they can both be halogen.

In certain embodiments, it can be a

IMPI

<img file="MX356509B_D0133.tif" />

single bond, R^4A can be fluoro, R^5A can be hydrogen and_

R^2nd can be a haloalkyl Ci-₆. In certain embodiments, ---- can be a single link, R^4A can be fluoro, R^5A can be hydrogen, R^2A can can be a haloalkyl Ci-₆ and B^1A it may be a cytosine.

In certain embodiments, R^2A it cannot be methoxy. In certain embodiments, R^2A cannot be methoxy when B^1A it is substituted or unsubstituted uracil. In certain embodiments, B^1A it is substituted or unsubstituted cytosine. In other embodiments, B^1A it is substituted or unsubstituted thymine. In still other embodiments, B^1A it cannot be an unsubstituted uracil. In certain embodiments, R^2A cannot be methoxy when _w f rSAq-pZ^1A is R^9A , where R^8A it is unsubstituted Ci-6 alkyl or para-substituted phenyl; and R^9A it is an optionally substituted N-link amino acid or an optionally substituted N-link amino acid ester derivative. In certain ways_M F

R^8A0 — P— realization, R^2A cannot be methoxy when Z^1A is R^9A .

In certain embodiments, R^2A cannot be an alkoxy

<img file="MX356509B_D0134.tif" />

ΪΜΡΟ

R^8A0 — Ρ (for example, when Z is j9A

). In certain embodiments, B cannot be cytosine when R is unsubstituted alkenyl or unsubstituted alkynyl. In certain embodiments, B^1A it cannot be thymine when, 2A is an optionally substituted alkyl. In certain embodiments, R^2A it cannot be an unsubstituted alkoxy (such as methoxy), an optionally substituted alkenyl (such as alenyl), an unsubstituted alkynyl (such as ethynyl), or a Ci-alkyl substituted with a non-halogenic substituent. In certain embodiments, R^2A it cannot be an unsubstituted alkoxy (such as methoxy), an optionally substituted alkenyl (such as alenyl), an optionally substituted alkynyl (such as ethynyl), or a Ci- alkyl₄ substituted with a non-halogenic substituent. In certain embodiments R^1A cannot be H. In certain embodiments, R cannot be H when B is an optionally substituted cytosine or an optionally substituted thymine.

Several optionally substituted heterocyclic bases can bind to the pentose ring. In certain embodiments, one or more of the amine and / or amino groups may be protected with a suitable protecting group. By

INFHTUTQ MitlCANO!> Ί THE RUOPUOAD INCWTIVAL example, an amino group can be protected twnu f awÍ'a'H ^ »··»¹! "Ou- * íu." Amine and / or amino group in an amide or a carbamate. In certain embodiments, an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with one or more protected amino groups can have one of the following structures:

<img file="MX356509B_D0135.tif" />

in which: R^A2 can be selected from hydrogen, halogen and NHR^J2, in which R^J2 can be selected from hydrogen, -C (= O) R^K2 and -C (= O) OR^L2; R^B2 can be halogen or NHR^W2, in which R^W2 may be selected from hydrogen, an optionally substituted Ci-6 alkyl, a C alkenyl₂.₆optionally substituted, a cycloalkyl C₃.₈ optionally substituted, -C (= O) R^M2 and -C (= O) OR^N2; R^C2 can be hydrogen or NHR⁰², in which R⁰² can be selected from hydrogen, 92

<img file="MX356509B_D0136.tif" />

C (= O) R^P2 and —C (= O) OR °²; R^D2 may be selected from hydrogen, halogen, an optionally substituted Ci-6 alkyl, an optionally substituted C2-s alkenyl, and an optionally substituted C2-6 alkynyl; R^E2 may be selected from hydrogen, hydroxy, an optionally substituted Ci-6 alkyl, a C cycloalkyl₃.₈ optionally substituted, -C (= O) R^r2 and C (= O) OR^S2; R^f2 can be selected from hydrogen, halogen, an alkyl Ci-₆ optionally substituted, an alkenyl C₂-₆ optionally substituted and an alkynyl C₂-e optionally substituted; AND² and Y³ they can be, independently, N (nitrogen) or CR¹², in which R¹² can be selected from hydrogen, halogen, an alkyl Ci-_S optionally substituted, an alkenyl C₂-₆ optionally substituted and an alkynyl C₂.₆optionally substituted; R^G2 it may be an optionally substituted Ci-6 alkyl; R^H2 can be hydrogen or NHR^T2, in which R^T2 can be independently selected from hydrogen, -C (= O) R^U2 and -C (= O) OR^V2; and R^K2, R^L2, R^M2, R^N2, R^p2, R⁰², R^R2, R^S2, R^U2 and R^V2 can be independently selected from Ci-6-alkyl, C-alkenyl₂-₆, alkynyl C₂.₆, cycloalkyl C₃.₆, cycloalkenyl C₃.₆, aryl C₆-io, heteroaryl, heteroalicyclyl, aryl (Ci- alkyl₆), heteroaryl (Ci- alkyl₆) and heteroalicyclyl (Ci- alkyl₆). In certain embodiments, the structures shown above

<img file="MX356509B_D0137.tif" />

IMPI

THE INDUSTRIAL PROPERTY MEXICAN TRUTH may be modified by replacing one or more hydrogens with substituents selected from the list of substituents provided for the definition of substituted.

In certain embodiments, B^1A can be

OR

Λ

N NH₂ . In other embodiments, B^1A can be

N

<img file="MX356509B_D0138.tif" />

Ν '

OR

<img file="MX356509B_D0139.tif" />

W^NH

In still other embodiments, B^1A can be

R

F2

<img file="MX356509B_D0140.tif" />

NH

<img file="MX356509B_D0141.tif" />

<img file="MX356509B_D0142.tif" />

NH

<img file="MX356509B_D0143.tif" />

NON 'O>^{ΛΛΛ /}', such as jvLp. In still other ways

<img file="MX356509B_D0144.tif" />

of realization, B^1A can be s / VW, for example, nh₂

<img file="MX356509B_D0145.tif" />

N

<img file="MX356509B_D0146.tif" />

NOT

I

Λ / W

<img file="MX356509B_D0147.tif" />

Mexican tNsrrnrro Say THE PROPERTY

INDUSTRIAL

<img file="MX356509B_D0148.tif" />

'. In certain embodiments, R °² it can be hydrogen. In other embodiments, B^1A can be

<img file="MX356509B_D0149.tif" />

> B2 be NH₂. In other embodiments, R^B2 may be NHR^W2,

M2 in which R^W2 can be -C (= O) R ”² or -C (= O) OR^J

In still others

0R^G2

N

N, N2

<img file="MX356509B_D0150.tif" />

'N

N-

<img file="MX356509B_D0151.tif" />

R¹

H2 embodiments, B^1A can be

In

<img file="MX356509B_D0152.tif" />

N

G2

N

<img file="MX356509B_D0153.tif" />

NH₂ certain embodiments, B^1A can be

In certain embodiments, a compound of the

Formula (I) can have a structure selected from one of the following:

IMPI @

MEXICAN INSTITUTE

OF PROPERTY 0¾

INDIISTftlAI.

<img file="MX356509B_D0154.tif" />

<img file="MX356509B_D0155.tif" />

<img file="MX356509B_D0156.tif" />

<img file="MX356509B_D0157.tif" />

<img file="MX356509B_D0158.tif" />

<img file="MX356509B_D0159.tif" />

<img file="MX356509B_D0160.tif" />

foregoing. In certain embodiments of this paragraph, B^1A it can be an optionally substituted purine base. In other embodiments of this paragraph, B^1A it may be an optionally substituted pyrimidine base. In certain embodiments of this paragraph, B^1A it may be guanine. In other embodiments of this paragraph, B^1A it may be thymine. In still other embodiments of this paragraph, B^1A it may be cytosine. In still other embodiments of this paragraph, B^1A it may be uracil. In certain embodiments of this paragraph, B^1A it may be adenine. In certain embodiments of this paragraph, R^1A it can be hydrogen. In other embodiments of this paragraph, R^1A it can be an optionally substituted acyl. In still other embodiments of this paragraph, R^1A it can be mono-, di- or tri-phosphate. In still other embodiments of this paragraph, R^1A it may be phosphorous amidate. In certain embodiments of this paragraph, R^1A It may be a

<img file="MX356509B_D0161.tif" />

acyloxyalkyl ester phosphate prodrug.

In certain embodiments, the compound can be a compound of Formula (II), or a pharmaceutically acceptable salt thereof, in which: B^{1 B} it can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with an amino group, being actuated between O ', OH,

<img file="MX356509B_D0162.tif" />

> 10B

<img file="MX356509B_D0163.tif" />

an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; R^2b may be selected from an optionally substituted Ci-6 alkyl, an optionally substituted C2-e alkenyl, an optionally substituted C2.6 alkynyl, an optionally substituted -O-Cx-6 alkyl, an optionally substituted -O-C3-6 alkenyl, a -O - optionally substituted C3.e-alkynyl and cyano; R^3B it can be a halogen; R^4B it can be hydrogen or halogen; R^5B, R^6B, R^8B and R^9B independently, hydrogen may be selected from an optionally substituted Ci-24 alkyl and an optionally substituted aryl; R^7B and R^10B can be selected independently from

IMPI

<img file="MX356509B_D0164.tif" />

hydrogen, an alkyl Ci-₂4 optionally substituted, an optionally substituted aryl, a -O-Ci_alkyl₂₄ optionally substituted and an optionally substituted -0-aryl; R^11B can be selected from hydrogen, an alkyl Ci-₂₄ optionally substituted and an optionally substituted aryl; Z^{1 B} and Z^2Bthey can independently be 0 or S.

In certain embodiments, R^{1 B} can be O. In other embodiments, R^{1 B} it can be OH.

In certain embodiments, R^{1 B} can be

<img file="MX356509B_D0165.tif" />

ual R^5B and R^6B independently, hydrogen may be selected from an optionally substituted CI_24 alkyl and an optionally substituted aryl; and R^7B may be selected from hydrogen, an optionally substituted Ci-24 alkyl, an optionally substituted aryl, an -O-Ci- alkyl₂₄ optionally substituted and an optionally substituted -O-aryl. In certain embodiments, R^5B and R^6B they can be hydrogen. In other embodiments, at least one of R^5B or R^6B, can be an alkyl Ci-₂₄ optionally substituted or optionally substituted aryl.

100

<img file="MX356509B_D0166.tif" />

In certain embodiments, R^7B it may be an optionally substituted C24 alkyl. In other embodiments, R^7B it can be an optionally substituted aryl. In still other embodiments, R^7B can be a -O-alkyl C! _₂₄optionally substituted or an optionally substituted -0-aryl.

In certain embodiments, R^{1 B} can be \ nn r-kS

QR \_Z2B ^_r10B in which R^8B and R^9B can independently be selected from hydrogen, an alkyl Ci-₂₄ optionally substituted and an optionally substituted aryl; R^10b can independently be selected from hydrogen, an alkyl Ci-₂₄ optionally substituted, an optionally substituted aryl, a -O-Ci-alkyl₂₄ optionally substituted and an optionally substituted -0-aryl; and Z^2B it can be, independently, O (oxygen) or S (sulfur). In certain embodiments, R^8B and R^9B they can be hydrogen. In other embodiments, at least one of R^8B or R^9B, can be an alkyl Ci-₂₄ optionally substituted or optionally substituted aryl. In certain embodiments, R^10b can be an alkyl Ci-₂₄ optionally substituted. In other embodiments, R^1ob can be an aril

<img file="MX356509B_D0167.tif" />

101

<img file="MX356509B_D0168.tif" />

INSTITUTO MEXICANO DI LA PU.0P1EDAO

INZXSTtlAL optionally substituted. In still other embodiments,

R^10B can be a -0-alkyl Ci_₂4 optionally substituted or an optionally substituted -0-aryl. In certain embodiments, Z^2B it can be O (oxygen). In other embodiments, Z^2B it can be S (sulfur). In certain embodiments, R^{1 B} it can be isopropylcarbonyloxymethyloxy. In, 1B can certain embodiments, pivaloyloxymethyloxy.

In certain embodiments, R^{1 B} can be

OR

<img file="MX356509B_D0169.tif" />

In certain embodiments, R^11B it can be hydrogen. In other embodiments, R^11B it may be an optionally substituted Ci-24 alkyl. In still other embodiments, R^11B it can be an optionally substituted aryl. In certain embodiments, R^11B it may be a Ci_6alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tere-butyl, pentyl (straight-chain and branched) and hexyl (straight-chain and branched).

In certain embodiments, R^{1 B} it may be an optionally substituted N-link amino acid or an optionally substituted N-link amino acid ester derivative. For example, R^{1 B} can be a version

102

<img file="MX356509B_D0170.tif" />

<img file="MX356509B_D0171.tif" />

optionally substituted what if

<img file="MX356509B_D0172.tif" />

asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, and ester derivatives thereof. In certain embodiments, R^{1 B} may be selected from alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester and leucine isopropyl ester. In certain embodiments, R^{1 B} can have the structure _r12Bq d13B _R14B

<img file="MX356509B_D0173.tif" />

in which R^12B may be selected from hydrogen, an optionally substituted Cx-6 alkyl, a C cycloalkyl₃.₆optionally substituted, one optionally substituted aryl, one aryl (Cx_alkyl₆) optionally substituted and an optionally substituted haloalkyl; R^13B may be selected from hydrogen, an optionally substituted Cx-6 alkyl, an optionally substituted Cx-6 alkyl, an optionally substituted C3.6 cycloalkyl , an optionally substituted C6 aryl, an optionally substituted C10 aryl, and an aryl (Cx-6 alkyl) optionally substituted; and R^14B it can be hydrogen or an optionally substituted Cx-4 alkyl; or R^13B and

103

- .. Α · ·

<img file="MX356509B_D0174.tif" />

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<img file="MX356509B_D0175.tif" />

R^14B can be taken together to form nn rírlnalginln r_{3 6} optionally substituted.

When R^13B is substituted, R^13B it may be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, 0-carboxy and amino. In certain embodiments, R^13B it may be an unsubstituted Ci.salkyl, such as those described herein. In certain embodiments, R^13B it can be hydrogen. In other embodiments, R^13B it may be methyl. In certain embodiments, R^12B it may be an optionally substituted Ci-6 alkyl. Examples of Ci_ alkyls₆ optionally substituted include optionally substituted variants of the following: methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, tere-butyl, pentyl (straight-chain and branched) and hexyl (straight-chain and branched). In certain embodiments, R^12Bit can be methyl or isopropyl. In certain embodiments, R^12B it can be ethyl or neopentyl. In other embodiments, R^12B can be a cycloalkyl C₃-₆optionally substituted. Examples of Cycloalkyl C₃.₆ optionally substituted include optionally substituted variants of the following: cyclopropyl, cyclobutyl,

104

MEXICAN INSTITUTE OF WOHEDAD

INDUSTRIAL

<img file="MX356509B_D0176.tif" />

cyclopentyl and cyclohexyl. In one embodiment, R^12Bit can be an optionally substituted cyclohexyl. In still other embodiments, R^12B it can be an optionally substituted aryl, such as phenyl and naphthyl. In still other embodiments, R^12B it may be an optionally substituted aryl (Ci-6 alkyl). In certain embodiments, R^12B it can be an optionally substituted benzyl. In certain embodiments, R^12B may be an optionally substituted Ci_6 haloalkyl, eg CF₃. In certain embodiments, R^14B it can be hydrogen. In other embodiments, R^14B it can be an optionally substituted Ci-4-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and terebutyl. In one embodiment, R^14B it may be methyl. In certain embodiments, R^13B and R^14B they can be taken together to form a C3 cycloalkyl.₆ optionally substituted. Examples of Cycloalkyl C₃._s optionally substituted include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. According to the groups selected for R^13B and R^14B, the carbon to which R^13B and R^14B they are linked can be a chiral center. In a certain embodiment, the carbon to which R^13B and R^14B are attached can be a chiral center (R).

105

In other embodiments, the carbon they are attached to can be a chiral center (S) _r12Bq r13B d14B

IMPI

<img file="MX356509B_D0177.tif" />

The examples

Or HN- £ of suitable groups include _R12BqR13B r14B _R12_BoR «| r14B

K, K 'the following:

r \

O HN-

<img file="MX356509B_D0178.tif" />

<img file="MX356509B_D0179.tif" />

<img file="MX356509B_D0180.tif" />

. -II iiiwoxwwwTirtro

<img file="MX356509B_D0181.tif" />

A variety of substituents may be present at the 4 'position of the pentose ring. In certain embodiments, R^2B can be an alkyl Ci-₆ optionally substituted. Examples of Ci- alkyls₆ Suitable include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tere-butyl, pentyl (straight and branched) and hexyl (straight and branched). In certain ways

<td>realization,</td><td>R^2B</td><td>It can be a</td><td>I rent</td><td>Cl-6</td><td>unsubstituted.</td><td>In</td>

<td>other forms</td><td>of</td><td>realization,</td><td>R^2b can</td><td>to be</td><td>an alkyl</td><td>Cl-6</td>

<td>replaced.</td><td>By</td><td>example R^2B</td><td>can </td><td>to be</td><td>an alkyl</td><td>Ci-6</td>

<td colspan="2">replaced with</td><td>halogen a</td><td>I rent</td><td>Cl-6</td><td>replaced</td><td>with</td>

hydroxy, an alkyl Ci-₆ substituted with alkoxy or an alkyl Ci₆ substituted with sulfenyl (for example, alkyl-Ci-₆-Salquilo Ci_₆). In other embodiments, R^2B can be a haloalkyl Ci-₆. .In other embodiments, R^2B can

107

<img file="MX356509B_D0182.tif" />

be an alkenyl C₂-6 optionally substituted. In certain embodiments, R^2B it may be a substituted C2.6 alkenyl. In other embodiments, R^2B it may be a C2 alkenyl.₆ unsubstituted. For example, R^2B it can be ethenyl, propenyl or alenyl. In still other embodiments, R^2B it may be an optionally substituted C2.6 alkynyl. In certain embodiments, R^2B it can be a C2 alkynyl.₆ replaced. In other embodiments, R^2Bit may be an unsubstituted C2.6 alkynyl. Suitable C2_6 alkynyls include ethynyl and propynyl. In still other embodiments, R^2B it can be a C3 cycloalkyl.₆optionally substituted. In certain embodiments, R^2b it may be a substituted C3.6 cycloalkyl. In other embodiments, R^2b can be a C3-cycloalkyl₆unsubstituted. A non-limiting list of cycloalkyls C₃.₆includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R^2B it may be an optionally substituted -O-Ci-6 alkyl. In certain embodiments, R^2B it may be a substituted -O-alkyl-6. In other embodiments, R^2B it may be an unsubstituted -O-Cx-6-alkyl. Examples of suitable Ci-6 O-alkyl groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy (straight-chain and

108

<img file="MX356509B_D0183.tif" />

INSTRI'UTO MEXICANO US THE INDUSTRIAL PROPERTY branched) and hexoxy (straight-chain and branched). In other embodiments, R^2B it may be an optionally substituted C3.6 -O-alkenyl. In certain embodiments, R^2B it may be a C3-O-alkenyl.₆ replaced. In other embodiments, R^2B it may be an unsubstituted C2.6 -O-alkenyl. In still other embodiments, R^2B it can be a -O- C3 alkynyl.₆ optionally substituted. In certain embodiments, R^2B it may be a substituted C3.6 -O-alkynyl. In other embodiments, R^2B it can be a C3-O-alkynyl._s unsubstituted. In still other embodiments, R^2B it can be cyano.

Various substituents may be present at the 2 'position of the pentose ring. In certain embodiments, R^4B it can be hydrogen. In other embodiments, R^4B it can be halogen, such as fluoro. In certain embodiments, R^3B it can be halogen, such as fluoro. In certain embodiments, R^4B can be hydrogen and R^3B it may be halogen. In other embodiments, R^3B and R^4B they can both be halogen. For example, R^3B and R^4B they can both be fluoro.

In certain embodiments, Z^{1 B} it can be O (oxygen). In other embodiments, Z^{1 B} it can be S (sulfur).

109

<img file="MX356509B_D0184.tif" />

RÍSTI fU'l OM £ XlCAí * ó DE LA PRQWEDAL ·

Various heterocyclic bases optionally á'ffi =^sE'i^TOtui &lt;fes can join the pentosa ring. In certain — embodiments, one or more of the amine and / or amino groups may be protected with a suitable protecting group. For example, it is possible to protect an amino group by transforming the amine and / or amino group into an amide or a carbamate. In certain embodiments, an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with one or more protected amino groups can have one of the following structures:

<img file="MX356509B_D0185.tif" />

<img file="MX356509B_D0186.tif" />

<img file="MX356509B_D0187.tif" />

<img file="MX356509B_D0188.tif" />

in which: R *³² can be selected from hydrogen, halogen and NHR⁰³², in which R³³² can be selected from hydrogen, -C (= O) R^KB2 and -C (= O) OR^lb2; R³³² it can be halogen or NHR ”³², in which R ™² can be selected from hydrogen, an alkyl Ci-₆optionally substituted, an alkenyl C₂-s optionally

110

<img file="MX356509B_D0189.tif" />

substituted, a cycloalkyl C₃.₈ optionally substituted,

C (= O) R^mb2 and -C (= O) OR^NB2; R^cb2 can be hydrogen or NHR^0B2, in the

PB2 which R^0B2 can be selected from hydrogen, -C (= O) R

C (= O) OR^QB2; R^db2 may be selected from hydrogen, halogen, an optionally substituted Ci-6 alkyl, an optionally substituted C2-6 alkenyl, and an optionally substituted C2-6 alkynyl; R^EB2 may be selected from hydrogen, hydroxy, an optionally substituted 0χ-6 alkyl, a C cycloalkyl₃.₈ optionally substituted, -C (= O) R^RB2 and -C (= O) OR^: , SB2

FB2 can be selected from hydrogen, halogen, an alkyl Ci_₆ optionally substituted, an alkenyl C₂.₆ optionally substituted and an alkynyl C₂-6 optionally substituted; AND^2B y y^3B can be, independently, N (nitrogen) or CR^IB2, in which R^ib2 may be selected from hydrogen, halogen, an optionally substituted C! -6 alkyl, an optionally substituted C2.6 alkenyl, and an optionally substituted C2.6 alkynyl; R^gb2 it may be an optionally substituted Ci-6 alkyl; R ™² can be hydrogen or NHR^NT2, in which R ™²can be independently selected from hydrogen, C (= O) R^UB2 and -C (= O) OR^VB2; and R¹®², R^LB2, R^MB2, R¹™², R^PB2, R^QB2, R¹^², R^SB2, r¹®² yr^TO2 can be independently selected from Ci_6-alkyl, C2_-alkenyl_s, alkynyl C₂_₆, cycloalkyl C₃-e, cycloalkenyl C₃-_S, aryl C₆_io, heteroaryl, aryl

<img file="MX356509B_D0190.tif" />

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<img file="MX356509B_D0191.tif" />

heteroalicyclyl, aryl (Ci- alkyl₆), heteroaryl (Ci- alkyl₆) and heteroalicyclyl (Cx-alkyl₆). In certain embodiments, the structures shown above can be modified by replacing one or more hydrogens with substituents selected from the list of substituents provided for the definition of substituted.

In certain embodiments, B^{1 B} can be

OR

<img file="MX356509B_D0192.tif" />

can be . In still other embodiments,

B^{1 B} can be

<img file="MX356509B_D0193.tif" />

, such as . In still others

112 embodiments, be

<img file="MX356509B_D0194.tif" />

<img file="MX356509B_D0195.tif" />

<img file="MX356509B_D0196.tif" />

In certain ways: no. In other ways

<img file="MX356509B_D0197.tif" />

realization, B can be realization, R^BB2 can be NH₂

In certain ways

In other ways

WB2, WB2 realization, R^BB2 can be NHR "^, in which R"^¿ can be C (= O) R^MB2 or -C (= 0) 0R^WB2. In still other embodiments, B, NB2

<img file="MX356509B_D0198.tif" />

? HB2 s ​​/ vw *

IB can be. In certain embodiments

113

<img file="MX356509B_D0199.tif" />

<img file="MX356509B_D0200.tif" />

In certain embodiments, a compound of the

Formula (II) can have the following structure:

1 B

<img file="MX356509B_D0201.tif" />

, or a pharmaceutically acceptable salt of the foregoing. In certain embodiments of this paragraph, B^{1 B} it can be an optionally substituted purine base. In other embodiments of this paragraph, B^{1 B} it may be an optionally substituted pyrimidine base. In certain embodiments of this paragraph, B^{1 B} it may be guanine. In other embodiments of this paragraph, B^{1 B} it may be thymine. In still other embodiments of this paragraph, B^{1 B} it may be cytosine. In still other embodiments of this paragraph, B^{1 B} it may be uracil. In certain embodiments of this paragraph, B^{1 B} it may be adenine. In certain embodiments of this paragraph, Z^{1 B} can

114 be oxygen. In certain

VP _,. . MEXICAN INSTINGTO ways to perform KwnrKonifer »eafeeú :. ' and

INDUSTRIAL paragraph, Z^{1 B} it may be sulfur. In still other embodiments of this paragraph, R^{1 B} it can be alkylcarbonyloxyalkoxy.

In certain embodiments, the compound can be a compound of Formula (III), or a pharmaceutically acceptable salt thereof, where: B^{1 C} it can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; R^{1 C} and R^{2 C} can independently be selected from 0 ', OH, a Ci- alkoxy₆ optionally substituted,

<img file="MX356509B_D0202.tif" />

, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; R^3C can be selected from an alkyl Ci-₆optionally substituted, an alkenyl C₂-6 optionally substituted, a C-alkynyl₂_₆ optionally substituted, a -Oxyl Cx-₆ optionally substituted, un-O-alkenyl C₃-₆optionally substituted, un-O-alkynyl C₃.₆ optionally substituted, a cycloalkyl C₃-s optionally substituted and cyano; R^4C can be selected from OH, -OC (= O) R '^c and a

115

-κ- »-w- Jí X - ^ '. 4

MEXICAN INSTITUTE &lt;Χ ·^{:; π}®5ί5! * '^ OF THE ΓβΟΠΕΡΛΓ. · &lt;

INDUSTRIAL optionally substituted O-linked amino acid; R^sc it can be a halogen; R^6C it can be hydrogen or halogen; R^9C, R^10C,

R^12C and R^13C can independently be selected from hydrogen, an alkyl Ci-₂4 optionally substituted and an optionally substituted aryl; R^11C and R^14C can independently be selected from hydrogen, an alkyl Ci-₂₄ optionally substituted, optionally substituted aryl, un-O-Ci-alkyl₂₄ optionally substituted and an optionally substituted 0-aryl; R^15C can be selected from hydrogen, an alkyl Ci-₂₄ optionally substituted and an optionally substituted aryl; ------- can be a single bond or a double bond; when ------- is a single link, each R^7C and each R^8C they can independently be hydrogen or halogen; and when ------- is a double bond, each R^7C is absent and every R^8C it can be independently hydrogen or halogen; Z^{1 C} it can be O (oxygen) or S (sulfur); yr ”^c can be an alkyl C! _₂₄optionally substituted.

In certain embodiments, ------- can be a single bond such that Formula (III) has the

116

<img file="MX356509B_D0203.tif" />

MEXICAN INSTITUTE Λ

OF THE PROPERTY

INDUSTRIAL

<img file="MX356509B_D0204.tif" />

structure R *¹⁰ R^ou , in which each R^7C and each R^8C it can independently be hydrogen or halogen. In certain embodiments, the R groups^7C and the R^8C they can all be hydrogen. In other embodiments, an R^7C can

<td>be halogen.</td><td>a R^7C can be</td><td>hydrogen</td><td>and both</td><td>groups</td><td>R^8C</td>

<td>They may be</td><td>all hydrogen.</td><td>In still</td><td>others</td><td>shapes</td><td>of</td>

<td>realization,</td><td>a R^7C can be</td><td>halogen,</td><td>a R^7C</td><td>can</td><td>to be</td>

<td>hydrogen a</td><td colspan="2">R^8C it can be halogen and</td><td>a R^8C</td><td>can</td><td>to be</td>

<td>hydrogen. In</td><td>certain ways</td><td colspan="2">of realization,</td><td colspan="2">carbon</td>

<td>adjacent to</td><td>match and the</td><td>carbon</td><td colspan="3">5 'can be,</td>

independently a chiral center (S). In certain embodiments, the carbon adjacent to the phosphor and the 5 'carbon can each independently be a chiral center (R).

In certain embodiments, ------- can be a double bond such that Formula (III) has the structure

<img file="MX356509B_D0205.tif" />

in which each R^7C be absent and every R^8C can independently be hydrogen or

<img file="MX356509B_D0206.tif" />

117

<img file="MX356509B_D0207.tif" />

halogen. In certain embodiments, the two R groups^8Cthey can be hydrogen. In other embodiments, an R^8Ccan be halogen and the other R^8C it can be hydrogen. In certain embodiments, the two R groups^8C they can be halogen. In certain embodiments, the double bond has a (Z) configuration. In certain embodiments, the double bond has a (£) configuration.

In certain embodiments, R^{1 C} and / or R^{2 C} They may be

OR'. In other embodiments, R^{1 C} and / or R^{2 C} they can be OH. In certain embodiments, R^{1 C} and R^{2 C} can be both

Oh

In certain embodiments, R and / or R can be

<img file="MX356509B_D0208.tif" />

j11C, where R^9C and R^10C can independently be selected from hydrogen, an alkyl Ci-₂₄optionally substituted and an optionally substituted aryl; and R^11C can be selected from hydrogen, an alkyl Ci_₂₄optionally substituted, an optionally substituted aryl, an -O-alkyl -Ci_₂₄ optionally substituted and an optionally substituted -0-aryl. In certain embodiments, R^9C and R^10C they can be hydrogen. In other embodiments, at least one of R^9C and R^10C'can be an alkyl

<img file="MX356509B_D0209.tif" />

118

Optionally substituted Ci-24 or a substituted aryl * - · upL.iuildillléiñ'ttí '. In certain embodiments, R^11C it may be an optionally substituted Ci-24 alkyl. In other embodiments, R^11C it can be an optionally substituted aryl. In still other embodiments, R^11C it can be an optionally substituted-0-Ci-24 alkyl or an optionally substituted -0-aryl. In certain embodiments,

<img file="MX356509B_D0210.tif" />

R

11C

In certain embodiments, R^{1 C} and / or R^{2 C} They may be _R12C _r13C O

CT r14C _in ,¿_on¿_and r^12C and _Ri3c p_EU(j_in independently selected from hydrogen, an optionally substituted Cx-24 alkyl and an optionally substituted aryl; R^14C an Cx-alkyl can be independently selected from hydrogen₂₄ optionally substituted, optionally substituted aryl, un-O-Cx-alkyl₂₄ optionally substituted and optionally substituted un-O-aryl; and Z^{1 C} it can independently be O (oxygen) or S (sulfur). In certain embodiments, R^12C and R^13C they can be hydrogen. In other embodiments, at least one of R^12C or R^13C, can be a Cx-alkyl₂₄ optionally substituted or an aryl

119

<img file="MX356509B_D0211.tif" />

optionally substituted. In certain embodiments / R^14C it may be an optionally substituted Ci-24 alkyl. In other embodiments, R^14C it can be an optionally substituted aryl. In still other embodiments, R^14C it may be an optionally substituted -0-Ci-24 alkyl or an optionally substituted -0-aryl. In certain embodiments, Z^{1 C} it can be O (oxygen). In other embodiments, Z^{1 C} it can be S (sulfur). In certain embodiments, R^{1 C} and / or R^{2 C} it can be isopropylcarbonyloxymethoxy. In certain embodiments, R^{1 C} and / or R^{2 C} they can be pivaloyloxymethoxy. In certain embodiments, R^{1 C} and R^{2 C}

<img file="MX356509B_D0212.tif" />

can both be V t- '' R^14C. In certain embodiments, R^{1 C} and R^{2 C} they can both be isopropylcarbonyloxymethoxy. In other embodiments, R^{1 C} and R^{2 C} they can be both pivaloyloxymethoxy.

In certain embodiments, R^{1 C} and / or R^{2 C} They may be

OR

<img file="MX356509B_D0213.tif" />

it can be hydrogen.

can be an alkyl

In certain embodiments, R^15CIn other embodiments, R^15CCi-₂₄ optionally substituted. In still other embodiments, R^15C can be an aril

<img file="MX356509B_D0214.tif" />

120 optionally substituted. In certain embodiments,, 15C can be a C! Alkyl.₆, eg, methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, tere-butyl, pentyl (straight and branched chain), and hexyl (straight and branched chain). In certain embodiments, R^{1 C} and

R^{2 C} can be both

<img file="MX356509B_D0215.tif" />

15C

In certain embodiments, R^{1 C} and / or R^{2 C} they may be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. For example, R^{1 C} and / or R^{2 C} may be an optionally substituted version of the following: alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine and ester derivatives thereof.

In certain embodiments, ilC and / or R^{2 C} alanine isopropyl ester, alanine cyclopropyl ester, alanine neopentyl ester, valine isopropyl ester and leucine isopropyl ester can be selected.

In certain embodiments, R^{1 C} and / or R^{2 C} can have the

<img file="MX356509B_D0216.tif" />

121

19Cq R20C _R21C ^{0 HN}-Ϊ 19C structure 5, in which R can be selected from hydrogen, an alkyl Ci-₆ optionally substituted, a cycloalkyl C₃.₆ optionally substituted, optionally substituted aryl, optionally substituted aryl (Ci-6 alkyl) and optionally substituted haloalkyl; R^20Ccan be selected from hydrogen, an alkyl Ci_₆ optionally substituted, a Ci- haloalkyl_and optionally substituted, a cycloalkyl C₃_₆ optionally substituted, a C aryl₆ optionally substituted, a Ci aryl₀ optionally substituted and an aryl (C! _ alkyl₆) optionally substituted; and

21C can be hydrogen or a Ci- alkyl₄ optionally substituted; or R^20C and R^21C can be taken together to form a cycloalkyl C₃.₆ optionally substituted.

When R^20C is substituted, R^20C it may be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy, and amino. In certain embodiments, R^20c can be an alkyl Ci-₆ unsubstituted, such as those described herein. In certain embodiments, R^20C it can be hydrogen. In other embodiments, R^20C it may be methyl. In certain embodiments, R^19C It can be a

122

<img file="MX356509B_D0217.tif" />

optionally substituted Cx-6 alkyl. Examples of Ci_ alkyls₆ optionally substituted include optionally substituted variants of the following: methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (straight and branched chain) and hexyl (straight and branched chain). In certain embodiments, R^19Cit can be methyl or isopropyl. In certain embodiments, R^19C it can be ethyl or neopentyl. In other embodiments, R^19C can be a cycloalkyl C₃.₆optionally substituted. Examples of Cycloalkyl C₃.₆ optionally substituted include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In one embodiment, R^19Cit can be an optionally substituted cyclohexyl. In still other embodiments, R^19C it can be an optionally substituted aryl, such as phenyl and naphthyl. In still other embodiments, R^19C it may be an optionally substituted aryl (Cx6 alkyl). In certain embodiments, R^19C it can be an optionally substituted benzyl. In certain embodiments, R^19C may be an optionally substituted Ci-6 haloalkyl, eg CF₃. In certain embodiments, R^21C it can be hydrogen. In other embodiments, R^21C It can be a

LSS-CA

123

<img file="MX356509B_D0218.tif" />

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<img file="MX356509B_D0219.tif" />

alkyl Ci-₄ optionally substituted, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tere-butyl. In one embodiment, R^21C it may be methyl. In certain embodiments, R^20C and R^21C can be taken together to form a cycloalkyl C₃_₆ optionally substituted. Examples of Cycloalkyl C₃-₆ optionally substituted include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Depending on the groups that are selected for R^20C and R^21C, the carbon to which R^20C and R^21Cthey are linked can be a chiral center. In a certain embodiment, the carbon to which R^20C and R^21C are attached can be a chiral center (R). In other embodiments, the carbon to which R^20C and R^21C are attached can be a chiral center (S).

the

The following examples:

<img file="MX356509B_D0220.tif" />

H₃C0 »h₃ch

<img file="MX356509B_D0221.tif" />

<img file="MX356509B_D0222.tif" />

124

<img file="MX356509B_D0223.tif" />

In certain embodiments, R^{1 C} and R^{2 C} they can be the same. In other embodiments, R^{1 C} and R^{2 C} they may be different.

125

<img file="MX356509B_D0224.tif" />

In certain embodiments,

R^{1 C} can ^16CO — P — Oor^17C

-p — o ¿r18C ^LJny r2c p_EU&lt;j_{in being} what- _or oh where R^16C, R^17C and

R^18C they may be absent or hydrogen; and n can be 0 or 1. Those skilled in the art will understand that when R^16C, R^17Cand / or R^18C are absent, the associated oxygen will be negatively charged. In certain embodiments, when n is 0, the compound of Formula (III) will be a diphosphate. In other embodiments, when n is 1, the compound of the

Formula (III) will be a triphosphate.

There may be a variety of substituents present at the 4 'position of the pentose ring. In certain embodiments, R^3C it can be a Ci alkyl.₆ optionally substituted. Examples of Ci- alkyls₆ Suitable include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tere-butyl, pentyl (branched and straight chain), and hexyl (branched and straight chain). In certain ways

<td>realization,</td><td colspan="3">R^3C can be an alkyl Ci-₆ unsubstituted.</td><td>In</td>

<td>other forms</td><td>of</td><td>realization,</td><td>R^3C can be an alkyl</td><td>Ci-₆</td>

<td>replaced.</td><td>By</td><td>example R^3C</td><td>can be an alkyl</td><td>Ci-6</td>

replaced with halogen. In other embodiments, R^3Ccan be an alkenyl C₂-₆ optionally substituted. In ► V

<img file="MX356509B_D0225.tif" />

126 certain embodiments, R^3C can be substituted. In other embodiments, R^3C it may be an unsubstituted C2-6 alkenyl. For example, R^3C it can be ethenyl, propenyl or alenyl. In still other embodiments, R^3C it may be an optionally substituted C2-6 alkynyl. In certain embodiments, R^3C it may be a substituted C2.6 alkynyl. In other embodiments, R^3Cit can be a C2 alkynyl.₆ unsubstituted. Alkynyls C₂.₆ Suitable include ethynyl and propynyl. In still other embodiments, R^3C it may be an optionally substituted C3_6 cycloalkyl. In certain embodiments, R^3C it can be a C3 cycloalkyl._s replaced. In other embodiments, R^3C it may be an unsubstituted C3.6 cycloalkyl. A non-limiting list of C3.6 cycloalkyls includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R^3C it may be an optionally substituted -0-Ci-6-alkyl. In certain embodiments, R^3C it may be a substituted -O-Cx-6-alkyl. In other embodiments, R^3C it may be an unsubstituted -0-Ci-6-alkyl. Examples of O-alkyl groups Ci-₆ Suitable include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy (straight-chain and branched) and hexoxy (straight-chain and branched). In others

<img file="MX356509B_D0226.tif" />

127

IMPI embodiments, R^3C may be an optionally substituted - &lt;^ - ril qiiinni 1 n ffljmr. In certain embodiments, R^3c it may be a substituted C3.6-O-alkenyl. In other embodiments, R^3C it may be a C3 -O-alkenyl.₆unsubstituted. In still other embodiments, R^3C it may be an optionally substituted -O- C3.6 alkynyl. In certain embodiments, R^3C it can be a -O-C3 alkynyl-₆replaced. In other embodiments, R^3C can be an O-alkynyl C₃-₆ unsubstituted. In still other embodiments, R^3C it can be cyano.

Substituents that may be present at the 3 'position of the pentose ring can vary. In certain embodiments, R^4C it can be OH. In other embodiments, R^4C it may be an optionally substituted O-linked amino acid. Examples of suitable O-linked amino acids include alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, usine, methionine, phenylalanine, threonine, tryptophan and valine. Additional examples of suitable amino acids include, but are not limited to, ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine, alpha-propyl-

<img file="MX356509B_D0227.tif" />

128

INSTITUTO MtílCANO V> 2. DE IA P2OPÍEEMD INDUSTRIAL glycine and norleucine. In certain forms of reaction_; ol. O-linked amino acid may have the structure

<img file="MX356509B_D0228.tif" />

O NH₂ in which R^22C can be selected from hydrogen, an alkyl Ci-₆ optionally substituted, a Ci- haloalkyl₆ optionally substituted, a cycloalkyl C₃_₆ optionally substituted, a C aryl₆ optionally substituted, a Ci aryl₀ optionally substituted and an aryl (Ci_alkyl₆) optionally substituted; and R^23C it can be hydrogen or an optionally substituted Ci_4 alkyl; or R^22C and R^23C can be taken together to form a C3_ cycloalkyl₆ optionally substituted.

When R is substituted, R may be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy and amino. In certain embodiments, R^22C can be an alkyl Ci-₆ unsubstituted, such as those described herein. In certain embodiments, R^22C it can be hydrogen. In other embodiments, R^22C it may be methyl. In certain embodiments, R^23C it can be hydrogen. In other embodiments, R^23C It can be a

129

IMPI

INSTITUTE ΜΗΠΓΑΝΠ Vi &lt;&amp; rxSÍÍ íS

MEXICAN INSTITUTE OF THE INDUSTRIAL PROPERTY

<td>I rent</td><td>Ci</td>

<td>ethyl,</td><td>np</td>

<td>butyl.</td><td>In</td>

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

<td>carbon</td><td>to the</td>

<td>chiral.</td><td>In</td>

<td colspan="2">R^22C and R^23C</td>

, 23C

According to the groups selected for R^22C y R ', 23C el y R^23C are attached can be a chiral center (R)

In 23C other embodiments, the carbon to which R and R are attached may be a chiral center (S).

&lt;—QR^22C(R^23C

The examples of

-OR²²· K nh₂ suitable include the

E> _{Λ d}22C p23C 2_q R²²MR^23C j-0 H₃<H following:

NH₂

NHo nh₂

<img file="MX356509B_D0229.tif" />

í or nh₂

In still other embodiments, R^4C can be

OC (= O) R "^c, in which r^c it may be an optionally substituted Ci-24 alkyl. In certain embodiments, R^c it may be a substituted Ci-i2 alkyl. In other embodiments, R "^c can be a Ci-i alkyl₂ unsubstituted. In still other embodiments, R "^c it can be a Ci alkyl.₈

130

<img file="MX356509B_D0230.tif" />

replaced. In still other embodiments, r^c it may be an unsubstituted Ci-8 alkyl. In certain embodiments, R^4C it can be an optionally substituted acyl. In other embodiments, R^4C can be -OC (= O) r ”^c, in which r "^c can be selected from an optionally substituted Ci-i2 alkyl, a C-alkenyl₂-_i2 optionally substituted, a C-alkynyl₂.₁₂ optionally substituted, a cycloalkyl C₃.₈ optionally substituted, a cycloalkenyl C₅_₈ optionally substituted, a C aryl₆optionally substituted -io, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an aryl (Ci- alkyl₆) optionally substituted, a heteroaryl (C! -alkyl -₆) optionally substituted and a heterocyclyl (Ci- alkyl₆) optionally substituted. In certain embodiments, R^c it may be a substituted Ci-i2 alkyl. In other embodiments, r^c it may be an unsubstituted Ci_i2 alkyl.

There may also be a variety of substituents present at the 2 'position of the pentose ring. In certain embodiments, R^6C it can be hydrogen. In other embodiments, R^sc it can be halogen, such as fluoro. In certain embodiments, R^5C it can be halogen, such as fluoro. In certain embodiments, R^sc can be hydrogen and R^5C it may be halogen.

131

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<img file="MX356509B_D0231.tif" />

In other embodiments, R^5C and R^6C they can both be halogen. For example, R^5C and R^6C they can both be fluoro.

Various optionally substituted heterocyclic bases can be attached to the pentose ring. In certain embodiments, one or more of the amine and / or amino groups may be protected with a suitable protecting group. For example, an amino group can be protected by transforming the amine and / or amino group into an amide or a carbamate. In certain embodiments, an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with one or more protected amino groups can have one of the following structures:

<img file="MX356509B_D0232.tif" />

in which: R^AC2 can be selected from hydrogen, halogen and NHR^JC2, in which R^JC2 can be selected from hydrogen, -C (= O) R^KC2 and -C (= 0) 0R^LC2; R^BC2 can be halogen or NHR^WC2, in

132

<img file="MX356509B_D0233.tif" />

where R can be selected from hydrogen, an alkyl Ci_₆ optionally substituted, an alkenyl C₂.₆ optionally substituted, a cycloalkyl C₃.₈ optionally substituted, 0C2

C (= O) R^MC2 and -C (= O) OR^NC2; R^CC2 can be hydrogen or NHR 'in

PC2 where R can be selected from hydrogen, -C (= O) R

C (= O) OR^qc2; R^DC2 can be selected from hydrogen, halogen, an alkyl Ci-_G optionally substituted, an alkenyl C₂.₆ optionally substituted and an alkynyl C₂.₆ optionally substituted; R^EC2 can be selected from hydrogen, hydroxy, an alkyl Ci-₆ optionally substituted, a cycloalkyl C₃.₈ optionally substituted, -C (= O) R^RC2 and -C (= O) OR ', SC2

R^J

FC2 can be selected from hydrogen, halogen, an alkyl Ci.₆ optionally substituted, an alkenyl C₂-_S optionally substituted and an alkynyl C₂-₆ optionally substituted; AND^{2 C} and Y^3C they can be, independently, N (nitrogen) or CR^IC2, where R^IC2 may be selected from hydrogen, halogen, an optionally substituted Ci-6 alkyl, an optionally substituted C2.6 alkenyl, and an optionally substituted C2.6 alkynyl; R^gc2 it may be an optionally substituted Ci-6 alkyl; R^HC2 can be hydrogen or NHR^TC2, where R^TC2can be independently selected from hydrogen, C (= O) R^UC2 and -C (= O) OR^VC2; and R^KC2, R^LC2, R^MC2, R^NC2, R^PC2, R^QC2, R^RC2, R^SC2, R^UC2 and R^VC2 can be selected independently from

133

<img file="MX356509B_D0234.tif" />

alkyl Ci-₆, alkenyl C₂-₆, alkynyl C₂.₆, cycloalkyl C₃-_fi, __ cycloalkenyl C₃._and aryl heteroaryl heteroalicyclyl, aryl (Ci- alkyl₆), heteroaryl (Ci- alkyl₆) and heteroalicyclyl (C ^ alkyl). In certain embodiments, the structures shown above can be modified by replacing one or more hydrogens with substituents selected from the list of substituents provided for the definition of substituted.

In certain embodiments, B^{1 C} can be

N NH₂ . In other embodiments, B^{1 C} can be

NH

In still other embodiments, B^{1 C} can be k / WV *, such as

ΛΑΛΑ. In still other ways

134 ____r i

MEXICAN INSTITUTE Γζ *

DS LA FROPIEDAO V VrrA Ji ^Λ ?

IN DUSTP.1AL) DC2

<img file="MX356509B_D0235.tif" />

nhr^EC2

Neither

N 'O of realization, B^{1 C} can be nh₂ nh₂

N for example

<img file="MX356509B_D0236.tif" />

<img file="MX356509B_D0237.tif" />

. In certain embodiments, R^DC2it can be hydrogen. In other embodiments, B^{1 C} can

<img file="MX356509B_D0238.tif" />

. In certain embodiments, R^BC2 can be NH₂. In other embodiments, R^BC2 may be NHR^WC2, to be

MC2 where R^WC2 can be -C (= 0) R "^C2 or -C (= 0) OR¹². In still others, NC2

<img file="MX356509B_D0239.tif" />

HC2 * / VW »embodiments, B^{1 C} can be

In

135 certain

In

Formula

<img file="MX356509B_D0240.tif" />

In certain embodiments, the compound of (III) can have one of the following structures:

<img file="MX356509B_D0241.tif" />

<img file="MX356509B_D0242.tif" />

<img file="MX356509B_D0243.tif" />

or R^4C R^5C . AND_n certain embodiments of this paragraph, B^{1 C} it can be an optionally substituted purine base. In other embodiments of this paragraph, B^{1 C} it may be an optionally substituted pyrimidine base. In certain embodiments of this paragraph, B^lc it may be guanine. In other embodiments of this paragraph, B^{1 C} it may be thymine. In still other embodiments of this paragraph, B^{1 C} it may be cytosine. In still other embodiments of this paragraph, B^{1 C} it may be uracil. In certain

136

<img file="MX356509B_D0244.tif" />

INDUSTRIAL embodiments of this paragraph, B^{1 C} it may be adenine. In certain embodiments of this paragraph, R^{1 C} and R^{2 C}they can each be an alkyl Ci-₄ optionally substituted. In other embodiments of this paragraph, R^1A it can be an optionally substituted acyl. In still other embodiments of this paragraph, R^{1 C} and R^{2 C} they can form a mono-, di- or tri-phosphate. In still other embodiments of this paragraph, R^{1 C} and R^{2 C} each of them can be an alkylcarbonyloxyalkoxy. In certain embodiments of this paragraph,, 4C may be OH. In certain embodiments of this paragraph, R^sc can be F and, R^6C it can be hydrogen.

Examples of suitable compounds of Formula (I) include, but are not limited to:

<img file="MX356509B_D0245.tif" />

<img file="MX356509B_D0246.tif" />

<img file="MX356509B_D0247.tif" />

<img file="MX356509B_D0248.tif" />

<img file="MX356509B_D0249.tif" />

137

<img file="MX356509B_D0250.tif" />

138

<img file="MX356509B_D0251.tif" />

<img file="MX356509B_D0252.tif" />

140

<img file="MX356509B_D0253.tif" />

foregoing.

Additional examples of a compound of Formula (I) include the following:

141

<img file="MX356509B_D0254.tif" />

<img file="MX356509B_D0255.tif" />

<img file="MX356509B_D0256.tif" />

'2

<img file="MX356509B_D0257.tif" />

<img file="MX356509B_D0258.tif" />

r

<img file="MX356509B_D0259.tif" />

142 nh₂

<img file="MX356509B_D0260.tif" />

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<img file="MX356509B_D0261.tif" />

<img file="MX356509B_D0262.tif" />

<img file="MX356509B_D0263.tif" />

<img file="MX356509B_D0264.tif" />

<img file="MX356509B_D0265.tif" />

143

<img file="MX356509B_D0266.tif" />

<img file="MX356509B_D0267.tif" />

<img file="MX356509B_D0268.tif" />

144

IMPI

<img file="MX356509B_D0269.tif" />

<img file="MX356509B_D0270.tif" />

<img file="MX356509B_D0271.tif" />

<img file="MX356509B_D0272.tif" />

145

<img file="MX356509B_D0273.tif" />

<img file="MX356509B_D0274.tif" />

<img file="MX356509B_D0275.tif" />

INSTITUTO MEXICANO OS LA PROPIEDAD industrial

<img file="MX356509B_D0276.tif" />

<img file="MX356509B_D0277.tif" />

<img file="MX356509B_D0278.tif" />

pharmaceutically acceptable from the above.

Other examples of a compound of Formula (I) include, but are not limited to, the following:

ΔΛ. ·

146

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX356509B_D0279.tif" />

<img file="MX356509B_D0280.tif" />

<img file="MX356509B_D0281.tif" />

<img file="MX356509B_D0282.tif" />

<img file="MX356509B_D0283.tif" />

<img file="MX356509B_D0284.tif" />

<img file="MX356509B_D0285.tif" />

<img file="MX356509B_D0286.tif" />

OR

147

<img file="MX356509B_D0287.tif" />

or

148

<img file="MX356509B_D0288.tif" />

<img file="MX356509B_D0289.tif" />

MEXICAN INSTITUTE

<img file="MX356509B_D0290.tif" />

<img file="MX356509B_D0291.tif" />

<img file="MX356509B_D0292.tif" />

NH₂

<img file="MX356509B_D0293.tif" />

149

<img file="MX356509B_D0294.tif" />

.or

150

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX356509B_D0295.tif" />

<img file="MX356509B_D0296.tif" />

<img file="MX356509B_D0297.tif" />

<img file="MX356509B_D0298.tif" />

<img file="MX356509B_D0299.tif" />

<img file="MX356509B_D0300.tif" />

or a salt

151

MEXICAN INSTITUTE OR £ la Mopiüia: ·

Pharmaceutically acceptable INDUSTBIAL of the above^-.'¹ —-- Examples of a compound of Formula (II)

<img file="MX356509B_D0301.tif" />

Examples of a compound of Formula (III) include, but are not limited to, the following:

nh₂

<img file="MX356509B_D0302.tif" />

HO '

<img file="MX356509B_D0303.tif" />

HO

<img file="MX356509B_D0304.tif" />

152

<img file="MX356509B_D0305.tif" />

<img file="MX356509B_D0306.tif" />

<img file="MX356509B_D0307.tif" />

<img file="MX356509B_D0308.tif" />

<img file="MX356509B_D0309.tif" />

a pharmaceutically acceptable salt of the above.

Other examples of a compound of Formula (III) include, but are not limited to:

<img file="MX356509B_D0310.tif" />

<img file="MX356509B_D0311.tif" />

a pharmaceutically acceptable salt of the above

153

IMPI

INSTITUTO MEXICANO Cí LA PROPIEDAD INDUSTRIAL

<img file="MX356509B_D0312.tif" />

Synthesis

The compounds of Formula (I), Formula (II) and Formula (III) and those described herein can be prepared in various ways. Certain compounds of the formulas (I), (II) and (III) can be obtained commercially and / or prepared using the known synthetic procedures. The general synthetic routes for the compounds of the formulas (I), (II) and (III) and some examples of starting materials used to synthesize the compounds of the formulas (I), (II) and (III) are shown and described herein. These pathways shown and described herein are for illustrative purposes only and are not intended to, nor should be construed to limit the scope of the claims in any way. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and create alternative pathways, based on the descriptions taught herein; All of these modifications and alternative routes are within the scope of the claims.

154

<img file="MX356509B_D0313.tif" />

Scheme 1

HO

<img file="MX356509B_D0314.tif" />

(A) (B)

<img file="MX356509B_D0315.tif" />

(C)

<img file="MX356509B_D0316.tif" />

As shown in Scheme 1, compounds of Formula (I) can be prepared from a nucleoside, for example, a nucleoside of formula (A). In scheme 1, R^3rd, R^4th, R^5th and B^the can be equal to R^3A, R^4A, R^5A and B^1A, as described herein for Formula (I) and PG¹ it is a suitable protecting group. A hydroxyalkyl group can be formed at the 4'-position of the pentose ring using suitable conditions known to those skilled in the art. Examples of the suitable conditions for forming a hydroxyalkyl include the use of 2-oxoxybenzoic acid (IBX), aqueous formaldehyde and borohydride of

155

<img file="MX356509B_D0317.tif" />

· ** »AV ^ LL Jj, MEXICAN INSTITUTE OF PROPERTY industrial sodium. A compound of formula (B) can be oxidized to an aldehyde using one or more suitable oxidizing agents, to form a compound of formula (C). An example of a suitable oxidizing agent is the Dess-Martin periodinan. Alkenyl C₂-₆ optionally substituted or a C-alkynyl₂.₆ optionally substituted can be formed at the 4 'position using methods known to those skilled in the art, for example, the Wittig and n-BuLi reagent, the Wittig-type reactions, the Peterson olefination reaction and the Corey reaction

Fuchs. An alkyl Ci-₆ optionally substituted can be obtained by hydrogenation of the unsaturated group attached at the 4 'position, for example, using hydrogen on palladium on carbon.

Alternatively, a compound of Formula (B) can be transformed into a haloalkyl using one or more suitable agents, for example, into a iodide using imidazole, triphenylphosphine and iodine; in a fluoro using diethylamino sulfur trifluoride (DAST); or in a chlorine using triphenylphosphine and carbon tetrachloride in dichloroethylene (DCE). An iodoalkyl can be transformed into an unsubstituted Ci-6 alkyl group, using methods known to those skilled in the art, for example, hydrogen on palladium on carbon. A compound of formula (C) can react with

156

<img file="MX356509B_D0318.tif" />

INDUSTRIAL hydroxylamine, to form an oxime. The oxime can.

transforming into a cyano group, implementing the methods known to those skilled in the art, for example, using methanesulfonyl chloride.

Scheme 2

<img file="MX356509B_D0319.tif" />

<img file="MX356509B_D0320.tif" />

<img file="MX356509B_D0321.tif" />

As shown in Scheme 2, the compounds of Formula (I), where is a -O-Ci_alkyl₆ optionally substituted, a -Oalkenyl C₃.₆ optionally substituted or a -O- alkynyl C₃.₆ optionally substituted, they can be prepared from a nucleoside, for example, a nucleoside of Formula (A). In scheme 2, R²³, R³³, R⁴³, R⁵³ and B¹³ can be equal to R²*, R³*, R ^, R ^ and B ^, as described herein for Formula (I) and PG² it may be a suitable protecting group. The nucleoside can go through elimination and form

157

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL «

an olefin having the general formula of Boanrn.ila (D) compound of Formula (D) can be treated with an iodinated reagent in the presence of lead carbonate and an alkoxy source to form a compound of Formula (E). A compound of Formula (E) can then be transformed into a compound of Formula (I) through displacement of iodine with an oxygen nucleophile.

158

Scheme 3

<img file="MX356509B_D0322.tif" />

<img file="MX356509B_D0323.tif" />

+ POCI₃

<img file="MX356509B_D0324.tif" />

<img file="MX356509B_D0325.tif" />

OR

<img file="MX356509B_D0326.tif" />

<img file="MX356509B_D0327.tif" />

159

IMPI

MEXICAN INSTITUTE

OF THE INDUSTRIAL PUOPIEDAD

<img file="MX356509B_D0328.tif" />

Scheme 4

OR

<img file="MX356509B_D0329.tif" />

<img file="MX356509B_D0330.tif" />

<img file="MX356509B_D0331.tif" />

Compounds of Formula (I) having a phosphorous-containing group attached at the 5 'position of the pentose ring can be prepared using various methods known to those skilled in the art. Examples of the methods are shown in Schemes 3 and 4. A phosphorous-containing precursor can be coupled to the nucleoside, for example, a compound of formula (F) or a compound of formula (G).

As shown in Scheme 3, following the coupling of the phosphorous-containing precursor, any starting group can be removed under suitable conditions, such as hydrolysis. Other groups containing matches

160

<img file="MX356509B_D0332.tif" />

MEXICAN INSTTNJTO.

Dt LA FBOPIEDAO V> Ss INDUSTRIAL can be added by implementing methods known to those skilled in the art, for example, using a pyrophosphate.

In certain embodiments, an alkoxide can be generated from a compound of formula (G) using an organometallic reagent, such as a Grignard reagent. The alkoxide can be coupled to the phosphorous-containing precursor. Suitable Grignard reagents are known to those skilled in the art and include, but are not limited to, alkyl magnesium chlorides and alkyl magnesium bromides. In certain embodiments, an appropriate base can be used. Examples of suitable bases include, but are not limited to, an amine base, such as an alkylamine (including mono-, di-, and tri-alkylamines (eg, triethylamine)), optionally substituted pyridines (eg collidine), and optionally imidazoles substituted (eg, N-methylimidazole)). Alternatively, it is possible to add a phosphorous-containing precursor to the nucleoside and form a phosphite. Phosphite can be oxidized to phosphate, under conditions known to those skilled in the art. Suitable conditions include, but are not limited to, meta-chloroperoxybenzoic acid (MCPBA) and iodine, as the oxidizing agent, and water as the oxygen donor.

When in the compounds of Formula (I) Z^1A, Z^2A or Z^3A

161

<img file="MX356509B_D0333.tif" />

is sulfur, sulfur can be added from diversag manovn ------ known to those skilled in the art. In certain embodiments, sulfur can be part of the phosphorous-containing precursor, for example, s

R^6A0 — P — cio · OH R^8AOR

S

<img file="MX356509B_D0334.tif" />

R^9A . Alternatively, sulfur can be added using a sulfurization reagent. Suitable sulfurizing agents are known to those of skill in the art and include, but are not limited to, elemental sulfur, Lawesson's reagent, cyclooctazulfre, 3H1,2-benzodithiol-3-one-1-dioxide (Beaucage's reagent), 3 ((N, N-dimethylamino-methylidene) amino) -3H-1,2,4-dithiazol-5-thione (DDTT) and bis (3-triethoxysilyl) propyl tetrasulfide (TEST).

Suitable phosphorous-containing precursors can be obtained commercially or prepared by synthetic methods known to those skilled in the art. Examples of general phosphorus-containing precursor structures are depicted in Schemes 3 and 4.

Scheme 5:

162

<img file="MX356509B_D0335.tif" />

Η (

<img file="MX356509B_D0336.tif" />

L¹ base

<img file="MX356509B_D0337.tif" />

Oxidation reagent (Z^{1 B} = O)

Sulfurization reagent (Z^{1 B} = S) S)

<img file="MX356509B_D0338.tif" />

A method of forming a compound of Formula (II) is shown in Scheme 5. In Scheme 5, R^lb, R^2b, R^3b, R^4b and B^lb can be the same as R^{1 B}, R^2B, R^3B, R^4B and B^{1 B}, as described herein for Formula (II), each L¹ it can be a halogen, a sulfonate ester or an amine (mono- or di-substituted) and X can be oxygen or sulfur. As shown in Scheme 5, a compound having a 3 'carbon-bonded hydroxy group and a 5' carbon-bonded hydroxy group can react with a compound having the formula, (R^lb) P (L¹) ₂, in the presence of a base, to produce a phosphite compound. Suitable bases are known to those skilled in the art and are described herein.

Phosphorus can then be oxidized to phosphorus (V) using a suitable oxidizing agent, to obtain a compound in which X is 0 (oxygen). Alternatively, the phosphite compound can be reacted with a sulfurization reagent

<img file="MX356509B_D0339.tif" />

163

IMPI to produce a compound in which X is S (sulfur). Suitable oxidation and sulfurizing agents are known to those of skill in the art. For example, oxidation can be carried out using iodine as the oxidizing agent and water as the oxygen donor. Suitable sulfurizing agents are described herein.

Scheme 6

<img file="MX356509B_D0340.tif" />

A method of forming a compound of Formula (III) is depicted in Scheme 6. In Scheme 6, R^lc, R^{2 C}, R^3c, R^4c, R^5c, R^6c and B^lc can be the same as R^{1 C}, R^{2 C}, R^3C, R^4C,

164

<img file="MX356509B_D0341.tif" />

IMPI

R^5C, R^6c and B^{1 C}, as described herein for Formula (III), and R^7C and R^8C not shown. The oxygen attached to the 5 'carbon of the compound of Formula (H) can be oxidized into a ketone, using methods and reagents known to those skilled in the art. For example, it is possible to use an oxidizing agent, such as the Dess-Martin periodinan. A phosphorous-containing reagent can then be added to a compound of Formula (J), in the presence of a strong base (eg, sodium hydride). The double bond can be hydrogenated, for example by using hydrogen gas or

PS / C in a single link. Additional phosphates can be added by phosphorylation to form di- or tri-phosphate using suitable reagents, such as a pyrophosphate (eg, tetrabutylammonium pyrophosphate).

An acyl group can be added to the 5 'and / or 3'-position of a compound of Formula (I) or (III) by using methods known to those skilled in the art.

A suitable method is to use a pyridine anhydride.

During the synthesis of any of the compounds described herein, if desired, any hydroxy groups attached to the pentose ring and any -NH and / or NH groups₂ present in B^the, B^lb and B^lc it can be protected with one or more suitable protecting groups. Protective groups

165

<img file="MX356509B_D0342.tif" />

IMPI

Suitable INDUSTRIAL are described herein. For example, when R^3rdand / or R^4c is a hydroxy group, R^3rd and / or R^4c it can be protected with a triarylmethyl group or a silyl group. Similarly, any -NH and / or NH group₂ present in B^the, B^lb and B^lc it can be protected, such as with one or more triarylmethyl and silyl groups. Examples of triarylmethyl groups include, but are not limited to, trityl, monomethoxytryl (MMTr), 4.4'dimethoxytryl (DMTr), 4.4 ', 4-trimethoxytryl (TMTr),

4.4 ', 4-tris- (benzoyloxy) trityl (TBTr), 4.4', 4-tris (4.5 dichlorophthalimido) trityl (CPTr), 4.4 ', 4-tris (levulinyloxy) trityl (TLTr), p-anisyl-1- Naphthylphenylmethyl, di-o-anisyl-1-naphthylmethyl, p-tolyldiphenylmethyl, 3 - (imidazolylmethyl) -4.4'dimethoxytryl, 9-phenylxanthene-9-yl (Pixyl), 9- (pmethoxyphenyl) xanten-9-yl (Mox), 4 -decyloxytryrityl, 4hexadecyloxytryrityl, 4.4'-dioctadecyltrityl, 9- (4octadecyloxyphenyl) xanten-9-yl, 1.1'-bis- (4-methoxyphenyl) -1 'pyrenylmethyl, 4.4 ', 4-tris- (tert-butylphenyl) methyl (TTTr) and 4.4'-di-3.5-hexadienexytrityl. Examples of silyl groups include, but are not limited to, trimethylsilyl (TMS), fcerc-jbutyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), tri-iso-propylsilyloxymethyl and [2- (trimethylsilyl) ethyloxy] . Alternatively, R^3rdand R^4th and / or R^4c and R^5c can be protected by a single group

166

<img file="MX356509B_D0343.tif" />

achiral or chiral protector, for example, by forming an 'orthoester, a cyclic acetal or a cyclic ketal. Suitable orthoesters include methoxymethylene acetal, ethoxymethylene acetal, 2-oxocyclopentylidene orthoester, dimethoxymethylene orthoester, 1-methoxyethylidene orthoester, 1-ethoxyethylidene orthoester, methylidene-alpha-ethoyethylene-ethoyethylene-orthodeoxy-ethoyethyl-ethoxy-ethoxy ester ; suitable cyclic acetals include methylene acetal, ethylidene acetal, t-butylmethylidene acetal, 3 (benzyloxy) propyl acetal, benzylidene acetal, 3,4-dimethoxybenzylidene acetal and p-acetoxybenzylidene acetal; and suitable cyclic ketals include 1-t-butylethylidene ketal,

1-phenylethylidene ketal, isopropylidene-ketal, cyclopentylidenetal, cyclohexylidene-ketal, cycloheptylidene-ketal and l- (4methoxyphenyl) ethylidene-ketal. Those skilled in the art will appreciate that the groups attached to the pentose ring and any -NH and / or NH groups₂ present in B^the, B^lb and B^lc they can be protected with various protecting groups and any protecting groups present can be exchanged for other protecting groups. The selection and exchange of protecting groups is within the capabilities of experts with common knowledge in the art. All group

167

ΪΜΡΙ

<img file="MX356509B_D0344.tif" />

Protectant can be removed by methods known in the art, eg, with an acid (eg, a mineral or organic acid), a base, or a source of fluoride.

Pharmaceutical compositions

Certain embodiments described herein refer to a pharmaceutical composition, which may include an effective amount of one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) ) and / or a compound of Formula (III), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof.

The phrase pharmaceutical composition refers to a mixture of one or more compounds described herein with other chemical components, such as diluents or vehicles. The pharmaceutical composition facilitates the administration of the compound to an organism. The pharmaceutical compositions can also be obtained by reacting compounds with organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-acid.

<img file="MX356509B_D0345.tif" />

168

<img file="MX356509B_D0346.tif" />

ίΝίΤΠντυ MEXICANO W LA RSOPIEDAL ·

INDUSTRIAL toluenesulfonic and salicylic acid. The ”“ compoS1CiOhesⁿPharmaceuticals will generally be designed for the specific route of administration sought.

The phrase "physiologically acceptable" defines a vehicle, diluent or excipient that does not nullify the biological activity and properties of the compound.

As used herein, a vehicle refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly used vehicle that facilitates the absorption of many organic compounds into a subject's cells or tissues.

As used herein, a diluent refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but that may be pharmaceutically necessary or convenient. For example, a diluent can be used to increase the volume of a potent drug whose mass is too small to manufacture and / or administer. It can also be a liquid for the dissolution of a drug to be administered by injection, intake or inhalation. A common form of diluent in the art consists of a buffered aqueous solution such as, without limitation, phosphate buffered saline that

169

<img file="MX356509B_D0347.tif" />

mimics the composition of human blood.

As used herein, an excipient refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, volume, consistency, stability, binding capacity, lubrication, disintegration capacity, etc., to the composition. . A diluent is a type of excipient.

The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions in which they are mixed with other active ingredients, such as in combination therapy or vehicles, diluents, excipients, or combinations thereof. The appropriate formulation depends on the chosen route of administration. Techniques for the formulation and administration of the compounds described herein are known to those of skill in the art.

The pharmaceutical compositions disclosed herein can be manufactured in a manner known per se, for example, by conventional processes such as mixing, dissolving, granulating, dragee making, levigation, emulsion, encapsulation, compression or tableting. On the other hand, the active ingredients are contained in an effective amount to achieve the objective

170

IMPI

MEXICAN INSTITUTE '¿X ·

FROM THE PROPERTY CJsa- —-4β £ ί>

INDUSTRIAL that is sought in them. Many of the compounds used in the pharmaceutical combinations described herein can be provided as salts with pharmaceutically compatible counterions.

There are multiple techniques for administering a compound in this field, including, but not limited to, the routes: oral, rectal, topical, aerosol, injection, and parenteral, including intramuscular, subcutaneous, intravenous, intramedullary, intrathecal, intraventricular injections. direct, intraperitoneal, intranasal and infraocular injections.

Also the compound can be administered in a local rather than systemic form, for example, by injecting the compound directly into the infected area, often in a depot or sustained release formulation.

Also, the compound can be administered in a targeted pharmacological delivery system, for example, in a liposome coated with a tissue specific antibody.

The liposomes will be selectively targeted and taken up by the organ.

If desired, the compositions may be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the

171

<img file="MX356509B_D0348.tif" />

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<img file="MX356509B_D0349.tif" />

active ingredient. The package, for example, may comprise a metal or plastic film, such as a blister pack. The package or dispensing device may come with instructions for administration. The package or dispensing device may also be accompanied by a notice regarding the container, in a manner prescribed by a government agency that regulates manufacturing,

<td>the use or</td><td>the</td><td>selling products</td><td>pharmacists, whose</td><td>notice should</td>

<td>reflect</td><td>the</td><td>approval of the</td><td>dependence on</td><td>way that</td>

<td>will adopt</td><td>the</td><td>drug for</td><td>administration in</td><td>human or</td>

veterinary administration. Such notice, for example, may be the labeling approved by the US Food and Drug Administration for 15 prescription drugs or the approved product insert. Compositions can also be prepared which may include a compound described herein, formulated in a compatible pharmaceutical carrier, placed in an appropriate container, and labeled for the treatment of an indicated condition.

Methods of use:

Certain embodiments described herein refer to a method of ameliorating, treating and / or preventing a viral infection selected from among an infection.

172

WtSTTTUTO MtXfCA wo I

DE LA MORWAC ζVx · - '

------ ---- ur

INDUSTRIAL paramyxovirus viral and orthomyxovirus viral infection, which may include administering to a subject an effective amount of one or more compounds described herein, or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing). In certain embodiments, the subject is identified as having the viral infection (eg, a paramyxovirus viral infection or an orthomyxovirus viral infection).

Other embodiments described herein relate to a method of inhibiting viral replication of a virus selected from a paramyxovirus and an orthomyxovirus, which may include contacting a cell infected with the virus with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, an effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition that includes one or more compounds

173

<img file="MX356509B_D0350.tif" />

described herein (eg, a compound of the

Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above).

In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing) can be used to treat and / or improve an infection by respiratory syncytial virus (RSV) virus). In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a

174

<img file="MX356509B_D0351.tif" />

pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to prevent a respiratory syncytial virus infection. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to inhibit the replication of a respiratory syncytial virus. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a salt

175

IMPI medical institute of INDUSTRIAL PROPERTY

<img file="MX356509B_D0352.tif" />

pharmaceutically acceptable thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to inhibit the RSV polymerase complex.

In other embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of the

Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to treat and / or ameliorate a viral influenza infection. In other embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount

176

ICβΒΤυΤβ MEXICANO de LA «QUEDAD industrial

<img file="MX356509B_D0353.tif" />

effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to prevent viral influenza infection. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to inhibit the replication of an influenza virus. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount

177

<img file="MX356509B_D0354.tif" />

IMPI

INSTITUTO M1XICANO DE LA FIOIUDAD effective of one or more compounds of the Formula (ΙΪΪΥ7 *^{, Α}δ pharmaceutically acceptable salt of the mi'STnTT and / δ "" ΏηΤ pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to inhibit the influenza polymerase complex.

In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of the

Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to treat and / or ameliorate a Hendra virus infection and / or a Nipah virus infection. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt of the

178

<img file="MX356509B_D0355.tif" />

itself, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an effective amount of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to prevent Hendra virus infection and / or Nipah virus infection. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to inhibit replication of Hendra virus and / or Nipah virus. In certain embodiments, an effective amount of one or more compounds of

179

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MEXICAN INSTITUTE OF THE MSOWEDAP

INDUSTRIAL

<img file="MX356509B_D0357.tif" />

Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an effective amount of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of the Formula (III), or a pharmaceutically acceptable salt of the above) can be used to inhibit the Hendra virus polymerase complex and / or the Nipah virus polymerase complex.

In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of the

Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to treat and / or improve measles. In certain ways

180

IMPI

MEXICAN INSTITUTE OF PROPERTY. INDUSTRIAL embodiment, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an effective amount of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (for example, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to prevent measles. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to inhibit the replication of a measles virus. In certain embodiments, a

<img file="MX356509B_D0358.tif" />

181

<img file="MX356509B_D0359.tif" />

effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an effective amount of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to inhibit the measles polymerase complex.

In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of the

Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to treat and / or improve mumps. In certain ways

<img file="MX356509B_D0360.tif" />

182 realization, an effective amount of one or

<img file="MX356509B_D0361.tif" />

MEXICAN INSTITUTE OE THE PROPERTY

INDUSTRIAL

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,_of.

Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an effective amount of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to prevent mumps. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to inhibit the replication of a mumps virus. In certain embodiments, a

183

<img file="MX356509B_D0363.tif" />

IMPI effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an effective amount of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to inhibit the mumps polymerase complex.

In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable aal thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to treat and / or ameliorate an infection with Sendai virus. In

184

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Certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an effective amount of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition that includes one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to prevent Sendai virus infection. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to inhibit the replication of a Sendai virus. In certain

185

<img file="MX356509B_D0365.tif" />

IMPI

ΙΝ ^ ΤΠΤΠν-MEXICANO IX ΙΑ MIOF! UMD embodiments, an effective amount of one or compounds of Formula (I), or an pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an effective amount of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to inhibit the virus polymerase complex Sendai.

In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used

186

IMPI

<img file="MX356509B_D0366.tif" />

to treat and / or improve an HPIV-1 infection and / or HPIV-3 infection. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to prevent HPIV-1 infection and / or HPIV-3 infection. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula

187

<img file="MX356509B_D0367.tif" />

(III), or a pharmaceutically acceptable salt of the above) can be used to inhibit the replication of an HPIV-1 and / or HPIV-3. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to inhibit the HPIV-1 polymerase complex and / or the HPIV-3 polymerase.

In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of the

Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a

<img file="MX356509B_D0368.tif" />

188 compound of Formula (I), a compound of Formula (ΪΪΤ and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to treat and / or ameliorate an HPIV infection -2 and / or an infection with HPIV-4. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing) can be used to prevent HPIV-2 infection and / or an HPIV-4 infection. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a composition

189

<img file="MX356509B_D0369.tif" />

- X,

INSTIWniMekCAMO '

Pharmaceutical MfAflorUtMn · '* including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to inhibit the replication of an HPIV-2 and / or HPIV-4. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to inhibit the HPIV-2 polymerase complex and / or the polymerase complex of HPIV-4.

In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of the

190

IMPI

<img file="MX356509B_D0370.tif" />

Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing) can be used to treat and / or ameliorate a human Metapneumovirus infection. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of the

Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to prevent an infection by the human Metapneumovirus. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount

191

IMPI

<img file="MX356509B_D0371.tif" />

effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to inhibit the replication of a human Metapneumovirus. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to inhibit the human Metapneumovirus polymerase complex.

In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds

192

<img file="MX356509B_D0372.tif" />

of Formula (II), or a pharmaceutically acceptable salt thereof, an effective amount of one or more compounds of the

Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to treat and / or ameliorate a viral upper respiratory infection caused by a virus selected from a henipavirus, a morbillivirus, a respirovirus, a rubulavirus, a pneumovirus, a metapneumovirus, and the influenza virus. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of the

Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used

193

<img file="MX356509B_D0373.tif" />

IMPI

INSTITUTO MEXICANO ΓΜί LA RBOUEDAP mmnflUAL to treat and / or improve a viral infection of the lower respiratory tract caused by a virus selected among a henipavirus, a morbillivirus, a respirovirus, a rubulavirus, a pneumovirus, a metapneumovirus and the influenza virus. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of the

Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to treat and / or improve one or more symptoms of an infection caused by a virus selected from a henipavirus, a morbillivirus, a respirovirus , a rubulavirus, a pneumovirus, a metapneumovirus, and influenza viruses (such as those described herein).

In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds

194

<img file="MX356509B_D0374.tif" />

• «τητιττο mexican · Di u iNDurritlu PROPERTY of Formula (II), or a pharmaceutically acceptable salt of itself, an effective amount of one or more compounds of the

Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to treat and / or ameliorate a viral upper respiratory infection caused by RSV infection, measles, mumps, parainfluenza infection, metapneumovirus and / or influenza infection. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to treat and / or improve a

195

<img file="MX356509B_D0375.tif" />

Viral lower respiratory tract infection caused by RSV infection, measles, mumps, parainfluenza infection, metapneumovirus, and / or influenza infection.

In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (for example, a compound of Formula (I) a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to treat and / or improve one or more symptoms of an infection caused by RSV infringement, measles, mumps, parainfluenza infection, metapneumovirus and / or influenza infection (such as those described herein).

In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of the

196

MEXICAN INSTITUTE OF THE PPOMfOAtl industMai

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Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to treat and / or improve bronchiolitis and / or tracheobronchitis due to RSV infection, an influenza infection and / or an infection with human parainfluenza virus 3 (HPIV-3). In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to treat and / or improve pneumonia due to RSV infection, infection from influenza and / or a parainfluenza virus infection

197

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Human IMPI 3 (HPIV-3). In certain embodiments, effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an effective amount of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to treat and / or improve croup due to RSV infection, infection influenza and / or an infection with human parainfluenza virus 1 (HPIV-1).

In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of the

Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II)

198

INSTITUTO MtMLCANG at inoKfBA »

INDUSTRIAL and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to treat and / or improve fever, cough, runny nose, red eyes, a generalized rash, pneumonia, an ear infection and / or bronchitis due to measles. In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of the

Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to treat and / or improve inflammation of the salivary glands, fever, loss of appetite and / or fatigue due to mumps.

In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt of the

199

IMPI

Mexican Institute of INDUSTRIAL PROPERTY itself, an effective amount of one or more compounds of Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (for example , a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing) can be used to prevent a viral influenza infection. In certain embodiments, the viral influenza infection may be a viral infection with influenza A. In other embodiments, the viral infection with influenza may be a viral infection with influenza B. In other embodiments, the viral infection with Influenza can be a viral infection with influenza C. In certain embodiments, one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, and / or one or more Compounds of Formula (III), or a pharmaceutically acceptable salt thereof, can be used to treat and / or improve one or more influenza subtypes. For example, one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or

<img file="MX356509B_D0378.tif" />

a salt

200

<img file="MX356509B_D0379.tif" />

more

IMPI

Pharmaceutically acceptable MEXICAN INDUSTRIAL PROPERTY KSTITUTE thereof, and / or one or compounds of Formula (III), or a pharmaceutically acceptable salt thereof, may be used to treat H1N1 and / or

H3N2.

In certain embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, an amount effective of one or more compounds of the

Formula (III), or a pharmaceutically acceptable salt thereof, and / or a pharmaceutical composition including one or more compounds described herein (eg, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the above) can be used to prevent a viral infection by human parainfluenza. In certain embodiments, the human parainfluenza virus infection can be a human parainfluenza virus 1 (HPIV-1). In other embodiments, the human parainfluenza virus infection can be a human parainfluenza virus 2 (HPIV-2). In other embodiments, the human parainfluenza virus infection can be a human parainfluenza virus 3 (HPIV-3). In

201

IMPI ^ B ^)

INSTITUTO MEXICANO other forms of infection ⁰W $$ S? {Ual human parainfluenza can be a paral nfl iipn? Ahumana 4 virus (HPIV-4). In certain embodiments, one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, and / or one or more Compounds of Formula (III), or a pharmaceutically acceptable salt thereof, can be used to treat and / or enhance one or more subtypes of human parainfluenza virus. For example, one or more compounds of the

Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, and / or one or more compounds of Formula (III), or a pharmaceutically acceptable salt Acceptable thereof, they can be used to treat HPIV-1 and / or HPIV-3.

The compound (s) of Formula (I) or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable salt thereof, and / or one or more compounds of Formula (III) , or a pharmaceutically acceptable salt thereof, which can be used to treat, ameliorate and / or prevent a viral infection by paramyxovirus and / or an orthomyxovirus can be a compound of

202

Ρϊ _____ru Jl 1

INSTITUTO MEX (PROPERTY CANO. 0¾¾¾ ^ ¾ ^ ¾ Formula (I), or pharmaceutically acceptable salt '¿J.'éT ^ ttlisrnbT' and / or a compound of Formula (II) ', ¹ A pharmaceutically acceptable salt thereof, and / or a compound of the

Formula (III), or a pharmaceutically acceptable salt thereof, provided in any of the embodiments described in paragraphs [0084] - [0170].

As used herein, the terms "prevent" and "prevent" refer to a subject not contracting an infection by virtue of having immunity against infection, or in case the subject becomes infected, the severity of their disease is less compared to the severity the disease would have had if the subject had not been administered or if the subject had not received the compound. Examples of forms of prevention include prophylactic administration to a subject who has been exposed or may be exposed to an infectious agent, such as a paramyxovirus (eg RSV) and / or an orthomyxovirus (eg influenza).

As used herein, the terms "treat," which treats, treatment, therapeutic / s, and therapy do not necessarily mean a total cure or the suppression of the disease or condition. Any relief from any unwanted signs or symptoms of an illness or

203

<img file="MX356509B_D0380.tif" />

condition, to any degree can be considered a treatment and / or a therapy. Also, treatment may include acts capable of worsening the subject's general feeling of well-being or appearance.

The phrases "therapeutically effective amount" and "effective amount" are used to indicate an amount of an active compound or a pharmaceutical agent, which produces the indicated biological or medicinal response. For example, a therapeutically effective amount of the compound may be the amount necessary to prevent, alleviate, or improve symptoms of the disease or prolong the survival of the subject being treated. This response can take place in a tissue, system, animal, or human and includes relief of the signs or symptoms of the disease being treated.

The determination of an effective amount is fully within the ability of those skilled in the art, in view of the description provided herein. The therapeutically effective amount of the compounds set forth herein required as a dose will depend on the route of administration, the type of animal, including the human being being treated, and the physical characteristics of the specific animal being considered. The dose can be designed in such a way that it achieves a desired effect, but it will depend on

204

<img file="MX356509B_D0381.tif" />

factors such as weight, diet, concurrent medication, and other factors that will be recognized by experts in medical science.

Various indicators for determining the efficacy of a method of treating a viral infection, such as an infection caused by paramyxovirus and / or an orthomyxovirus, are known to those skilled in the art. Examples of suitable indicators include, but are not limited to, a reduction in viral load, a reduction in viral replication, a reduction in time to seroconversion (virus not detectable in patient serum), a reduction in morbidity, or mortality in clinical results and / or another indicator of disease response.

In certain embodiments, an effective amount of a compound of formulas (I), (II) and / or (III), or a pharmaceutically acceptable salt of the foregoing, is an amount that is effective in reducing viral titers. at undetectable levels, for example, at values ​​of between about 1000 and about 5000, and between about 500 and about 1000, or between about 100 and about 500 genomic copies / ml of serum.

In certain embodiments, a quantity

205

<img file="MX356509B_D0382.tif" />

IMPI

Mexican Institute of Industrial Property

<img file="MX356509B_D0383.tif" />

effective amount of a compound of formulas (I), (II) and / or (III), or a pharmaceutically acceptable salt of the foregoing, is an amount that is effective in reducing viral load compared to viral load before administration of the compound of formulas (I), (II) and / or (III), or a pharmaceutically acceptable salt of the foregoing. For example, when viral load is measured before administration of the compound of formulas (I), (II) and / or (III), or a pharmaceutically acceptable salt of the above and once again after completing the regimen therapeutic with the compound of the formulas (I), (II) and / or (III), or a pharmaceutically acceptable salt of the above (eg, week after completion). In certain embodiments, an effective amount of a compound of formulas (I), (II) and / or (III), or a pharmaceutically acceptable salt of the foregoing, may be an amount that is effective in reducing the load. viral to less than about 100 genomic copies / ml of serum. In certain embodiments, an effective amount of a compound of formulas (I), (II) and / or (III), or a pharmaceutically acceptable salt of the foregoing, is an amount that is effective in achieving a reduction in Viral titer in the subject's serum comprised in the approximate range of 1.5-log

206

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<img file="MX356509B_D0385.tif" />

MEXICAN INSTITUTE

FROM INDUSTRIAL PROPERTY up to about 2.5-log reduction, from 3-log to about 4-log reduction or more than about 5-log reduction, compared to viral load before administration of the compound of the formulas (I ), (II) and / or (III), or a pharmaceutically acceptable salt of the foregoing. For example, when the viral load is measured before the administration of the compound of the formulas (I), (II) and / or (III), or a pharmaceutically acceptable salt of the above and once again, after completing the treatment regimen with the compound of the formulas (I), (II) and / or (III), or a pharmaceutically acceptable salt of the above (eg 1 week after completion).

In certain embodiments, a compound of formulas (I), (II) and / or (III), or a pharmaceutically acceptable salt of the above, can result in a reduction of at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75,

100 times or more in the replication of a paramyxovirus and / or an orthomyxovirus, relative to pretreatment levels in a subject, as determined after completion of the therapeutic regimen (eg, 1 week after completion). In certain embodiments, a compound of formulas (I), (II) and / or (III), or a salt

207 pharmaceutically acceptable from what anJe ^^ e ^

MEXICAN INSTITUTE ΖΙ5Ζ

J3E LA HRO '.' IEDaD as a result a reduction of the affliction replio^-a paramyxovirus and / or an orthomyxovirus with reLa &amp; ion at pretreatment levels in the range of about 2 to

<td>approximately</td><td> 5</td><td>times,</td><td>since</td><td>approximately</td><td> 10</td><td>until</td>

<td>approximately</td><td> 20</td><td>times,</td><td>since</td><td>approximately</td><td> 15</td><td>until</td>

<td>approximately</td><td> 40</td><td colspan="2">times or since</td><td>approximately</td><td> 50</td><td>until</td>

about 100 times. In certain embodiments, a compound of formulas (I), (II) and / or (III), or a pharmaceutically acceptable salt of the above, can result in a reduction in the replication of paramyxovirus in the range from 1 to 1.5 log; 1.5 log to 2 log; 2 log to 2.5 log; 2.5 to 3 log; 3 log to 3.5 log or 3.5 to 4 log plus reduction of paramyxovirus replication compared to paramyxovirus reduction that ribavirin (Virazole®) would achieve, or may achieve the same reduction as ribavirin (Virazole®) therapy over a period shorter, for example in one week, two weeks, one month, two months or three months, compared to the reduction achieved after six months of ribavirin (Virazole®) therapy. In certain embodiments, a compound of formulas (I), (II) and / or (III), or a pharmaceutically acceptable salt of the above, can result in a

208

IJ ^ ZL PI

MEXICAN INSTITUTE

DE LA FROFIEDAp * 2reduction of the replication of the orthomyxovirus compürenwidar ^ R - the range from 1 to 1.5 log; 1.5 log to 2 log; 2- log »8.'5 leg, ··^F »'2.5 to 3 log; 3 log to 3.5 log; or 3.5 to 4 log more reduction of orthomyxovirus replication compared to reduction of orthomyxovirus that would be achieved by oseltamivir (Tamiflu®), or may achieve the same reduction as that achieved by therapy with oseltamivir (Tamiflu®) in a shorter period, for example in one week, two weeks, one month, two months or three months, compared to the reduction achieved after six months of therapy with oseltamivir (Tamiflu®).

In certain embodiments, an effective amount of a compound of Formula (I), a compound of Formula

<td colspan="2">(II) and / or a compound of</td><td>the</td><td>Formula</td><td>(III), or a</td><td>Salt</td>

<td>pharmaceutically</td><td>acceptable</td><td>of</td><td colspan="2">the above is</td><td>a</td>

<td>quantity that is</td><td colspan="2">effective for</td><td>achieve</td><td colspan="2">a viral response</td>

<td>sustained by</td><td>example,</td><td>the</td><td>RNA</td><td>not detectable</td><td>or</td>

<td>substantially</td><td colspan="2">not detectable</td><td>of the</td><td>paramyxovirus</td><td>me</td>

<td colspan="2">orthomyxovirus (for example,</td><td colspan="2">smaller than</td><td>approximately</td><td> 500,</td>

less than about 4 00, less than about 200, or less than about 100 genomic copies per milliliter of serum) is found in the subject's serum for a minimum period of approximately one week, two weeks, one month,

209

MEXICAN INSTITUTE OF PROPERTY of at least approximately two months, of at least^ΙΝΙ&amp; Ρ £ * &amp; · me, at least four months api * &lt;55 {lffláfla! TlSrrcS '(1S at least approximately five months or at least approximately six months, after the end of therapy.

After a period, infectious agents can develop resistance to one or more therapeutic agents. The term resistance, as used herein, refers to a viral strain that demonstrates a late, minor, and / or no response to one or more therapeutic agents. For example, after treatment with an antiviral agent, the viral load of a subject infected with a resistant virus may be reduced to a lesser degree, compared to the amount of reduction in viral load exhibited by a subject infected with a non-resistant strain. . In certain embodiments, a compound of Formula (I), a compound of Formula (II), and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing, can be administered to a subject infected with RSV that is resistant to one or more different anti-RSV agents (eg ribavirin). In certain embodiments, the development of RSV resistant strains can be delayed when subjects are treated with a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula

210

MEXICAN INSTITUTE¹ THE PROPERTY * ~

<img file="MX356509B_D0386.tif" />

(III), or a pharmaceutically acceptable salt ^{, r}S ^^TRlAthe above, compared to the development of — the dé'páá cié

RSV resistant to other drugs against RSV. In certain embodiments, a compound of Formula (I), a compound of Formula (II), and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing, can be administered to a subject infected with an influenza virus that is resistant to one or more different anti-influenza agents (eg amantadine and rimantadine). In certain embodiments, the development of resistant strains of influenza may be delayed when subjects are treated with a compound of Formula (I), a compound of Formula (II), and / or a compound of Formula (III) , or a pharmaceutically acceptable salt of the above, compared to the development of influenza strains resistant to other influenza drugs.

In certain embodiments, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing, can reduce the percentage of subjects suffering complications of a viral RSV infection compared to the percentage of subjects suffering a

211

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INDUSTRIAL

<img file="MX356509B_D0387.tif" />

complication being treated with ribavirin. In certain embodiments, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing, can reduce the percentage of subjects experiencing complications from a viral influenza infection, compared to the percentage of subjects experiencing a complication while being treated with oseltamivir. For example, the percentage of subjects being treated with a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing , who suffer complications can be 10%, 25%,

40%, 50%, 60%, 70%, 80%, and 90% lower, compared to subjects who are being treated with ribavirin or oseltamivir.

In certain embodiments, a compound of the

Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition including a compound described herein, can be used in combination with one or more additional agents. In certain embodiments, a compound of Formula (I), a compound of Formula (II), and / or a compound of Formula

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(III), or a pharmaceutically acceptable salt of the foregoing, can be used in combination with one or more agents currently employed to treat RSV. For example, the additional agent may be ribavirin, palivizumab, and RSV-IGIV. For the treatment of RSV, additional agents include, but are not limited to, ALN-RSV01 (Alnilam Pharmaceuticals), BMS-433771 (l-cyclopropyl-3 - [[1- (4-hydroxybutyl) benzimidazol2-yl] methyl] imidazo [ 4.5-c] pyridin-2-one), RFI-641 ((acid

4.4-bis- {4.6-bis- [3- (bis-carbamoylmethyl-sulfamoyl) phenylamino] - (1.3.5) triazin-2-ylamino} -biphenyl-2.2-disulfonic)), RSV604 ((S) -1- ( 2-fluorophenyl) -3- (2-oxo-5phenyl-2.3-dihydro-lH-benzo [e] [1,4] di-azepin-3-yl) -urea), MDT637 ((4Z) -2-methylsulfanil -4 - [(E) -3-thiophene-2-ylprop-2enyliden] -1.3-thiazol-5-one), BTA9881, TMC-353121 (Tibotec),

MBX-300, YM-53403 (N-cyclopropyl-6- [4- [(2phenylbenzoyl) amino] benzoyl] -4.5-dihydrothiene [3.2d] [1] benzazepin-2-carboxamide), motavizumab (Medi-524,

Medlmmune), Medi-559, Medi-534, Medi-557, Medi-557, RV568 and a RSV-F particulate vaccine (Novavax). In certain embodiments, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing, can be used in combination with one or more agents

213

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INSTITUTO MEXICANO DE LA ttOPÍSDAD currently employed to treat influenza. For example, the additional agent may be amantadiñá, ir imantádina, zanamivir and oseltamivir. For the treatment of influenza, additional agents include, but are not limited to, peramivir ((1S, 2S, 3S, 4R) -3 - [(1S) -l-acetamido-2-ethylbutyl] -4- (diaminomethylidenamino) -2 -hydroxycyclopentan-l-carboxylic acid), laninamivir ((4S, 5R, 6R) -5-acetamido-4carbamimidamido-6 - [(IR, 2R) -3-hydroxy-2-methoxypropyl] -5.6dihydro-4H-pyran-2- carboxylic), favipiravir (T-705, 6-fluoro-3-hydroxy-2-pyrazinecarboxamide), enlighten (DAS181,

NexBio), ADS-8902 (Adamas Pharmaceuticals), IFN-b (Synairgen), beraprost (4- [2-hydroxy-l - [(E) -3-hydroxy4-methyloct-l-en-6-ynyl) acid - 2.3.3a, 8b-tetrahydro-lH-cyclopenta [b] [1] benzofuran-5-yl] butanoic), Neugene® and VGX3400X (Inovio).

In certain embodiments, a compound of Formula (I), a compound of Formula (II), and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing, may be administered with one or plus additional agents together in a single pharmaceutical composition. In certain embodiments, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of .34 *

<img file="MX356509B_D0391.tif" />

above, it can be administered with one or more additional agents as two or more separate pharmaceutical compositions. For example, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing, can be administered in a pharmaceutical composition and to the At least one of the additional agents can be administered in a second pharmaceutical composition. If there are at least two additional agents, one or more of the additional agents may be in a first pharmaceutical composition that includes a compound of Formula (I), a compound of the

Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing, and at least one of the other additional agents may be in a second pharmaceutical composition.

The order of administration of a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing, with one or more additional agents may vary.

In certain embodiments, a compound of Formula (I), a compound of Formula (II), and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing, may be administered before all the agents

215

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additional. In other embodiments, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing, may be administered prior to minus one additional agent. In still other embodiments, a compound of Formula (I), a compound of Formula (II), and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing, may be administered concomitantly with one or more additional agents. In still other embodiments, a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing, can be administered after the administration of at least one additional agent. In certain embodiments, a compound of Formula (I), a compound of Formula (II), and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing, may be administered subsequent to all additional agents.

A potential advantage of using a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing, in combination with one or more agents

216 iVÍ i * '¿

MEXICAN INSTITUTE Ά '· Λ -— DE LA PROPIEDAD V'ií, —S »·.

INDUSTRIAL

r.:.·

Gí>

Further described in paragraph [0221], even the pharmaceutically acceptable salts and prodrugs thereof, may be a reduction in the or the required amounts of one or more compounds of paragraph [0221] (including the pharmaceutically acceptable salts and prodrugs of the same) that are effective in the treatment of a pathological condition disclosed herein (eg RSV and / or influenza), compared to the amount required to achieve the same therapeutic result when one or more compounds described in paragraph [0221], including the pharmaceutically acceptable salts thereof and prodrugs, are administered without a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing. For example, the amount of a compound described in paragraph [0221], including a pharmaceutically acceptable salt and prodrug thereof, may be less, compared to the amount of the compound described in paragraph [0221], even a pharmaceutically salt acceptable and prodrug of it, necessary to achieve the same reduction in viral load when administered as monotherapy. Another potential advantage of using a compound of the Formula (I), a compound of the Formula (II) and / or a compound of the

217

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<img file="MX356509B_D0394.tif" />

MEXICAN INSTITUTE OF LA PRORIBDAD

INDUSTRY!.

Formula (III), or a pharmaceutically acceptable salt of the foregoing, in combination with one or more additional agents described in paragraph [0221], including the pharmaceutically acceptable salts and prodrugs thereof, resides in the use of two or more compounds that have different mechanisms of action can create a stronger barrier against the development of resistant viral strains, compared to the barrier achieved when a compound is administered as monotherapy.

The additional advantages of using a compound from the

Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing, in combination with one or more additional agents described in paragraph [0221] , even the pharmaceutically acceptable salts and prodrugs thereof, may include little or no cross resistance, between a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III) , or a pharmaceutically acceptable salt of the foregoing and one or more additional agents described in paragraph [0221] (including the pharmaceutically acceptable salts and prodrugs thereof); different routes for the elimination of a compound of Formula (I), a compound of Formula (II) and / or a

218

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Composed of Formula (III), or a pharmaceutically-inactive salt _tacceptable from the foregoing and one or more additional agents described in paragraph [0221] (including pharmaceutically acceptable salts and prodrugs thereof); little or no toxicity overlap between a compound of Formula (I), a compound of Formula (II) and / or a compound of Formula (III), or a pharmaceutically acceptable salt of the foregoing and one or more agents additional described in paragraph [0221] (including pharmaceutically acceptable salts and prodrugs thereof); little or no significant effect on cytochrome P450; and / or few or no pharmacokinetic interactions between a compound of Formula (I), or a pharmaceutically acceptable salt thereof and one or more additional agents described in paragraph [0221], including the pharmaceutically acceptable salts and prodrugs thereof) .

As will be readily understood by one skilled in the art, the live dosage to be administered and the particular mode of administration will vary depending on the age, weight, severity of the affliction and the species of the mammal being treated, the particular compounds employed. and the specific use for which these compounds are used.

Determination of effective dosage levels is

219

IM

<img file="MX356509B_D0396.tif" />

ra _v.

INSTITUTO MEXICANO DE LA PROPERTY CVINDUSTRIAL say, the dosage levels necessary to achieve the desired result, can be achieved by the person skilled in the art using routine methods, for example, human clinical trials and in vitro studies.

The dosage can vary widely, depending on the desired effects and the therapeutic indication. Alternatively, dosages can be based and calculated on the patient's surface area, as understood by those skilled in the art. Although the exact dosage will be determined on a drug-by-drug basis, in most cases, certain generalizations regarding dosage can be made. The daily dosage regimen for a human adult patient may be, for example, an oral dose of between 0.01 mg and 3000 mg of each active ingredient, preferably between 1 mg and 700 mg, for example, between 5 and 200 mg. The dosage may consist of a single dose or a series of two or more, administered over the course of one or more days, depending on the needs of the subject. In certain embodiments, the compounds will be administered over a period of continuous therapy, for example, for a week or more, or for months or years.

In cases where human dosages have been established for the compounds, for at least

220

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a certain condition, it is possible to use^- the —myomadosages, or dosages ranging from about 0.1% to 500%, most preferably from about 25% to 250% of the established dosage for humans. When there is no established dosage for humans, as will be the case for the newly discovered pharmaceutical compositions, a dosage suitable for humans can be inferred from the values

ED₅₀ or ID₅₀, or other appropriate values ​​derived from in vitro or in vivo studies, as qualified in toxicity studies and efficacy studies in animals.

In the cases of administration of a pharmaceutically acceptable salt, the dosages can be calculated as the free base. As will be understood by those skilled in the art, in certain situations, it may be necessary to administer the compounds disclosed herein in amounts exceeding, or even greatly exceeding, the above preferred dosage range, to treat effective and aggressive, particularly aggressive diseases or infections.

The amount and dosing interval can be individually adjusted to provide plasma levels of the active fraction that are sufficient to maintain

221

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ΙΜΡΪ

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY modulating effects or the minimum effective concentration (MEC). The MEC will vary for each compound, but can be calculated from the data in vi tro. The dosages necessary to achieve MEC will depend on the individual characteristics and the route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage ranges can also be determined using the MEC value. The compositions should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably between 30 and 90%, and more preferably between 50 and 90%. In cases of local administration or selective absorption, the effective local concentration of the drug may not be related to the plasma concentration.

Importantly, the treating physician would know how and when to terminate, discontinue, or adjust administration due to toxicity or organ dysfunction. Conversely, the treating physician would also know how to adjust treatment to higher levels if the clinical response was not adequate (exclude toxicity). The magnitude of an administered dose in the management of the disorder of interest will vary.

<img file="MX356509B_D0399.tif" />

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IM3TITIJTQ MEXICANO DE LA PXOHSOAD

INLU5TÍIAL with the severity of the condition to be treated ^^ _ the route of administration. The severity of the condition, for example, can be assessed, in part, by standard prognostic assessment methods. Furthermore, the dose and perhaps the frequency of the dose will also vary according to the age, body weight and individual patient response. It is possible to use a program comparable to that discussed above in veterinary medicine.

The compounds described herein can be evaluated to determine their efficacy and toxicity, applying the known methods. For example, the toxicology of a particular compound, or of a subset of the compounds that share certain chemical fractions, can be established by determining toxicity in vitro towards a cell line, such as, a cell line of a mammal and, preferably, of a human being. Often, the results of such studies are predictive of toxicity in animals, such as mammals, or more specifically, in humans.

Alternatively, the toxicity of particular compounds in the animal model, such as mice, rats, rabbits, or monkeys, can be determined using known methods. The efficacy of a particular compound can be established using various recognized methods, such as the methods in

223

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<td>vitro,</td><td>animal models</td><td>or the</td><td>clinical trials</td><td>in</td>

<td>humans.</td><td>When selecting a</td><td>model</td><td>to determine</td><td>the</td>

<td>effectiveness</td><td>, the expert can</td><td>guide</td><td>by the state of</td><td>the</td>

<td>technique</td><td>current to choose a</td><td>model,</td><td>one dose, one way</td><td>of</td>

appropriate administration and / or regimen.

EXAMPLES

<td>In</td><td>the</td><td>following</td><td>examples,</td><td>are presented</td><td>shapes</td><td>of</td>

<td colspan="2">realization</td><td>additional</td><td>with more</td><td>detail, the</td><td>which</td><td>of</td>

<td>no</td><td colspan="2">mode pretend</td><td>limit</td><td>the reaching</td><td>of</td><td>the</td>

claims.

EXAMPLE 1

Preparation of the compound

HO

NH,

NHMMTr &lt;^Z 'n

HO F P1-1

HO

MMTrO F P1-2

<img file="MX356509B_D0401.tif" />

P1-3

NHMMTr

NHMMTr

NH,

MMTrO HO MMTrO F P1-4

MMTrOA ^ Oy^N^ o

MMTrO F P1-5

HO)

HO F 1a

Preparation of (Pl-2): To an ice cold solution of Pl-1 (10.0 g, 40.8 mmol) in dry pyridine (100 ml) TBSC1 in pyridine (1M, 53 ml) was added dropwise, at temperature

224

IM F!

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<img file="MX356509B_D0402.tif" />

environment (RT, room tempera ture). The reaction mixture was stirred at RT for 16 hours. The reaction mixture was then quenched with water and concentrated to obtain a residue. The residue was separated by ethyl acetate (EA) and saturated in an aqueous NaHCO solution₃. The organic phase was dried and concentrated. The residue was purified on a silica gel column (5% MeOH in DCM), to obtain a crude 5'-O-TBS protected intermediate as a white solid (13.4g, 91%). The intermediate was dissolved in anhydrous DCM (100 ml) and sim-collidine (17.9 g, 149.2 mmol), AgNO were added₃ (25g, 149.2mmol) and MMTrCl (45g, 149.2mmol). The mixture was stirred at RT for 16 hours.

The mixture was quenched with water and the organic layer was separated and concentrated. The residue was purified on a column of silica gel (30% PE in EA), to obtain the crude product. The crude product was dissolved in 1M TBAF (50 ml) in THF. The mixture was stirred at RT, for 2 hours. The solvent was removed and the residue was purified on a column of silica gel (50% PE in EA), to obtain Pl-2 as a white solid (21.4 g, 66% for three steps).

Preparation of (Pl-3): To a solution of pyridine (521 mg, 6.59 mmol) in anhydrous DMSO (5 ml), TFA (636 mg, 5.58 mmol) was added, dropwise, at 10 ° C under nitrogen atmosphere. The

IMPI

<img file="MX356509B_D0403.tif" />

225 Reaction mixture was stirred until the solution became clear. The solution was then incorporated into a mixture of Pl-2 (4.0 g, 5.07 mmol) and DCC (3.86 g, 18.76 mmol) in anhydrous DMSO (18 ml) at RT under a nitrogen atmosphere. The reaction mixture was stirred at 30 ° C overnight. Water (80 ml) was added to the mixture, diluted with EtOAc (100 ml) and filtered. The filtrate was extracted with DCM (100 ml x 6). The organic layer was washed with NaHCO₃ saturated aqueous, dried in Na₂SW₄ and concentrated in a vacuum. The residue was purified on a silica gel column, eluted with 1% MeOH in DCM, to obtain the intermediate (3.5 g, 87.7%) as a yellow solid. The intermediate (3.5g, 4.45mmol) was dissolved in dioxane (25ml) and aqueous HCHO (668mg, 22.25mmol) was added to RT then 2N NaOH (4.5ml, 8.9mmol) was added. The reaction mixture was stirred at 30 ° C overnight). NaBH added₄ (593 mg, 15.6 mmol portionwise, at 5 ° C and the mixture was stirred at

RT, for 15 minutes. The reaction was quenched with water and the mixture was extracted with EtOAc (100 ml x 3). The organic layer was dried in Na₂SW₄ and concentrated in a vacuum. The residue was purified on a silica gel column, eluted with 1% MeOH in

DCM, to obtain Pl-3 as a yellow solid (2.5 g, 67%).

³Η NMR (CDC1₃, 400 MHz) δ 6.82-7.50 (m, 29H), 5.40 (d, J =

23.2 Hz, 1H), 4.99 (d, J = 7.6 Hz, 1H), 4.46 (dd, J₂ = 6.0

226 nWTlTUTO MEXICANO d »the property

INDUSTRIAL

<td>Hz,</td><td> =</td><td> 54.4</td><td>Hz,</td><td>1H), 3.94</td><td>(dd,</td><td>Jl</td>

<td>1 HOUR)</td><td> , 3.78</td><td>(s,</td><td>6H),</td><td> 3.42-3.69</td><td>(m,</td><td>2H)</td>

<td>(m,</td><td>1 HOUR) .</td><td></td><td></td><td></td><td></td><td></td>

: 4.4 Hgy »- ^ 12.4 HZ7

2.71-3.05 (m, 2H), 2.45

Preparation of (Pl-4): To an ice cold solution of Pl-3 (4.0 g, 4.9 mmol) in dry pyridine (20 ml), TBSC1 was added dropwise, in pyridine (1M, 5.88 ml). The reaction mixture was stirred at RT, for 16 hours. The reaction mixture was then quenched with water, concentrated to obtain a residue. The residue was separated in EA and saturated in

NaHCO₃ aqueous. The organic layer was separated and dried, and then concentrated. The residue was purified on a column of silica gel (1% MeOH in DCM), to obtain the intermediate as a yellow solid (3.2 g, 70%).¹H NMR (CDC1₃, 400 MHz) δ 7.53-6.83 (m, 29H), 5.51 (d, J = 21.2 Hz, 1H), 4.98 (d, J =

7.6 Hz, 1H), 4.67 (dd, Ji = 5.6 Hz, J₂ = 22.4 Hz, 1H), 4.22 (dd, J₂ = 5.6 Hz, J₂ = 53.2 Hz, 1H), 4.07 (m, 1H), 3.89 (m,

1H), 3.80 (s, 6H), 3.70-3.67 (m, 1H), 3.03-2.98 (m, 1H), 2.26 (m, 1H), 0.93 (s, 9H), 0.10 (s, 6H).

The obtained intermediate was dissolved in anhydrous DCM (20 ml) and collidine (360 mg, 3 mmol) and AgNO were added₃ (500 mg, 3 mmol) and MMTrCl (606 mg, 2 mmol). The mixture was stirred at RT, for 16 hours. The reaction mixture was quenched with water and the organic layer was separated and concentrated. The residue is

227

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<img file="MX356509B_D0405.tif" />

• «UTUTO MEXICANO DELA PROPIEDAD

INDUSTRIAL purified on a column of silica gel (0.5% MeOH in DCM), to obtain the fully processed intermediate as a yellow solid (3.3 g, 80%). The intermediate was dissolved in 1M TBAF, in THF (5 ml) and stirred at RT, for 2 hours. The solution was concentrated and the residue was purified on a silica gel column (1% MeOH in DCM), to obtain a mixture of Pl-3 and Pl-4, which was separated by separation by HPLC (MeCN and HCOOH 0.1% in water), to obtain Pl-4 as a white solid (1.5 g, 25%).

Preparation of (Pl-5): Pl-4 (1.5g, 1.22mmol) was suspended in anhydrous DCM (50ml) and Dess Martin periodinan (1.2g, 2.73mmol) was added at 0 ° C. The reaction mixture was stirred at RT, for 3 hours. The reaction mixture was then quenched with Na₂S₂OR₃ saturated aqueous and Na₂CO₃. The organic layer was separated and dried and then concentrated, to obtain the aldehyde intermediate as a white solid.

A ClCH solution₂PPh₃Br (2.19 g, 5.6 mmol) in anhydrous THF (4 0 ml) was cooled to -78 ° C. N-BuLi (2.5 M, 2.3 mi) added by drip. After adding, the mixture was stirred at 0 ° C for 2 hours. Then a solution of the aldehyde in anhydrous THF (10 ml) was incorporated. The mixture was stirred at RT, for 16 hours. The reaction was quenched with NH₄Aqueous C1 saturated and extracted by EA. The organic layer is

<img file="MX356509B_D0406.tif" />

228

<img file="MX356509B_D0407.tif" />

separated, dried and concentrated. The residue was dried on a silica gel column (1% MeOH in DCM), to obtain the intermediate as a yellow solid (1.1 g, 73%). To a solution of the intermediate (1.1 g, 0.98 mmol) in anhydrous THF (40 ml) was added n-BuLi (2.5M, 6 ml) -78 ° C drip. The mixture was stirred at -78 ° C for 5 hours and then quenched with a NH solution₄C1 saturated aqueous. The mixture was extracted with EA. The organic layer was separated, dried, and concentrated.

The residue was purified on a silica gel column (2% MeOH in DCM), to obtain Pl-5 as a yellow solid (910 mg, 86%).

Preparation of (la): Pl-5 (910 mg, 0.84 mmol) was suspended in CH₃80% COOH (50 ml) and the reaction mixture was stirred at 40 ° C for 15 hours. Solvents were evaporated and the residue was co-evaporated with toluene, to remove traces of acid and water. The residue was purified by HPLC separation (MeCN and 0.1% HCOOH in water), to obtain the pure compound la as a white solid (101 mg, 45%).^XH NMR (MeOD, 400 MHz) δ 7.90 (d, J = 7.2 Hz, 1H), 6.04 (d, J = 19.6

<td>Hz, 1H), 5.87</td><td>(d, J = 7.6 Hz, 1H)</td><td> , 5.00</td><td>(dd,</td><td>= 5.2 Hz, J₂ =</td>

<td>53.6 Hz, 1H),</td><td>4.47 (dd, J₂ = 5.2</td><td>Hz, J₂</td><td> = 22.8</td><td>Hz, 1H), 3.86</td>

<td>(d, J = 12.4</td><td>Hz, 1H), 3.73 (d,</td><td>J = 12</td><td>.4 Hz,</td><td>1H), 3.08 (s,</td>

1 HOUR); ESI-TOF-MS: m / z 270.09 [Μ + H]⁺, 539.17 [2M + H]⁺.

229

<img file="MX356509B_D0408.tif" />

EXAMPLE 2

Preparation of compound (2a) l

<img file="MX356509B_D0409.tif" />

NH₂

1st

<img file="MX356509B_D0410.tif" />

HO F

2nd

NH₂

To a stirred solution of compound la (50mg, 0.186mmol) in anhydrous THF (3ml), a solution of t-BuMgCl (0.37ml, 1M in THF) was added dropwise at -78 ° C. The mixture was then stirred at 0 ° C for 30 minutes and cooled back to -78 ° C.

A solution of phenyl (isopropoxy-L-alaninyl) f osf hydrochloride (104 mg, 0.4 mmol) in THF (0.5 ml) was added dropwise. After addition, the mixture was stirred at

25 ° C for 16 hours. The reaction was quenched with HCOOH (80% aq) at 0 ° C. The solvent was removed and the residue was purified on silica gel (DCM: MeOH = 50: 1 to 10: 1), to obtain compound 2a as a white solid (a mixture of two P isomers, 8.0 mg, 7.9%) .^ΧΗ NMR (MeOD, 400 MHz) δ 7.71, 7.68 (2d, J = 7.6 Hz, 1H), 7.17-7.37 (m, 5H), 6.02, 6.00 (2d, J =

20.4 Hz, 1H), 5.90, 5.86 (2d, J = 7.6 Hz, 1H), 5.03-5.18 (m,

1H), 4.91-4.99 (m, 1H), 4.45-4.55 (m, 1H), 4.34-4.43 (m, 1H),

4.26-4.33 (m, 1H), 3.87-3.95 (m, 1H), 3.25, 3.22 (2s, 1H), 1.29-1.34 (m, 3H), 1.20-1.22 (m, 6H). ³¹P NMR (MeOD, 162 MHz)

230 jL

MEXICAN INSTITUTE OF INDUSTRIAL RRORIEDAD

<img file="MX356509B_D0411.tif" />

&lt;5 3.44, 3.27, ESI-LCMS: m / z 539.0 [Μ + H] ⁺.

ΆΤΕΜΒΙλΟ 3

Preparation of compound (3a)

<img file="MX356509B_D0412.tif" />

slH

TBSÓ F

<img file="MX356509B_D0413.tif" />

<img file="MX356509B_D0414.tif" />

<img file="MX356509B_D0415.tif" />

P3-5

<img file="MX356509B_D0416.tif" />

<img file="MX356509B_D0417.tif" />

TBDPSO

NHo

P3-6

<img file="MX356509B_D0418.tif" />

TBSÓ F

P3-7 P3-8 3a

Preparation of (P3-2): To a solution of P3-1 (100.0 g,

406.5 mmol) in pyridine (750 ml) DMTrCl (164.9 g,

487.8 mmol). The solution was stirred at RT, for 15 hours.

MeOH (300 ml) was added and the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc and washed with water. The organic layer was dried in Na₂SW₄ and concentrated.

The residue was dissolved in DCM (500 ml). Imidazole (44.3 g, 650.4 mmol) and TBSC1 (91.9 g, 609.8 mmol) were added. The reaction mixture was stirred at RT, for 14 hours. The solution of

231 . ΪΜΡΙ0>

• MEXICAN ISTITUTE. OF THE V &amp; PROPERTY. · Industrial reaction washed with NaHCO₃ and brine. Organic lid dried on Na₂S0₄ and concentrated to obtain the crude product as a light yellow solid. The crude product (236.4 g,

356.6 mmol) was dissolved in an 80% aqueous solution of HOAc (500 ml). The mixture was stirred at RT, for 15 hours. The mixture was diluted with EtOAc and washed with a solution of

NaHCO₃ and brine. The organic layer was dried in Na₂SW₄ and purified by silica gel column chromatography (2% 1MeOH in DCM), to obtain P3-2 (131.2 g, 89.6%) as a light yellow solid. ¹H NMR (DMSO-d6 400 MHz) δ 11.39 (s,

1H), 7.88 (d, J = 7.2 Hz, 1H), 5.89 (dd, J₂ = 18.0 Hz, J₂ =

2.0 Hz, 1H), 5.64 (d, J = 8.0 Hz, 1H), 5.21 (dd, J₂ = J₂ = 7.2

Ηζ, ΙΗ), 5.18-5.03 (m, 1H), 4.37-4.29 (m, 1H), 3.86 (dd, J₂ =

J₂ = 3.2 Hz, 3H), 3.78-3.73 (m, 1H), 3.51-3.56 (m, 1H), 3.31 (S, 1H), 0.89 (S, 9H), 0.11 (s, 6H); ESI-MS: m / z 802 [M +

H]⁺.

Preparation of (P3-3): To a solution of P3-2 (131.2 g,

364.0 mmol) in CH₃Anhydrous CN (1200 ml) IBX (121.2 g, 432.8 mmol) was added at RT The reaction mixture was refluxed for 3 hours and then warmed to 0 ° C. The precipitate was filtered and the filtrate was concentrated, to obtain the crude aldehyde (121.3 g) as a yellow solid.

The aldehyde was dissolved in 1,4-dioxane (1000 ml). I know

232

<img file="MX356509B_D0419.tif" />

added CH₂Or 37% (81.1 ml, 1.3536 mol) and a 2M NaOH aqueous solution (253.8 ml, 507.6 mmol). The mixture was stirred at

RT, for 2 hours and then neutralized with AcOH to pH = 7. EtOH (400 ml) and NaBH were added to the solution₄ (51.2 g, 1,354 mol). The mixture was stirred at RT, for 30 minutes.

The mixture was quenched with NH₄Aqueous C1 saturated and extracted with EA. The organic layer was dried in Na₂SW₄ and concentrated. The residue was purified by silica gel column chromatography (1-3% MeOH in DCM), to obtain P3-3 (51.4 g,

38.9%) as a white solid.

Preparation of (P3-4): To a solution of P3-3 (51.4 g,

131.6 mmol) in anhydrous DCM (400 ml), pyridine (80 ml) and DMTrCl (49.1 g, 144.7 mmol) were added at 0 ° C. The reaction was stirred at RT for 14 hours and then treated with MeOH (30 ml). The solvent was removed and the residue was purified by column chromatography with silica gel (1-3% MeOH in

DCM), to obtain a mono-DMTr protected intermediate as a yellow foam (57.4 g, 62.9%). To the intermediate (57.4 g, 82.8 mmol) in CH₂C1₂ (400 ml) imidazole (8.4 g, 124.2 mmol) and TBDPSC1 (34.1 g, 124.2 mmol) were added. The mixture was stirred at RT, for 14 hours. The precipitate was filtered off and the filtrate was washed with brine and dried over Na₂SW₄, The solvent was removed to obtain the residue (72.45

233

<img file="MX356509B_D0420.tif" />

g) as a white solid. The solid was dissolved in an 80% aqueous solution of HOAc (400 ml). The mixture was stirred at RT, for 15 hours. The mixture was diluted with EtOAc and washed with a NaHCO solution₃ and brine. The organic layer was dried in Na₂SW₄ and purified by silica gel column chromatography (2% 1-MeOH in DCM), to obtain P3-4 (37.6 g, 84.2%), as a white solid. ^XH NMR (CD₃OD, 400

MHz) δ 7.76 (d, J = 4.0 Hz, 1H), 7.70 (dd, = 1.6 Hz, J₂ =

8.0 Hz, 2H), 7.66-7.64 (m, 2H), 7.48-7.37 (m, 6H), 6.12 (dd,

Chi = 2.8 Hz, J₂ = 16.8 Hz, 1H), 5.22 (d, J = 8.0 Hz,

1H) .5.20-5.05 (m, 1H), 4.74 (dd, = 5.6 Hz, J₂ = 17.6 Hz,

1H), 4.16 (d, J = 12.0 Hz, 1H), 3.87-3.80 (m, 2H), 3.56 (d, J = 12.0 Hz, 1H), 1.16 (s, 9H), 0.92 (s, 9H), 0.14 (s, 6H).

Preparation of (P3-5); To a solution of P3-4 (11.8 g,

18.8 mmol) in anhydrous DCM (100 ml) periodinan was added

Dess-Martin (16.3 g, 37.6 mmol) at 0 ° C under a nitrogen atmosphere. The reaction was stirred at RT, for 2.5 hours. Water (100 ml) was added and the mixture was then filtered. The filtrate was washed with NaHCO₃ saturated aqueous and concentrated.

The crude residue was purified by column chromatography on silica gel (20% EtOAc in hexane), to obtain P3-5 as a white solid (10.1 g, 86.0%).

Preparation of (P3-6): To a mixture of bromide of

234

<img file="MX356509B_D0421.tif" />

methyltriphenylphosphonium (15.7 g, 48.5 mmol) in anhydrous THF (100 ml) n-BuLi (19.4 ml, 48.48 mmol) was added at -78 ° C under nitrogen atmosphere. The reaction was stirred at 0 ° C for 30 minutes. A solution of P3-5 (10.1 g, 16.2 mmol) in anhydrous THF (70 ml) was added dropwise, at 0 ° C under a nitrogen atmosphere. The reaction was stirred at RT, for 1.5 hours. The reaction was quenched by NH₄C1 and extracted with EtOAc. The crude product was purified by column chromatography with silica gel (20% EtOAc in hexane), to obtain P3-6 as a white solid (8.3 g, 82.2%). ^ NMR (CDC1₃, 400 MHz) δ 8.16

<td>(s,</td><td>1 HOUR) ,</td><td> 8.81</td><td>(d.</td><td>J = 8.0 Hz, i:</td><td>H), 7.58-7.67 (m,</td><td>4H), 7.37-</td>

<td> 7.46</td><td>(m,</td><td>6H),</td><td> 6.17</td><td>(d, J = 16.0</td><td>Hz, 1H), 5.91 (dd,</td><td>Jj = 10.8</td>

<td>Hz,</td><td>J₂ =</td><td> 17.6</td><td>Hz,</td><td>1H), 5.42 (d,</td><td>J = 17.6 Hz, 1H),</td><td> 5.22-5.30</td>

<td>(m,</td><td>2H),</td><td> 4.60-</td><td> 4.84</td><td>(m, 2H), 3.69</td><td>(dd, J₂ = 11.6 Hz,</td><td>J₂ = 21.2</td>

<td>Hz,</td><td>2H),</td><td> 1.10</td><td>(s,</td><td>9H), 0.91 (s,</td><td>1H), 0.12 (d, J</td><td>= 8.0 Hz,</td>

6H).

Preparation of (P3-7): To a solution of P3-6 (6.3 g,

10.09 mmol) in CH₃Anhydrous CN (50 ml) TPSC1 (6.1 g, 20.2 mmol), DMAP (2.5 g, 20.2 mmol) and NEt were added₃ (3 ml) at RT The reaction was stirred at RT, for 2 hours. NH added₄OH (25 ml) and the reaction was stirred for 1 hour. The mixture was diluted with DCM (150 ml) and washed with water, 0.1 M HC1 and NaHCO₃ saturated aqueous. The solvent was removed and the product

235

<img file="MX356509B_D0422.tif" />

Crude was purified by chromatography on colTIííSlá '' Cóñ yel de silica (2% MeOH in DCM), to obtain P3-7 as a yellow solid (5.9 g, 93.6%).

Preparation of (P3-8): To a solution of P3-7 (5.9 g, 9.5 mmol) in MeOH (10 ml) Pd / C (1.5 g) was added to RT The reaction was stirred at RT, for 2 hours under H₂ (ball). The mixture was filtered and the filtrate was concentrated in vacuo, to obtain P3-8 as a white solid (5.4 g, 91.3%).

Preparation of (3a): To a solution of P3-8 (5.4 g, 8.6 mmol) in MeOH (60 ml) NH was added₄F (10.0 g) and the reaction mixture was refluxed overnight. After cooling to RT, the mixture was filtered and the filtrate was concentrated. The crude product was purified by column chromatography with silica gel (10% MeOH in DCM), to obtain compound 3a as a white solid (1.6 g, 67.8%).¹H NMR (CD₃OD, 400 Μ Hz) δ 8.08 (d, J = 7.6 Hz, 1H), 6.07 (dd, =

3.2 Hz, J₂ = 15.6 Hz, 1H), 5.88 (d, J = 7.2 Hz, 1H), 5.04 (ddd, J₂ = 3.2 Hz, J₂ = 5.2 Hz, J₃ = 54.0 Hz, 1H), 4.45 (dd,

J₂ = 5.2 Hz, J₂ = 17.2 Hz, 1H), 3.76 (d, J = 12.0 Hz, 1H), 3.57 (d, J = 12.0 Hz, 1H), 1.78-1.85 (m, 1H), 1.58-1.67 (m, 1H),

0.95 (t, J = 7.6 Hz, 3H); ESI-MS: m / z 274 [M + H]⁺, 547 [2M +

H]⁺.

236

<img file="MX356509B_D0423.tif" />

EXAMPLE 4

Preparation of compound (4a)

TBDPSO

<img file="MX356509B_D0424.tif" />

TBSÓ F

P3-7

NH₂ ° v^NTO _.

<img file="MX356509B_D0425.tif" />

h &lt;5 f

4th

NH

NH was added to a solution of P3-7 (28 0 mg, 0.4 5 mmol) in MeOH (10 ml)₄F (1.0 g) at RT The reaction mixture was refluxed for 5 hours. After cooling to RT, the mixture was filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (10% MeOH in DCM), to obtain compound 4a as a white solid (82mg, 67.2% 1.6g, 67.8%).^TH NMR (CD₃OD,

400 Μ Hz) δ 8.11 (d, J = 7.6 Hz, 1H), 5.99-6.08 (m, 2H), 5.88 (d, J = 7.6 Hz, 1H), 5.47 (dd, J_T = 1.2 Hz, J₂ = 17.2 Hz, 1H),

5.26 (dd, Chi = 1.6 Hz, J₂ = 11.2 Hz, 1H), 4.97 (d, J = 5.2 Hz,

0.5H), 4.82 (d, J = 7.6 Hz, 0.5H), 4.52 (dd, Ji = 5.2 Hz, J₂ =

23.2 Hz, 1H), 3.65 (d, J = 12.4 Hz, 1H), 3.54 (d, J = 12.4 Hz,

1 HOUR) ; ESI-MS: m / z 272 [M + H]⁺, 543 [2M + H]⁺.

<img file="MX356509B_D0426.tif" />

237

EXAMPLE 5

Preparation of compound (5a)

<img file="MX356509B_D0427.tif" />

NH

HO

<img file="MX356509B_D0428.tif" />

5th

Htí F ⁰

Preparation of (P5-1): To a solution of P3-6 (600 mg,

0.96 mmol) in MeOH (30 ml) 10% Pd / C (320 mg) was added to RT The mixture was shaken in an H balloon₂ at RT, for 3 hours. The reaction mixture was filtered and the filtrate was concentrated to obtain P5-1 (540 mg, 89.8%) as a colorless solid. The crude product was used directly for the next step without purification.

Preparation of (5a): To a solution of P5-1 (54 0 mg,

0.86 mmol) in MeOH (8 ml) NH was added₄F (1.2 g, 32.4 mmol)

RT The mixture was refluxed for 30 hours. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel column chromatography (2.5% -9% MeOH in DCM), to obtain compound 5a (190 mg, 80.6%) as a colorless solid.¹H NMR (CD₃OD, 400

<td>MHz)</td><td>δ 8.05 (d, J</td><td> = 8.0</td><td>Hz, 1H)</td><td>, 6.09 (dd,</td><td> =4 .</td><td>0 Hz</td><td>, J₂</td>

<td> = 14.8</td><td>Hz, 1H), 5.04</td><td> -5.20</td><td>(m, 1H),</td><td>4.42 (dd, Chi =</td><td> 5.2</td><td>Hz,</td><td>J₂ =</td>

<td> 13.6</td><td>Hz, 1H), 3.71</td><td>(d, J</td><td> = 11.6</td><td>Hz, 1H), 3.57</td><td>(d,</td><td>J =</td><td> 12.0</td>

238

Ηζ, 1Η), 1.61-1.82 (m

<img file="MX356509B_D0429.tif" />

. from the PRiiFieDaij

INDUSTRIAL

J = 7.2 Ηζ, 3H).

2Η), O .94 (t,

EXAMPLE 6

Preparation of compound (6a)

<img file="MX356509B_D0430.tif" />

TBSÓ F TBSÓ F HÓ F

<td rowspan="2"></td><td colspan="2">P3-3</td><td colspan="2">P6-1</td><td colspan="2">6th</td>

<td>Preparation of (P6-1)</td><td>: TO</td><td>a</td><td>solution of</td><td>P3-3 (800</td><td>mg,</td>

<td> 2.05</td><td>mmol) in anhydrous DCM</td><td> (15</td><td>me)</td><td>were added</td><td>imidazole</td><td> (558</td>

<td colspan="2">mg, 8.2 mmol), TBSC1 (1.2</td><td> 9/</td><td> 8.2</td><td>mmol) and AgNO₃</td><td>(700 mg,</td><td> 4.1</td>

<td>mmol)</td><td>to RT The mix of</td><td colspan="2">reaction</td><td>R stirred,</td><td colspan="2">.T. during the</td>

night. The mixture was filtered and the filtrate was washed with brine and concentrated in vacuo. The residue was purified by column chromatography on silica gel, to obtain P6-1 as a white solid (950 mg, 79.2%).

Preparation of (6a): To a solution of P6-1 (600 mg,

0.97 mmol) in CH₃Anhydrous CN (18 ml) added DMAP (239 mg, 2.91 mmol), NEt₃ (294 mg, 2.91 mmol) and TPSC1 (879 mg, 2.91 mmol) at RT The reaction was stirred at RT, for 1 hour. NH added₄OH (9 ml) and the reaction was stirred for 3 hours.

The mixture was diluted with EtOAc (200 ml) and washed with water,

0.1 M HC1 and NaHCO₃ saturated aqueous. The organic layer was separated, dried and concentrated, to obtain a residue

<img file="MX356509B_D0431.tif" />

239 ί · '

<img file="MX356509B_D0432.tif" />

raw. The crude residue was purified by a silica gel column column to obtain the product as a white solid (500 mg, 83.3%). The solid was treated with NH4F (1.0 g) in MeOH (20 ml) at reflux temperature for 5 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (5% lMeOH in DCM), to obtain compound 6a as a white solid (132 mg, 59.3%).. NMR (DMSO-CI6, 400

MHz) δ 7.89 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 18.8 Hz, 2H),

6.09 (dd, J₂ = 4.4 Hz, J₂ = 14.8 Hz, 1H), 5.73 (d, J = 5.2 Hz,

<td>1H), 5.52</td><td>(d,</td><td>J =</td><td> 5.6</td><td>Hz,</td><td>1H), 5.12</td><td>(t, J = 4.8 Hz,</td><td>1 HOUR) ,</td>

<td> 4.90-5.06</td><td>(m,</td><td>1 HOUR) ,</td><td> 4.50</td><td>(t,</td><td>J = 6.0</td><td>Hz, 1H), 4.27-4.33</td><td>(m.</td>

<td>1H), 3.66</td><td>(dd.</td><td>Chi =</td><td> 5.2</td><td>Hz,</td><td>J₂ = 12.0</td><td>Hz, 1H), 3.47-3.58</td><td>(m,</td>

3H); ESI-MS: m / z 276 [Μ + H]⁺, 551 [2M + H]⁺.

240

EXAMPLE 7

Preparation of compound (7a)

TBDPSO

<img file="MX356509B_D0433.tif" />

HOTBSÓ F

P3-4

TBDPSO

OR

<img file="MX356509B_D0434.tif" />

ClTBSÓ F P7-1

NH₂ nh₄F

M

HO

Cl-

<img file="MX356509B_D0435.tif" />

HÓ F 7a

<img file="MX356509B_D0436.tif" />

TBDPSO ci-

<img file="MX356509B_D0437.tif" />

OR

N

TBSO F P7-2,^NH2

Preparation of (P7-1): To a mixture of P3-4 (1.60 g, 2.5 mmol), PPh₃ (1.3 g, 5.0 mmol) and CC1₄ (0.76g, 5.0mmol) in DCE (20ml) heated to 130 ° C with microwave irradiation, under N₂ for 40 minutes. After cooling to RT, the solvent was removed and the residue was purified on a silica gel column (PE / EA = 50/1 to 10/1), to obtain P7-1 (1.1 g, 68.8%) as a white solid.

Preparation of (P7-2): P7-1 (0.80 g, 1.3 mmol), DMAP (0.3 g, 2.6 mmol), TPSC1 (0.8 g, 2.6 mmol) and Et₃N (0.3g, 2.6mmol) were dissolved in MeCN (30ml). The mixture was stirred at

RT, for 14 hours. NH₃ in THF (saturated at 0 ° C, 100 ml) was added to the mixture, and the mixture was stirred at RT, for 2 hours. The solvent was removed and the residue was purified by column (DCM / MeOH = 100: 1 to 50: 1), to obtain P7-2 (0.63 g,

241

<img file="MX356509B_D0438.tif" />

78.8%) as a white solid.

Preparation of (7a): To a solution of P7-2 (0.63 g, 0.98 mmol) in MeOH (10 ml) NH was added₄F (0.3 g) and the reaction was refluxed for 12 hours. The reaction was cooled to RT and the precipitate was filtered off.

The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (10% MeOH in DCM), to obtain compound 7a as a white solid (153 mg,

53.5%). ³H NMR (CD₃OD, 400 M Hz) ¿8.05 (d, J = 7.2 Hz, 1H),

6.14 (dd, = 3.6 Hz, J₂ = 15.2 Hz, 1H), 5.92 (d, J = 7.2 Hz,

1H), 5.15 (ddd, &lt;J₇ = 4.0 Hz, J₂ = 5.2 Hz, J₃ = 53.6 Hz, 1H),

4.57 (dd, J₂ = 4.8 Hz, J₂ = 15.2 Hz, 1H), 3.93 (d, J = 11.6

Hz, 1H), 3.75-3.84 (m, 3H); ESI-MS: m / z 294 [Μ + H]⁺, 587 [2M + H]⁺.

EXAMPLE 8

Preparation of compound (8a)

<img file="MX356509B_D0439.tif" />

P7-1

<img file="MX356509B_D0440.tif" />

8a

NH was added to a solution of P7-1 (63 0 mg, 0.5 mmol) in MeOH (10 ml)₄F (0.1 g) and the reaction was refluxed for 12 hours. The mixture was filtered and the filtrate was

242

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY concentrated in a vacuum. The crude product was purified by column chromatography on silica gel (10% MeOH in DCM), to obtain compound 8a as a white solid (153 mg,

53.5%). ^bH NMR (CD₃OD, 400 Μ Hz) δ 7.99 (d, J = 8.0 Hz, 1H),

6.17 (dd, Chi = 4.4 Hz, J₂ = 14.4 Hz, 1H), 5.70 (d, J = 8.0 Hz,

1H), 5.22 (ddd, «Λ = J₂ = 4.8 Hz, J₃ = 53.2 Hz, 1H), 4.55 (dd,

Chi = 5.2 Hz, J₂ = 12.4 Hz, 1H), 3.88 (d, J = 12.0 Hz, 1H),

3.76-3.79 (m, 3H); Negative ESI-MS: m / z 293 [Μ - H] '.

EXAMPLE 9

<img file="MX356509B_D0441.tif" />

Preparation of compound (9a)

TBDPSO HO TBSO F

P3-4

TBDPSO

I

TBSO F

P9-1

NH₉ nh₉

TBDPSO

0./¼

HO

0./¼

TBDPSO

A ((NH

0./¼

OR

TBSO F P9-2

TBSO F

P9-3

HO F 9a

Preparation of (P9-1): A mixture of P3-4 (3.2 g, 5.0 mmol), Ph₃P (5.2g, 20mmol), iodine (2.60g, 10.2mmol) and imidazole (1.4g, 20mmol) in anhydrous THF (40ml) were stirred at 80 ° C for 14 hours. The reaction was cooled to RT and quenched with Na₂S₂OR₃ saturated aqueous. The solution was extracted with EA. The organic layer was dried in Na₂SW₄ and concentrated. The residue is

243

<img file="MX356509B_D0442.tif" />

Purified by column chromatography on silica gel (2050% EA in PE), to obtain P9-1 (1.6 g, 68.2%) as a white solid.

Preparation of (P9-2): A mixture of P9-1 (1.4 g, 0.2 mmol), Et₃N (40mg, 0.4mmol) and Pd / C in EtOH (20ml) were stirred at RT under H₂ (ball) during the night. The precipitate was filtered off and the filtrate was concentrated. The residue was purified on a silica gel column (20% -50% EtOAc in PE), to obtain P9-2 as a white solid (1.1 g, 78%).

³Η NMR (CDC1₃, 400 MHz) δ 8.11 (br s, 1H), 7.76 (d, J = 8.0

<td>Hz,</td><td>1H), 7.39-7.67 (m,</td><td>10H),</td><td> 6.18</td><td>(dd, Jí</td><td>= 3.2 Hz,</td><td>J₂ = 14.4</td>

<td>Hz,</td><td>1H), 5.26-5.30 (m,</td><td>1 HOUR) ,</td><td> 4.86</td><td>(m, 1H),</td><td>4.42 (dd,</td><td>Jl = 5.2</td>

<td>Hz,</td><td>J₂ = 15.2 Hz, 1H),</td><td> 3.81</td><td>(d, J</td><td> = 11.2</td><td>Hz, 1H), 3</td><td>.58 (d, J</td>

= 11.2 Hz, 1H), 1.16 (S, 3H), 1.11 (s, 9H), 0.91 (s, 9H),

0.13 (s, 3H), 0.08 (s, 3H).

Preparation of (P9-3): P9-2 (650 mg, 1.1 mmol), DMAP (270 mg, 2.2 mmol), TPSCl (664 mg, 2.2 mol) and Et₃N (222 mg, 2.2 mmol) were dissolved in MeCN (20 ml). The mixture was stirred at RT, for 14 hours. NH reaction was added₃ in THF (saturated at 0 ° C) and the mixture was stirred at RT, for 2 hours. The solvent was removed and the residue was purified on a silica gel column (1-10% MeOH in DCM), to obtain P9-3 (430 mg, crude) as a light yellow syrup.

244

<img file="MX356509B_D0443.tif" />

Preparation of (9a): A mixture of P9-3 (430 mg, 0.7.

mmol) and NH₄F (97 mg, 2.1mmol) in MeOH (10 ml) was refluxed for 14 hours. The solvent was removed and the residue was purified on a silica gel column (5% -10% MeOH in DCM), to obtain compound 9a as a white solid (64.8 mg, 35.4%).³Η NMR (CD₃OD, 400 MHz) δ 8.10 (d, J = 7.6

Hz, 1H), 6.03 (dd, J₂ = 2.0 Hz, J₂ = 16.8 Hz, 1H), 5.87 (d, J = 7.6 Hz, 1H), 4.98 (m, 1H), 4.37 (dd, J₂ = 5.2 Hz, J₂ = 21.6

Hz, 1H), 3.59 (dd, J₂ = 12.0 Hz, J₂ = 28.4 Hz, 2H), 1.23 (d, J = 0.8 Hz, 3H).

EXAMPLE 10

Preparation of compound (10a)

<img file="MX356509B_D0444.tif" />

<img file="MX356509B_D0445.tif" />

P9-2 10a

To a stirred solution of P9-2 (400 mg, 0.65 mmol) in

MeOH (20 mi) NH was added₄F (52mg, 1.5mmol). The mixture was refluxed overnight. The solvent was removed and the residue was purified on a silica gel column (5-10% MeOH in DCM), to obtain compound 10a (140 mg, 82.4%) as a white solid.^XH NMR (CD₃OD, 400 MHz) δ 8.05 (d, J =

8.4 Hz, 1H), 6.06 (dd, J₂ = 2.8 Hz, J₂ = 16.4 Hz, 1H), 5.67 (d

245

INSTITUTO MÉXlCAKO ORLA PROPERTY

INDUSTRIAL

<td>, J = 8.0 Hz,</td><td>1 HOUR) ,</td><td> 5.08</td><td>(m, 1H), 4.37</td>

<td>18.8 Hz, 1H),</td><td> 3.59</td><td>(dd,</td><td>Chi = 12.0 Hz, J₂</td>

<td colspan="2">(S, 3H). ESI-TOF-MS</td><td>: m / z</td><td>283 [M + Na] ⁺.</td>

<td></td><td></td><td></td><td>EXAMPLE 11</td>

Preparation of compound (lia)

TBDPSO

OR

NH

Of / 1 TBDPSO

HO rr ° Kh

TBSO F P3-S

TBSO

<img file="MX356509B_D0446.tif" />

<img file="MX356509B_D0447.tif" />

TBSO F P11-2

Preparation of (Pll-1): To a solution of P3-5 (2.1 g,

3.5 mmol) in anhydrous THF (25 ml) ethynylmagnesium bromide (5.1 mmol) was added at -78 ° C. The reaction was stirred at 0 ° C for 3 hours. The reaction was quenched with NH₄C1 saturated aqueous (10 mi). The mixture was diluted with EtOAc (200 ml) and washed with water and brine. The organic layer was dried and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluting with DCM: MeOH = 60: 1), to obtain Pll-1 as a white solid (870 mg, 83.3%).

Preparation of (Pll-2): Pll-1 (870 mg, 1.34 mmol) is

246

WSTITUTO MEXICANO DE LA PROPERTY

INDUSTRIAL

<img file="MX356509B_D0448.tif" />

Dissolved in anhydrous DCM (12 ml), and methyl chloroformate (2.3 ml) and pyridine (2.5 ml) were added at RT. The reaction mixture was stirred at RT, for 1 hour. The mixture was diluted with DCM and washed with NaHCO₃ saturated aqueous. The organic layer was separated, dried, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluting with PE: EtOAc = 8: 1), to obtain a crude product as a white solid (830 mg,

88.4%). To a mixture of Pd₂(dba)₃ (55 mg, 0.06 mmol) in anhydrous DMF (12 ml) P (nBu) was added₃ (35 mg, 0.17 mmol) and

HCOONH4 (108 mg, 1.7 mmol) at RT under a nitrogen atmosphere.

The reaction mixture was stirred at RT, for 30 min. A solution of the crude product (830 mg, 1.16 mmol) in anhydrous DMF (16 ml) was added and the reaction mixture was stirred at 70 ° C for 3 hours. The reaction was diluted with EtOAc and washed with brine. The organic layer was separated, dried, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluting with PE:

EtOAc = 9: 1), to obtain Pll-2 as a white solid (510 mg, 67.6%).¹HNMR (CD₃OD, 400 MHz) δ 7.61-7.75 (m, 5H), 7,367.47 (m, 6H), 6.04 (d, J = 18.8 Hz, 1H), 5.34 (t, J = 6.8 Hz,

1H), 5.21 (dd, Ji = 1.2 Hz, J₂ = 7.2 Hz, 1H), 5.10 (q, =

5.2 Hz, J₂ = 53.6 Hz, 1H), 4.80-4.92 (m, 1H), 4.59-4.79 (m,

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MEXICAN INSTITUTE OF PROPERTY

INDUSTBIAl

<img file="MX356509B_D0449.tif" />

2Η),

1.09

6Η).

3.86 (d, J = (s, 9H), 0.92

12.0 Hz, 1H), 3.75 (d, J = 4.4 Hz, 9H), (d,

J =

12.0 HZ, 1H),

0.15 (t, J = 4.0 Hz,

Preparation of (Pll-3): To a solution of Pll-2 (490 mg,

0.77 mmol) in anhydrous MeCN (15 ml) TPSC1 (700 mg, 2.31 mmol), DMAP (282 mg, 2.31 mmol) and TEA (234 mg, 2.31 mmol) were added to RT The reaction mixture was stirred at room temperature for 1 hour. Then NH was added₄OH (8 ml) and the reaction mixture was stirred for another 4 hours. The mixture was diluted with EtOAc and washed with water, 1.0M aqueous HC1 and NaHCO₃ saturated aqueous. The organic layer was separated and dried, concentrated to obtain the residue which was purified by HPLC separation (MeCN and 0.1% HCOOH in water), to obtain Pll-3 as a white solid (190 mg, 38.8%).¹H NMR

<td>(CD₃OD, 400 MHz) δ 7.88</td><td>(d,</td><td>J = 7.2 Hz, 1H), 7.63-7.70 (m,</td>

<td>4H), 7.37-7.48 (m, 6H),</td><td> 6.12</td><td>(d, J = 18.4 Hz, 1H), 5.49 (d, J</td>

<td>= 7.6 Hz, 1H), 5.34 (t,</td><td>J =</td><td>6.8 Hz, 1H), 4.84-5.01 (m, 2H),</td>

<td>4.66-4.78 (m, 2H), 3.89</td><td>(d,</td><td>J = 11.6 Hz, 1H), 3.75 (d, J =</td>

<td>11.6 Hz, 1H), 1.10 (s,</td><td>9H),</td><td>0.91 (d, J = 3.2 Hz, 9H), 0.13</td>

(t, J = 5.2 Hz, 6H).

Preparation of (lia): To a solution of Pll-3 (13 0 mg,

0.21 mmol) in MeOH (8 ml) NH was added₄F (1 g) and the reaction mixture was refluxed for 6 hours. The mixture is

248

IMPI

<img file="MX356509B_D0450.tif" />

Filtered and the filtrate was concentrated in vacuo. Residued 85 'purified by silica gel column chromatography (eluting with DCM: MeOH = 13: 1), to obtain compound lia as a white solid (47mg, 79.1%).¹H NMR (CD₃OD, 400 MHz) δ 8.07 (d, J = 7.6 Hz, 1H), 6.05 (dd, = 1.2 Hz, J₂ = 16.8 Hz,

1H), 5.86 (d, J = 7.6 Hz, 1H), 5.40 (dd, J₂ = J₂ = 6.8 Hz,

1H), 4.87-4.99 (m, 3H), 4.46-4.80 (m, 1H), 3.75 (d, J = 12.4

Hz, 1H), 3.68 (d, J = 12.4 Hz, 1H); ESI-MS: m / z 284.02 [M +

H] ⁺, 567.08 [2M + H] ⁺ .

EXAMPLE 12

Preparation of compound (12a)

<img file="MX356509B_D0451.tif" />

P3-4

TBDPSO

<img file="MX356509B_D0452.tif" />

TBDPSO

<img file="MX356509B_D0453.tif" />

NH₂ —- έ

OF 12a

Preparation of (P12-1): To a solution of P3-4 (500 mg,

0.8 mmol) in anhydrous toluene (12 ml) DAST (0.3 ml, 2 mmol) was added at -65 ° C under a nitrogen atmosphere. The reaction mixture was stirred at RT, for 2 hours. The reaction was quenched with NaHCO₃ saturated aqueous and extracted with EtOAc. The

<img file="MX356509B_D0454.tif" />

249 Organic layer was separated, dried and concentrated, to oht-pngr the residue. The residue was purified by column chromatography on silica gel (eluting with PE: EtOAc = 9: 1), to obtain P12-1 as a yellow solid (170 mg, 42.5%).

¹H NMR (CD₃OD, 400 MHz) δ 7.66 (dd, J₂ = 1.6 Hz, J₂ = 18.0 Hz,

<td>4H), 7.54</td><td>(d, J = 7.6 Hz, 1H), 7.35-7.47 (m, 6H), 6.59</td><td>(dd,</td>

<td>J₂ = 5.6</td><td>Hz, J₂ = 14.0 Hz, 1H), 5.78 (d, J = 7.6 Hz,</td><td>1 HOUR) ,</td>

<td> 5.05-5.24</td><td>(m, 2H), 4.93 (d, J = 7.6 Hz, 1H), 4.57 (d, J</td><td> = 7.6</td>

Hz, 1H), 3.93-4.00 (m, 2H), 1.07 (d, J = 2.4 Hz, 9H).

Preparation of (P12-2): To a solution of P12-1 (100 mg,

0.2 mmol) in anhydrous MeCN (5 ml) TPSC1 (182 mg, 0.6 mmol), DMAP (68 mg, 0.6 mmol) and TEA (61 mg, 0.6 mmol) were added to RT under nitrogen atmosphere. The reaction mixture was stirred at RT, for 1 hour. NH added₄OH (3ml) and the reaction was stirred for 2 hours. The mixture was diluted with

EtOAc and washed with water, 1.0 M HC1 and NaHCO₃ saturated aqueous.

The organic layer was separated, dried, and concentrated to obtain a residue. The residue was purified by column chromatography on silica gel (DCM: MeOH = 50: 1), to obtain

P12-2 as a yellow solid (96mg, 96%).

Preparation of (12a): To a solution of P12-2 (96 mg,

0.2 mmol) in MeOH (5 ml) NH was added₄F (500 mg) at RT The reaction was refluxed for 3 hours. The mixture is

250

<img file="MX356509B_D0455.tif" />

Filtered and the residue was purified by RP HPLC (MeCN and 0.1% HCOOH in water), to obtain compound 12a as a white solid (25mg, 48.7%). ^XH NMR (CD₃OD, 400 MHz) &lt;5 7.85 (d, J =

<td> 7.6</td><td>Hz,</td><td>1H), 6.59</td><td>(dd, Chi = 5.2</td><td>Hz,</td><td>J₂ = 12.8 Hz, 1H),</td><td> 6.04</td>

<td>(d,</td><td>J =</td><td>7.6 Hz,</td><td>1H), 5.10-5.26</td><td>(m,</td><td>2H), 4.79-4.90 (m,</td><td>1 HOUR) ,</td>

<td> 4.57</td><td>(d,</td><td>J = 7.6</td><td>Hz, 1H), 3.82</td><td>(d,</td><td>J = 12.4 Hz, 1H),</td><td> 3.76</td>

<td>(dd,</td><td>Hee</td><td>= 1.6 Hz,</td><td>J₂ = 12.4 Hz,</td><td>1 HOUR) ;</td><td>ESI-MS: m / z 257.9</td><td>[M +</td>

H]⁺, 514.8 [2M + H]⁺.

EXAMPLE 13

Preparation of compound (13a)

NH,

Ηο-χφ, Μθ _

HO F 3a

NHMMTr

N

Saw -

MMTrÓ F P13-1

<img file="MX356509B_D0456.tif" />

Preparation of (P13-1): To a solution of compound 3a (700 mg, 2.56 mmol) in anhydrous pyridine (5 ml) were added

<td>TBDPSC1 (2.8 g,</td><td> 10.24</td><td>mmol), imidazole (522 mg,</td><td>7.68 mmol)</td><td>and</td>

<td>AgNO₃ (870 mg,</td><td> 5.12</td><td>mmol) at RT under N₂.</td><td>Mix</td><td>of</td>

<td colspan="2">reaction stirred at</td><td>RT, for 3 hours.</td><td>Mix</td><td>I know</td>

<td>diluted with MeOH</td><td>and</td><td colspan="2">filter. The mixture was concentrated and</td><td>the</td>

residue was purified by gel column chromatography from

251

<img file="MX356509B_D0457.tif" />

silica (eluting with DCM: MeOH = 80: 1 ~ 40: 1), to obtain the crude intermediate as a yellow solid (1.05 g,

80.8%).^xH NMR (DMSO-do, 400 MHz) δ 7.75 (d, J = 7.6 Hz, 1H),

7.61-7.65 (m, 4H), 7.41-7.50 (m, 7H), 6.02 (dd, J₂ = 2.8 Hz,

J₂ = 17.2 Hz, 1H), 5.69 (d, J = 6.0 Hz, 1H), 5.56 (d, J = 7.6

Hz, 1H), 4.96-5.11 (m, 1H), 4.37-4.46 (m, 1H), 3.82 (d, J =

10.8 Hz, 1H), 3.62 (d, J = 10.8 Hz, 1H), 1.70-1.78 (m, 1H),

1.53-1.59 (m, 1H), 1.02 (s, 9H), 0.79 (t, J = 7.6 Hz, 3H). To a solution of the crude intermediate (1.0 g, 1.96 mmol) in

Anhydrous DCM (15 ml) sim-collidine (1.4 g, 11.76 mmol), AgNO was added₃ (1.0 g, 5.88 mmol) and MMTrCl (4.8 g, 15.6 mmol) at RT, under N₂. The reaction mixture was stirred at RT overnight. The mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with PE: EtOAc = 2: 1), to obtain crude complete protected intermediates as a white solid (1.1 g, 53.1%). To a solution of the crude intermediate (600 mg, 0.57 mmol) in THF (5 ml) was added TBAF (446 mg, 1.71 mmol)) at RT The reaction was stirred at 40 ~ 50 ° C overnight. The crude product was purified by column chromatography on silica gel, eluted with PE: EtOAc = 3: 2 to obtain crude P13-1 (350 mg, 75.1%) as a yellow solid.

Preparation of (13a): To a solution of P13-1 (300 mg,

252

<img file="MX356509B_D0458.tif" />

0.37 mmol) in CH₃CN (2.5 ml) NMI (2.5 ml) and a solution of phenyl (isopropoxy-L-alaninyl) phosphorochloride were added

<td>(2.55 g,</td><td>7.4 mmol)</td><td>in</td><td>CH₃CN</td><td> (2</td><td> .5</td><td>mi) to RT,</td><td>low N₂,</td><td>The</td>

<td>mix of</td><td>reaction</td><td>I know</td><td>waved</td><td>to</td><td>R.</td><td>T., during</td><td>3 hours.</td><td>The</td>

<td>mix it</td><td>concentrated</td><td>to the</td><td>empty</td><td> •</td><td>The</td><td>waste is</td><td>purified</td><td>by</td>

column chromatography on silica gel (PE: EtOAc = 1: 1), to obtain the crude product as a yellow oil (500 mg, 81%). The crude product was re-treated with HCOOH at

80% (70 mi) at RT overnight. The mixture was concentrated in vacuo and the crude product was purified by RP HPLC (MeCN and 0.1% HCOOH in water), to obtain compound 13a as a white solid (a mixture of two P isomers, 86 mg, 40.3% two steps ), 'ή NMR (CD₃OD, 400 MHz) δ 7.75, 7.71 (2d, J = 7.6 Hz,

1H), 7.33-7.38 (m, 2H), 7.19-7.26 (m, 3H), 6.02-6.10 (m, 1H),

5.87, 5.82 (2d, J = 7.6 Hz, 1H), 4.99-5.02 (m, 0.5H), 4.724.82 (m, 1.5H), 4.14-4.43 (m, 3H), 3.89-3.94 (m, 1H ), 1,681.81 (m, 6H), 1.51-1.56 (m, 1H), 1.30-1.43 (m, 8H), 0.96-1.01 (m, 3H); ESI-MS: m / z 582.93 [M + H]⁺.

253

<img file="MX356509B_D0459.tif" />

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EXAMPLE 14

Preparation of compound (14a)

NHMMTr

<img file="MX356509B_D0460.tif" />

MMTrO F P13-1

MMTrÓ F

P14-1

NHMMTr

<img file="MX356509B_D0461.tif" />

HÓ F 14a nh₂

Preparation of (P14-1): To a stirred solution of P13-1 (451 mg, 0.55 mmol) and NMI (1 ml) in anhydrous acetonitrile (2 ml), a solution of 2-chloro-8-methyl was added dropwise -4Hbenzo [d] [1,3,2] dioxaphosphinine (855 mg, 4.2 mmol) in acetonitrile (0.2 ml) at 0 ° C under N ₂, The mixture was stirred at

RT, for 2 hours. Added a solution of I₂ (3.2 g,

12.6 mmol), pyridine (9 ml), H₂Or (3 mi) and DCM (3 mi). The reaction mixture was stirred for 30 minutes. The reaction was quenched with NaS solution₂OR₃ and EA was extracted. The organic layer was dried in Na₂SW₄ and concentrated. The residue was purified by a column on silica gel (PE: EA = 1: 1 to 1: 2), to obtain P14-1 (205 mg, 37%) as a white solid.

Preparation of (14a): P14-1 (205 mg, 0.21) was dissolved

254

<img file="MX356509B_D0462.tif" />

mmol) in an aqueous solution stirred at RT, for 16 hours.

The residue was purified by RP HPLC compound 14a as a mixture of 2 P-isomers (24 mg,

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

80% HCOOH and the mixture is

The solvent was removed and the (HCOOH system), to obtain

<td> 18%) . ^XH NMR (CD₃OD, 400 MHz) δ</td><td> 7.60,</td><td> 7.53</td><td>(2d,</td><td>J = 8.0 Hz,</td>

<td>1H), 7.21-7.25 (m, 1H), 7.02-7.</td><td>12 (m,</td><td>2H),</td><td> 5.95</td><td>, 5.87 (2dd,</td>

<td>&lt;J₂ = 2.4 Hz, J₂ = 18.0 Hz, 1H),</td><td> 5.71,</td><td> 5.69</td><td>(2d,</td><td>J = 8.0 Hz,</td>

1H), 5.38-5.53 (m, 2H), 5.06, 5.04 (2ddd, &lt;J₂ = 2.4 Hz, J₂ =

5.6 Hz, J₃ = 54.0 Hz, 1H), 4.32-4.49 (m, 2H), 2.26 (d, J =

3.6 Hz, 3H), 1.83-1.92 (m, 1H), 1.64-1.72 (m, 1H), 0.96, 0.93 (2t, J = 7.6 Hz, 3H). ³¹P NMR (CD₃OD, 162 MHz) δ -8.22, -8.50;

ESI-LCMS: m / z 456 [M + H]⁺.

EXAMPLE 15

Preparation of compound (15a)

<img file="MX356509B_D0463.tif" />

(2.2 g, 2.5 mmol), AgNO₃ (844 mg, 5.0 mmol) and collidine (907 mg, 7.5 mmol) in anhydrous DCM (10 ml) MMTrCl (1.54 g, 5.0 mmol) was added under N ₂. The reaction mixture was stirred at RT

255

IMPI

<img file="MX356509B_D0464.tif" />

overnight. The reaction mixture was filtered through a Büchner funnel. The filtrate was washed with NaHCO solution₃ saturated and brine. The organic layer was separated, dried in Na₂SW₄ anhydrous and filtered. The filtrate was concentrated to dryness. The residue was purified by a column on silica gel (PE: EA = 10: 1 to 1: 2), to obtain the intermediate (2.3 g, 84%), which was dissolved in a solution of TBAF in THF (1M, 2.6 mi) under N₂. The reaction mixture was stirred at RT overnight. The residue was dissolved in EA (200 ml) and washed with water and brine. The organic layer was separated, dried in Na₂SW₄

<td>anhydrous and</td><td>I know</td><td>filter. Filtering is</td><td>concentrated until dry and</td>

<td>the residue</td><td>I know</td><td>purified by column in</td><td>silica gel (DCM / MeOH</td>

<td>= 100: 1 a</td><td> 30:</td><td>1), to get P15-1,</td><td>like a white foam</td>

<td>(1.3 g, 94</td><td> %) </td><td></td><td></td>

Preparation of (15a): A proton sponge (235 mg, 1.1 mmol) in anhydrous MeCN (9 ml) with a solution of

POC1₃ (169 mg, 1.1 mmol) in MeCN (1 ml) with a syringe at 0 ° C. The mixture was stirred at RT, for 40 minutes. A mixture of (S) -cyclohexyl 2aminopropanoate hydrochloride (525 mg, 2.55 mmol) and TEA (0.1 ml) was added at 0 ° C. The mixture was heated to RT and stirred for 3 hours. The reaction mixture was quenched with NaHCO₃ saturated and extracted

256

<img file="MX356509B_D0465.tif" />

with EA (100 ml x 2). Organic Layers Dried in Na₂S0₄They were concentrated purified by a column of silica gel (1 ~ 4% MeOH in DCM), to obtain the crude product (400 mg, 78.15%) as a yellow solid. The crude product was treated with 80% HCOOH (50 ml) at RT, for 16 hours. The solvent was removed and the residue was purified by RP HPLC to obtain compound 15a as a white solid (40 mg, 14%).³H NMR (MeOD, 400 MHz) δ 7.82 (d, J = 7.6 Hz, 1H),

6.09 (dd, J₂ = 2.8 Hz, J₂ = 14.0 Ηζ, ΙΗ), 5.98 (d, J = 7.6 Hz,

1H), 5.04 (ddd, J₂ = 3.2 Hz, J₂ = 5.6 Hz, J₃ = 53.6 Hz, 1H),

4.71-4.77 (m, 2H), 4.45 (dd, J₂ = 5.6 Hz, J₂ = 12.4 Hz, 1H),

4.14-4.18 (m, 1H), 3.97-4.01 (m, 1H), 3.84-3.92 (m, 2H),

1.31-1.87 (m, 28H), 0.99 (t, J = 7.2 Hz, 3H). ³¹P NMR (CD₃OD,

162 MHz) δ 13.94; ESI-LCMS: m / z 660 [M + H]⁺.

EXAMPLE 16

Preparation of compound (16a)

<img file="MX356509B_D0466.tif" />

NH₂

16a

4th

To a stirred solution of compound 4a (150mg, 0.56mmol) in anhydrous THF (3ml) was added dropwise a solution of t-BuMgCl (1.2ml, 1M in THF) at -78 ° C. The mixture was stirred at

257

IMPI

MEXICAN INSTITUTE OF PROPERTY ° C for 30 minutes and cooled again to '^Nn-7 ^ C.

phenyl hydrochloride solution (isopropoxy-L-alaninyl) -

<img file="MX356509B_D0467.tif" />

Phosphorous (312 mg, 1.2 mmol) in THF (1.0 ml) was added dropwise. After addition, the mixture was stirred at 25 ° C for 16 hours. The reaction was quenched with HCOOH (80% aq) at 0 ° C. The solvent was removed and the residue was purified on silica gel (DCM: MeOH = 50: 1 to 10: 1), to obtain compound 16a as a white solid (24.0 mg,

15%) / H NMR (MeOD, 400 MHz) ¿7.76 (d, J = 7.2 Ηζ, 1H), 7.177.38 (m, 5H), 6.01-6.08 (m, 2H), 5.81 (d, J = 7.6 Ηζ, 1H),

<td> 5.54-5.58</td><td>(m,</td><td>1H), 5.35-5.38</td><td>(m,</td><td>1H), 4.92-4.97</td><td>(m,</td><td>2H),</td>

<td> 4.45-4.52</td><td>(m,</td><td>1H), 4.08-4.19</td><td>(m,</td><td>2H), 3.88-3.92</td><td>(m,</td><td>1 HOUR) ,</td>

<td> 1.28-1.33</td><td>(m,</td><td>3H), 1.20-1.22 (m,</td><td>6H)</td><td> ; ³¹P NMR (CD₃OD,</td><td> 162</td><td>MHz)</td>

δ 7.36; ESI-LCMS: m / z 541.0 [M + H]⁺.

EXAMPLE 17

Preparation of compound (17a)

<img file="MX356509B_D0468.tif" />

17a

258

<img file="MX356509B_D0469.tif" />

Preparation of (P17-1): To a solution of P3-7 (1.4 g,

2.3 mmol) in MeOH (50 ml) NH was added₄F (8.0 g) at RT The reaction mixture was refluxed overnight.

After cooling to RT, the mixture was filtered and the filtrate was concentrated. The crude product was purified by column chromatography with silica gel (10% MeOH in DCM), to obtain

P17-1 as a white solid (410mg, 77.8%).

Preparation of (P17): To a stirred solution of P17-1 (60 mg, 0.19 mmol) in anhydrous THF (3 ml), a solution of t-BuMgCl (0.38 ml, 1M in THF) was added dropwise at -78 ° C. The mixture was stirred at 0 ° C for 30 minutes and cooled back to -78 ° C. A solution of phenyl (isopropoxy-L-alaninyl) phosphorous hydrochloride (104mg, 0.4mmol) in THF (0.5ml) was added dropwise. After addition, the mixture was stirred at 25 ° C for 16 hours. The reaction was quenched with HCOOH (80% aq.) At 0 ° C. The solvent was removed and the residue was purified on silica gel (DCM: MeOH = 50: 1 to 10: 1), to obtain compound 17a as a white solid (a mixture of two P isomers, 11.0 mg, 11%) . ¹H NMR (MeOD,

400 MHz) δ 7.71 (2d, J = 8.0 Hz, 1H), 7.17-7.37 (m, 5H),

5.98-6.07 (m, 2H), 5.61.5.68 (2d, J = 8.0 Hz, 1H), 5.53-5.58 (m, 1H), 5.35-5.40 (m, 1H), 5.08-5.10 (m, 1H), 4.93-4.99 (m,

1H), 4.52-4.53 (m, 1H), 4.16-4.21 (m, 1H), 4.06-4.11 (m, 1H),

259

<img file="MX356509B_D0470.tif" />

IMPI usTrnrro mexicana / 2DE LA FROFBDAD &lt;* · INDUSTRIAL

3.86-3.94 (τη, 1H), 1.28-1.34 (m, 3H), 1.20-1.22 (m, 6H). ³¹

NMR (MeOD, 162 MHz) δ 3.72, 3.45, ESI-LCMS: m / z 542.0 [M +

H]⁺.

EXAMPLE 18

Preparation of compound (18a)

TBDPSO

TBDPSO

CF

X

NH

OR_X,^N^ o TBDPSO'AO_s>^n_^ ^ \ J

TBSO 'F

P18-2

TBSO F

P3-5

TBSO F

P18-1

<img file="MX356509B_D0471.tif" />

(Chloromethyl) triphenylphosphonium (2.1g, 6.0mmol) in anhydrous THF (10ml) n-BuLi (4.6ml, 6.0mmol) was added dropwise at -70 ° C under a nitrogen atmosphere. The reaction was stirred at -70 ° C for 50 minutes. A solution of compound P3-9 (950 mg,

1.5 mmol) in anhydrous THF (5 ml) was added at -70 ° C and the reaction was stirred at 0 ° C for 3 hours. The reaction was quenched by NH₄Aqueous C1 saturated and extracted with EtOAc. The organic layer was separated, dried, and concentrated to obtain a residue. The residue was purified by chromatography on

<img file="MX356509B_D0472.tif" />

260 silica gel column (eluting with PE: EtOAc = 6: 1), to * obtain P18-1 as a yellow gum (900 mg, 91.2%).

[Preparation of (P18-2): To a solution of compound P18-1 (600 mg, 0.91 mmol) in anhydrous THF (18 ml) nBuLi was added dropwise (4.7 ml, 10.9 mmol) at -70 ° C in atmosphere nitrogen. The reaction was stirred at -70 ° C for 3 hours. The reaction was quenched by NH₄Aqueous C1 saturated and extracted with EtOAc. The organic layer was separated, dried, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluting with PE: EtOAc = 8: 1-5: 1), to obtain P18-2 as a white solid (300 mg, 53.0%).

Preparation of (P18-3): To a solution of P18-2 (300 mg, 0.44 mmol) in MeOH (10 ml) NH was added₄F (1.0 g) at RT The reaction was refluxed for 3 hours. After cooling to RT, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with DCM: MeOH 50: 1-30: 1), to obtain P18-3 as a white solid (135 mg,

78.1%) ¾ NMR (CD₃OD, 400 MHz) δ 7.84 (d, J = 8.0 Hz, 1H),

6.06 (dd, J₂ = 1.6 Hz, J₂ = 19.6 Hz, 1H), 5.67 (d, J = 8.4 Hz,

1H), 5.18-5.03 (m, 1H), 4.50 (dd, J₂ = 5.2 Hz, J₂ = 21.6 Hz,

1H), 3.85 (d, J = 12.4 Hz, 1H), 3.72 (d, J =

12.4 Hz, 1H),

261

<img file="MX356509B_D0473.tif" />

3.09 (s, 1H).

Preparation of (18a): To a solution of P18-3 (130 mg,

0.5 mmol) in anhydrous THF (4 ml) t-BuMgCl was added dropwise (1.0 ml, 1.0 mmol) at -70 ° C under a nitrogen atmosphere. The reaction was stirred at RT, for 30 minutes. A solution of phenyl (isopropoxy-L-alaninyl) phosphorous hydrochloride in anhydrous THF (1M, 0.8 ml, 0.78 mmol) was added at -70 ° C and the reaction mixture was stirred at RT, for 5 hours. The reaction was quenched by HCOOH and the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM: MeOH = 60: 1), to obtain compound 18a as a white solid (a mixture of two P isomers, 25 mg, 7.7%).

³H NMR (CD₃OD, 400 MHz) δ 7.64, 7.60 (2d, J = 7.6 Hz, 1H),

7.32-7.36 (m, 2H), 7.16-7.25 (m, 3H), 5.95-6.01 (m, 1H),

5.67, 5.62 (2d, J = 8.0 Hz, 1H), 5.10-5.25 (m, 1H), 4.93-4.97 (m, 1H), 4.49-4.59 (m, 1H), 4.33-4.42 (m, 1H), 4.24-4.29 (m,

1H), 3.86-3.94 (m, 1H), 3.25, 3.22 (2s, 1H), 1.28-1.34 (m,

3H), 1.20-1.23 (m, 6H); ESI-MS: m / z 540.2 [M + H]⁺.

<img file="MX356509B_D0474.tif" />

262

Preparation of compound (19a)

NHMMTr

EXAMPLE 19

O = P-_OR'' F ⁰

HO F P15-1

NC

P19-1 ^z,or.

° TW

OR

NHMMTr

<img file="MX356509B_D0475.tif" />

OR

O = PI ° x / °

0'

P19-3

IMPI

MEXICAN INSTITUTE

OF THE INDUSTRIAL PROVINCE '* _r NHMMTr \ NHMMTr «τού

0 = P-o ''> o

OR

P19-2

NH.,

<img file="MX356509B_D0476.tif" />

O = PO^C F ° ^ -O 19a

Preparation of (P19-1): P15-2 (1.2g, 2.2mmol) was dissolved in dry acetonitrile (20ml) and 0.45M tetrazole (24.0mmol)

11.0

39 / and (bis (diisopropylamino) phosphinooxy) propanonitrile (1.13

3.74 mmol). The reaction mixture was stirred for 1 hour under N 2 at RT. TBDPH (2.7 ml, 15 mmol) was added and the mixture was stirred for 1 hour. The reaction was tempered by Na₂S₂OR₃solution and extracted with EA. The organic layer was dried in

Na₂SW₄ and concentrated. The residue was purified by a column on silica gel (DCM: MeOH = 100: 1 to 40: 1), to obtain P19-1 as a white solid (759 mg, 52%).

263

<img file="MX356509B_D0477.tif" />

Preparation of (P19-2): P19-1 (750 mg, 1.14 mmol) was dissolved in NH₃ saturated in MeOH solution. The mixture was stirred for 2 hours at RT. The solution was concentrated to dryness.

<td>to get</td><td>P19-2 raw</td><td>as a</td><td>solid yellow</td><td> (662</td><td>mg,</td>

<td> 100%). ³H NMR</td><td>(DMSO-CÍ6, 400</td><td>MHz) δ</td><td>8.60 (s, 1H), 8.28</td><td>(s,</td><td>1 HOUR) ,</td>

<td>7.48 (d, J =</td><td>7.6 Hz, 1H),</td><td> 7.12-7.</td><td>29 (m, 12H), 6.83</td><td>(d,</td><td>J =</td>

<td>8.8 Hz, 2H),</td><td>6.29 (d, J =</td><td>7.6 Hz,</td><td>1H), 5.88 (d, J =</td><td> 8.8</td><td>Hz,</td>

1H), 5.10 (d, J = 4.8 Hz, 1H), 4.42-4.45 (m, 1H), 3.72 (s,

3H), 1.64-1.91 (m, 2H), 1.10-1.13 (m, 2H), 0.83-0.86 (m,

3H). ³¹P NMR (CD₃OD, 400 MHz) δ -4.48; ESI-LCMS negative: m / z

606 [Μ - H].

Preparation of (P19-3): P19-2 (292 mg, 0.47 mmol) was coevaporated with pyridine twice and dissolved in anhydrous DMF (0.5 ml). DIPEA (1.2 ml) was added followed by 2,2-dimethyl-propionic acid iodomethyl ester (680 mg, 2.8 mmol). The reaction mixture was stirred at RT, under N₂ during hours. The reaction was quenched by Na solution₂S₂OR₃ and extracted with EA. The organic layer was dried in Na₂SW₄ and concentrated. The residue was purified by a column on silica gel (DCM: MeOH = 100: 1 to 30: 1), to obtain P19-3 as a white solid (95 mg, 30%).

264

<img file="MX356509B_D0478.tif" />

WSTITUT · MEXICAN Dt LA BROHtDAD INtXISTFIAt

Preparation of (19a): P19-3 (95 mg, 0.13 mmol) was dissolved in an aqueous 80% HCOOH solution and the mixture was stirred at RT, for 16 hours. The solvent was removed and the residue was purified by RP HPLC (MeCN and 0.1% HCOOH in water), to obtain compound 19a as a white solid (10 mg, 17%).^XH NMR (CD₃OD, 400 MHz) δ 7.69 (d, J = 7.2 Hz,

1H), 5.91 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 22.0 Hz, 1H),

5.73 (d, J = 14.0 Hz, 2H), 5.52 (d, J = 5.2 Hz, 1H), 5.135.22 (m, 1H), 4.53-4.61 (m, 1H), 4.31 (d, J = 9.6 Hz , 1H), 1.92-2.08 (m, 2H), 1.23 (s, 9H), 1.03-1.07 (m, 3H); ³¹P NMR (CD₃OD, 162 MHz) δ -7.93; ESI-LCMS: m / z 450 [M + H]⁺.

265

IMPI

<img file="MX356509B_D0479.tif" />

Preparation of compound (20a)

EXAMPLE 20

Hh hcHY HÓ F

P3-1

TO

NH vy^NlTBSÓ F

P20-3 &lt;^z NH

TBSO ^ K Ό. >^N7 oTBSÓ F P20-6

HO F P20-1 _Λ &lt;^z NH

/.γ/ΛTBSO F P20-4

NH,

TBSO'X Ό. *^N7

TBSÓ F P20-7

<img file="MX356509B_D0480.tif" />

H H

- γ / Λ _

HÓ F P20-2 &lt;^z NH

TBSÓ F

P20-5

NHMMTr

TBSO^-\.OR_X*^N~^ * / ⁰

TBSO F

P20-8

20 a

Preparation of (P20-1): to a stirred suspension of P3-1 (20.0 g, 81.3mmol), imidazole (15.9 g, 234.0 mmol), PPh₃ (53.5 g, 203.3 mmol) and pyridine (90 ml) in anhydrous THF (360 ml) a solution of I was added dropwise₂ (41.3 g, 162.6mmol) in THF (350 ml) at 0 ° C. After the addition, the mixture was warmed to RT and stirred for 14 hours. The solution was quenched with Na₂S₂OR₃ aqueous (150 ml) and extracted with EA. The

266

<img file="MX356509B_D0481.tif" />

IMPI organic layer dried in Na₂SW₄ and concentrated. The residue was purified on a silica gel column (DCM: MeOH = 100: 1 to 10: 1), to obtain P20-1 as a white solid (22.1 g,

76.4%). ³H NMR (CD₃OD, 400 MHz) δ 7.70 (d, J = 8.0 Hz, 1H),

5.88 (dd, = 1.6 Hz, J₂ = 20.8 Hz, 1H), 5.71 (d, J = 8.4 Hz,

1H), 5.24 (dd, J₂ = 2.0 Hz, J₂ = 5.2 Hz, 1H), 5.10 (dd, J₂ =

2.0 Hz, J₂ = 5.2 Hz 1H), 3.78-3.83 (m, 1H), 3.61-3.65 (m,

1H), 3.44 (dd, J₂ = J₂ = 6.0 Hz, 1H).

Preparation of (P20-2): To a stirred solution of P20-1 (22.1g, 62.1mmol) in anhydrous THF (200ml) DBU (14.2g, 93.1mmol) in THF (50ml) was added dropwise at 0 ° C for minutes. The mixture was stirred at 60 ° C for 6 hours. The reaction was quenched with NaHCO₃ aqueous (200 ml) and was extracted with

EA. The organic layer was washed with brine and dried over Na₂S0₄,

The solvent was removed and the residue was purified on a silica gel column (MeOH: DCM = 1/100 to 1/30), to obtain P202 as a white solid (8.7 g, 61.5%). '' Ή NMR (CD₃OD, 400

MHz) δ 7.51 (d, J = 8.0 Hz, 1H), 6.05 (dd, J₂ = 1.2 Hz, J₂ =

17.2 Hz, 1H), 5.73 (d, J = 8.0 Hz, 1H), 5.26 (dd, J₂ = 1.2

Hz, J₂ = 4.8 Hz, 1H), 5.13 (dd, J₂ = 1.2 Hz, J₂ = 4.8 Hz, 1H),

4.63 (dd, J₂ = 2.0 Hz, J₂ = 3.2 Hz, 1H), 4.41 (dd, J₂ = J₂ = 2.0

Hz, 1H).

Preparation of (P20-3): To a stirred solution of P20-2

267

IMPI

<img file="MX356509B_D0482.tif" />

(3.2 g, 14.0 mmol) in anhydrous pyridine (10 mil- and dcm (loo mi), a solution of TBSC1 (4.2 g, 28.0 mmol) was added dropwise at 0 ° C. The stirring continued at RT for 18 hours. The mixture was diluted with DCM The organic layer was washed with brine and dried over Na₂SW₄₍ The solvent was removed and the residue was purified on a column of silica gel (10% MeOH in DCM), to obtain P20-3 as a white solid (3.4 g,

70.8%).

Preparation of (P20-4): To a stirred NaHCO solution₃ in H₂Or (250 ml) and acetone (200 ml), oxone (30.0 x 4 g) was added at 0 ° C. The mixture was heated to RT and the distillate was collected at -78 ° C (120 ml) under slightly reduced pressure to obtain a solution of DMDO in acetone. To a stirred solution of P20-3 (250.0 mg, 0.7 mmol) in DCM (20 ml), a solution of DMDO (120 ml) at -40 ° C and MgSO was added₄. The mixture was heated to RT and then stirred for 2 hours. The solution was filtered and the filtrate was used for the next step directly.

Preparation of (P20-5): To a stirred solution of P20-4 (500.0 mg, 1.4 mmol) in anhydrous DCM (50 ml) was added allyltrimethylsilane (760.0 mg, 6.7 mmol) and SnCl₄ (1.2 g, 4.5 mmol) at -40 ° C. The mixture was heated and stirred at 0 ° C for 1 hour. The reaction was quenched with NaHCO₃ saturated and it

268

<img file="MX356509B_D0483.tif" />

extracted with DCM. The organic layer was dried in Na₂SW₄ and concentrated. The residue was purified on a column of silica gel (20-50% EA in PE), to obtain P20-5 as a foam

<td>white (120</td><td>mg, 41</td><td> %) .</td><td>³H nmr</td><td>(CD₃OD,</td><td> 400</td><td>MHz) δ 8.01 (d, J =</td>

<td>8.4 Hz, 1H),</td><td> 6.12</td><td>(dd,</td><td> =</td><td>3.6 Hz,</td><td>J₂ =</td><td>15.2 Hz, 1H), 5.87-</td>

<td>5.96 (m, lH),</td><td> 5.71</td><td>(d,</td><td>J =</td><td>8.4 Hz,</td><td>1 HOUR) ,</td><td>5.06-5.22 (m, 3H),</td>

<td>4.60 (dd, J₂</td><td> = 5.6</td><td>Hz,</td><td>J₂ =</td><td>14.4 Hz</td><td>, 1 HOUR)</td><td>, 3.72 (d, J = 11.6</td>

Hz, 1H), 3.48 (d, J = 11.6 Hz, 1H), 2.62-2.67 (m, 1H), 2,232.29 (m, 1H); ESI-LCMS: m / z = 422 [M + Na]⁺.

Preparation of (P20-6): To a stirred solution of P20-5 (270.0 mg, 0.7 mmol) in dry DCM, imidazole (400.0 mg, 5.9 mmol) and TBSC1 (390.0 mg, 2.6 mmol) were added to RT. The mixture was stirred at RT, for 18 hours. The solution was diluted with EA. The solvent was washed with brine and dried in Na₂SW₄₍ The solvent was removed and the residue was purified on a column of silica gel (20-40% EA in PE), to obtain compound P20-6 as a white foam (280 mg, 80.7%). ESI-LCMS: m / z 537 [M + Na]⁺.

Preparation of (P20-7): To a stirred solution of P20-6 (280.0 mg, 0.5 mmol) in dry MeCN was added TPSC1 (350.0 mg, 1.2 mmol), NEt₃ (400.0 mg, 4.0 mmol) and DMAP (270.0 mg, 2.2 mmol) at RT The mixture was stirred at RT, for 18 hours. The solution was quenched with ammonia. The organic layer was washed

269

<img file="MX356509B_D0484.tif" />

with brine and dried in Na₂SW₄. The solvent was removed and the residue was purified by TLC (using EA), to provide compound P20-7 as a white foam (240.0 mg, 85.7%).

ESI-LCMS: m / z 514 [M + H]⁺.

Preparation of (P20-8): AgNO was added to a stirred solution of P20-7 (270.0 mg, 0.5 mmol) in dry DCM₃ (1.5 g, 8.8mmol), MMTrCl (450.0 mg, 1.5 mmol) and collidine (500.0 mg,

4.1 mmol) at RT The mixture was stirred at RT, for 18 hours. The solution was diluted with DCM. The organic layer was washed with brine and dried over Na₂SW₄. The solvent was removed and the residue was purified on a column of silica gel (20-40% EA in PE) to provide compound P20-8 as a white foam (300 mg, 81.6%). ESI-LCMS: m / z 786 [M + H]⁺.

Preparation of (20a): To a stirred solution of P20-8 (170.0 mg, 0.3 mmol) in dry MeOH was added NH₄F (300.0 mg,

8.1 mmol) and the mixture was refluxed for 24 hours. The solvent was removed under reduced pressure and the residue was purified on a column of silica gel (2 ~ 5% MeOH in

DCM), to obtain the raw product. The crude product was further purified by RP HPLC (water and 0.1% HCOOH in MeCN), to provide compound 20a as a white solid (47.0 mg, 49.8%).^XH NMR (CD₃OD, 400 MHz) δ 8.13 (d, J = 8.4 Hz, 1H), 6.12 (dd, Jj = 3.2 Hz, J₂ = 12.0 Hz, 1H), 5.87t ··

5.97 (m, 2H), 4.98-5.14 (m,

17.6 Hz, 1H), 3.71 (d, J =

Hz, 1H), 2.54-2.59 (m, 1H),

286 [M + H]⁺.

270

3H), 4.45

11.6 Hz,

2.33-2.39

IMPI

MEXICAN INSTITUTE IJE LA PROPIEDAD

INDUSTRIAL (dd, Jl = 5.2

<img file="MX356509B_D0485.tif" />

1H), 3.54 (d, J = 11.6 (m, 1H); ESI-LCMS: m / z

EXAMPLE 21

Preparation of compound (21a)

NHMMTr

TBSO

<img file="MX356509B_D0486.tif" />

P21-1

TBSO 'F

P20-8

<img file="MX356509B_D0487.tif" />

<img file="MX356509B_D0488.tif" />

P21-2 21a

Preparation of (P21-1): To a stirred solution of P20-8 (250.0 mg, 0.3 mmol) in MeOH Pd / C (500.0 mg) was added and the mixture was stirred at H₂ (balloon) for 18 hours at RT The reaction was filtered and the solvent was removed under reduced pressure. The residue was purified by preparative TLC (30% EtOAc in PE) to obtain P21-1 as a white foam (210.0 mg, 84.0%).

Preparation of (P21-2): To a stirred solution of P21-1 (210.0 mg, 0.3 mmol) in dry THF was added TBAF (1 ml, 1

271

<img file="MX356509B_D0489.tif" />

INDUSTRIAL PROPERTY mmol) and the mixture was stirred at RT for 18 hours. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (30% EtOAc in PE), to obtain compound 21a as a white foam (111.2 mg,

<td> 74.6%</td><td> ) · ^XH</td><td>NMR</td><td>(DMSO-CÍ6, 400 MHz) δ 8.49</td><td>(s,</td><td>1H), 7.</td><td>.75 (d, J</td>

<td> = 6.8</td><td>Hz,</td><td>1 HOUR) ,</td><td>6.83-7.32 (m, 14H), 6.25</td><td>(d.</td><td>J = 7.6</td><td>Hz, 1H),</td>

<td> 5.95</td><td>(dd,</td><td>Chi =</td><td>4.8 Hz, J₂ = 14.8 Hz, 1H),</td><td colspan="2">5.48 (d, J </td><td>= 5.6 Hz,</td>

<td>1 HOUR) ,</td><td> 4.86-</td><td> -5.15</td><td>(m, 2H), 4.15-4.21 (m,</td><td>1 HOUR)</td><td> , 3.72</td><td>(s, 3H),</td>

<td> 3.38-</td><td> 3.49</td><td>(m,</td><td>2H), 1.24-1.58 (m, 4H), 0</td><td> . 84</td><td>(t, J =</td><td>: 7.2 Hz,</td>

3H); ESI-MS: m / z 560 [M + H]⁺.

Preparation of (P21): Compound P21-2 (81 mg) was dissolved in a mixture (5 ml) of formic acid (80%) and water (20%). The resulting solution was stirred at RT for 3 hours and then concentrated. The residue was co-evaporated with methanol / toluene three times. Chromatography on silica gel with 5-12% methanol in DCM provided a mixture of two compounds, which was dissolved in methanol with a drop of concentrated aqueous ammonia and concentrated. The residue was purified on silica gel with 5-12% methanol in DCM, to obtain compound 21a (27 mg) as a white solid; ¹H

NMR (CD₃OD, 400 MHz) δ 8.05 (d, J = 7.6 Hz, 1H), 6.06 (dd, Ji = 2.8 Hz, J₂ = 16 Hz, 1H), 5.87 (d, J = 7.6 Hz, 1H), 5.10 (dd, J = 3.2, 5.2 Hz, 0.5H), 4.96 (dd, 3.2, 5.2 Hz, 0.5H),

272

<img file="MX356509B_D0490.tif" />

4.42 (dd, J = 5.6, 17.2 Hz, 1H), 3.67 (dd, · 7 fi. Fiz.

2H), 1.70-1.79 (m, 1H), 1.31-1.61 (m, m, 3H), 0.94 (t, J =

6.8 Hz, 3H). MS: m / z 417 [M + 2-methylheptylamine]⁺.

EXAMPLE 22

Preparation of compound (22a)

V / lHÓ F P20-2

<img file="MX356509B_D0491.tif" />

<img file="MX356509B_D0492.tif" />

<img file="MX356509B_D0493.tif" />

P22-3 P22-4 P22

Preparation of (P22-1): To a solution of P20-2 (5.23 g,

23.1 mmol) in anhydrous MeOH (50 ml) PbCO was added₃(12.7 g,

46.3 mmol) at RT A solution of I₂ (11.7 g, 46.3 mmol) in

MeOH (10 ml) was then added dropwise at 0 ° C. The reaction mixture was stirred at RT, overnight. The reaction was quenched with Na₂S₂OR₃ and dissolved in EA. The organic layer was dried in Na₂SW₄ and concentrated. The residue was purified by column (DCM / MeOH = 100/1 to 20/1), to obtain P22-1 as a white solid (5.6 g, 71.8%).³Η NMR (CD₃OD, 400 MHz) δ 7.67

273

IMPI

MEXICAN INSTITUTE OF PROPERTY

<td>(d,</td><td>J =</td><td>8.0 Hz, 1H), 5.88</td><td>(dd, J₂ = J₂</td><td>IN = 7.6 Hz,</td><td>INDUSTSUAL 1H), 5.</td><td></td>

<td>J =</td><td> 8.0</td><td>Hz, 1H), 5.24 (dd,</td><td>Chi = 4.4 Hz</td><td>, J₂ = 6.4</td><td>Hz, HI)</td><td> , 5.11</td>

<td>(dd,</td><td>Jl</td><td>= 6.4 Hz, J₂ = 6.0</td><td>Hz, 1H); Four.</td><td>65 (dd, hee</td><td> = 20.0</td><td>HZ, J₂</td>

<td> = 20</td><td> 1.4</td><td>Hz, 1H), 3.67 (d,</td><td>J = 11.6 Hz,</td><td>1H), 3.54</td><td>(d, J</td><td> = 11.6</td>

<td>Hz,</td><td>1 HOUR)</td><td>, 3.43 (s, 3H).</td><td></td><td></td><td></td><td></td>

Preparation of (P22-2): To a stirred solution of P22-1 (5.6 g, 14.5 mmol) in anhydrous pyridine (20 ml), BzCl (2.9 g, 20.9 mmol) was added dropwise at 0 ° C. The mixture was stirred at

RT, for 10 hours. The reaction was quenched with H₂0 and the solution was concentrated. The residue was dissolved in EA and washed with NaHCO₃ saturated, The organic layer was dried in Na₂SW₄ and concentrated. The residue was purified on a silica gel column (20-40% EA in PE), to obtain P22-2 as a white foam (4.9 g, 74.2%).

Preparation of (P22-3): P22-2 (4.9g, 10.0mmol), BzONa (14.4g, 100mmol) and 15-corona-5 (22.0g, 100mmol) were suspended in DMF (200ml). The mixture was stirred at 60-70 ° C for 3 days. The precipitate was removed by filtration and the filtrate was diluted with EA. The solvent was washed with brine and dried in Na₂SW₄, The solvent was removed and the residue was purified on a column of silica gel (20-60% EA in PE) to obtain P22-3 as a white foam (2.3 g, 47.9%).

Preparation of (P22-4): P22-3 (2.3 g, 4.8 mmol), DMAP

<img file="MX356509B_D0494.tif" />

274

MEXICAN INSTITUTE CE THE PROPERTY

INDUSTRIAL (1.2g, 9.6mmol), TPSC1 (2.9g, 9.6mmol) and Et₃N (0.97 g, '9.6 mmol) were suspended in MeCN (10 ml). The mixture was stirred at RT, for 14 hours. NH₃ in THF (saturated at 0 ° C, 100 ml) was added to the mixture, and the mixture was stirred at RT, for 2 hours. The solvent was removed and the residue was purified by column (DCM / MeOH = 100: 1 to 50: 1), to obtain the crude product (1.2 g). The crude product was dissolved in pyridine and BzCl (0.42 g, 3.0 mmol) was added. The mixture was stirred at RT for 16 hours and quenched with water. The solvent was removed and the residue was purified on a column of silica gel (PE: EA = 2: 1 to 1: 1), to obtain P22-4 as a white foam (460 mg, 31%).

Preparation of (22a): P22-4 (0.46 g, 0.8 mmol) was dissolved in saturated methanolic ammonia (100 ml) and the mixture was stirred at RT, for 14 hours. The solvent was removed and the residue was dissolved in H₂0 and washed with DCM. The aqueous phase was lyophilized and re-purified by prep HPLC. (0.1% formic acid in water / acetonitrile), to obtain compound 22a as a white solid (145 mg, 78.9%).^XH NMR (CD₃OD, 400 MHz) δ 7.88 (d, J = 7.6 Hz, 1H), 6.03 (d, J =

18.4 Hz, 1H), 5.87 (d, J = 7.6 Hz, 1H), 4.86-5.00 (m, 1H),

4.49 (dd, J₂ = 23.2 Hz, J₂ = 22.8 Hz, 1H), 3.90 (d, J = 12.0

Hz, 1H), 3.66 (d, J = 12.0 Hz, 1H), 3.41 (s, 3H); ESI-MS: m / z

275

<img file="MX356509B_D0495.tif" />

276 [Μ + Η] ⁺

EXAMPLE 23

Preparation of compound (23a)

<img file="MX356509B_D0496.tif" />

P23-1

BnO

HO &lt;^z NPMB

FOR _

Λ &lt;(NPMB BnO-A ^ Oy^N_4

BnO F

P23-2

A &lt;^z NH ^Β,^ χ / Α _

NH,

BnO

Bn (í F

P23-5,^N~ Í

BnO F P23-3

<img file="MX356509B_D0497.tif" />

P23-6

BnO F P23-4

<img file="MX356509B_D0498.tif" />

P23-7

NH, ^HF ° s \ yA

HO F

23a

Preparation of (P23-2): To a solution of P23-1 (3.1 g,

4.5 mmol) in DMF (30 ml) K was added₂CO₃ anhydrous (1.24 g, 9.03 mmol) and PMBC1 (1.40 g, 9.03 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted by EA. The organic layer was concentrated and the residue was purified on a gel column of

276

<img file="MX356509B_D0499.tif" />

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY silica (PE: EA = 10: 1 to 4: 1), to obtain the intermediate as a white solid (2.36 g, 74.8%). ¹H NMR (CDC1₃, 400 MHz) δ 7.29-7.88 (m, 23H), 6.83-6.98 (m, 6H), 6.35-6.45 (m, 1H),

4.51-5.50 (m, 6H), 3.89-3.95 (m, 9H), 3.66-3.71 (m, 2H), 3.03 (d, J = 11.2Hz, 1H), 1.21 (s, 9H), 0.89 (m, 9H), 0.01-0.11 (m,

6H). The broker was used in the next step.

To a stirred solution of the intermediate (11.0 g, 10.47 mmol) in anhydrous THF (100 ml), TBAF (8.20 g, 31.42 mmol) was added to RT and the mixture was stirred at RT for 5 hours. The solution was removed and the residue was purified on a silica gel column (PE: EA = 5: 1 to 1: 1), to obtain a second intermediate as a white solid (5.99 g, 82%).

To a stirred solution of the second intermediate (500mg, 0.716mmol) in anhydrous DMF (10ml) NaH (51.5mg, 2.14mmol) and BnBr (365mg, 2.14mmol) were added, dropwise, at 0 ° C. The mixture was stirred at RT, overnight. The solution was quenched with water and extracted with EA. The concentrated organic phase was purified on a column of silica gel (PE: EA = 10: 1 to 4: 1), to obtain a third intermediate as a white solid (496 mg, 79%).

The third intermediate (2.5g, 2.84mmol) was dissolved in 80% HOAc (25ml) at RT and the mixture was stirred at RT, overnight. The reaction was quenched with MeOH and the

277

IMPI

<img file="MX356509B_D0500.tif" />

solvent was removed. The crude product was purified on a column of silica gel (PE: EA = 5: 1 to 1: 1), to obtain P23-2 as a white solid (1.2 g, 73%).

Preparation of (P23-3): To a stirred solution of DAST (1.39 g, 8.68 mmol) in anhydrous toluene (15 ml), a solution of P23-2 (1.0 g, 1.73 mmol) was added dropwise at -78 ° C . The mixture was stirred at -78 ° C for 30 minutes. The solution was gradually warmed to 60 ° C and then stirred overnight. The mixture was poured into Na solution₂CO₃ saturated. The concentrated organic phase was purified on a silica gel column (PE: EA = 10: 1 to 4: 1), to obtain P23-3, as a white solid (449 mg, 45%).³H NMR (CD₃OD, 400 MHz) δ 7.87 (d, J = 8.4 Hz, 1H), 7.27-7.37 (m, 12H), 6.82-6.84 (m, 2H),

6.14 (dd, J = 16.8.2.0Hz, 1H), 5.18-5.50 (m, 4H), 4.96 (s,

2H), 4.45-4.88 (m, 7H), 3.67-3.89 (m, 5H).

Preparation of (P23-4): A mixture of P23-3 (1.20 g,

2.07 mmol) and CAN (3.41 g, 6.23 mmol), in a solution of

MeCN: water (3: 1, 10 ml) was stirred at RT overnight.

Brine (10 ml) was added and the mixture was extracted with EA. The combined organic extracts were dried and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (PE: EA = 10: 1 to 2: 1), to obtain P23-4 as a yellow solid (475 mg, 49.8%).

<img file="MX356509B_D0501.tif" />

278

Preparation of (P23-5): To a stirred solution dp. P23-4 (550mg, 210mmol) in anhydrous MeCN (10ml) TPSC1 (725mg, 2.40mmol), DMAP (293mg, 2.40mmol) and TEA (242mg, 2.40mmol) were added to RT and the mixture stirred at RT overnight. NH added₄OH (25 ml) and the mixture was stirred for 2 hours. The solvent was removed and the residue was purified on a silica gel column (PE: EA = 8: 1 to 2: 1), to obtain P23-5 as a white solid (700 mg crude) .¾ NMR (CD₃OD, 400

MHz) δ 7.86 (d, J = 8.4 Hz, 1H), 7.27-7.36 (m, 10H), 6.13 (dd, J₂ = 17.2 Hz, J₂ = 2.0 Hz, 1H), 5.48-5.53 (m, 1H), 5.115.26 (m, 1H), 4.44-4.74 (m, 7H), 3.89 (dd, J₂ = 10.4 Hz, J₂ =

2.0 Hz, 1H), 3.69 (dd, J₂ = 10.8 Hz, J₂ = 1.6 Hz, 1H).

Preparation of (P23-6): To a stirred solution of P23-5 (1.0g, 2.18mmol) in anhydrous DCM (15ml) was added MMTrCl (2.02g, 6.56mmol) and AgNO₃ (1.11 g, 6.56 mmol) at RT and the mixture was stirred at RT overnight. The solid was filtered off and washed with DCM. The filtrate was washed with brine and dried over Na₂SW₄, The organic phase was concentrated and the residue was purified on a silica gel column (PE: EA = 8: 1 to 2: 1), to obtain P23-6 as a white solid (520 mg, 41%).

Preparation of (P23-7): To a stirred solution of P23-6 (520 mg, 0.713 mmol) in acetone was added format of

279 / g OT. r I

INSTn UTO MEXICANO JA

OF THE PROPERTY ^V ammonia (2.0 g, 31.7 mmol, in portions) and ^l'p ^ í¹^ 'áio^aiL^ on 10% carbon (1.0 g). The mixture was held at ± U.JU for 12 hours. The catalyst was removed by filtration and washed with solvent. The filtrate was added EA and washed with brine. The concentrated organic phase was purified by column chromatography (DCM: MeOH = 100: 1 to 15: 1) and prep TLC. to obtain P23-7 as a white solid (270 mg,

69.0%).^χΗ NMR (CD₃OD, 400 MHz) δ 8.54 (s, 1H), 7.73 (d, J =

7.6 Hz, 1H), 7.13-7.32 (m, 12H), 6.83 (d, J = 8.4 Hz, 2H),

6.29 (d, J = 7.6 Hz, 1H), 5.99-6.04 (m, 1H), 5.82 (d, J = 5.6

Hz, 1H), 5.39 (t, J = 5.2 Hz, 1H), 5.09 (t, J = 5.2 Hz,

1H), 4.32-4.58 (m, 3H), 3.54-3.72 (m, 5H). ESI-MS: m / z 549.6 [Μ + H]⁺.

Preparation of (23a): P23-7 (130mg, 0.236mmol) was dissolved in 80% HCOOH (20ml) at RT and the mixture was stirred at

50 ° C for 12 hours. The solvent was removed and the residue was co-evaporated with toluene, twice. The residue was redissolved in MeOH (20 ml) at 60 ° C and stirring continued for 48 hours. The solvent was removed and the residue was purified by column chromatography (DCM: MeOH = 100: 1 to 10: 1), to obtain compound 23a as a white solid (45 mg,

69.0%).^xH NMR (CD₃OD, 400 MHz) δ 8.00 (d, J = 7.6 Hz, 1H),

6.13 (dd, J₂ = 16.0 Hz, J₂ = 4.0 Hz, 1H), 5.89 (d, J = 7.6 Hz,

<img file="MX356509B_D0502.tif" />

280

1H), 5.18-5.21 (ΤΠ, 1H), 5.05-5.07 (m, 1H), 4.60 (s, 1H),

4.51-4.57 (m, 2H), 3.84 (dd, J₂ = 12? 0 Hz, J₂ = 2.0 Hz, 1H), 3.75 (dd, Ji = 12.0 Hz, J₂ = 2.0 Hz, 1H). ESI-MS: m / z 277.8 [M + H]⁺, 554.8 [2M + H] ⁺ .

EXAMPLE 24

<img file="MX356509B_D0503.tif" />

NH-.HCI

<img file="MX356509B_D0504.tif" />

P244

<img file="MX356509B_D0505.tif" />

TBSO 'F P24-7

TBDPSO

TBSO 'F

P24-10

HO • O.

-Ύχ

HO F 24a

NH

<img file="MX356509B_D0506.tif" />

P24-2

BzO

Bzd f

P24-3 &lt;K, H

0. ,^N-4.

^Η° ΛΧ

TBSO F P24-5 &lt;Hnh

TBDPSO ^ v^ORsZ¹^. ^{O = V}'WF TBSO' F

P24-8

<img file="MX356509B_D0507.tif" />

TBSO F

NHMMTr

TBDPSO τΧΪ

TBSO 'F

P24-11

NH-í

<img file="MX356509B_D0508.tif" />

HO, 0

HO 'F

P24-12

281

MEXICAN INSTITUTE Q

OF THE PROPERTY

INDUSTRIAL

Preparation of (P24-2): To a solution of P24-1 (30.0 a.

100.0 mmol) in pyridine (300 ml) BzCl (56.0 g, 400 mmol) was added at 25 ° C. The mixture was stirred at 25 ° C for 15 hours. The mixture was concentrated and purified by column chromatography (PE: EA = 20: 1 to 2: 1), to obtain crude P24-2 (55.0 g, 81%).

Preparation of (P24-3): P24-2 (55.0 g, 92 mmol) was dissolved in 80% aqueous HOAc solution and the mixture was refluxed for 14 hours. The solvent was removed under reduced pressure and the residue was co-evaporated with toluene. The residue was purified on a silica gel column (PE / EA =

4: 1 to 2: 1), to obtain P24-3 as a white solid (39.2 g,

83%) .

Preparation of (P24-4): P24-3 (39.2 g, 83 mmol) was dissolved in saturated methanolic ammonia and the resulting solution was stirred at RT, for 15 hours. The solvent was removed and the residue was purified on a silica gel column (DCM / MeOH = 50: 1 to 20: 1), to obtain P24-4 (21.0 g,

95.8%).

Preparation of (P24-5): To a solution of P24-4 (21.0 g,

79.5 mmol) in pyridine (250 ml) DMTrCl (28.2 g,

83.5 mmol) at 0 ° C. The solution was stirred at RT, for 15 hours. The reaction was quenched with MeOH and concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc and

282

<td>washed with water. The</td><td>cap</td><td>organic se</td><td>MEXICAN INSTITUTE OF PROPERTY INDUSTRIAL dried up in Na₂SW₄ and</td><td>I know</td>

<td>concentrated. The residue</td><td>I know</td><td>dissolved in</td><td>DCM (300 mi).</td><td>I know</td>

<td>they added imidazole (13</td><td>.6 g,</td><td>200 mmol) and</td><td>TBSC1 (30.0 g,</td><td> 200</td>

mmol). The reaction mixture was stirred at RT, for 12 hours. The reaction mixture was washed with NaHCO₃ and brine.

The organic layer was dried in Na₂SW₄ and concentrated. The residue (48.5 g, 79.5 mmol) was dissolved in an aqueous solution of

HOAc at 80% (400 mi). The mixture was stirred at RT, for 20 hours. The mixture was diluted with EtOAc and washed with a NaHCO solution₃ and brine. The organic layer was dried in

Na₂SW₄ and purified by silica gel column chromatography (2% 1-MeOH in DCM), to obtain P24-5 as a white solid (21.0 g, 70%). ^XH NMR (400 MHz, MeOD) δ 7.83 (d, J = 8.0 Hz, 1H), 6.14 (dd, Ji = 6.0 Hz, J₂ = 10.0 Hz,

1H), 5.73 (d, J = 8.4 Hz, 1H), 4.38-4.46 (m, 1H), 3.89-3.91 (m, 1H), 3.88 (dd, J₂ = 2.8 Hz, J₂ = 5.2 Hz, 1H), 3.72 (dd,

J₂ = 2.8 Hz, J₂ = 5.2 Hz, 1H), 0.93 (s, 9H), 0.15 (m, 6H).

ESI-MS: m / z 379.1 [M + H]⁺.

Preparation of (P24-6): To a solution of P24-5 (21.0 g,

55.6 mmol) in CH₃Anhydrous CN (200 ml) IBX (17.1 g, 61.1 mmol) was added at RT. The reaction mixture was refluxed for 1 hour and then cooled to 0 ° C. The precipitate was filtered off and the filtrate was concentrated, to

283

USTITíJTO MEXICANA) OF THE PROPERTY

INDUSTRIAL

<img file="MX356509B_D0509.tif" />

obtain aldehyde as a yellow solid (21.0 g, 55.6 mmol). CH was added to a solution of the aldehyde (21.0 g, 55.6 mmol) in dioxane (200 ml)₂Or 37% (22.2 ml, 222.4 mmol) and a 2N NaOH aqueous solution (55.6 ml, 111.2 mmol). The mixture was stirred at RT for 2 hours and then neutralized with AcOH to pH = 7. EtOH (50 ml) and NaBH were added to the reaction₄ (12.7 g, 333.6 mmol). The mixture was stirred at RT, for 30 minutes. The reaction was quenched with NH₄Aqueous saturated C1 was extracted with EA. The organic layer was dried in Na₂SW₄ and concentrated. The residue was purified by column chromatography on silica gel (1-3% MeOH in

DCM), to obtain P24-6 as a white solid (13.5 g,

59.5%) .

Preparation of (P24-7): To a solution of P24-6 (13.5 g,

33.1 mmol) in DCM (100 ml) pyridine (20 ml) was added and

DMTrCl (11.2 g, 33.1 mmol) at 0 ° C. The solution was stirred at 25 ° C for 3 hours and then treated with MeOH (30 ml). The solvent was removed and the residue was purified by column chromatography on silica gel (DCM: MeOH = 300: 1 to 100: 1), to obtain a residue. The residue was dissolved in anhydrous pyridine (150 ml) and TBDPSC1 (16.5 g, 60 mmol) and AgNO were added₃ (10.2 g, 60 mmol). The mixture was stirred at 25 ° C for 15 hours and then filtered and concentrated. The mixture dissolved

284

<img file="MX356509B_D0510.tif" />

IM ΡI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY in EtOAc and washed with brine. The organic layer was dried in Na₂SW₄. Purified by silica gel column chromatography (DCM: MeOH = 300: 1 to 100: 1), whereby the product was obtained as a yellow solid (16.2 g, 85.3%). The solid was dissolved in an 80% aqueous solution of HOAc (400 ml). The mixture was stirred at RT, for 15 hours. The mixture was diluted with EtOAc and washed with a NaHCO solution₃ and brine. The organic layer was dried in Na₂S0₄ and purified by column chromatography on silica gel (DCM: MeOH = 200: 1 to 50: 1), to obtain P24-7 as a white solid (9.5 g, 86.5%).¹H NMR (CD₃OD, 400 MHz) δ 7.39-7.70 (m, 11H), 6.34-6.38 (m, 1H), 5.12 (d, J = 8.0 Hz, 1H), 4.79 (dd, J₂ = 10.0 Hz, J₂ = 16.0 Hz, 1H), 4.14 (dd, J₂ = 1.6 Hz, J₂ = 11.6 Hz, 1H),

3.48-3.84 (m, 2H), 3.49 (dd, J₂ = 1.6 Hz, J₂ = 11.6 Hz,

1H), 1.12 (s, 9H), 0.92 (s, 9H), 0.16 (s, 6H).

Preparation of (P24-8): To a solution of P24-7 (6.0 g,

9.3 mmol) in anhydrous DCM (80 ml) DessMartin periodinan (7.9 g, 18.6 mmol) was added at 0 ° C under nitrogen atmosphere. The reaction was stirred at RT, for 1 hour. The solvent was removed in vacuo and the residue was triturated with diethyl ether (50 ml). The mixture was filtered through a pad of

MgSO₄ and the organic solvent was stirred with an equivalent volume of Na₂S₂OR₃.₅H₂Or in NaHCO₃ saturated (50 mi) up

285

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL, T that the organic layer became clear (approx. 10 min). The organic layer was separated, washed with brine and dried over MgS0₄. After concentrating in vacuo, P24-8 was obtained as a red solid (5.8 g.98%).

Preparation of (P24-9): To a mixture of methyl triphenylphosphonium bromide (9.6 g, 27.0 mmol) in anhydrous THF (60 ml), n-BuLi (10.8 ml, 27.0 mmol) was added at -70 ° C under nitrogen atmosphere . The reaction was stirred at 0 ° C for 30 minutes. A solution of P24-8 (5.8 g, 9.0 mmol) in anhydrous THF (20 ml) was added dropwise at 0 ° C, under nitrogen atmosphere. The reaction was stirred at RT, for 12 hours. The reaction was quenched with NH₄C1 and extracted with EtOAc. The organic layer was separated, dried and concentrated and the residue was purified by column chromatography with silica gel (DCM: MeOH = 300: 1 to 100: 1), to obtain P24-9 as a white solid (3.0 g , 51%).

Preparation of (P24-10): To a solution of P24-9 (2.9 g,

4.5 mmol) in anhydrous MeOH (20 ml) Pd / C (1.4 g) was added at 25 ° C under a hydrogen atmosphere. The mixture was stirred at 25 ° C for 1 hour. The solution was filtered, evaporated to dryness and purified on a column of silica gel (DCM: MeOH = 300: 1 to 100: 1), to obtain P24-10 as a white solid (2.3 g, 79.3%).

286

<img file="MX356509B_D0511.tif" />

Preparation of (P24-11): To a solution of P24-10 (1.0 g, 1.55 mmol) in CH₃Anhydrous CN (20 ml) TPSC1 (940 mg, 3.1 mmol), DMAP (380 mg, 3.1 mmol) and NEt were added₃ (470 mg,

4.6 mmol) at RT The reaction was stirred at RT, for 5 hours. NH added₄OH (8 ml) and the reaction was stirred for one hour. The mixture was diluted with DCM (150 ml) and washed with water, 0.1 M HCl and NaHCO₃ saturated aqueous. The solvent was removed and the residue was purified by column chromatography with silica gel (PE: EA = 10: 1 to 1: 1), to obtain the crude product as a yellow solid (900 mg, 90%). MMTrCl (930 mg, 3.0 mmol), AgNO was added to a solution of the crude product in DCM (10 ml)₃ (510 mg, 3.0 mmol) and colliding (720 mg, 6.0 mmol) at RT The reaction was stirred for 12 hours at RT The reaction was filtered, concentrated and purified by silica gel column chromatography (DCM: MeOH = 200: 1 to 50: 1), to obtain P24-11 as a yellow solid (11 g, 77.6%).

Preparation of (P24-12): To a solution of P24-11 (1.1 g, 1.2 mmol) in MeOH (40 ml) was added NH₄F (1.0g, 30mmol) at 25 ° C and stirred at 70 ° C for 15 hours. The solution was filtered and evaporated to dryness and the residue was purified by a column of silica gel (DCM: MeOH = 200: 1 to 20: 1), to obtain P24-12 as a white solid (450 mg, 66.6%) .^XH NMR

287

IMPI

<img file="MX356509B_D0512.tif" />

(400 MHz, MeOD) δ 8.58 (s, 1H), 7.62 (d, · 7- = 7 fi fiz. 1H).

7.13-7.30 (m, 12H), 6.83-6.85 (m, 2H), 6.29 (d, J = 7.6 Hz,

1H), 6.18 (d, J = 6.0 Hz, 1H), 5.94 (t, J = 8.0Hz, 1H), 5.22 (t, J = 5.2 Hz, 1H), 4.28-4.37 (m, 1H), 3.72 ( s, 3H), 3,573.62 (m, 1H), 1.39-1.60 (m, 2H), 0.79-0.84 (m, 3H). ESI-LCMS:

m / z 563.6 [M + H]⁺.

Preparation of (24a): P24-12 (250 mg, 0.44 mmol) was dissolved in 80% HCOOH in H₂Or (6.0 g) at 25 ° C. The mixture was stirred at 35 ° C for 15 hours. The solution was evaporated to dryness, dissolved in MeOH (30 ml) and stirred at 60 ° C for hours. The solution was evaporated to dryness and purified by silica gel column chromatography (DCM: MeOH = 100: 1 to 100: 1), to obtain compound 24a as a white solid (125.6 mg, 97%).^XH NMR (400 MHz, MeOD) δ 7.91 (d, J =

7.6 Hz, 1H), 6.19 (t, J = 7.6 Hz, 1H), 5.90 (d, J = 7.2 Hz,

1H), 4.47 (t, J = 13.6 Hz, 1H), 3.67 (d, J = 12.0 Hz, 1H),

3.52 (d, J = 12.0 Hz, 1H), 1.73-1.82 (m, 1H), 1.53-1.63 (m,

1H), 095 (t, J = 7.6 Hz, 3H). ESI-LCMS: m / z 291.9 [Μ + H]⁺.

IMPI

<img file="MX356509B_D0513.tif" />

288

EXAMPLE 25

Preparation of compound (25a)

<img file="MX356509B_D0514.tif" />

P25-3 P25-4

<img file="MX356509B_D0515.tif" />

<img file="MX356509B_D0516.tif" />

<img file="MX356509B_D0517.tif" />

<img file="MX356509B_D0518.tif" />

P25-8

<img file="MX356509B_D0519.tif" />

25a