EA039042B1 - Ectonucleotidase inhibitors and methods of use thereof - Google Patents

Abstract

The invention relates to novel heterocyclic compounds of general formula (I) and pharmaceutical compositions thereof. The invention further relates to methods of inhibiting 5'-nucleotidase in a cell and methods of treating a disease or disorder selected from cancer, cerebral and cardiac ischemic diseases, fibrosis, immune and inflammatory disorders, inflammatory gut motility disorder, neurological, neurodegenerative and CNS disorders and diseases, depression, Parkinson's disease, and sleep disorders using the compounds of the invention.

Description

Related applications

This application claims priority under US Provisional Patent Applications Nos. 62/437915, filed December 22, 2016, 62/437935, filed December 22, 2016, and

62/555791, filed September 8, 2017, each of which is incorporated herein by reference in its entirety.

Background of the invention

CD73, also called 5'-nucleotidase (5'-NT) or ecto-5'-nucleotidase (Ecto 5'NTase), is a membrane-bound cell surface enzyme whose primary role is to catalyze the conversion of extracellular nucleotides (e.g. AMP) into their corresponding nucleosides (eg adenosine). CD73 is found in most tissues and is expressed in lymphocytes, endothelial cells, and epithelial cells. It is also widely expressed in many tumor cell lines and, in particular, is activated in cancer tissues (Antonioli et al., Nat. Rev. Cancer, 13: 842-857, 2013).

In tandem with CD39 (ecto-ATPase), CD73 generates adenosine from ATP / AMP, which is often released from damaged or inflamed cells into the extracellular environment. The extracellular adenosine produced by CD73 interacts with G-protein coupled receptors on target cells. An important downstream effect of this signaling is enhanced immunosuppression through a number of pathways. For example, CD73 is a co-signaling molecule on T lymphocytes. Under normal conditions, extracellular adenosine levels promote a self-limiting immune response that prevents excessive inflammation and tissue damage. For tumors, the effect of abnormally elevated CD73 is that the resulting elevated adenosine levels catalyzed by CD73 result in inhibition of the anti-tumor response of the immune system.

Although CD73 plays a role in cancer immunosuppression, higher expression of CD73 is associated with various stages of tumor progression, including tumor vascularization, invasiveness and metastasis, as well as shorter survival times in breast cancer patients. Some of these observations are the result of the enzyme-independent function of CD73 as an adhesion molecule required for the binding of lymphocytes to the endothelium.

Overall, CD73 has become an important target for the development of new treatments for malignant neoplasm, either as stand-alone drugs or in combination with other anti-cancer drugs. Indeed, combining anti-CD73 monoclonal antibodies with antibodies for other chemotherapeutic targets enhances response and survival in animal cancer models (Allard et al., Clin. Cancer Res. 19: 5626-35, 2013).

Many of the current cancer therapies and chemotherapeutic agents cannot successfully treat all patients or all symptoms in treated patients, and many of these treatments are associated with unwanted side effects. Because some cancers develop resistance to various chemotherapeutic agents, alternative cancer treatments are needed. Thus, there is a need for additional compounds and methods for the treatment of cancer and other diseases.

The essence of the invention

This document describes compounds of formula (I)

R ⁴ R ³

(I) or a pharmaceutically acceptable salt and / or prodrug thereof, wherein

X is O, NR ⁷ or CR ⁷ R ⁸ ;

Y represents O or S;

Z represents NR ¹⁹ , O or S;

Het is heterocyclyl or heteroaryl;

R ^{1a is} selected from H, halogen, hydroxy, cyano, azido, amino, C _1-6 alkyl, hydroxy _{C 1-6} alkyl, amino-C _1-6 alkyl, C _1-6 acyloxy, -OC (O) -OC _{1 -6} alkyl, C _1-6 alkoxy, C _2-6 alkenyl, and C _2-6 alkynyl; and

R ^{1b is} selected from H, halogen, C _1-6 alkyl, hydroxy-C _1-6 alkyl, amino-C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl; or

R ^1a and R ^1b together with the carbon atom to which they are attached form C = CH ₂ or C = C (H) C _1-6 alkyl;

R ^{2a is} selected from H, halogen, hydroxy, cyano, azido, amino, C _1-6 alkyl, hydroxy-C _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 acyloxy, -OC (O) -OC _{1 -6} alkyl, C _1-6 alkoxy, C _2-6 alkenyl, and C _2-6 alkynyl;

R ^{2b is} selected from H, halogen, C _1-6 alkyl, hydroxy-C _1-6 alkyl, amino-C _1-6 alkyl, C _2-6 alkenyl, and C _2-6

- 1 039042 alkynyl; or

R ^2a and R ^2b together with the carbon atom to which they are attached form C = CH ₂ or C = C (H) C ₁ - ₆ alkyl;

R ^{3 is} selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and - (CH ₂ ) —C (O) OR ⁹ ;

R ^{4 is} selected from heteroaryl, alkyl, —C (O) OR ⁹ , —C (O) NR11R ¹² , —S (O) ₂ R ¹⁰ , —P (O) (OR11) (OR ¹² ), and —P (O ) (OR ¹¹ ) (NR ¹³ R ¹⁵ );

R ^{5 is} selected from H, cyano, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroaralkyl, and —C (O) OR ⁹ ;

R ^{6 is} selected from —C (O) OR ⁹ and —P (O) (OR11) (OR ¹² );

each of R ⁷ and R ⁸ is H;

R ^{9 is} independently selected from H, alkyl, acyloxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl and - (CHR ¹³ ) mZC (O) -R ¹⁴ ;

each R ^{i0 is} independently selected from alkyl, alkenyl, alkynyl, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and each of R ⁱⁱ and R ^{i2 is} independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and - (CHR ¹³ ) _m —ZC (O) —R ¹⁴ ; or

R ¹¹ and R ¹² together with the atoms to which they are attached form a 5-7 membered heterocyclyl; and each R ^{13 is} independently H or alkyl;

each R ^{14 is} independently selected from alkyl, aminoalkyl, heterocyclyl, and heterocyclylalkyl;

R ^{15 is} selected from alkyl, aralkyl, —C (R ¹⁶ ) (R ¹⁷ ) —C (O) OR ¹⁸ ;

each of R ¹⁶ and R ^{17 is} selected from H, alkyl, aminoalkyl, hydroxyalkyl, mercaptoalkyl, sulfonylalkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, heteroaralkyl, and (CH2) C (O) OR ⁹ ;

R ^{18 is} selected from H, alkyl, alkoxyalkyl, aminoalkyl, haloalkyl, amido, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl;

R ¹⁹ is H or alkyl, preferably H; and m is 1 or 2;

with the proviso that either R ⁴ is tetrazolyl or R ⁵ is aralkyl or heteroaralkyl, or both.

In some embodiments, the present invention provides a pharmaceutical composition suitable for use in a subject in the treatment or prevention of cancer, comprising an effective amount of any of the compounds described herein (e.g., a compound of the invention, such as a compound of formula (I) ) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. In some embodiments, pharmaceutical preparations can be used to treat or prevent a condition or disease described herein.

This document describes methods of treating diseases and conditions in which the inhibition of CD73 is effective, comprising administering to a subject in need thereof an effective amount of a compound described herein (e.g., a compound of formula (I) or any of the variants thereof described herein implementation). In some embodiments, the human patient is in need of such treatment. These diseases include, but are not limited to, malignant neoplasms such as lung cancer, kidney cancer, skin cancer, breast cancer, and ovarian cancer. Other diseases and conditions that can be treated using the methods described herein include, but are not limited to, neurological, neurodegenerative and CNS disorders such as depression and Parkinson's disease, cerebral and cardiac ischemic diseases, sleep disorders, fibrosis, immune and inflammatory disorders.

Provided herein are combination formulations of compounds of formula (I) with monoclonal antibodies and other chemotherapeutic agents that can enhance therapeutic benefits beyond adjuvant therapy alone.

Detailed description of the invention

Definitions.

Unless otherwise indicated, all technical and scientific terms used in this document have the meanings generally accepted by a person skilled in the art in the present description. The following references provide one skilled in the art with a general definition of many of the terms used in this description: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used in this document, the following terms have the meanings attributed to them below, unless otherwise indicated.

In some embodiments, chemical structures are presented together with the corresponding chemical name. In case of inconsistencies, the chemical structure prevails over the name.

In this specification, the terms include, containing, including and having, and the like. may have the meaning ascribed to them in the US Patent Law and may mean includes, including, etc .; expressions essentially consisting of or consists essentially in the same way have the meanings specified in the US Patent Law, and the term is open, which allows the presence of more than that indicated, if the basic or new characteristics of what is said do not change in the presence of more what is indicated, but excludes the embodiments of the prior art.

Unless specifically indicated or obvious from context, then as used herein, the term or is understood to be inclusive. Unless specifically indicated or obvious from context, as used herein, the singular is understood to encompass both the singular and the plural.

The term acyl is art-recognized and refers to a group represented by the general formula hydrocarbylC (O) -, preferably alkylC (O) -.

The term acylamino is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC (O) NH-.

The term acyloxy is art-recognized and refers to a group represented by the general formula hydrocarbyl C (O) O-, preferably alkyl C (O) O-.

The term alkoxy refers to an alkyl group, preferably a lower alkyl group, having an oxygen atom attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

The term alkenyl, as used herein, refers to an aliphatic group containing at least one double bond, and is intended to include both unsubstituted alkenyls and substituted alkenyls, the latter of which refer to alkenyl moieties having substituents replacing hydrogen on one or more carbon atoms of the alkenyl group. Such substituents can be on one or more carbon atoms, which are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability does not permit. For example, substitution of an alkenyl group with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

An alkyl group or alkane is a straight or branched non-aromatic hydrocarbon that is fully saturated. Typically, a straight or branched chain alkyl group has from 1 to 20 carbon atoms, preferably from 1 to 10, unless otherwise indicated. Examples of straight and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, hexyl, pentyl, and octyl. A straight or branched chain C1-C6 alkyl group is also referred to as a lower alkyl group.

Moreover, the term alkyl (or lower alkyl), as used throughout the description, in the examples and in the claims, is intended to include both unsubstituted alkyls and substituted alkyls, the latter of which refers to alkyl moieties having substituents replacing hydrogen on one or more carbon atoms of the hydrocarbon skeleton. Such substituents, unless otherwise indicated, may include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. Those skilled in the art will understand that the moieties substituted on the hydrocarbon chain may themselves be substituted, if desired. For example, substituted alkyl substituents may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthio, carbonyls (including ketones, aldehydes, carboxylates, and esters), —CF ₃ , —CN, and the like. Examples of substituted alkyls are described below. Cycloalkyls can be further substituted by alkyls, alkenyls, alkoxy, alkylthio, aminoalkyls, carbonyl-substituted alkyls, —CF ₃ , —CN, and the like.

The term C _x _ _y , when used in combination with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is intended to include groups that contain from x to y carbon atoms in the chain. For example, the term C _x-y alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight chain and branched alkyl, which contain from x to y carbon atoms in the chain, including haloalkyl groups such as trifluoromethyl and 2,2 , 2-trifluoroethyl, etc. C ₀ alkyl denotes hydrogen, where the group is at the terminal

- 3 039042, the connection is internal. The terms C _2-y alkenyl and C _2-y alkynyl refer to substituted or unsubstituted unsaturated aliphatic groups, similar in length and possible substitution on the alkyls described above, but which contain at least one double or triple bond, respectively.

The term alkylamino, as used herein, refers to an amino group substituted with at least one alkyl group.

The term alkylthio, as used herein, refers to a thiol group substituted with an alkyl group, and may be represented by the general formula alkyl S-.

The term alkynyl, as used herein, refers to an aliphatic group containing at least one triple bond, and is intended to include both unsubstituted alkynyls and substituted alkynyls, the latter of which refer to alkynyl moieties having substituents replacing hydrogen on one or more carbon atoms of an alkynyl group. Such substituents can be on one or more carbon atoms, which are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups as discussed above, except where stability does not permit. For example, substitution of an alkenyl group with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

The term amide, as used herein, refers to the group

A ”where each R ^{30 is} independently hydrogen or a hydrocarbyl group, or two R ³⁰ taken together with the N atom to which they are attached form a heterocycle containing from 4 to 8 atoms in a ring structure.

The terms amine and amino are known in the art and refer to both unsubstituted and substituted amines and their salts, for example, a group that may be represented by

where each R ^{31 is} independently hydrogen or a hydrocarbyl group, or two R ³¹ taken together with the N atom to which they are attached form a heterocycle containing from 4 to 8 atoms in a ring structure. The term aminoalkyl, as used herein, refers to an alkyl group substituted with an amino group.

The term aralkyl, as used herein, refers to an alkyl group substituted with an aryl group.

The term aryl, as used herein, includes substituted or unsubstituted single ring aromatic groups in which each ring atom is carbon. Preferably the ring is a 5-7 membered ring, more preferably a 6 membered ring. The term aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbon atoms are common to two adjacent rings, where at least one of the rings is aromatic, for example, the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls , aryl, heteroaryl and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

The term carbamate is accepted in the art and belongs to the group

where R ³² and R ³³ independently represent hydrogen or a hydrocarbyl group such as an alkyl group, or R ³² and R ³³ taken together with the intermediate atom (s) form a heterocycle containing from 4 to 8 atoms in a ring structure.

The terms carbocycle and carbocyclic, as used herein, refer to a saturated or unsaturated ring in which each ring atom is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond.

The term carbocycle includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each bicyclic carbocycle ring can be selected from saturated, unsaturated and

- 4 039042 aromatic rings. A carbocycle includes bicyclic molecules in which one, two, or three or more atoms are common to two rings. The term fused carbocycle refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each fused carbocycle ring can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, eg phenyl, may be fused with a saturated or unsaturated ring, eg, cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as far as valence permits, is included in the definition of carbocyclic. Examples of carbocycles include cyclopentane, cyclohexane, bicyclo [2.2.1] heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo [4.2.0] oct-3-ene, naphthalene, and adamantane. ... Examples of condensed carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo [4.2.0] octane, 4,5,6,7 tetrahydro-III-indene, and bicyclo [4.1.0] hept- 3-en. Carbocycles may be substituted at any or more positions capable of carrying a hydrogen atom.

A cycloalkyl group is a cyclic hydrocarbon that is fully saturated. Cycloalkyl includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group contains from 3 to about 10 carbon atoms, more usually from 3 to 8 carbon atoms, unless otherwise indicated. The second ring of the bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two, or three or more atoms are common to two rings. The term fused cycloalkyl refers to a bicyclic cycloalkyl in which each of the rings has two adjacent atoms in common with the other ring. The second ring of the fused bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings.

A cycloalkenyl group is a cyclic hydrocarbon group containing one or more double bonds.

The term carbocyclylalkyl, as used herein, refers to an alkyl group substituted with a carbocyclic group.

The term carbonate is art-recognized and refers to the group —OCO2 — R ³⁴ , where R ³⁴ is a hydrocarbyl group.

The term carboxy, as used herein, refers to a group represented by the formula —CO ₂ H.

The term ester, as used herein, refers to the group —C (O) OR ³⁵ , where R ³⁵ is a hydrocarbyl group.

The term ether, as used herein, refers to a hydrocarbyl group linked through an oxygen atom to another hydrocarbyl group. Accordingly, the ether substituent of the hydrocarbyl group may be hydrocarbyl-O-. Ethers can be either symmetrical or unbalanced. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include alkoxyalkyl groups, which may be represented by the general formula alkyl-O-alkyl.

The terms halo and halogen, as used herein, mean halogen and include chlorine, fluorine, bromine, and iodine.

The terms hetaralkyl and heteroaralkyl, as used herein, refer to an alkyl group substituted with a hetaryl group.

The term heteroalkyl, as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, where the two heteroatoms are not adjacent.

The terms heteroaryl and hetaryl include substituted or unsubstituted aromatic single ring structures, preferably 5-7 membered rings, more preferably 5-6 membered rings, wherein the ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms heteroaryl and hetaryl also include polycyclic ring systems containing two or more cyclic rings in which two or more carbon atoms are common to two adjacent rings, where at least one of the rings is heteroaromatic, for example, the other cyclic rings may be cycloalkyl, cycloalkenyls, cycloalkynyls, aryls, heteroaryls and / or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

The term heteroatom, as used herein, means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen and sulfur.

The terms heterocyclyl, heterocycle and heterocyclic refer to substituted or unsubstituted non-aromatic ring structures, preferably 3-10 membered rings, more preferably 3-7 membered rings, wherein the ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two goethe

- 5 039042 Roatoma. The terms heterocyclyl and heterocyclic also include polycyclic ring systems containing two or more cyclic rings in which two or more carbon atoms are common to two adjacent rings, where at least one of the rings is heterocyclic, for example, the other cyclic rings may be cycloalkyl, cycloalkenyls, cycloalkynyls, aryls, heteroaryls and / or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

The term heterocyclylalkyl, as used herein, refers to an alkyl group substituted with a heterocyclic group.

The term hydrocarbyl, as used herein, refers to a group that is bonded through a carbon atom that does not have an = O or = S substituent, and typically contains at least one carbon-hydrogen bond and predominantly a carbon skeleton, but optionally may include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl for the purposes of this application, but not such substituents as acetyl (which has an = O substituent on the linking carbon atom) and ethoxy (which is attached through an oxygen atom , not a carbon atom). Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

The term hydroxyalkyl, as used herein, refers to an alkyl group substituted with a hydroxy group.

The term lower when used in combination with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is intended to include groups where there are ten or less non-hydrogen atoms in the substituent, preferably six or fewer. Lower alkyl, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In some embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents as defined herein are, respectively, lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they are themselves alone or in combination with other substituents such as hydroxyalkyl and aralkyl in the descriptions (in which case, for example, the atoms in the aryl group are not counted when calculating the carbon atoms in the alkyl substituent).

The terms polycyclyl, polycyclic, and polycyclic refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls and / or heterocyclyls) in which two or more atoms are common to two adjacent rings, for example, the rings are fused rings. Each of the rings of the polycycle can be substituted or unsubstituted. In some embodiments, each ring of the polycycle contains 3 to 10 ring atoms, preferably 5 to 7.

The term silyl refers to a silicon group with three hydrocarbyl moieties attached thereto.

The term substituted refers to moieties having substituents replacing hydrogen on one or more carbon atoms of the main chain. It is understood that a substitution or substituted includes the implicit condition that such a substitution corresponds to the permissible valence of the substituted atom and the substituent, and that the substitution leads to a stable compound, for example, which does not spontaneously undergo transformation, such as rearrangement, cyclization, elimination, etc. ... As used herein, the term substituted is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic, organic substituents. The permissible substituents can be one or more and the same or different for the respective organic compounds. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatoms. Substituents can include any substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioether, thioacetate or thioformate) alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino , amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the substituents themselves may be substituted if necessary. Unless specifically indicated that they are unsubstituted, references to chemical fragments in this description are understood to include substituted variants. For example, reference to an aryl group or moiety implicitly includes both substituted and unsubstituted variants.

The term sulfate is known in the art and refers to the group —OSO3H or a pharmaceutically acceptable salt thereof.

The term sulfonamide is known in the art and refers to a group represented by the general formulas

- 6 039042 lSN. ₃₇ Ν '° о R ³⁷ „or R ³⁷ , where R ³⁶ and R ³⁷ independently represent hydrogen or hydrocarbyl, such as alkyl, or R ³⁶ and R ³⁷ , taken together with the intermediate atom (s), form a heterocycle containing from 4 up to 8 atoms in a ring structure.

The term sulfoxide is art-recognized and refers to the group —S (O) —R ³⁸ , where R ³⁸ is hydrocarbyl.

The term sulfonate is art-recognized and refers to the group —SO ₃ H or a pharmaceutically acceptable salt thereof.

The term sulfone is art-recognized and refers to the group —S (O) 2 — R ³⁹ , where R ³⁹ is hydrocarbyl.

The term thioalkyl, as used herein, refers to an alkyl group substituted with a thiol group.

The term thioester as used herein refers to the group —C (O) SR ⁴⁰ or —SC (O) R ⁴⁰ , where R ¹⁰ is hydrocarbyl.

The term thioether, as used herein, is equivalent to an ether where an oxygen atom is replaced by a sulfur atom.

The term urea is accepted in the art and can be represented by the general formula

where R ⁴¹ and R ⁴² independently represent hydrogen or hydrocarbyl such as alkyl, or any presence of R ⁴¹ taken together with R ⁴² and the intermediate atom (s) forms a heterocycle containing from 4 to 8 atoms in the ring structure.

The term protecting group refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group. Typically, the protecting group can be selectively removed as desired during synthesis. Examples of protecting groups can be found in reviews Greene and Wuts, Protective Groups in Organic Chemistry, 3 ^rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethylsilyl (TMS), 2-trimethylsilyl-ethanesulfonyl (TES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitroveratryloxycarbonyl (NVOC) and the like. Representative hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers such as ethylene glycol and propylene glycol derivatives and allyl ethers.

In a graphical representation of the compounds shown in this application, the thickened conical line () denotes a substituent that is located above the plane of the ring to which the asymmetric carbon atom belongs, and the dashed line () denotes a substituent that is located below the plane of the ring to which the asymmetric atom belongs carbon.

In some embodiments, the implementation of the compounds of the present invention may be racemic. In some embodiments, the implementation of the compounds of the present invention can be enriched in one enantiomer. For example, a compound of the invention may have an ee. more than about 30% ee, about 40% ee, about 50% ee, about 60% ee, about 70% ee, about 80% ee, approximately 90% ee. or even about 95% ee. or more. In some embodiments, compounds of the invention may have more than one stereocenter. In some such embodiments, the compounds of the invention may be enriched in one or more diastereomers. For example, a compound of the invention may have D.I. more than about 30% d.i., about 40% d.i., about 50% d.i., about 60% d.i., about 70% d.i., about 80% d.i., approximately 90% e.i. or even about 95% D.I. or more.

In some embodiments, a therapeutic agent can be enriched to preferentially contain one enantiomer of a compound (eg, Formula (I)). The enantiomerically enriched mixture may contain, for example, at least about 60 mol% of one enantiomer, or more preferably at least about 75, about 90, about 95, or even eye

- 7 039 042 lo 99 mol%. In some embodiments, a compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially does not mean that the substance in question is less than about 10%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1% as compared to the amount of the other enantiomer, for example, in a composition or mixture of compounds. For example, if a composition or mixture of compounds contains about 98 g of the first enantiomer and about 2 g of the second enantiomer, it can be said to contain about 98 mol% of the first enantiomer and only about 2% of the second enantiomer.

In some embodiments, the therapeutic can be enriched to preferentially contain one diastereomer of a compound (eg, Formula (I)). The diastereomerically enriched mixture may contain, for example, at least about 60 mol% of a single diastereomer, or more preferably at least about 75, about 90, about 95, or even about 99 mol%.

The term subject to which the administration is applied includes, but is not limited to, humans (i.e. men or women of any age group, e.g., pediatric subject (e.g., infants, children, adolescents) or adults (e.g., young adult, adult middle-aged or elderly)) and / or other primates (for example, Javanese macaques, rhesus monkeys); mammals, including commercially significant mammals such as cattle, pigs, horses, sheep, goats, cats and / or dogs; and / or birds, including commercially significant birds such as chickens, ducks, geese, quails and / or turkeys. The preferred subjects are humans.

As used herein, a therapeutic agent that prevents a disorder or condition refers to a compound that, in a statistical sample, results in a reduction in the occurrence of a disorder or condition in a treated sample relative to an untreated control sample, or delays the occurrence, or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control.

The term treatment includes prophylactic and / or therapeutic treatment. The term prophylactic or therapeutic treatment is known in the art and includes administering to a subject one or more of the described compositions. When administered before the clinical manifestation of an undesirable condition (for example, a disease or other undesirable condition of a subject), the treatment is prophylactic (i.e., protects the subject from the development of an undesirable condition), and when administered after the manifestation of an undesirable condition, the treatment is therapeutic (i.e., intended for reduce, alleviate or stabilize an existing undesirable condition or its side effects).

The term prodrug is intended to encompass compounds that, under physiological conditions, are converted to the therapeutically active agents of the present invention (eg, a compound of Formula I). A general method for preparing a prodrug is to include one or more selected moieties that hydrolyze under physiological conditions to release the desired molecule. In other embodiments, the prodrug is converted by enzymatic activity in the subject. For example, esters or carbonates (eg esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present invention. In some embodiments, some or all of the compounds of formula (I) in the formulation above may be replaced with an appropriate suitable prodrug, for example, where the hydroxyl in the parent compound is either an ester of either a carbonate or a carboxylic acid.

An effective amount, as used herein, refers to an amount that is sufficient to achieve the desired biological effect. A therapeutically effective amount, as used herein, refers to an amount that is sufficient to achieve the desired therapeutic effect. For example, a therapeutically effective amount can refer to an amount that is sufficient to improve at least one sign or symptom of cancer.

The response to a treatment modality may include, but is not limited to, a decrease or decrease in negative symptoms, a decrease in the progression of a disease or its symptoms, an increase in favorable symptoms or clinical outcomes, a decrease in side effects, stabilization of the disease, partial or complete cure of the disease.

The present invention relates to compounds of formula (I)

- 8 039042

R ⁴ R ³

(I) or their pharmaceutically acceptable salts and / or prodrugs, where

X is O, NR ⁷ or CR7R ⁸ ;

Y represents O or S;

Z represents NR ¹⁹ , O or S;

Het is heterocyclyl or heteroaryl;

R ^{1a is} selected from H, halogen, hydroxy, cyano, azido, amino, C _1-6 alkyl, hydroxy _{C 1-6} alkyl, amino-C _1-6 alkyl, C _1-6 acyloxy, -OC (O) -OC _{1 -6} αalkyl, C _1-6 alkoxy, C _2-6 α alkenyl and C _2-6 alkynyl; and

R ^{1b is} selected from H, halogen, C _1-6 alkyl, hydroxy-C _1-6 alkyl, amino-C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl; or

R ^1a and R ^1b together with the carbon atom to which they are attached form C = CH ₂ or C = C (H) C _1-6 alkyl;

R ^{2a is} selected from H, halogen, hydroxy, cyano, azido, amino, C _1-6 alkyl, hydroxy-C _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 acyloxy, -OC (O) -OC _{1 -6} αalkyl, C _1-6 alkoxy, C _2-6 alkenyl, and C _2-6 alkynyl;

R ^{2b is} selected from H, halogen, C _1-6 alkyl, hydroxy-C _1-6 alkyl, amino-C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl; or

R ^2a and R ^2b together with the carbon atom to which they are attached form C = CH ₂ or C = C (H) C _1-6 alkyl;

R ^{3 is} selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and - (CH2) —C (O) OR ⁹ ;

R ^{4 is} selected from heteroaryl, alkyl, —C (O) OR ⁹ , —C (O) NR ¹¹ R ¹² , —S (O) 2R ¹⁰ , —P (O) (OR ¹¹ ) (OR ¹² ), and —P (O) (OR ¹¹ ) (NR ¹³ R ¹⁵ );

R ^{5 is} selected from H, cyano, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroaralkyl, and —C (O) OR ⁹ ;

R ^{6 is} selected from —C (O) OR ⁹ and —P (O) (OR ¹¹ ) (OR ¹² );

each of R ⁷ and R ⁸ is H;

R ^{9 is} independently selected from H, alkyl, acyloxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl and - (CHR ¹³ ) mZC (O) -R ¹⁴ ;

each R ^{10 is} independently selected from alkyl, alkenyl, alkynyl, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and R ¹¹ and R ^{12 are} each independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and - (CHR ¹³ ) _m —ZC (O) —R ¹⁴ ; or

R ¹¹ and R ¹² together with the atoms to which they are attached form a 5-7 membered heterocyclyl; and each R ^{13 is} independently H or alkyl;

each R ^{14 is} independently selected from alkyl, aminoalkyl, heterocyclyl, and heterocyclylalkyl;

R ^{15 is} selected from alkyl, aralkyl, —C (R ¹⁶ ) (R ¹⁷ ) —C (O) OR ¹⁸ ;

each of R ¹⁶ and R ^{17 is} selected from H, alkyl, aminoalkyl, hydroxyalkyl, mercaptoalkyl, sulfonylalkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, heteroaralkyl, and (CH2) C (O) OR ⁹ ;

R ^{18 is} selected from H, alkyl, alkoxyalkyl, aminoalkyl, haloalkyl, amido, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl;

R ¹⁹ is H or alkyl, preferably H; and m is 1 or 2;

with the proviso that either R ⁴ is tetrazolyl or R ⁵ is aralkyl or heteroaralkyl, or both.

In some embodiments, R ^{1a is} selected from H, halogen, hydroxy, cyano, azido, amino, C1-6 alkyl, hydroxy C1-6 alkyl, amino C1-6 alkyl, C1-6 acyloxy, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl ... In some embodiments, R ^1a is fluoro, chloro, or bromo, preferably fluoro. In some embodiments, R ^1a is C1-6 alkoxy. In some embodiments, R ^1a is C _1-6 alkyl. In some embodiments, R ^1a is hydroxy. In some embodiments, R ^1a is ethynyl or vinyl. In some embodiments, R ^1a is cyano. In some embodiments, R ^1a is azido. In some embodiments, R ^1a is

- 9 039042 is an amino. In some embodiments, R ^1a is hydrogen.

In some embodiments, R ^{2a is} selected from H, halogen, hydroxy, cyano, azido, amino, C1-6αalkyl, hydroxyC1-6alkyl, amino-C1-6αalkyl, C1-6acyloxy, C1-6αalkoxy, C2-6alkenyl, and C2-6alkynyl. In other embodiments, R ^2a is fluoro, chloro, or bromo, preferably fluoro. In some embodiments, R ^2a is C1-6α alkoxy. In some embodiments, R ^2a is C1-6αalkyl. In some embodiments, R ^2a is hydroxy. In some embodiments, R ^2a is cyano. In some embodiments, R ^2a is azido. In some embodiments, R ^2a is amino. In some embodiments, R ^2a is C1-6 acyloxy.

In some embodiments, R ^1b is H. In other embodiments, R ^1b is fluoro. In other embodiments, R ^1b is C1-6αalkyl. In some embodiments, R ^2b is H. In other embodiments, R ^2b is fluoro. In other embodiments, R ^2b is C1-6alkyl.

In some embodiments, R ^1a is fluoro and R ^1b is H. In other embodiments, R ^2a is fluoro and R ^2b is H. In some embodiments, R ^1a and R ^1b are each fluoro. In other embodiments, R ^2a and R ^2b are each fluoro. In some embodiments, R ^1a is fluoro and R ^2a is C1-6 alkoxy. in some embodiments, R ^1a is fluoro and R ^2a is C1-6αalkyl, such as methyl or ethyl. In some embodiments, R ^2a is hydroxy and R ^2b is methyl.

In some embodiments, R ^1a is fluoro and R ^2a is hydroxy. In some embodiments, R ^1a is chloro and R ^2a is hydroxy. In some embodiments, R ^1a is hydroxy and R ^2a is hydrogen. In some embodiments, R ^1a is fluoro and R ^2a is hydrogen. In some embodiments, R ^1a is hydroxy and R ^2a is C1-6α alkoxy such as methoxy. In some embodiments, R ^1a is hydroxy and R ^2a is fluoro. In some embodiments, R ^1a is hydroxy and R ^2a and R ^2b together with the carbon atom to which they are attached form ethynyl. In some embodiments, R ^1a is hydroxy and R ^2a is C1-6αalkyl, such as methyl. In some embodiments, R ^1a is fluoro, R ^2a is fluoro, and R ^2a is hydroxy. In some embodiments, R ^1a is hydroxy, R ^2a is hydroxyl, and R ^2b is C1-6αalkynyl, such as ethynyl. In some embodiments, R ^1a is hydroxy and R ^2a is C1-6αalkynyl, such as ethynyl. In some embodiments, R ^1a is hydroxy and R ^2a is C2-6αalkenyl. In some embodiments, R ^1a is hydroxy and R ^2a is amino. In some embodiments, R ^1a is hydroxy and R ^2a is azido. In some embodiments, R ^1a is azido and R ^2a is hydroxy. In some embodiments, R ^1a is C1-6αalkyl, such as methyl, and R ^2a is hydroxy.

In some embodiments, the compound of formula (I) has the following structure:

In some embodiments, the implementation of R ^1a has the α-configuration. In some such embodiments, the compound of formula (I) has structure (IA)

R ⁴ R ³ (IA)

In other embodiments, R ^1a has the β configuration. In some such embodiments, the compound of formula (I) has structure (IB)

- 10 039042

In some embodiments, the implementation of R ^2a has the α-configuration. In some such embodiments, the implementation of the compound of formula (I) has the structure (IC)

In other embodiments, R ^2a has the β configuration. In some embodiments, a compound of formula (I) has structure (ID)

In some embodiments, the implementation of the compound of formula (I) has the structure (IE)

In some embodiments, R ³ is alkyl and alkyl is unsubstituted or substituted, for example, with one or more substituents selected from halogen, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate and phosphinate. In some embodiments, the substituents are selected from halogen, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl. In some preferred embodiments, R ³ is H. In other preferred embodiments, R ³ is unsubstituted C1-6αalkyl.

In some embodiments, R ⁴ is heteroaryl. In some preferred embodiments, R ⁴ is tetrazolyl.

In some embodiments, R ^{4 is} selected from —C (O) OR ⁹ , —C (O) NR11R ¹² , —S (O) 2R ^10, and —P (O) (OR ¹¹ ) (OR ¹² ). In some preferred embodiments, R ⁴ is —C (O) OR ⁹ . In some embodiments, R ⁹ is H or C1-6alkyl. In some embodiments, R ⁴ is —C (O) NR11R ¹² . In some such embodiments, R ¹¹ and R ¹² are each alkyl, such as methyl. In an alternative to such embodiments, R ¹¹ is alkyl and R ¹² is hydrogen. In other embodiments, R ⁴ is alkyl substituted with a carboxyl or ester group (eg, alkoxycarbonyl).

In some embodiments, R ^{5 is} selected from H, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, and heteroaralkyl.

In some embodiments, R ⁵ is H, aralkyl, or heteroaralkyl. As an example, R ⁵ may be —CH ₂ -pyridinyl, —CH ₂ -thiophenyl, benzyl, or β-naphthyl. In some embodiments, R ⁴ is heteroaryl such as tetrazolyl, R ⁵ is unsubstituted or substituted benzyl, and R ⁶ is —COOH.

In some embodiments, R ^{5 is} selected from H, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, and heteroaralkyl. In some embodiments, R ^{5 is} selected from alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, and heteroaralkyl, and each is unsubstituted or substituted with one or more substituents, for example, selected from halogen, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl , thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, phosphinate, cycloalkyl, heteroaryl, heterocyclyl, arylalkyl and hetero. In some embodiments, the substituents are selected from halogen, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl , phosphoryl, phosphate, phosphonate, phosphinate, cycloalkyl, heterocyclyl, arylalkyl, and heteroarylalkyl. In some embodiments, the substituents are selected from halogen, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl. In other embodiments, the substituents are selected from chlorine, trifluoromethyl, trifluoromethoxy, phenyloxy, dimethylamido, methylsulfonyl, CN, and carboxylic acid. In some preferred embodiments, R ⁵ is H or aralkyl.

In some embodiments, R ⁵ is aralkyl, for example, where the aryl ring is substituted or unsubstituted phenyl or naphthyl. In other embodiments, R ⁵ is heteroaralkyl, for example, wherein the heteroaryl ring is selected from substituted or unsubstituted benzofuranyl, benzothienyl, benzothiazolyl, pyridyl, thienyl, furanyl, pyrazolyl, thiazolyl, oxazolyl, and oxadiazolyl.

In some embodiments, R ⁵ is aralkyl or heteroaralkyl, where the aryl or heteroaryl ring, respectively, is unsubstituted or substituted with one or more substituents, for example, selected from halogen, CN, OH, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy , aryloxy, aralkyloxy, alkylsulfonyl, sulfonamido, amido, amino, carboxyl, ester group (e.g. lower alkyl ester group), heterocyclyl, heteroaryl, aryl, aralkyl, and heteroaralkyl. In some embodiments, the substituents are selected from halogen, CN, OH, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylsulfonyl, sulfonamido, amido, amino, carboxyl, ester (e.g., alkyl ester), lower heteroaryl, aryl, aralkyl, and heteroaralkyl. In some such embodiments, the substituents on the aryl or heteroaryl ring of the aralkyl or heteroaralkyl, respectively, are selected from halogen, CN, haloalkyl, haloalkoxy, carboxy, an ester group (e.g., a lower alkyl ester group), and aryl. In other such embodiments, the substituents on the aryl or heteroaryl ring of the aralkyl or heteroaralkyl, respectively, are selected from tetrazolyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl.

In some embodiments, R ⁶ is —C (O) OR ⁹ . In some embodiments, R ⁹ is H or C1.6αalkyl. In other embodiments, R ⁶ is —P (O) (OR ⁿ ) (OR ¹² ) and R ¹¹ and R ¹² are each H. In some embodiments, R ⁷ is H or C1. ₆ alkyl. In some embodiments, R ⁸ is H. In some embodiments, R ⁹ is H or C ₁ . ₆ alkyl such as methyl or ethyl. In some embodiments, R ¹¹ and R ¹² are each H.

In some embodiments, each R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^11, and R ^{12 is} independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, and each , is unsubstituted or substituted, for example, by one or more substituents selected from halogen, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido , sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate and phosphinate. In some embodiments, the substituents are selected from halogen, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl.

In some embodiments, X is O. In some embodiments, Y is O. In some embodiments, the substituent bearing Y has the R configuration. In other embodiments, the Y-bearing substituent has the S-configuration. In some embodiments, Z is O. In other embodiments, Z is NH.

In some embodiments, Het is a nitrogen-containing heterocyclyl or heteroaryl. In some embodiments, Het is attached through a nitrogen atom. In other embodiments, Het is attached through a carbon atom. In some embodiments, Het is 5-8 membered monocyclic or 5-10 membered bicyclic heteroaryl, and is

- 12 039042 is unsubstituted or substituted, for example, by one or more substituents selected from halogen, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, cyclothioalkyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate , urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate and phosphinate. In some embodiments, substituents are selected from halogen, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl , phosphoryl, phosphate, phosphonate and phosphinate. In some embodiments, the substituents are selected from halogen, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl. In some preferred embodiments, Het is selected from purinyl, imidazopyrimidinyl, and pyrrolopyrimidinyl. In other embodiments, Het is substituted with one or two substituents independently selected from halogen, aralkyl, amino, azido, and hydroxy. In some embodiments, Het is substituted with one halogen and one amino substituent. In some preferred embodiments, Het is

In some embodiments, Het is selected from

In some embodiments, Het is selected from

In some embodiments, Het is a group of formula (i) - (xiv) below

- 13 039042

where R ^u represents hydrogen, halogen, cyano, —NH2, —NHR ²⁰ , —NHCOR ²⁰ , —NR ²⁰ R ²¹ , —R ²⁰ , —SR ²⁰ , —OH and —OR ²⁰ ;

R ^w represents hydrogen, halogen, —NHR ²² , —NR ²² R ²³ , R ²² , —OH and —OR ²² ;

R ^v and R ^x independently represent hydrogen, halogen, halogen C1.6 alkyl, -NH2, -NHR ²⁴ , -NR ²⁴ R ²⁵ , -R ²⁴ , -SR ²⁴ , cyano, -OH, -OR ²⁴ , -SO2R ²⁴ , -C ^ alkylene NH2, -O ^ alkylene NHR ²⁴ , -C1.6 alkylene NR ²⁴ R ²⁵ , -R ²⁴ , -C1.6 alkylene SR ²⁴ , -C ^ alkylene OH, -C1. ₆ alkylene OR ²⁴ , -C _1-6 alkylene SO2R ²⁴ ,

R ^s and Rt are independently hydrogen, halogen, or C _1-6 alkyl; and where R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ and R ^{25 are} optionally independently C ₁ . ₆ alkyl, —C ₂ C ₆ alkenyl, —C ₂ -C ₆ alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl _{C 1} . ₆ alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylC ₁ . ₆ alkyl, optionally substituted aryl, optionally substituted arylC1. ₆ alkyl, optionally substituted heteroaryl, or optionally substituted heteroarylC ₁ . ₆ alkyl;

or R ²⁰ and R ²¹ , R ²² and R ²³ and R ²⁴ and R ²⁵ together with the nitrogen atom to which they are attached form an optionally substituted nitrogen-containing heterocyclyl.

In some embodiments

represents

- 14 039042

V // ο-, sk _ ^, he \ / k ^L 7 "/ H J unit unit Ν, Ν // ,. HO Ξ 7 \ \ ___ / 0, ^ OH \ ---- y ηΔ / L units ^but ^ o, F ₃ C - 4 / / = / ____ // H H ₂ N --- L units CHH units n TG ⁰ 0, □ __ / \ // 3 ^ / -on - / o unit. ⁰ / Me0 _; 5 \ ^ _x EHD \ / X ^ns k'z>/> t w lU. Inf about about ₂ but with / / ⁰ X --- · ^0Η but N. ΓΙ '° about. In some embodiments, R 'R ⁵ —X R ⁶ is he / o. —On ^ her. ^ H. unit no. unit ^OL t °, ° _{/ O} n h_ / °% ^ noos units | '''''A HN - T ^ o-Y unit 4Z / A 0 he A Ο ^, ΟΗ / - ^0H \ ^{from ===} / unit x ed / o a Ϊ ^l to 0, but, - / ° ^{he RGU} units ° \ ^ eded ^he o / u / \ but / U h / (d / r U 0, 0, the CI T / C # to ^h // \\ ^ -.. ° ¹¹ bUT / CPU <-.>) - unit C) g / F ₃ C ^ .OI \ I λ, Λ ^Η0 - ^ Α, ⁰ or 4 -, ¾ / ⁿ U U ** ^H0 \ ChkCh units ^ ογ. food food or ⁰ .

- 15 039042

In some embodiments

represents

In some embodiments, the implementation is

- 16 039042

- 17 039042

- 18 039042 represents

In some embodiments, wherein each R _{A is} independently selected from halogen, CN, OH, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy (e.g., substituted or unsubstituted benzyloxy), alkylsulfonyl, sulfonamido, amido, amino, hydroxycarbonyl, alkoxycarbonyl , heterocyclyl, heteroaryl, aryl, aralkyl, and heteroaralkyl; and

- 19 039042 k stands for 1, 2 or 3.

In some embodiments, RA is selected from halogen, CN, OH, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy (e.g., substituted or unsubstituted benzyloxy), alkylsulfonyl, sulfonamido, amido, amino, hydroxycarbonyl, alkoxycarbonyl, arylaero , aralkyl and heteroaralkyl. In some embodiments, R _{A is} selected from pyridyl, pyrazolyl, pyrrolidinoyl, azapanonyl, morpholinonyl, piperazonyl, tetrahydropyrimidinoyl, phenyl, and benzyloxy.

Further embodiments

In the following numbered embodiments, unless otherwise indicated,

C _1-6 alkyl is unsubstituted;

C _1-6 alkyl in C ₁ . ₆ alkyloxy is unsubstituted;

haloC _1-6 alkyl is C _1-6 alkyl substituted with one to five halogen atoms;

haloC _1-6 alkyloxy is C _1-6 αalkyloxy substituted with one to five halogen atoms;

C _2-6 alkenyl is unsubstituted;

C _2-6 alkynyl is unsubstituted;

^^ alkylene group is unsubstituted;

C _2-6 α-alkenylene group is unsubstituted;

optionally substituted C _1-6 alkyl optionally substituted with one or two substituents independently selected from hydroxy, C _1-6 alkyloxy, halogen, haloC _1-6 alkyl, haloC _1-6 alkyloxy, cyano, -NH ₂ , -NH (C _{1 -6} alkyl), -N (C _1-6 αalkyl) ₂ , optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;

carbocyclyl is an unsubstituted saturated or partially unsaturated mono or bicyclic ring containing from 3 to 10 carbon atoms;

optionally substituted carbocyclyl is optionally substituted with one, two or three substituents independently selected from C _1-6 alkyl, halogen, hydroxy, or C _1-6 alkoxy;

aryl is phenyl or naphthyl;

optionally substituted aryl is optionally substituted with one, two or three substituents independently selected from hydroxy, C _1-6 alkyloxy, halogen, haloC _1-6 alkyl, haloC _1-6 alkyloxy, cyano, -NH2, -NH (C _1-6 alkyl ), —N (C _1-6 αalkyl) ₂ , optionally substituted carbocyclyl, aryl [optionally substituted with one, two or three substituents independently selected from hydroxy, C _1-6 alkyloxy, halogen, haloC _1-6 alkyl, haloC _{1- 6} alkyloxy, cyano, —NH2, —NH (C _1-6 alkyl), and —N (C _1-6 alkyl) ₂ ], heteroaryl [optionally substituted with one, two or three substituents independently selected from hydroxy, C _{1- 6} alkyloxy, halogen, haloC _1-6 alkyl, haloC _1-6 alkyloxy, cyano, -NH2, -NH (C _1-6 αalkyl), -N (C _1-6 alkyl) ₂ ] and heterocyclyl [optionally substituted with one, two or three substituents independently selected from hydroxy, C _1-6 αalkyloxy, halogen, haloC _1-6 alkyl, haloC _1-6 alkyloxy, cyano, -NH2, -NH (C _1-6 alkyl), -M (unsubstituted C _1-6 alkyl k) ₂ ];

heteroaryl is an unsubstituted five to ten membered or five to six membered aromatic ring containing one to four or one to three heteroatoms independently selected from N, O and S, where the remaining ring members are carbon;

an optionally substituted heteroaryl is a five to ten membered aromatic ring containing one to four heteroatoms independently selected from N, O and S, where the remaining ring members are carbon, which is optionally substituted with one, two or three substituents independently selected from hydroxy, C _1-6 αalkyloxy, halogen, haloC _1-6 alkyl, haloC _1-6 alkyloxy, cyano, -NH2, -NH (C _1-6 alkyl), -N (C _1-6 alkyl) ₂ , optionally substituted carbocyclyl, aryl [optionally substituted with one, two or three substituents independently selected from hydroxy, C _1-6 αalkyloxy, halogen, haloC _1-6 alkyl, haloC _1-6 alkyloxy, cyano, —NH2, NH (C _1-6 alkyl) and -N (C _1-6 alkyl) ₂ ], heteroaryl [optionally substituted with one, two or three substituents independently selected from hydroxy, unsubstituted C _1-6 αalkyloxy, halogen, haloC _1-6 alkyl, haloC _1-6 alkyloxy, cyano , -NH2, -NH (C _1-6 alkyl), -N (C _1-6 alkyl) ₂ ] and heterocyclyl [optional substituted with one, two or three substituents independently selected from hydroxy, C _1-6 αalkyloxy, halogen, haloC _1-6 alkyl, haloC _1-6 alkyloxy, cyano, -NH2, -NH (C _1-6 alkyl), - N (C _1-6 alkyl) ₂ ];

heterocyclyl is an unsubstituted monocyclic, saturated or partially unsaturated 4-8 membered ring containing one to three heteroatoms independently selected from N, O, S, SO and SO2, and optionally containing one or two CO, where the remaining atoms in the ring are carbon, and which is optionally fused to phenyl or a 5-6 membered carbocyclic or 5 or 6 membered heteroaryl ring;

nitrogen-containing heterocyclyl is a heterocyclyl ring that contains at least one nitrogen atom;

optionally substituted heterocyclyl is heterocyclyl, which is optionally substituted with one, two or three substituents independently selected from hydroxy, C ₁ . ₆ al

- 20 039042 kyloxy, halogen, haloC _1-6 alkyl, haloC _1-6 alkyloxy, cyano, —NH2, —MNC _1-6 alkyl), —M (C _1-6 alkyl) ₂ , optionally substituted carbocyclyl, aryl [optionally substituted with one, two or three substituents independently selected from hydroxy, C _1-6 alkyloxy, halogen, haloC _1-6 alkyl, haloC _1-6 alkyloxy, cyano, —NH ₂ , —NH (C _1-6 α alkyl) and - N (C _{1. 6} alkyl) ₂ ], heteroaryl [optionally substituted with one, two or three substituents independently selected from hydroxy, C _1-6 alkyloxy, halogen, haloC _1-6 alkyl, haloC _1-6 alkyloxy, cyano, - NH2, NH (C _1-6 alkyl), -N (C _1-6 alkyl) ₂ ] and heterocyclyl optionally substituted with one, two or three substituents independently selected from hydroxy, C _1-6 alkyloxy, halogen, haloC _{1- 6} alkyl, haloC _1-6 alkyloxy, cyano, —NH2, —NH (C _1-6 alkyl), —N (C _1-6 alkyl) ₂ ];

optionally substituted carbocyclylC _1-6 alkyl is an optionally substituted carbocyclyl linked through a C _1-6 alkyl;

optionally substituted heterocyclylC _1-6 alkyl is optionally substituted heterocyclyl linked through C _1-6 alkyl;

optionally substituted arylC _1-6 alkyl is optionally substituted aryl linked through C _1-6 alkyl; and optionally substituted heteroarylC _1-6 alkyl is optionally substituted heteroaryl linked through C _1-6 alkyl.

Embodiment 1

In Embodiment 1, the compound of formula (I) is defined in the Summary of the Invention.

In a sub-embodiment of Embodiment 1, the compounds of formula (I) are those wherein when R ⁵ is hydrogen, R ^1a and R ^{1b are} independently hydrogen, hydroxy, halogen, C1-C3 alkyl, C1-C3 alkoxy, C2-C3 alkenyl, or C2 -C3 alkynyl, R ^2a , R ^2b and R ³ are hydrogen, then Het is not 2,4-dioxo-3,4-dihydropyrimidinyl, 2,4-dioxo-3,4,5,6 tetrahydropyrimidinyl, 6-oxopurinyl, 6-amino-9H-purin-9-yl or oxopyrimidinyl, wherein each ring of the above rings is optionally substituted with C1-6αalkyl.

Embodiment 2

In Embodiment 2, the compounds of Embodiment 1 and sub-embodiments herein are those wherein R ⁵ is phenylC1-6alkyl or naphthylC1-6alkyl, preferably benzyl, wherein phenyl and naphthyl are optionally substituted with one, two or three substituents, independently selected from -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro substituents, OC1-6αalkyl (substituted with one to five fluorine atoms), -C1-6αalkylene-CO2H, -C1-6alkylene- CO2C1-6alkyl, -C2-6αalkenylene-CO2H, -OC1-6alkylene-CO2H, -OC1-6alkylene-CO2C1-6alkyl, -C1-6αalkyl substituted with one or two hydroxy substituents, -OC1-6alkyl substituted with one or two hydroxy, -C1-6αalkyl substituted with one or two -OC1-6alkyls, -OC1-6αalkyl (substituted with one or two -OC1-6αalkyls), -СО2Н, -COOC1-6alkyl, hydroxy, halogen, nitro, -PO3H2, cyano, -NH2 , -NH (C1-6αalkyl), -N (C1-6alkyl) 2, -CONReRf (where R ^e and Rf independently represent hydrogen , -C1-6alkyl, -C _1-6 αalkylene-CO ₂ H, -C _1-6 alkylene-CO ₂ C _1-6 alkyl or -C _1-6 alkylene- substituted with one or two substituents independently selected from hydroxy , NH2, -NHC _1-6 alkyl or -N (C _1-6 alkyl) ₂ ), -SO ₂ (C _1-6 alkyl), -SO2NR ^s R ^h (where R ^s and R ^h independently represent hydrogen, -C1-6αalkyl, -C1-6alkylene-CO2H or -C1-6alkylene-CO2C1-6alkyl), -SC1-6alkyl, -SOC1-6αalkyl, -SO2NHCOR '(where Rj represents -C1-6alkyl, -NHC1-6αalkyl or -N (C1-6alkyl) 2), phenyl, -C1-6alkylenephenyl, phenoxy, -OC1-6alkylenephenyl, 5- or 6-membered monocyclic heteroaryl containing from one to four heteroatoms independently selected from O, N and S [where the heteroaryl ring is optionally substituted with one, two or three substituents independently selected from hydroxyl, halogen, CN, -CO2H, -COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl (substituted with one to five fluorine atoms ), -OC1-6alkyl (substituted with one to five fluorine atoms), -C1-6alkylene-CO2H, -C1-6 alkyl en-CO2C1-6alkyl, tetrazolyl, -SO2C1, 6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N (C1-6alkyl) 2, -CONH2, CONHC1-6alkyl and -CON (C1-6alkyl) 2], -OR ¹ , -C1-6αlkilen-R ^1, -OC1-6alkilen-R ^1, -SR ^1, -SC1-6alkilen-R ^1, the heterocyclyl, -S1-6alkilengeterotsiklila, -OS1-6alkilengeterotsiklila, -SC1-6alkilengeterotsiklila, -CONR ^m C1 -6αalkylene heterocyclyl, -NR ^m COC1-6 alkylene-NR ^o R ^p , -NR ^m CO-heterocyclyl, -NR ^m COC1-6 alkylene heterocyclyl, -COheterocyclyl, -CONRmR ¹ , -CONR ^m C _1-6 alkylene-R ¹ , -OCONR ^m R ^m , -NR ^m -COR ^y , -NR ^m -CO-NR ^m R ^y , -NR ^m -SO2-R ^y , -NR ^m -SO2-NR ^m R ^y and -CONHSO2R ^z ; where each R ^m is hydrogen or —C _1-6 alkyl;

R °, R ^p , and R ^{y are} independently hydrogen or —C _1-6 alkyl;

R ^z is —C _1-6 alkyl, _{—NHC 1-6} α alkyl, or —N (C _1-6 alkyl) ₂ ;

phenyl by itself or as part of —C _1-6 alkylenephenyl, phenoxy or —OC _1-6 alkylenephenyl is optionally substituted with one, two or three substituents independently selected from hydroxyl, halogen, CN, —CO2H, —COOC _1-6 alkyl, -C _1-6 alkyl, -OC _1-6 alkyl, -C _1-6 alkyl substituted with one to five fluoro substituents, -OC _1-6 alkyl (substituted with one to five fluorine atoms), -C _1-6 alkylene-CO ₂ H, -C _1-6 alkylene-CO ₂ C _1-6 alkyl, tetrazolyl, -SO ₂ C _1-6 α-alkyl, -SO2NH2, -SO ₂ NHC _1-6 α-alkyl, -SO ₂ N (C _1-6 alkyl) ₂ , —CONH2, CONHC _1-6 alkyl and —CON (C _1-6 alkyl) ₂ ;

each R ¹ independently represents a 5- or 6-membered monocyclic heteroaryl containing

21 039042 straining from one to four heteroatoms independently selected from O, N and S, and wherein the heteroaryl ring is optionally substituted with one, two or three substituents independently selected from hydroxyl, halogen, CN, —CO2H, —COOC _1-6 αalkyl , —C _1-6 αalkyl, —OC _1-6 alkyl, —C _1-6 αalkyl substituted with one to five fluoro substituents, —OC ₁ . ₆ alkyl (substituted with one to five fluorine atoms), —C ₁ . ₆ αalkylene-CO ₂ H and -C _1-6 alkylene-CO ₂ C _1-6 alkyl, tetrazolyl, -SO ₂ C ₁ . ₆ αalkyl, -SO2NH2, -SO ₂ NHC ₁ . ₆ alkyl, —SO ₂ N (C _1-6 alkyl) ₂ , —CONH2, CONHC _1-6 alkyl, and —CON (C _1-6 αalkyl) ₂ ;

heterocyclyl alone or as part of —C _1-6 alkylene heterocyclyl, —OC ₁ . ₆ alkyleneheterocyclyl, —SC ₁ . Αlkilengeterotsiklila _6, -CONR ^m C1-6αlkilengeterotsiklila, -NR ^m COC1-6alkilengeterotsiklila, -SOgeterotsiklila -NR ^m CO or heterocyclyl optionally substituted with one, two or three substituents independently selected from hydroxy, halogen, -COOC _{1. 6} alkyl, -O ^ alkyl, -OC ₁ . ₆ alkyl or -C ₁ . ₆ αalkyl (substituted with hydroxy or —OC _1-b alkyl).

Embodiment 3

In Embodiment 3, a compound of Embodiment 1 or 2 and subvariants embodiments contained herein are those wherein R ⁵ represents fenilS16alkil naftilS1-6alkil or, preferably benzyl, wherein the phenyl and naphthyl (also referred to below as R ^5, phenyl and naphthyl rings respectively) are optionally substituted, preferably substituted with one or two substituents independently selected from —C1-balkyl, —OC _1-b alkyl, —C _1-b α-alkyl substituted with one to five fluoro substituents, —OC _1-b alkyl substituted from one to five fluorine atoms, -C _1-b αalkylene-CO ₂ H, -C _1-b alkylene-CO ₂ C _1-b alkyl, -OC _1-6 alkylene-CO ₂ H, -OC _1-6 alkylene —CO ₂ C _1-6 alkyl, —C ₁ . ₆ alkyl substituted with one or two hydroxy, —OC ₁ . ₆ αalkyl substituted with one or two hydroxy, —C ₁ . ₆ alkyl substituted with one or two substituents independently selected from —OC ₁ . ₆ alkyl, -OC ₁ . ₆ α alkyl (substituted with one or two —OC _{1. 6} α alkyl), —CO ₂ H, —COOC ₁ . _b αlkila, halogen, hydroxy, nitro, PO3H2, cyano, -NH2, -NH (C _{1. 6} alkyl), -N (C _{1. 6} αlkil) _2, -CONR ^e Rf (wherein R ^e and Rf are independently hydrogen, -C1.6alkyl, -C1.Balkylene-CO2H, -C1.6alkylene-CO2C1_6alkyl or -C1.6αalkyl substituted with one or two substituents independently selected from hydroxyl, NH2, -NHC1.6alkyl or -N (C1. ) 2), -SO2 (C1.bαlkyl), -SO2NR ^g R ^h (where R ^g and R ^h independently represent hydrogen, -C1. _B alkyl, -C _{1. B} alkylene-CO ₂ H or -C ₁ . _b alkylene-CO ₂ C _{1. b} alkyl), -SC ₁ . ₆ alkyl, -SOC ₁ . _b αlkulα, -SO2NHCOR '(where Rj represents -C _{1. 6} alkyl, -NHC _{1. 6} alkyl or -N (C ₁ _ ₆ alkyl) ₂ ), phenyl, phenoxy, benzyl, -OC ₁ . ₆ alkylenephenyl, 5- or 6-membered monocyclic heteroaryl containing from one to four heteroatoms independently selected from O, N and S [wherein the heteroaryl ring is optionally substituted with one, two or three substituents independently selected from hydroxyl, halogen, CN, - CO2H, -COOC ₁ . _b α-alkyl, -C ₁ . ₆ alkyl, -OC ₁ . ₆ αalkyl, -C ₁ . ₆ alkyl substituted with one to five fluorine atoms, —OC ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), —C ₁ . _b alkylene-CO ₂ H, -C ₁ . ₆ αalkylene-CO ₂ C ₁ . ₆ alkyl, tetrazolyl, —SO ₂ C ₁ . ₆ alkyl, -SO2NH2, -SO ₂ NHC ₁ . Αlkila _6, -SO ₂ N (C _{1. 6} αlkil) _2, -CONH2, -CONHC _{1. 6} alkyl and —CON (C _{1. 6} alkyl) ₂ ], —OR ¹ , —C1.6 alkylene-R ¹ , —OC1. _b alkylene-R ¹ , -SRi, -SC1, alkylene-R ¹ , heterocyclyl, -C1. _b alkylene heterocyclyl, -OC ₁ . ₆ alkyleneheterocyclyl, —SC ₁ . Alkilengeterotsiklila _6, -CONR ^m C1.balkilengeterotsiklila, -NR ^m COC1. ₆ alkyleneNR ^o R ^p , -NR ^m CO-heterocyclyl, -NRmCOC1 balkylene heterocyclyl, -CO heterocyclyl, -CONRmRi, -CONR ^m alkylene-R ¹ and -CONHSO2R ^z ; and further, the R ⁵ phenyl and naphthyl rings are optionally substituted with a third substituent selected from —C ₁ . ₆ alkyl, -C ₁ . ₆ αalkyl (where alkyl is substituted with one to five fluorine atoms), —OC ₁ . _b α-alkyl, -OC ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), halogen, CN, —NH2, and hydroxy;

where each R ^m is hydrogen or —C ₁ . _b αalkyl;

R ° and R ^{p are} independently hydrogen or —C ₁ . _b alkyl;

R ^z is -C ₁ . _b alkyl, -NHC ₁ . _b alkyl or —N (C _{1. b} alkyl) ₂ ;

phenyl alone or as part of phenoxy, benzyl, or —OC ₁ . _b alkylenephenyl is optionally substituted with one, two or three substituents independently selected from hydroxyl, halogen, CN, —CO2H, —COOC ₁ . _b α-alkyl, -C ₁ . _b α-alkyl, -OC ₁ . _b alkyl, -C ₁ . _b alkyl substituted with one to five fluorine atoms, —OC ₁ . _b αalkyl (substituted with one to five fluorine atoms), -C ₁ . _b αalkylene-CO ₂ H, -C ₁ . _b alkylene-CO ₂ C ₁ . _b alkyl, tetrazolyl, -SO ₂ C ₁ . _b alkyl, -SO2NH2, SO ₂ NHC ₁ . _b alkyl, —SO ₂ N (C _{1. b} alkyl) ₂ , —CONH2, —CONHC ₁ _ ₆ alkyl, and CON (C _{1. 6} alkyl) ₂ ;

each Ri is independently a 5 or 6 membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N and S, and wherein the heteroaryl ring is optionally substituted with one, two or three substituents independently selected from hydroxyl, halogen, CN, —CO ₂ H, —COOC ₁ . ₆ αalkyl, -C ₁ . ₆ α-alkyl, -OC ₁ . ₆ alkyl, -C ₁ . ₆ α-alkyl substituted with one to five fluorine atoms, —OC ₁ . ₆ alkyl (substituted with one to five fluorine atoms), —C ₁ . ₆ alkylene-CO ₂ H and -C ₁ . ₆ alkylene-CO ₂ C ₁ . ₆ alkyl, tetrazolyl, —SO ₂ C ₁ . ₆ alkyl, -SO2NH2, SO ₂ NHC ₁ . ₆ alkyl, —SO ₂ N (C _{1. 6} alkyl) ₂ , —CONH2, —CONHC ₁ . ₆ α-alkyl and CoN (C _{1. 6} alkyl) ₂ ;

heterocyclyl alone or as part of —C ₁ . ₆ alkylene heterocyclyl, —OC ₁ . ₆ alkyleneheterocyclyl, —SC ₁ . Αlkilengeterotsiklila _6, -CONR ^m C1.6alkilengeterotsiklila, NR ^m CO-heterocyclyl, -SOgeterotsiklila or -NR ^m COC1. ₆ alkyleneheterocyclyl is optionally substituted with one, two or three substituents independently selected from hydroxy, halogen, —COOC ₁ . ₆ alkyl, -C ₁ . ₆ alkyl, -OC ₁ . ₆ alkyl or

- 22 039042

-C _1- balkyl (substituted with hydroxy or -OC _1- balkyl).

Embodiment 4

In embodiment 4, the compounds of embodiment 1 or 2 and sub-embodiments contained herein are those wherein R ⁵ is phenylC1_6alkyl, preferably benzyl, wherein phenyl is substituted with one substituent in the meta or para position, preferably para, by the carbon atom of the phenyl ring which is attached to the —C1_6 alkyl in —C1. 6alkylphenyl or to -CH2- in benzyl, respectively, where one substituent is selected from -C1_6 alkyl, -OC1. 6alkyl, -C1_6alkyl substituted with one to five fluorine atoms, -OC1.6alkyl (substituted with one to five fluorine atoms), -C1.6alkylene-CO2H, -C1.6alkylene-CO2C1.6alkyl, -OC1.6 alkylene-CO2H , -OC1. 6alkylene-CO2C1_6alkyl, -CO2H, -COOC1.6alkyl, halogen, hydroxy, cyano, nitro, -PO3H2, -CONReRf (where R ^e and Rf independently represent hydrogen, -C1. ₆ alkyl, -C _{1. 6} alkylene-CO ₂ H, —C _{1 .6} alkylene — CO ₂ C _{1 .6} alkyl or —C _{1 .6} alkyl substituted with one or two substituents independently selected from hydroxy, NH2, —NHCl. ₆ αlkulα or —N (C ₁ . ₆ alkyl) ₂ ), SO ₂ (C _{1. 6} alkyl), —SO ₂ NR ^s R ^h (where R ^s and R ^h independently represent hydrogen, —C1-6alkyl, —C1-6alkylene —CO2H, or —C1. 6alkylene-CO2C1.6alkyl), phenyl, phenoxy, benzyl, benzyloxy, 5- or 6-membered monocyclic heteroaryl containing from one to four heteroatoms independently selected from O, N and S [where the heteroaryl ring is optionally substituted with one, two or three substituents independently selected from hydroxy, halogen, CN, -CO2H, -COOC1_6alkyl, -C1_6alkyl, -OC1.6alkyl, -C1_6alkyl (where alkyl is substituted with one to five fluorine atoms), -OC1.6alkyl (where alkyl is substituted from one to five atoms fluorine), -C1_6alkylene-CO2H, -C1.6alkylene-CO2C1.6alkyl, tetrazolyl, -SO2C1.6alkyl, -SO2NH2, -SO2NHC1.6alkyl, -SO2N (C1.6alkyl) 2, -CONH2, -CONHC1.6alkyl and - CON (C1.6alkyl) 2], —OR ¹ , —C1. ₆ alkylene-K ¹ , -OC1. ^{6 alkylene R 1} , -SR ¹ , -SC1. ₆ alkylene-R ¹ , heterocyclyl, -C1-6alkyleneheterocyclyl, -OC1.6alkyleneheterocyclyl, -SC1.6 alkyleneheterocyclyl, -CONR ^m C1. Alkilengeterotsiklila _6, -NR ^m COC1.6alkilen-NR ^o R ^p, -NR ^m COgeterotsiklila, -NR ^m COC1. ₆ alkyleneheterocyclyl, -COheterocyclyl, -CONRmR ¹ and -CONR ^m -alkylene-R ¹ ; and

The R ⁵ phenyl ring is optionally further substituted with one or two substituents independently selected from —C 1_ ₆ alkyl, —C 1_ ₆ alkyl (where the alkyl is substituted with one to five fluorine atoms), —OC ₁ . ₆ alkyl, -OC ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), halogen, CN, —NH _2, and hydroxy; wherein each R ^m is hydrogen or -S1_ ₆ alkyl;

R ° and Rp are independently hydrogen or -S1_ ₆ alkyl;

phenyl itself or as part of a benzyl, phenoxy or benzyloxy optionally substituted with one, two or three substituents independently selected from hydroxyl, halogen, CN, -CO ₂ H, -COOC1.6 alkyl -S1- ₆ alkyl, -OC ₁ ... ₆ alkyl, -S1- ₆ alkyl substituted with from one to five fluorine atoms, -OS1- ₆ alkyl (substituted by one to five fluorine atoms), -S1- ₆ alkylene-CO ₂ H, -C1. ₆ alkylene-CO ₂ C1. ₆ alkyl, tetrazolyl, —SO ₂ C ₁ . ₆ alkyl, -SO2NH2, SO ₂ NHC ₁ . ₆ alkyl, —SO ₂ N (C _{1. 6} alkyl) ₂ , —CONH2, —CONHC ₁ . ₆ alkyl and CON (C _{1 6} alkyl) ₂ ;

each R ^{1 is} independently a 5 or 6 membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N and S, and wherein the heteroaryl ring is optionally substituted with one, two or three substituents independently selected from hydroxyl, halogen , CN, —CO ₂ H, —COOC1_ ₆ alkyl, —C1_ ₆ alkyl, —OC ₁ . ₆ alkyl, -S1_ ₆ alkyl substituted with from one to five fluorine atoms, -OC _{1. 6} alkyl (substituted by one to five fluorine atoms), -S1_ ₆ alkylene-CO ₂ H and -C1. ₆ alkylene-CO ₂ C1. ₆ alkyl, tetrazolyl, —SO ₂ C ₁ . ₆ alkyl, -SO2NH2, SO ₂ NHC ₁ . ₆ alkyl, —SO ₂ N (C _{1. 6} alkyl) ₂ , —CONH2, —CONHC ₁ . ₆ alkyl and CoN (C _{1. 6} alkyl) ₂ ;

heterocyclyl alone or as part of —C 1_ ₆ alkylene heterocyclyl, —OC ₁ . ₆ alkyleneheterocyclyl, —SC ₁ . Alkilengeterotsiklila _6, -CONR ^m C1.6alkilengeterotsiklila, NR ^m CO-heterocyclyl, -SOgeterotsiklila or -NR ^m COC1. ₆ alkyleneheterocyclyl is optionally substituted with one, two or three substituents independently selected from hydroxy, halogen, —COOC ₁ . ₆ alkyl, -S1- ₆ alkyl, -OC _{1. 6} alkyl or —C1_ ₆ alkyl (substituted with hydroxy or —OC _{1. 6} alkyl).

Embodiment 5

In Embodiment 5, the compounds of Embodiment 1 or 2 and sub-embodiments herein are those wherein R ⁵ is —CH 2 phenyl or - (CH 2) 2 phenyl, preferably —CH 2 phenyl (benzyl), wherein phenyl is optionally substituted, preferably substituted one substituent in the meta or para position, preferably a pair, on the carbon atom of the phenyl ring which is attached to -C1_6alkyl in -C1_6alkylphenyl and to -CH2- in -CH2phenyl (benzyl), respectively, where one substituent is selected from -OC1.6alkyl , -C1-6alkyl substituted with one to five fluorine atoms, -OC1.6alkyl (substituted with one to five fluorine atoms), -C1-6alkyl substituted with hydroxy, -C1_6alkylene-CO2H, -C1.6alkylene-CO2C1.6alkyl, -OS1-6alkilenSO2N, -OS1.6alkilen-SO2S1.6alkila, -CO2H, nitro, COOC1.6alkila, halogen, hydroxy, cyano, -CONReRf (wherein R ^e represents hydrogen or -S1_6alkil and Rf represents -S1- _C6alkyl , ₆ -S1- alkilenSO ₂ H, -C1. ₆ alkilenSO ₂ C one. ₆ -S1_ ₆ alkyl or alkyl substituted with one or two hydroxyl substituents, -NH _2, -NHC _{1. 6} alkyl or —N (C _{1. 6} alkyl) ₂ ), —SO ₂ (C _{1. 6} alkyl), —SO ₂ NR ^s R ^h (where R ^s is in

- 23 039042 portly or -S1- ₆ alkyl and R ^h is hydrogen, alkyl -S1- _{6, 6} -S1- alkilenSO ₂ H ₆ alkilenSO -S1- or _{2 C1-C6} alkyl), oxadiazolyl, tetrazolyl, pyridinyl , pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, furanyl, thienyl, pyrrolyl or isoxazolyl (where each of the above heteroaryl rings is optionally substituted with one or two substituents independently selected from C _{1 ha 6} alkyl) , CN, -CO2H, -COOC1.6 alkyl, -C _{1. 6} alkylα, -OC _{1. 6} alkyl, -C _{1. 6} alkyl substituted with one to five fluorine atoms, -OC _{1. 6} alkyl (substituted from one to five fluorine atoms), tetrazolyl, SO ₂ C _{1. 6} alkyl, -SO2NH2, -SO2NHC1.6 alkyl, -SO ₂ N (C _{1. 6} alkyl) ₂ , -CONH2, -CONHC _{1. 6} alkyl and - CON (C _{1. 6} alkyl) _2), and

The R ⁵ phenyl ring is optionally further substituted with one or two substituents independently selected from —C ₁ . ₆ alkyl, -C ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), —O — Cl. ₆ alkula, -OC ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), halogen, CN, —NH2, and hydroxy.

Embodiment 6

In the embodiment 6, the compounds of Embodiment 1 or 2 and subvariants embodiments contained herein are those wherein R ⁵ represents fenilS1_ ₆ alkyl, preferably benzyl, wherein the phenyl ring in fenilS1_ ₆ alkyl and benzyl substituted in the meta para position, preferably a pair, on the carbon atom of the phenyl ring which is attached to —C ₁ . ₆ α-alkyl in -C ₁ . ₆ alkylphenyl and to -CH2- in benzyl, respectively, phenyl, benzyl, benzyloxy or phenoxy [where the phenyl ring either alone or as part of benzyl, benzyloxy and phenoxy is optionally substituted with one, two or three substituents independently selected from hydroxy, halogen , CN, —CO ₂ H, —COOC ₁ . ₆ alkyl, -C ₁ . ₆ alkyl, -OC ₁ . ₆ alkyl, -C ₁ . ₆ αalkyl (substituted with one to five fluorine atoms), —OC ₁ . ₆ alkyl (substituted with one to five fluorine atoms), —C ₁ . ₆ alkylene-CO ₂ H, -C ₁ . ₆ αalkylene-CO ₂ C ₁ . ₆ alkyl, tetrazolyl, —SO ₂ C ₁ . ₆ αalkyl, -SO2NH2, -SO ₂ NHC ₁ . ₆ alkyl,

-SO ₂ N (Cl. ₆ alkyl) ₂ , -CONH2, -CONHC ₁ . ₆ α-alkyl and —CON (C _{1. 6} α-alkyl) ₂ ]; and

R ⁵ phenyl is optionally further substituted with one or two substituents independently selected from —Cl. ₆ alkula, -C ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), —OC ₁ . ₆ alkyl, -OC ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), halogen, CN, —NH2, and hydroxy.

Embodiment 7

In Embodiment 7, the compounds of Embodiment 1 or 2 and sub-embodiments herein are those wherein R ⁵ is —CH2-phenyl, —CH2-naphthyl, - (CH2) 2-phenyl, or - (CH2) 2 -naphthyl, preferably -CH2-phenyl, where the phenyl and naphthyl rings are optionally substituted with one, two or three substituents independently selected from methyl, ethyl, methoxy, ethoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -CH2CO2H, -CH2CH2CO2H, -OCH2CO2H , -OCH2CH2CO2H, -CH2CO2CH3, -CH2CH2CO2CH3, -CH2CO2ethyl, -CH2CH2CO2ethyl, -CH2OH, -CH2CH2OH, -OCH2OCH3, -OCH2CH2OCH3, -CO2H, -COOmethyl, hydroxy-CO2, ethyloxy , methylcarbonylaminosulfonyl, ethylcarbonylaminosulfonyl, fluorine, chlorine, cyano, -NH2, -NHCH3, -NH ethyl, -I (methyl) 2, -N (ethyl) 2, -CONR ^e Rf (where R ^e represents hydrogen, methyl, ethyl or propyl and Rf is hydrogen, methyl, ethyl, propyl, - (CH2) ₂ -CO ₂ H, - (CH ₂ ) ₃ -CO ₂ H, - (CH ₂ ) ₂ -CO ₂ Me, - (CH ₂ ) ₃ -CO ₂ Me, - (CH ₂ ) ₂ -CO ₂ ethyl, - (CH ₂ ) ₃ -CO ₂ ethyl, - (CH ₂ ) ₂ -NH ₂ , - (CH ₂ ) ₃ -NH ₂ , - (CH ₂ ) ₂ -NHMe, - (CH2) ₃ NHMe, - (CH ₂ ) ₂ - N (CH ₃ ) ₂ or - (CH ₂ ) ₃ -N (CH ₃ ) ₂ ), -SO ₂ Me, -SO ₂ NR ^g R ^h (where R ^g is hydrogen, methyl, ethyl or propyl and R ^h represents hydrogen, methyl, ethyl, propyl, - (CH2) 2-CO2H, - (CH2) 3CO2H, - (CH2) 2-CO2Me, - (CH2) 3-CO2Me, - (CH2) 2-CO2ethyl or - ( CH2) 3-CO2ethyl) phenyl, phenoxy, -CH2phenyl, -CH2-CH2-phenyl, -OCH2-phenyl or -OCH2-CH2-phenyl -CH2-CH2-phenyl, -OCH2-phenyl and -OCH2-CH2-phenyl optionally substituted with one, two or three substituents independently selected from hydroxyl, chlorine, fluorine, -CO2H, CN, -CO2Me, -CO2ethyl, methyl, ethyl , methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl, -CH2-CO2H, -CH2-CO2-methyl, -CH2-CO2-ethyl, tetrazolyl, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N-(CH3) 2, NH2, -CONHCH3 and -CON (CH3) 2], a 5- or 6-membered monocyclic heteroaryl containing from one to four heteroatoms independently selected from O, N and S [wherein the heteroaryl ring is optionally substituted with one, two or three substituents, independently selected from hydroxyl, chlorine, fluorine, CN, —CO2H, —CO2Me, —CO2ethyl, methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl, —CH2 — CO2H, —CH2 — CO2methyl, and CH2 — CO2ethyl] , -OR ¹ , SR ¹ , -OCH2R ¹ , -O (CH2) ₂ -R ', -CH2R ¹ and - (CH2) 2-R' [where each R ¹ independently represents a 5- or 6-membered monocyclic heteroaryl containing from one to four heteroatoms independently selected from O, N and S, and wherein the heteroaryl ring is optionally substituted with one, two or three substituents independently selected from hydroxyl, chlorine, fluorine, CN, —CO2H, —CO2Me, —CO2 ethyl , methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl, -CH2-CO2H, -CH2-CO ₂ methyl, -CH ₂ -CO ₂ ethyl, tetrazolyl, —SO ₂ CH ₃ , —SO2NH2, —SO2NHCH3, —SO2N (CH3) 2, —CONH2, —CONHCH3 and —CON (CH3) 2].

Embodiment 8

In Embodiment 8, the compounds of Embodiment 1 or 2 and sub-options are implemented

24 039042 phenomena contained herein are those wherein R ⁵ is —CH2-phenyl, —CH2-naphthyl, - (CH2) 2-phenyl, or - (CH2) 2-naphthyl, preferably —CH2-phenyl, where the phenyl and naphthyl rings are substituted by one or two substituents independently selected from difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -CH2CO2H, -CH2CH2CO2H, -OCH2CO2H, -OCH2CH2CO2H, -CH2CO2CH3, -CH2CH2CH2CO2Hla CH2CH2OH, -OCH2OCH3, -OCH2CH2OCH3, -CO2H, -COOmethyl, -CO2ethyl, hydroxy, nitro, PO3H2, methylthio, ethylthio, methylsulfoxide, ethylsulfoxide, methylcarbonylaminosulfonyl, cyanobylamino-N-HH-CH ethyl, -K (methyl) 2, -K (ethyl) 2, -CONReRf (where R ^e is hydrogen, methyl, ethyl or propyl and Rf is hydrogen, methyl, ethyl, propyl, - (CH2) 2-CO2H , - (CH2) s-CO2H, - (CH2) 2-CO2Me, - (CH2) s-CO2Me, - (CH2) 2-CO2ETHYL, - (CH2) s-CO2Ethyl, - (CH2) 2-NH2, - (CH2) 3-NH2, - (CH2) 2-NHMe, - (CH2) 3-NHMe, - (CH2) 2-N (CH3) 2 or - (CH2) ₃ -N (CH ₃ ) 2), -SO2Me, -SO ₂ NR ^g R ^h (where R ^g is hydrogen, methyl, ethyl or propyl and R ^h represents hydrogen, methyl, ethyl, propyl, - (CH2) 2-CO2H, - (CH2) s-CO2H, - (CH2) 2-CO2Me, - (CH2) 3-CO2Me, - (CH2) 2- CO2ethyl or - (CH2) 3-CO2ethyl), phenyl, phenoxy, -CH2-phenyl, -CH2-CH2-phenyl, -OCH2-phenyl or -OCH2-CH2phenyl [where the phenyl ring itself or as part of phenoxy, -CH2 -phenyl, -CH2-CH2-phenyl, -OCH2-phenyl and -OCH2-CH2-phenyl optionally substituted with one, two or three substituents independently selected from hydroxyl, chlorine, fluorine, -CO2H, CN, -CO2Me, ethyl CO2, methyl , ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl, -CH2-CO2H, -CH2CO2methyl, -CH2-CO2-ethyl, tetrazolyl, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N-(CH3) 2 CONHCH3 and -CON (CH3) 2], a 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N and S [where the heteroaryl ring is optionally substituted with one, two or three substituents independently selected from hydroxyl, chlorine, fluorine, CN, -CO2H, -CO2Me, -CO2ethyl, methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl, -CH2-CO2H, - CH2-CO2methyl, -CH2-CO2ethyl, tetrazolyl, -SO2CH3, -SO2NH2, -SO2NHCH3, .- SO2N (CH3) 2, -CONH2, -CONHCH3 and -CON (CH3) 2], -OR ¹ , -SR ¹ , -OCH2R ¹ , -O (CH2) 2R ¹ , -CH2R ¹ and - (CH2) ₂ -R ¹ [where each R ^{1 is} independently a 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected of O, N and S, and wherein the heteroaryl ring is optionally substituted with one, two or three substituents independently selected from hydroxyl, chlorine, fluoro, CN, —CO ₂ H, —CO ₂ Me, —CO ₂ ethyl, methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl, —CH ₂ —CO ₂ H, —CH 2 —CO 2 methyl and CH ₂ —CO ₂ ethyl]; and

R ⁵ phenyl and naphthyl rings are optionally substituted with a third substituent independently selected from methyl, ethyl, fluoro, chloro, methoxy, ethoxy, hydroxy, —NH 2, and cyano.

Embodiment 9

In Embodiment 9, the compounds of Embodiment 1 or 2 and sub-embodiments herein are those wherein R ⁵ is —CH2-phenyl or - (CH2) 2-phenyl, preferably —CH2-phenyl, wherein phenyl is substituted with one substituent at the meta or para position, preferably para, on the carbon atom of the phenyl ring which is attached to CH2- or to - (CH2) 2- in -CH2-phenyl or - (CH2) 2-phenyl, respectively, and is selected from trifluoromethyl, difluoromethoxy, trifluoromethoxy, -CH2CO2H, -CH2CH2CO2H, -OCH2CO2H, -OCH2CH2CO2H, -CH2CO2CH3, CH2CH2CO2CH3, -CH2CO2ethyl, -CH2CH2CO2CO2ethyl, -CH2CH2CH2OH, -CH2OCOCO2-ethyl, -CH2CH2CH2OH, -COOethyl, hydroxy, fluorine, chlorine, cyano, -CONR ^e R ^f (where R ^e is hydrogen, methyl, ethyl or propyl and Rf is hydrogen, methyl, ethyl, propyl, - (CH2) 2-CO2H, - (CH2) s-CO2H, - (CH2) 2-CO2Me, - (CH2) s-CO2Me, - (CH2) 2-CO2ETHYL, - (CH2) s-CO2ETHYL, - (CH2) 2-NH2, - (CH2 ) 3-NH2, - (CH2) 2-NHMe, - (CH2) 3-N HMe, - (CH2) 2-NHCH3, - (CH2) 3-N (CH3) 2), -SO2Me or -SO2NR ^g R ^h (where R ^g is hydrogen, methyl, ethyl or propyl and R ^h is hydrogen , methyl, ethyl, propyl, - (CH ₂ ) ₂ -CO ₂ H, - (CH ₂ ) _s -CO ₂ H, - (CH ₂ ) ₂ -CO ₂ Me, - (CH ₂ ) ₃ -CO ₂ Me , - (CH ₂ ) ₂ -CO ₂ ethyl or - (CH2) 3-CO2 ethyl), tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, furanyl, thienyl, isox wherein each of the above heteroaryl rings is optionally substituted with one or two substituents independently selected from C1_ ₆ alkyl, halogen, CN, —CO2H, —COOC ₁ . ₆ alkyl, -C1.6 alkyl, -OC ₁ . ₆ alkyl, —C1_ ₆ alkyl substituted with one to five fluorine atoms, or —OC ₁ . ₆ alkyl (substituted with one to five fluorine atoms); and

The R ⁵ phenyl ring is optionally further substituted with one or two substituents independently selected from methyl, ethyl, fluoro, chloro, methoxy, ethoxy, hydroxy, —NH 2, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, and cyano.

Embodiment 10

In Embodiment 10, the compounds of Embodiment 1 or 2 and sub-embodiments herein are those wherein R ⁵ _{is —CH 2} phenyl or - (CH ₂ ) ₂ phenyl, preferably —CH 2 phenyl, wherein the phenyl ring in -CH ₂ -phenyl and - (CH ₂ ) ₂ phenyl is substituted at the met- or para-position on the carbon atom of the phenyl ring, which is attached to the -CH ₂ -group in -CH ₂ -phenyl and - (CH ₂ ) ₂ -phenyl galogenS1_ ring ₆ alkoxy or alkylaryl galogenS1_ ₆ 25 039 042 scrap and R ⁵ on the phenyl ring is optionally further substituted with one or two substituents independently selected from -C _{1. 6} αlkila, -C _1- 6alkila (wherein alkyl is substituted with from one to five fluorine atoms), -OC _{1. 6} alkyl, -OC ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), halogen, CN,

-NH2 and hydroxy.

Embodiment 11

In Embodiment 11, the compounds of Embodiment 1 or 2 and sub-embodiments herein are those wherein R ⁵ is —CH2phenyl or - (CH2) 2-phenyl, preferably —CH2-phenyl, wherein phenyl is substituted with a substituent in meta - or para-position, preferably para-position, on the carbon atom of the phenyl ring which is attached to -CH2- or - (CH2) 2- in -CH2-phenyl or - (CH2) 2-phenyl, where the substituent is selected from -CONR ^e Rf (wherein R ^e represents hydrogen or -C1. ₆ alkyl and Rf represents -C _1- 6alkilen- substituted with one or two substituents independently selected from hydroxyl, NH2, -NHC _{1. 6} αlkila or -N (C1 - ₆ alkyl) ₂ ), -OR ¹ , -C1-6 alkylene-R ¹ , -OC1. ₆ alkylene-R ^1, -SR ^1, -SC1.6alkilen-R ^{1, -CONR m R ', -CONR m} C1. ₆ alkylene R ¹ [wherein each Ri is independently a 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N and S, and wherein the heteroaryl ring is optionally substituted with one, two or three substituents independently selected from hydroxyl, halogen, CN, -COOC1.6alkyl, -C1.6alkyl, -OC1.6αalkyl, -C1.6alkyl (where alkyl is substituted with one to five fluorine atoms) or -OC1.6alkyl (where alkyl is substituted with one to five fluorine atoms), heterocyclyl, -C1.6alkyleneheterocyclyl, -OC1.6alkyleneheterocyclyl, -SC1.6alkyleneheterocyclyl, -CONR ^m C1. ₆ alkyleneheterocyclyl, NR ^m CO-heterocyclyl, -COheterocyclyl, -NR ^m COC1.6αalkylene heterocyclyl [where each R ^m is hydrogen or -C1. _{6 is an} alkyl and a heterocyclyl ring by itself or as part of —C ₁ . ₆ alkylene heterocyclyl, —OC ₁ . ₆ alkyleneheterocyclyl, —SC ₁ . ₆ αalkyleneheterocyclyl, -CONR ^m C1. 6alkyleneheterocyclyl, -COheterocyclyl, -NR ^m CO-heterocyclyl and -NR ^m COC1. ₆ alkyleneheterocyclyl is optionally substituted with one, two or three substituents independently selected from hydroxy, halogen, —COOC ₁ . ₆ alkyl, -C ₁ . ₆ alkyl, -OC ₁ . ₆ alkyl or -C ₁ . ₆ alkylα (where alkyl is substituted with hydroxy or —OC _{1. 6} alkyl)] and —NR ^m COC1.6 alkylene-NR ^o R ^p (where R ^m , R ° and R ^{p are} independently hydrogen or C1. ₆ alkyl); and

The R ⁵ phenyl ring is optionally further substituted with one or two substituents independently selected from —C ₁ . ₆ αalkyl, -C ₁ . ₆ αalkyl (where alkyl is substituted with one to five fluorine atoms), —OC ₁ . ₆ alkyl, -OC ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), halogen, CN, —NH _2, and hydroxy.

Embodiment 12

In Embodiment 12, the compounds of Embodiment 1 or 2 and sub-embodiments herein are those wherein R ⁵ _{is —CH 2} phenyl or - (CH ₂ ) ₂ -phenyl, preferably —CH 2 -phenyl, wherein phenyl is substituted with - CH = CHCO ₂ H, -CH2CO2H or -CH2CH2CO2 in the meta- or para-position, preferably pair, on the carbon atom of the phenyl ring which is attached to -CH2- or - (CH ₂ ) ₂ - in -CH ₂ -phenyl or - (CH ₂ ) ₂ -phenyl; and the phenyl ring is optionally further substituted with one or two substituents independently selected from —C ₁ . ₆ alkyl, -C ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), —OC ₁ . ₆ alkyl, -OC ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), halogen, CN, —NH2, and hydroxy.

Embodiment 13

In Embodiment 13, the compounds of Embodiment 1 or 2 and sub-embodiments herein are those wherein R ⁵ _{is —CH 2} phenyl or - (CH ₂ ) ₂ -phenyl, preferably —CH 2 -phenyl, wherein phenyl is substituted with - CH ₂ CO ₂ CH ₃ , -CH ₂ CH ₂ CO ₂ CH ₃ , -CH ₂ CO _{2 with} ethyl or CH ₂ CH ₂ CO _{2 with} ethyl in the met- or para-position, preferably pair, on the carbon atom of the phenyl ring, which is attached to -CH2 - or - (CH ₂ ) ₂ - in -CH ₂ -phenyl or - (CH ₂ ) ₂ -phenyl; and

The R ⁵ phenyl ring is optionally further substituted with one or two substituents independently selected from —C ₁ . ₆ αalkyl, -C ₁ . ₆ αalkyl (where alkyl is substituted with one to five fluorine atoms), —OC ₁ . ₆ alkyl, -OC ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), halogen, CN, —NH _2, and hydroxy.

Embodiment 14

In Embodiment 14, the compounds of Embodiment 1 or 2 and sub-embodiments herein are those wherein R ⁵ is —CH2phenyl or - (CH2) 2-phenyl, preferably —CH2-phenyl (benzyl), wherein phenyl is substituted CO2H in the met- or para-position, preferably pair, on the carbon atom of the phenyl ring which is attached to -CH2- or - (CH2) 2- in -CH2-phenyl (benzyl) or - (CH2) 2-phenyl, and R ^{5, the} phenyl ring is optionally further substituted with one or two substituents independently selected from —C1. ₆ αlkila, -C1- ₆ alkyl (wherein alkyl is substituted with from one to five fluorine atoms), -OC _{1. 6} alkyl, -OC ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), halogen, CN, —NH _2, and hydroxy.

- 26 039042

Embodiment 15

In Embodiment 15, the compounds of Embodiment 1 or 2 and sub-embodiments herein are those wherein R ⁵ is —CH2phenyl (benzyl) or - (CH2) 2-phenyl, preferably —CH2-phenyl (benzyl), where phenyl is substituted with -COOmethyl or -COOethyl in the met- or para-position, preferably para, on the carbon atom of the phenyl ring which is attached to -CH2- or - (CH2) 2- in -CH2-phenyl (benzyl) or - (CH2 ) 2fenile and R ⁵ on the phenyl ring is optionally further substituted with one or two substituents independently selected from -C1-6αlkila, -C _1-6 αlkila (wherein alkyl is substituted with from one to five fluorine atoms), -OC _1- 6alkila, -OC _1- 6αlkila (wherein alkyl is substituted with from one to five fluorine atoms), halogen, CN, -NH2, and hydroxy.

Embodiment 16

In Embodiment 16, the compounds of Embodiment 1 or 2 and sub-embodiments herein are those wherein R ⁵ is —CH2phenyl or - (CH2) 2-phenyl, preferably —CH2-phenyl, wherein phenyl is substituted with fluorine, chlorine or cyano in the meta or para position, preferably pair, on the carbon atom of the phenyl ring which is attached to -CH2- or - (CH2) 2- in -CH2-phenyl or - (CH2) 2-phenyl, and R ^{5 is} phenyl the ring is optionally further substituted with one or two substituents independently selected from —C1-6αalkyl, —C _1-6 alkyl (where alkyl is substituted with one to five fluorine atoms), —OC _1-6 alkyl, —OC _1-6 alkyl (where alkyl is substituted with one to five fluorine atoms), halogen, CN, NH ₂ and hydroxy.

Embodiment 17

In Embodiment 17, the compounds of Embodiment 1 or 2 and sub-embodiments herein are those wherein R ⁵ is —CH2phenyl or - (CH2) 2-phenyl, preferably —CH2-phenyl, wherein phenyl is substituted with —CONR ^e Rf (where R ^e is hydrogen, methyl, ethyl or propyl and R ^f is hydrogen, methyl, ethyl, propyl, - (CH2) 2-CO2H, - (CH2) s-CO2H, - (CH2) 2-CO2Me , - (CHb-COMe, - (CH2) 2-CO2ethyl, - (CH2) s-CO2Ethyl, - (CH2) 2NH2, - (CH ₂ ) ₃ -NH ₂ , - (CH ₂ ) ₂ -NHMe, - ( CH ₂ ) ₃ -NHMe, - (CH ₂ ) ₂ -NHCH ₃ , - (CH ₂ ) ₃ -N (CH ₃ ) ₂ ) or -CONHSO ₂ R ^z , where R ^z is -C1_ ₆ alkyl, -NHC _{1. 6} alkyl or —N (C _{1. 6} αalkyl) ₂ in the meta or para position, preferably pair, on the carbon atom of the phenyl ring which is attached to —CH ₂ - or - (CH ₂ ) ₂ - in —CH ₂ -phenyl or - (CH ₂ ) ₂ -phenyl; and

The R ⁵ phenyl ring is optionally further substituted with one or two substituents independently selected from —C 1_ ₆ alkyl, —C 1_ ₆ alkyl (where the alkyl is substituted with one to five fluorine atoms), —OC ₁ . ₆ alkyl, -OC ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), halogen, CN, —NH2, and hydroxy.

Embodiment 18

In Embodiment 18, the compounds of Embodiment 1 or 2 and sub-embodiments herein are those wherein R ⁵ is —CH2phenyl or - (CH2) 2-phenyl, preferably —CH2-phenyl, wherein phenyl is substituted with —SO2NR ^g R ^h (where R ^g is hydrogen, methyl, ethyl or propyl and R ^h is hydrogen, methyl, ethyl, propyl, - (CH2) ₂ -CO ₂ H, - (CH ₂ ) ₃ -CO ₂ H, - (CH ₂ ) ₂ -CO ₂ Me, - (CH ₂ ) ₃ -CO ₂ Me, - (CH ₂ ) ₂ -CO ₂ ethyl or - (CH ₂ ) ₃ -CO ₂ ethyl) or -SO2NHCOR '(where Rj It represents -S1_ ₆ alkyl, -NHC _{January 6} alkyl or -N (C _{1 June} alkyl.) ₂₎ in the meta or para position, preferably para, to the carbon atom of the phenyl ring, which is attached to or -CH ₂ -. (CH ₂ ) ₂ - in -CH ₂ -phenyl or - (CH ₂ ) ₂ -phenyl; and

R ⁵ on the phenyl ring is optionally further substituted with one or two substituents independently selected from -S1- ₆ alkyl, -S1- ₆ alkyl (wherein alkyl is substituted with from one to five fluorine atoms), -OC _{1. 6} alkyl, -OC ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), halogen, CN, —NH2, and hydroxy.

Embodiment 19

In Embodiment 19, the compounds of Embodiment 1 or 2 and sub-embodiments herein are those wherein R ⁵ is —CH ₂ phenyl or - (CH ₂ ) ₂ -phenyl, preferably —CH ₂ -phenyl, wherein phenyl substituted with tetrazol-5-yl in the meta- or para-position, preferably pair, on the carbon atom of the phenyl ring which is attached to -CH2- or - (CH ₂ ) ₂ - in -CH ₂ -phenyl or - (CH ₂ ) ₂ -phenyl; and

The R ⁵ phenyl ring is optionally further substituted with one or two substituents independently selected from —C 1_ ₆ alkyl, —C 1_ ₆ alkyl (where the alkyl is substituted with one to five fluorine atoms), —OC ₁ . ₆ alkyl, -OC ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), halogen, CN, —NH2, and hydroxy.

Embodiment 20

In an embodiment, compound 20 of the embodiment 1 and subvariants embodiments contained herein are those wherein R ⁵ represents a 5-10 membered geteroarilS1-6alkil (also referred to below as R ⁵ heteroaryl), preferably -CH2- or - ( CH ₂ ) ₂ 5-10 membered heteroaryl containing one to three heteroatoms independently selected from N, O or S, and optionally substituted, preferably substituted with one or two substituents,

- 27 039042 more preferably one substituent independently selected from —C _1-6 alkyl, —OC _1-6 alkyl, —C _1-6 alkyl substituted with one to five fluorine atoms, —OC _1-6 alkyl substituted with one up to five fluorine atoms, -C _1-6 alkylene-CO ₂ H, -C _1-6 alkylene-CO ₂ C _1-6 alkyl, -C _2-6 α-alkenylene-CO ₂ H, -C _1-6 alkyl substituted one or two substituents independently selected from hydroxy, —OC ₁ . ₆ αalkyl substituted with hydroxy, —C ₁ . ₆ αlkylα substituted with one or two —OC ₁ . ₆ alkylamu, -OC ₁ . ₆ alkyl (substituted with one or two —OC _{1. 6} alkulamu), —CO2H, —COOC ₁ . ₆ alkyl, hydroxy, halogen, nitro, PO3H2, cyano, -NH2, -NH (C _1-6 alkyl), -N (C _1-6 alkyl) ₂ , -CONR ^e Rf (where R ^e and Rf are independently hydrogen, -C1-6 alkyl, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl or -C1-6alkyl substituted with one or two substituents independently selected from hydroxyl, -NHC1-6alkyl or -N (C1- 6alkyl) 2), -SO2 (C1-6alkyl), SO2NR ^s R ^h (where R ^s and R ^h independently represent hydrogen, -C1-6αalkyl, -C _1-6 alkylene-CO ₂ H or -C _1-6 alkylene-CO ₂ C _1-6 alkyl), —SC _1-6 alkyl, —SOC _1-6 alkyl, —SO2NHCOR '(where R is —C _1-6 alkyl, —NH2, —NHC _1-6 alkyl, or -N (C _1-6 alkyl) ₂ ), phenyl, -C _1-6 alkylenephenyl, phenoxy, -OC _1-6 alkylene phenyl, 5- or 6-membered monocyclic heteroaryl containing from one to four heteroatoms independently selected from O , N and S [wherein the heteroaryl ring is optionally substituted with one, two or three substituents independently selected from hydroxyl, halogen, CN, —CO ₂ H, —COOC _1-6 alkyl, —C _{1-6 alkyl} la, -OC _1-6 alkyl, -C _1-6 alkyl (substituted with one to five fluorine atoms), -OC _1-6 alkyl (substituted with one to five fluorine atoms), -C _1-6 alkylene-CO ₂ H, —C _1-6 alkylene — CO ₂ C _1-6 alkyl, tetrazolyl, —SO ₂ C _1-6 alkyl, —SO2NH2, —SO ₂ NHC _1-6 alkyl, —SO ₂ N (C ₁ . ₆ alkyl) ₂ , -CONH ₂ , CONHC _1-6 alkyl and -CON (C _1-6 alkyl) ₂ ], -OR ¹ , -C _1-6 alkylene-R ¹ , -OC1-6 ^{alkylene-R 1} , - SR ¹ , -SC1-6 alkylene-R ¹ , heterocyclyl, -C _1-6 alkylene _{heterocyclyl, -OC 1-6} alkylene _{heterocyclyl, -SC 1-6} alkylene heterocyclyl, -CONR ^m C1-6 alkylene ^{heterocyclyl, -NR m} COC1-6 alkylene-NR ^o R ^p , -NR ^m CO-heterocyclyl, -NR ^m COC1-6 alkylene heterocyclyl, -CO heterocyclyl, -CONR ^m R ¹ , -CONR ^m -alkylene-R ¹ , -OCONR ^m R ^m , -NR ^m -COR ^y , - NR ^m -CONR ^m R ^y , -NR ^m -SO2-R ^y , -NR ^m -SO2-NR ^m R ^y and -CONHSO2R ^z ; and

The R ⁵ heteroaryl ring is optionally further substituted with an additional substituent selected from —C _1-6 alkyl, —C _1-6 alkyl (where the alkyl is substituted with one to five fluorine atoms), —O — C _1-6 alkyl, —OC _{1- 6} alkyl (where alkyl is substituted with one to five fluorine atoms), halogen, CN, —NH2, and hydroxy; where each R ^m is hydrogen or —C _1-6 alkyl;

R °, Rp and R ^{y are} independently hydrogen or —C _1-6 alkyl;

R ^z is —C _1-6 alkyl, —NHC _1-6 alkyl, or —N (C _1-6 alkyl) ₂ ;

phenyl by itself or as part of —C _1-6 alkylenephenyl, phenoxy or —OC _1-6 alkylenephenyl is optionally substituted with one, two or three substituents independently selected from hydroxyl, halogen, CN, —CO2H, —COOC _1-6 alkyl, -C _1-6 alkyl, -OC _1-6 alkyl, -C _1-6 alkyl substituted with one to five fluorine atoms, -OC _1-6 alkyl (substituted with one to five fluorine atoms), -C _1-6 alkylene-CO ₂ H, -C _1-6 alkylene-CO ₂ C _1-6 alkyl, tetrazolyl, -SO ₂ C _1-6 alkyl, -SO2NH2, SO ₂ NHC _1-6 alkyl, -SO ₂ N (C _{1 -6} alkyl) ₂ , -CONH ₂ , -CONHC _1-6 alkyl and -CON (C _1-6 alkyl) ₂ ;

each R ^{1 is} independently a 5 or 6 membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N and S, and wherein the heteroaryl ring is optionally substituted with one, two or three substituents independently selected from hydroxyl, halogen , CN, -CO2H, -COOC _1-6 alkyl, -C _1-6 alkyl, -OC _1-6 alkyl, -C _1-6 alkyl substituted with one to five fluorine atoms, -OC _1-6 alkyl (substituted from one to five fluorine atoms), -C _1-6 alkylene-CO ₂ H, and -C _1-6 alkylene-CO ₂ C _1-6 alkyl, tetrazolyl, -SO ₂ C _1-6 alkyl, -SO2NH2, - SO ₂ NHC _1-6 alkyl, —SO ₂ N (C _1-6 alkyl) ₂ , —CONH ₂ , —CONHC _1-6 alkyl and CON (C _1-6 alkyl) ₂ ;

heterocyclyl by itself or as part of -C _1-6 alkilengeterotsiklila, -OC _1-6 alkilengeterotsiklila, -SC _1-6 alkilengeterotsiklila, -CONR ^m S1-6alkilengeterotsiklila, NR ^m CO-heterocyclyl, and -NR ^m -SOgeterotsiklila SOS1-6alkilengeterotsiklila optionally substituted with one, two or three substituents independently selected from hydroxy, halogen, —COOC _1-6 alkyl, —C _1-6 alkyl, —OC _1-6 alkyl, or —C _1-6 alkyl (substituted with hydroxy or —OC _{1 -6} alkyl).

Embodiment 21

In Embodiment 21, the compounds of Embodiment 1 or 20 and sub-embodiments contained herein are where R ⁵ is —CH ₂ - or - (CH ₂ ) ₂ - (5-9 membered heteroaryl ring), wherein the heteroaryl ring is optionally substituted with one or two substituents, preferably one substituent independently selected from difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, —CH ₂ CO ₂ H, —CH ₂ CH ₂ CO ₂ H,

-SSCH ^ SCH, -SCHSCH ^ SCH, -CH2CO2 ethyl, -SCHSCH ^ ethyl, -SCHSCH-SCHSCHOC -OCHSCHOC -OCH ₂ OCHz, -OCH ₂ CH ₂ OCHz, -CO ₂ H, -COOmethyl, -CO ₂ ethyl, hydroxy , nitro, PO ₃ H ₂ , methylthio, ethylthio, methyl sulfoxide, ethyl sulfoxide, methylcarbonylaminosulfonyl, ethylcarbonylaminosulfonyl, fluorine, chlorine, cyano, -NH2, -NHCH3, -NH-ethyl, -N (methyl) ₂ , -N (ethyl) ₂ , -CONR ^e R ^f (where R ^e is hydrogen, methyl, ethyl or propyl and R ^f is hydrogen, methyl, ethyl, propyl, - (CH2) 2-CO2H, - (CH2) s-CO2H, - ( CH2) 2-CO2Me, - (CH2) s-CO2Me, - (CH2) 2-CO2ethyl, - (CH2) s-CO2ethyl, - (CH ^ NH2, - (CH ₂ ) s-NH ₂ , - (CH ₂ ) ₂ -NHMe, - (CH ₂ ) s-NHMe, - (CH ₂ ) ₂ -N (CH3) ₂ or - (CH ₂ ) ₃ -N (CH3) ₂ ), -SO ₂ Me, -SO ₂ NR ^s R ^h (where R ^s is hydrogen, methyl, ethyl or propyl and R ^h is water

- 28 039042 genus, methyl, ethyl, propyl, - (CH ₂ ) ₂ -CO ₂ H, - (CH ₂ ) ₃ -CO ₂ H, - (CH ₂ ) ₂ -CO ₂ Me, - (CH ₂ ) ₃ -CO ₂ Me, - (CH ₂ ) ₂ -CO ₂ ethyl, or - (CH ₂ ) ₃ -CO ₂ ethyl), phenyl, phenoxy, CH ₂ -phenyl, -CH ₂ -CH ₂ -phenyl, -OCH ₂ -phenyl or -OCH2-CH2phenyl [wherein the phenyl ring by itself or as part of phenoxy, -CH ₂ -phenyl, -CH ₂ -CH ₂ -phenyl, -OCH ₂ -phenyl and -OCH ₂ -CH ₂ -phenyl is optionally substituted one, two or three substituents independently selected from hydroxyl, chlorine, fluorine, —CO2H, CN, —CO ₂ Me, CO ₂ ethyl, methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl, —CH ₂ - CO ₂ H, -CH ₂ CO ₂ methyl, -CH ₂ -CO ₂ ethyl, tetrazolyl, -SO ₂ CH ₃ , -SO2NH2, -SO2NHCH3, -SO2N (CH ₃ ) 2, -CONH2, -CONHCH3 and -CON ( CH ₃ ) 2], a 5- or 6-membered monocyclic heteroaryl containing from one to four heteroatoms independently selected from O, N and S [wherein the heteroaryl ring is optionally substituted with one, two or three substituents, independently selected from hydroxyl, chlorine, fluorine, CN, -CO2H, -CO2Me, -CO2 ethyl, methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl, -CH ₂ -CO ₂ H, -CH ₂ -CO ₂ methyl , -CH ₂ -CO ₂ ethyl, tetrazolyl, -SO ₂ CH ₃ , -SO2NH2, -SO2NHCH3, -SO2N (CH3) 2, -CONH2, -CONHCH3 and -CON (CH ₃ ) ₂ ], -OR ¹ , - SR ¹ , -OCH2R ¹ , -O (CH2) 2R ¹ , -CH2R ¹ and - (CH2) ₂ -R ^I [where each K ', independently represents a 5- or 6-membered monocyclic heteroaryl containing from one to four heteroatoms independently selected from O, N and S, and wherein the heteroaryl ring is optionally substituted with one, two or three substituents independently selected from hydroxyl, chlorine, fluorine, CN, —CO ₂ H, —CO ₂ Me, —CO ₂ ethyl, methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl, —CH2 — CO2H, —CH ₂ —CO ₂ methyl and CH ₂ —CO ₂ ethyl]; and

The R ⁵ heteroaryl ring is optionally further substituted with a substituent selected from methyl, ethyl, fluoro, chloro, methoxy, ethoxy, hydroxy, —NH, and cyano.

Embodiment 22

In Embodiment 22, the compounds of Embodiment 1 or 20 and sub-embodiments contained herein are where R ⁵ is - (CH2) 1.2- (5-10 membered heteroaryl ring) containing one to three heteroatoms, independently selected from N, O or S, preferably -CH2- (5-9 membered heteroaryl ring) having from one to 3 heteroatoms independently selected from N, O or S, wherein the heteroaryl ring is substituted with one or two substituents independently selected from -OC1.6 alkyl, -C1.6 alkyl substituted with one to five fluorine atoms, -OC1_6 alkyl (where alkyl is substituted with one to five fluorine atoms), -C1.6 alkylene-CO2H, -C1.6 alkylene-CO2C1.6 alkyl, -CO2H, nitro, -COOC1.6alkyl, halogen, hydroxy, cyano, -CONReRf (where R ^e is hydrogen or -C1. ₆ alkyl and Rf is -C _{1. 6} alkyl, -C1.6 alkylene-CO ₂ H or -C _{1. 6} alkylene-CO ₂ C _{1. 6} alkyl), -SO ₂ (C _{1. 6} alkyl), SO ₂ NR ^g R ^h (where R ^g is a th hydrogen or -C1.6alkyl and R ^h is hydrogen, -C1. ₆ alkyl, -C ₁ . ₆ alkylene-CO ₂ H or -C ₁ . ₆ alkyleneCO ₂ C1. ₆ alkyl), tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, furanyl, thienyl, pyrrolyl or isoxazolyl (where each of the aforementioned heteroaryl, independently selected rings, optionally C _{January 6} alkyl, halogen, CN, -CO2H, -COOC _{January 6} alkyl, -C _{January 6} alkyl, -OC _{1 June} alkyl, -C _{January 6} alkyl substituted with from one to five fluorine atoms,..... - OC _{1. 6} alkyl (substituted with one to five fluorine atoms, tetrazolyl, SO ₂ C _{1. 6} alkyl, -SO ₂ NH 2, -SO 2 NHC _{1. 6} alkyl, -SO ₂ N (C _{1. 6} alkyl) ₂ , - CONH2, -CONHC _{1. 6} alkyl and -CON (C _{1. 6} alkyl) ₂ ); and

The R ⁵ heteroaryl ring is optionally further substituted with one or two substituents independently selected from —C ₁ . ₆ alkyl, -C ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), —OC ₁ . ₆ alkyl, -OC ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), halogen, CN, —NH2, and hydroxy.

Embodiment 23

In an embodiment, compound 23 of the embodiment 1 or 20 and subvariants embodiments contained herein are those wherein R ⁵ represents 5-10chlenny geteroarilS1- ₆ alkyl having one to three heteroatoms independently selected from N, O or S where the heteroaryl ring is substituted with phenyl [where the phenyl ring is optionally substituted with one, two or three substituents independently selected from hydroxyl, halogen, CN, —CO ₂ H, —COOC ₁ . ₆ alkyl, -C ₁ . ₆ alkyl, -OS1_ ₆ alkyl, -C _{1. 6} alkyl (wherein alkyl is substituted with from one to five fluorine atoms), -OS1_ ₆ alkyl (wherein alkyl is substituted with from one to five fluorine atoms), -C _{1. 6} alkylene-CO ₂ H, -C1.6 alkylene-CO ₂ S1_ ₆ alkyl, tetrazolyl, -SO ₂ C _{1. 6} alkyl, -SO2NH2, -SO ₂ NHC ₁ . ₆ alkyl, —SO ₂ N (C _{1. 6} alkyl) ₂ , —CONH2, —CONHC ₁ . ₆ alkyl and —CON (C _{1 6} alkyl) ₂ ]; and

The R ⁵ heteroaryl ring is further optionally substituted with two substituents independently selected from —C ₁ . ₆ alkyl, -C ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), —O — C1-6 alkyl, —OC ₁ . ₆ alkyl (where alkyl is substituted with one to five fluorine atoms), halogen, CN, —NH2, and hydroxy.

Embodiment 24

In Embodiment 24, the compounds of Embodiment 1, 20, 21, 22 or 23 and sub-embodiments contained herein are where the heteroaryl ring in —CH ₂ - (5-10 membered heteroaryl ring) in R ^{5 is} selected from thienyl, furanyl, pyrazolil, imidazo

- 29 039042 lila, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, indolyl and benzothienyl. In one sub-embodiment of Embodiment 24, the heteroaryl ring is a 9 or 10 membered heteroaryl ring selected from benzimidazol-5-yl, benzoxazol-5-yl, indol-5-yl, benzimidazol-2-yl, benzoxazol-2- sludge, benzofuran-5-yl, indol-2-yl, quinolinyl or isoquinolinyl. In one sub-embodiment of Embodiment 24, the heteroaryl ring is a 5 membered heteroaryl ring that is preferably substituted at the 3 position relative to the ring atom of the 5 membered ring that is bonded to —CH2— and the 6 membered heteroaryl ring is substituted in the meta or para position with respect to the ring atom that is bonded to —CH2—, and furthermore, the aforementioned rings are optionally substituted, preferably substituted with one or more substituents, as indicated in embodiments 20, 21, 22 or 23 above.

Embodiment 25

In embodiment 25, the compounds of any one of Embodiments 1-24 and sub-embodiments contained herein are those wherein R ³ is hydrogen, X is O, and Y is O.

Embodiment 26

In Embodiment 26, the compounds of any one of Embodiments 1-24 and sub-embodiments herein are those wherein R ³ is hydrogen, C _1-6 alkyl or benzyl, X is CH 2, and Y is O. In one group of compounds in Embodiment 26, R ³ is hydrogen, X is CH2, and Y is O.

Embodiment 27

In Embodiment 27, the compounds of any one of Embodiments 1-24 and sub-embodiments herein are those wherein R ³ is hydrogen, X is N. In Embodiment 27, in one group of compounds, Y is O. In embodiment 27, in another group of compounds, Y is S.

Embodiment 28

In Embodiment 28, the compounds of any one of Embodiments 1-24 and sub-embodiments contained herein are those wherein R ³ is hydrogen, X is O, and Y is S.

Embodiment 29

In Embodiment 29, the compounds of any one of Embodiments 1-24 and sub-embodiments contained herein and the groups contained herein are where R ³ is hydrogen, X is CH2, and Y is S.

Embodiment 30

In embodiment 30, the compounds of any one of Embodiments 1-29 and sub-embodiments contained herein and the groups contained herein are where

R ^1a is hydroxy, halogen, C ₁ . ₆ alkyl, cyano, azido, NH2, C _{1. 6} alkylcarbonyloxy, ethynyl or vinyl; preferably hydroxy, fluorine, chlorine, cyano, azido, NH2 or methyl;

R ^1b is hydrogen;

R ^2a represents hydrogen, hydroxy, halogen, C ₁ . ₆ alkyl, NH2, cyano, azido, ethynyl, or vinyl; and

R ^2b is hydrogen.

Embodiment 31

In Embodiment 31, the compounds of Embodiment 30 are where

R ^1a is hydroxy, fluoro or methyl;

R ^1b is hydrogen;

R ^2a is hydroxy, fluoro or methyl; and

R ^2b is hydrogen.

Embodiment 32

In Embodiment 32, the compounds of Embodiment 30 are where

R ^1a is fluorine;

R ^1b is hydrogen;

R ^2a is hydroxy, hydrogen, methyl or NH2; and

R ^2b is hydrogen.

In embodiment 32, in one group of compounds, R ^2a is hydrogen.

In embodiment 32, in another group of compounds, R ^2a is hydroxy.

In embodiment 32, in yet another group of compounds, R ^2a is methyl.

In embodiment 32, in another group of compounds, R ^2a is NH2.

- 30 039042

Embodiment 33

In Embodiment 33, the compounds of Embodiments 30, 31 herein are those wherein the groups containing

Embodiment 34

In Embodiment 34, the compounds of Embodiments 30, 31 herein are those wherein the groups containing

Embodiment 35

In Embodiment 35, the compounds of Embodiments 30, 31 herein are those wherein the groups containing

Embodiment 36

In Embodiment 36, the compounds of Embodiments 30, 31 herein are those wherein the groups containing

Embodiment 37

In Embodiment 37, the compounds of Embodiments 30, 31 herein are those wherein groups containing - 31 039042

Represents

Embodiment 38

In Embodiment 38, the compounds of Embodiments 30, 31, and 32 and the groups contained herein are where

R ³

Represents

R ^2a 'Ria

Embodiment 39

In Embodiment 39, the compounds of any one of Embodiments 1-29 are where

R ^1a is halogen, C ₁ . ₆ alkyl, cyano, azido, NH ₂ , C ₁ . ₆ αalkylcarbonyloxy, ethynyl or vinyl;

R ^1b is hydroxy or fluoro;

R ^2a represents hydrogen, halogen, hydroxy, C ₁ . ₆ αalkyl, C ₁ . ₆ alkyloxy, NH2, ethynyl or vinyl; and

R ^2b is hydrogen.

Embodiment 40

In Embodiment 40, the compounds of Embodiment 39 are where

R ^1a is fluorine or methyl;

R ^1b is fluorine or hydroxy;

R ^2a is hydrogen, hydroxy, NH2, methyl, methoxy, ethoxy, or propoxy; and

R ^2b is hydrogen.

Embodiment 41

In Embodiment 41, the connections of embodiments of any one of Embodiments 1-29 are where

R ^1a is hydroxy, halogen, C ₁ . ₆ alkyl or cyano;

R ^1b is hydrogen;

R ^2a is hydroxy, halogen, C ₁ . ₆ alkyl, cyano, ethynyl or vinyl; and

R ^2b is halogen, hydroxy or C ₁ . ₆ alkyl.

Embodiment 42

In Embodiment 42, the connections of Embodiment 42 are where

R ^1a is hydroxy, fluoro or methyl;

R ^1b is hydrogen;

R ^2a is methyl, fluoro, cyano, or hydroxy; and

R ^2b is fluorine, hydroxyl, or methyl.

Embodiment 43

In Embodiment 43, the connections of Embodiment 42 are where

R ^1a is fluorine or methyl;

R ^1b is hydrogen;

R ^2a is methyl; and

R ^2b is fluorine, hydroxy, or methyl.

- 32 039042

Embodiment 44

In embodiment 44, a compound according to any one of embodiments 1-29 and sub-embodiments and groups of compounds contained herein are those where

R ^1a is halogen, C _1-6 alkyl, cyano, azido, NH2, C _1-6 alkylcarbonyloxy, ethynyl or vinyl;

R ^1b is hydroxy or fluoro;

R ^2a is hydroxy, halogen, C _1-6 alkyl, or cyano; and

R ^2b is halogen, hydroxy, or C _1-6 alkyl.

Embodiment 45

In embodiment 45, the compounds of any one of Embodiments 1 to 45 and sub-embodiments and groups of compounds contained herein are where

R ^{4 is} selected from -C (O) OR ⁹ , -C (O) NR ¹¹ R ¹² , -S (O) 2R ¹⁰ , P (O) (OR ¹¹ ) (OR ¹² ) and -P (O) (OR ¹¹ ) (NR ¹³ R ¹⁵ ); and

R ^{6 is} selected from —C (O) OR ⁹ and —P (O) (OR ¹¹ ) (OR ¹² ); where R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁵ independently represent hydrogen or C _1-6 alkyl.

In the compound groups in Embodiment 46, in one compound group, R ⁴ and R ⁶ are —C (O) OR ⁹ , where R ⁹ is as defined above, preferably R ⁹ is hydrogen or C _1-6 alkyl.

In the compound groups in Embodiment 46, in the other compound group, R ⁴ and R ⁶ are —C (O) OH.

In the compound groups in Embodiment 46, in yet another compound group, R ^{4 is} selected from —C (O) NR ¹¹ R ¹² or —S (O) 2R ¹¹ ; and R ^{6 is} selected from —C (O) OR ⁹ and —P (O) (OR ¹¹ ) (OR ¹² ); where R ⁹ , R ¹¹ and R ¹² independently represent hydrogen or C1-6 alkyl. In one embodiment, the compounds are those wherein R ⁹ , R ¹¹ and R ^{12 are} independently hydrogen, methyl, or ethyl.

In the compound groups in Embodiment 46, in yet another compound group, R ⁴ is P (O) (OR11) (OR ¹² ); and R ⁶ is —P (O) (OR ¹¹ ) (OR ¹² ); where R ¹¹ and R ¹² independently represent hydrogen or C _1-6 alkyl, preferably R ¹¹ , and R ¹² independently represent hydrogen, methyl or ethyl.

Embodiment 46

In embodiment 46, the compounds of embodiments 1 to 46 and sub-embodiments and groups of compounds contained herein are where

Het is a group selected from the group of formulas (i) to (xiv) below

where R ^u represents hydrogen, halogen, cyano, —NH2, —NHR ²⁰ , —NHCOR ²⁰ , —NR ²⁰ R ²¹ , —R ²⁰ , —SR ²⁰ , —OH and —OR ²⁰ ;

R ^w is hydrogen, halogen, —NHR ²² , —NR22R ²³ , R ²² , —OH and —OR ²² ;

R ^v and R ^x independently represent hydrogen, halogen, haloC _1-6 alkyl, -NH ₂ , -NHR ²⁴ , -NR ²⁴ R ²⁵ ,

- 33 039042

-R ²⁴ , -SR ²⁴ , cyano, -OH, -OR ²⁴ , -SO2R ²⁴ , -C1.6αalkylene-NH2, -C1-6alkylene-NHR ²⁴ , -C1.6alkylene-NR ²⁴ R ²⁵ , -R ²⁴ , —C1-6alkylene — SR ²⁴ , —C ^ alkylene OH, —C1.6αalkylene — OR ²⁴ , —C1-6alkylene — SO ₂ R ²⁴ , R ^s and Rt are independently hydrogen, halogen or C1.6 alkyl; and where R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ and R ^{25 are} optionally independently C1. ₆ αlkil, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, optionally substituted cycloalkyl, optionally substituted tsikloalkilS1_ ₆ alkyl, optionally substituted heterocyclyl, optionally substituted geterotsiklilS1_ ₆ alkyl, optionally substituted aryl, optionally substituted arilS1. ₆ alkyl, optionally substituted heteroaryl or optionally substituted geteroarilS1_ ₆ alkyl; or R ²⁰ and R ²¹ , R ²² and R ²³ and R ²⁴ and R ²⁵ together with the nitrogen atom to which they are attached form an optionally substituted nitrogen-containing heterocyclyl.

Embodiment 47

In Embodiment 47, the compounds of Embodiment 47 are those wherein Het is a group of formula (i).

Embodiment 48

In Embodiment 48, the compounds of Embodiment 47 are those wherein Het is a group of formula (ii).

Embodiment 49

In Embodiment 49, the compounds of Embodiment 47 are those wherein Het is a group of formula (iii).

Embodiment 50

In Embodiment 50, the compounds of Embodiment 47 are those wherein Het is a group of formula (iv).

Embodiment 51

In Embodiment 51, the compounds of Embodiment 47 are those wherein Het is a group of formula (vi).

Embodiment 52

In Embodiment 52, the compounds of Embodiment 47 are those wherein Het is a group of formula (vii).

Embodiment 53

In Embodiment 53, the compounds of Embodiment 47 are those wherein Het is a group of formula (viii).

Embodiment 54

In Embodiment 54, the compounds of any one of Embodiments 47-54 and sub-embodiments and groups of compounds contained herein are those wherein R ^s is hydrogen.

Embodiment 55

In embodiment 55, the compounds of any one of embodiments 47 to 55 and sub-embodiments and groups of compounds contained herein are those wherein R ^w and R ^d are hydrogen.

Embodiment 56

In Embodiment 56, the compounds of any one of Embodiments 47-56 and the embodiments and groups of compounds contained herein are where

R ^u is hydrogen, halogen, cyano, —NH2, —NHR ²⁰ , —NHCOR ²⁰ , —NR ²⁰ R ²¹ , —R ²⁰ , —SR ^20, or —OR ²⁰ , where R ²⁰ and R ^{21 are} optionally independently substituted C1. ₆ alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylC _1-6 alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylC _1-6 alkyl, optionally substituted aryl, optionally substituted arylC _1-6 alkyl, optionally substituted heteroaryl, or optionally substituted heteroarylC _1-6 alkyl ; or R ²⁰ and R ²¹ together with the nitrogen atom to which they are attached form an optionally substituted nitrogen-containing heterocyclyl;

R ^v is hydrogen, halogen, haloC1_6alkyl, cyano, —R ²⁴ , —SR ²⁴ , —OR ^24, or —SO2R ²⁴ ; where R ²⁴ is optionally substituted C1. ₆ alkyl, -C ₂ -C ₆ -alkenyl, -C ₂ -C ₆ -alkynyl, optionally substituted cycloalkyl, optionally substituted tsikloalkilS1_ ₆ alkyl, optionally substituted heterocyclyl, optionally substituted geterotsiklilS1_ ₆ alkyl, optionally substituted aryl, optionally substituted alkyl arilS1_ ₆ optionally substituted heteroaryl, or optionally substituted geteroarilS1_ ₆ alkyl.

Embodiment 57

In embodiment 57, the compounds of any one of embodiments 47-56 and sub-embodiments and groups of compounds contained herein are where

R ^u is —NH2, —NHR ^20, or —NR ²⁰ R ²¹ , where R ²⁰ and R ^{21 are} optionally independently substituted C1. ₆ alkyl, optionally substituted cycloalkyl, optionally substituted tsikloalkilS _1-6 alkyl, optionally substituted heterocyclyl, optionally substituted geterotsiklilS1_ ₆ alkyl, optionally substituted aryl, optionally substituted arilS1_ ₆ alkyl, optionally substituted heteroaryl or optionally substituted geteroarilS1_ ₆ alkyl; or R ²⁰ and R ²¹ together with the nitrogen atom to which they are attached form an optionally substituted nitrogen-containing heterocyclyl; preferably -NH2, and

R ^v is halogen, preferably chlorine.

Representative compounds of formula (I) include compounds shown in table. 1A.

Table 1A

No. conn. Compound Name 6 ΣΓ, ____, O ... O / VY \ _ /> 0 .o '- o 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydro-furan-2yl) methoxy) -2-benzylmalonic acid 7 о nh ₂ V> ^0H Н0 ₂ С ^ ^but ' ^F 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydro-furan-2- yl) methoxy) -2- (4-carboxybenzyl) - malonic acid eight о nh ₂ V ^0H _C | / ~ N ^Z HO ⁷ 'F 2 - (((.2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydro-furan-2- yl) methoxy) -2 - ((6-chloropyridine-Zyl) methyl) malonic acid 10 o nh ₂ % ^C -J ^{J Έ} Ο Μ but 'G 2- (((2R _r 3RMR _r 5R) -5- (6-amino-9Hpurin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2-benzylmalonic acid 12 о NH ₂ О, у-ОН s А ⁰ A- ° y ^{Jnci but} ' ^F ОН 2- (((2R, 3RMS, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -2- (4- (2- carboxyethyl) benzyl) malonic acid

- 35 039042

thirteen 0 NH ₂ ъЛ еУу ^H0 [° a ο _γ ^ΝΛ Ν ^Λ α ₀ JO ho 'f and 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -2- (3- phenoxybenzyl) malonic acid 15 F ₃ CO 2 X A ^{...... H0} HO F 2 - (((2R, 3RdS, 5R) -5- (b-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -2- (3- (trifluoromethoxy) benzyl) malonic acid sixteen F ₃ C. UL Λ ^{2 H0} H> 0 Η ^Ηϋ HO F 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -2- (3- (trifluoromethyl) benzyl) malonic acid 17 AJ NH ₂ y / M Vl ⁰ dUvl ^H0 Ao H ^H0 HO 'F 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -2- (naphthalene-2ylmethyl) malonic acid twenty ΞΕ O..O О УуУУа _T OJ ~~ z τι H> ω ° Г О γΛ о 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -2- (4- (trifluoromethyl) benzyl) malonic acid 21 ΞΕ Ltd UU 1U-A ° R about 2- (((2R, 3R, 4S, 5R'l -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -2- (4- (methylsulfonyl) benzyl) malonic acid

- 36 039042

22 0 Y ^νΑ = ι ^Η0 > = 0 Μ ^Н0 HO F 2 - (((2R, 3R, 4S, 5R} -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -2- (3- (dimethylcarbamoyl) benzyl) malonic acid 23 ZE Oh oh A d-z) - η y O 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -2- (thiophene-3ylmethyl) malonic acid 25 0 y - νη ₂ ⁰ K ⁰ N b <(TY A ° f ° D / 0y Va Ko F_0 - (y ^ξ diethyl 2 - (((2R, 3R, 4S, 5R) -5- (6amino-2-chloro-9H-purin-9-yl) -4fluoro-3- (isobutyryloxy) tetrahydrofuran-2-yl) methoxy) - 2 (4- (trifluoromethoxy) benzyl) malonate 27 0 ΝΗ ₂ 0 'Con Ν.Α. ^but UUUU U m NO F H ₂ N 2 - (((2R, 3R, 4S, 5Rj-5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -2- (3aminobenzyl) malonic acid 28 0 NH 0. У ^0Н М ^ D _m Tu W ^Н0 L О NО F 2-benzyl-2 - (((2R, 3R, 4S, 5R) -5- (6 (benzylamino) -2-chloro-9H-purine-9- yl) -4-fluoro-3- hydroxytetrahydrofuran-2- yl) methoxy) malonic acid 32 MH ₂ CF ₃ (Τ '£ ^ D _{M C} | G r> ^{F HO} YyoH ^Lh 0 0 2 - (((2R, 3R, 4S, 5Rj-5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -2 - ((6- (trifluoromethyl) pyridin-3yl) methyl) malonic acid

- 37 039042

34 CN A nh ₂ ff ⁰ A> ° y ^{N 74} ^ ^{c | H0} C> 0 M ^H0 HO F 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -2- (4cyanobenzyl) malonic acid 35 0 nh ₂ ^H0 'fA / f N ^ CI ff H / ¾ ^ HO F NC 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -2- (3cyanobenzyl) malonic acid 36 o nh ₂ XK ^{0H N} -f> M Y <'J, ϊ ^H ° z-Xxf' ⁴ ^ ⁰¹ f / HO F OCF ₃ 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -2- (4- (trifluoromethoxy) benzyl) malonic acid 37 0 NH ₂ %> ^ΟΗ ^ dff ^ V ° y ^N ^ ^N ^ ci fl H HO F OCF ₃ isomer 1 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -3-ethoxy-3-oxo-2- (4 (trifluoromethoxy) benzyl) propane acid 38 O NH ₂ 0, Won ____X \ fX fTf ⁰ L ^ Oy ^ N ^ CI o n HO F OCF ₃ isomer 2 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -3-ethoxy-3-oxo-2- (4 (trifluoromethoxy) benzyl) propane acid 39 0 nh ₂ o yon N_X y y, ^h0 (° \ Λ / ΓκΌ fi n f'HO 'F ^ OH 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -2- (4- (hydroxymethyl) benzyl) malonic acid

- 38 039042

40 0 NH ₂ 0 3 ^- OH [\ n X χκ < ^ζ ΖΟ ^Η0 / X but 'F NC 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2azido-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -2- (3cyanobenzyl) malonic acid 41 0 ι Л X 0 ΗΝ ^ οΧ γ> ^0Η XX HO F NC 2 - (((2R, 3R, 4S, 5R) -5- (2-azido-6- ((tert-butoxycarbonyl) amino) -9H- purin-9-yl) -4-fluoro-3- hydroxytetrahydrofuran-2- yl) methoxy) -2- (3- cyanobenzyl) malonic acid 42 o nh ₂ 0 ΧοΗ NX XK (Ϊ1 HO X \ qX _n A _{c |} ο ^{Hci F} OH 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydro-furan-2- yl) methoxy) -2- (3-carboxybenzyl) malonic acid 43 0 NH ₂ 0 XoH N- ^ X χ (^ л! ^H ° ΗνΧ ^ ^{Η6 F} X 2- (3- (1Н-tetrazol-5-yl) benzyl) -2 (((2R, 3R, 4S, 5R} -5- (6-amino-2- azido-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) malonic acid 44 0 NH ₂ χΧ rX ^H0 Χ ^^ 'ΧΛοι _F XX HO' F 2 - (((2R, 3R, 4S, 5Rj-5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -2- (3- fluorobenzyl) malonic acid 45 0 / - NH ₂ AX ° ^Ν -Χίκ, X <<X / ~ ° Χγ ^ ΛΧι XX HO F F diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6amino-2-chloro-9H-purin-9-yl) -4fluoro-3-hydroxytetrahydrofuran-2yl) methoxy) -2- (3fluorobenzyl) malonate 46 О у - nh ₂ 0 Xo N_X _M X <X x ° νχχΧ ^ Χχ fX H X / HO F F diethyl-2- (((2R, 3R _r 4S _r 5R) -5- (6amino-2-chloro-9H-purin-9-yl) -4fluoro-3-hydroxytetrahydrofuran-2yl) methoxy) -2- (4-

- 39 039042

fluorobenzyl) malonate 47 0 NH ₂ AK ^0H MA> B < ^z B B M ho F F 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -2- (4fluorobenzyl) malonic acid 48 0 _/ - nh ₂ ^O x / ^ ⁰ M_D. _m b <<'Yj HO F ^f VF diethyl-2- (((22,32,4S _r 5R) -5- (6amino-2-chloro-9H-purin-9-yl) -4fluoro-3-hydroxytetrahydrofuran-2yl) methoxy) -2- (4- (trifluoromethoxy) benzyl) malonate 49 o nh ₂ o Voh> B <Βϊ ^H0 AQ, n οι but 'F -o 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -2- (3methoxybenzyl) malonic acid 50 o nh ₂ V ^oh Μ ^H0 v ^ \ A ^ v ^{N n} ^ ^ci нВ В Ν ^ίΝ H0 F 2 - ((1H-tetrazol-5-yl) methyl) -2- (((22,32,4S, 5R) -5- (6-amino-2-chloro- 9Н-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) malonic acid 51 О BB c '/' lTj / ^ ° m. \ / ^m o / = \ ¹ ιΧ o 2 - (((23,33,42,52) -3-amino-5- (6amino-2-chloro-9H-purin-9-yl) -4hydroxytetrahydrofuran-2yl) methoxy) -2-benzylmalonic acid 53 o nh ₂ AK ^0H N_A _hl .fo 'N, / T nn 2- (3- (1H-tetrazol-5-yl) benzyl) -2 (((2R, 3R, 45.5R) -5- (6-amino-2-chloro9H-purin-9-yl) -4-fluoro -Z- hydroxytetrahydrofuran-2yl) methoxy) malonic acid

- 40 039042

54 0 ΝΗ ₂ о Don n A ^{H (} 3 kJ HO ⁴ F Hn3 N = N 2- (4- (1H-tetrazol-5-yl) benzyl) -2- (((2R, 3R, 4S, 5R1-5- (b-amino-2-chloro- 9H-purin-9-yl) -4-fluoro-3- hydroxytetrahydro-furan-2- yl) methoxy) malonic acid 55 ho 7— (\ II but 'X ^N y ^N Cl 2- (((, 2R, 3S, 4R, 5R) -4-amino-5- (6amino-2-chloro-9H-purin-9-yl) -3hydroxytetrahydrofuran-2yl) methoxy) -2-benzylmalonic acid 56 73 o f o, D, o. -. ° -ph__ / - \ 1 tl St O \ ¹ o ΞΕ 2 - (((2R, 3R, 4S, 5fl -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -2- (3hydroxybenzyl) malonic acid 57 nh about ₂ Cl A ^0H NX fl JJ 3 p Y 3 Xxv ^H0 (/ OH 2 - (((2R, 3R, 4S, 5fl -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -2- (4-carboxy-2fluorobenzyl) malonic acid 58 0 NH ₂ 0 AoH FL A A <^ 31 ^H0 1 ^{04: 1} HO F 0 ^ 0 H 2- (((2R, 3R, 4Srfl -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydro-furan-2- yl) methoxy) -2- (4-carboxy-3fluorobenzyl) malonic acid 59 0 NH ₂ о Don n A ^H 3 ⁰ AQ ^NN 'A ¹ 3 ^F 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3- hydroxytetrahydro-furan-2- yl) methoxy) -2 - ((5- (trifluoromethyl) furan-2-yl) methyl) malonic acid

- 41 039042

60 nh ₂ Λ YX- ^Η °? γθΗ δΗ ο 0 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydro-furan-2yl) methoxy) -2- (3- fluorine-4- (trifluoromethyl) benzyl) malonic acid 61 7 οζ Ζ ^ Ν N> j ^ _C | ZU A ™ 6h 0 0 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -2 - ((3-phenylisoxazole- 5-yl) methyl) malonic acid 62 0 χ nh ₂ °, Up to N_A _m A ⁰ ~ V- ⁰ γ ^Ν Ο Μ Ε ₃ Ζ ^ ^{Η0 F} dimethyl-2 - (((2R, 3R, 45.5R) -5- (6amino-2-chloro-9H-purin-9-yl) -4fluoro-3-hydroxytetrahydrofuran-2yl) methoxy) -2- (4- (trifluoromethyl) benzyl) malonate 63 ο _{νη 2} V Κθ ^Η ν - ^, Α κχ <1% ^Η0 I ^Ν <01 Ν-Ν HO '' F 8 2- (((.2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydro-furan-2- yl) methoxy) -2 - ((1-benzyl-1Hpyrazol-4-yl) methyl) malonic acid 64 0 ΝΗ ₂ ° ₃ Κ ^0Η ν ^ Α _κι h <<'Χζ ^Η0 J θΑ, οΑ ^^ Ν ^ ΟΙ ΗΝ-Ν HO' ^ F 2 - ((1H-pyrazol-4-yl) methyl) -2- (((2R, 3R _r 45 _r 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4 -fluoro-3hydroxytetrahydrofuran-2yl) methoxy) malonic acid 65 0 νη ₂ Ο _λ VOH N_A # _V PA phL O 2- (((.2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -2- (4- (benzyloxy) benzyl) malonic acid

- 42 039042

66 0 nh ₂ o Voh m A ^H0 ζρ HO '''F OH 2- (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -2- (4- hydroxybenzyl) malonic acid 67 o nh ₂ Η ^ θ ^ οΝ ^ Ν ^ οΐ nV but 'F r ° HO 2- (((2R, 3R, 4S, 5R ') -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydro-furan-2- yl) methoxy) -2 - ((2-carboxythiazol5-yl) methyl) malonic acid 68 о nh ₂ yr <“A ^H0 ί ° WO ν ^λ _ν % Л Μ Vs but F H ° - / О 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2- chloro-9H-purin-9-yl) -4-fluoro-3- hydroxytetrahydro-furan-2- yl) methoxy) -2 - ((2-carboxythiazole- 4-yl) methyl) malonic acid 69 o nh ₂ θ. GoH Ν ^.% V Π < ^? Ji tu ⁰ A / ° J O M lm no F o isomer 1 2 - ([1, 1'-biphenyl] -4-ylmethyl) -2- (((2R _f 3R _f 4S _r 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydro-furan-2- yl) methoxy) -3-ethoxy-Zoxopropanoic acid 70 o _/ - nh ₂ A% ° A / I y ⁰ £ ¹ `` ^l 0 ^ diethyl-2 - (((2R ^ 3R ^ 45.5R) -5- (6amino-2-chloro-9H-purin-9-yl) -4fluoro-3-hydroxytetrahydrofuran-2yl) methoxy) -2- (4- ( 2-methoxy-2oxoethyl) benzyl) malonate 71 О / - NH ₂ о Vo NV b <Ϊ у ⁰ [ ^o yyV nAsi Ey ⁰ - \ diethyl 2- (((2R, 3R, 45 _r 5R) -5- (6amino-2-chloro-9H-purin-9-yl) -4fluoro-3- (isobutyryloxy) tetrahydrofuran-2yl) methoxy) -2- ((5- (methoxycarbonyl) thiophen-3- yl) methyl) malonate

- 43 039042

72 nh ₂ L I rV diethyl-2 - (((2R, 3R, 45.5R) -5- (6amino-2-chloro-9H-purin-9-yl) -4fluoro-3-hydroxytetrahydrofuran-2yl) methoxy) -2- ((5 - (methoxycarbonyl) -1-methyl-1Hpyrazol-3-yl) methyl) malonate 73 nh _{2 ΗΟ} γ “'ll _δΗ 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -2 - ((5-carboxy-1methyl-1H-pyrazole-3- yl) methyl) malonic acid 74 О ОН О VoH N_Jx b << ^Ζ 2Ο о Μ NO 'F 2-benzyl-2- (((.2R, 3R, 4S, 5R} -5- (2chlor-6-hydroxy-9H-purin-9-yl) -4fluoro-3-hydroxytetrahydrofuran-2yl) methoxy) malonic acid 75 NH2 _F C _N ^N / 2 N ^ N ^ CI G ^NO ¥ Yon όΗ 0 O 2- (((.2R, 3R, 4S, 5R} -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -2- (4-cyano-3fluorobenzyl) malonic acid 76 0 νη ₂ U ° ^H · θά ^but [° x, 0 Ν ^Λ _Ν Α _α / -S HO 'F ° h he 2- (((.2R, 3R, 4S, 5R} -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydro-furan-2- yl) methoxy) -2 - ((5-carboxythiophen3-yl) methyl) malonic acid 77 0 NH ₂ 0 VoH b <U Ϊ ^H0 (Ao \ __ / HO 'F) = 0 HO 2- (((.2R, 3R, 4S, 5R} -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydro-furan-2- yl) methoxy) -2 - ((5-carboxythiophen2-yl) methyl) malonic acid

- 44 039042

78 0 nh ₂ 0 / he N unit bГ unit ϊ HO £ ° l _Ο / ^Λ ν / | o <h chad but f / o he 2- (((2R _r 3R _r 45 _r 5R} -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -2- (4- (carboxymethyl ) benzyl) malonic acid 79 о nh ₂ А Ζ ^0Η ν, Ζ ,, unit <unit ϊ unit / ° unit ° unit / | To? BUT F O 2 - ([1, 1'-biphenyl] -4-ylmethyl) -2- (((2R _r 3R _r 45.5R) -5- (6-amino-2-chloro-9H-purin-9-yl) - 4-fluoro-3hydroxytetrahydro-furan-2yl) methoxy) malonic acid 80 Head of ^{he F 4/0} y = N PLA _on / ° umedn2) - ^(ν / ν HO F y Cl 2- (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -2- (4-chloro-2fluorobenzyl) malonic acid 81 o _z nh ₂ ° y ° eedo neded, h'- ^Y isomer 1 2 - ([1, 1'-biphenyl] - 4-ylmethyl) -2- (((2R, 3R, 45.5R) -5- (6-amino-2-chloro9H-purin-9-yl) -4-fluoro-3- hydroxytetrahydrofuran-2yl) methoxy) -3-methoxy-Zoxopropanoic acid 82 o, nh ₂ A K ⁰ n_A unitG / j] bJ ° edo / -ed unit o'- <isomer 2 2 - ([1, 1'-biphenyl] - 4-ylmethyl) -2- (((RR.SR, 45.5R) -5- (6-amino-2-chloro- 9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -3-methoxy-3- oxopropanoic acid 83 nh ₂ ⁿ ° h food ^ 'HCHu PZ “? unit _δΗ 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -2 - ((3- carboxyisoxazole-5- yl) methyl) malonic acid

- 45 039042

84 o nh ₂ θ Yon ν Η < ⁷ Y1 ^H0 F isomer 2 2 - ([1, 1'-biphenyl] -4-ylmethyl) -2- (((2R, 3R, 45.5R) -5- (6-amino-2-chloro9H-purin-9-yl) -4-fluoro-3- hydroxytetrahydro-furan-2yl) methoxy) -3-ethoxy-Zoxopropanoic acid 85 o nh ₂ o yon ν D, yx <lϊ ^Η ° ρ ^ ο ν ^ νΑοι A ^ .0 2- (((.2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -2- (3-chloro-4methoxybenzyl) malonic acid 86 ΖΞ Ο, ___, C), Ο ζ-ώ — UU— ΞΓ II \ __ /> 5 .ο _{ο ο} '-' ο Y about 2 - ((<, 2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -2- (4- sulfamoylbenzyl) malonic acid 87 ο νη ₂ ° ν Y ^0H Ν ^ Α _μ YX κΤι ^but 1 ° p / ° Y ^ Y TsU NO 'F suin o-Hen 2 - (((2R, 3R, 4S, 5R) -5- (b-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydro-furan-2yl) methoxy) -2- (4- ((2-carboxyethyl) carbamoyl) benzyl) malonic acid 88 o nh ₂ h U ⁿ n_A- _m xy < ^ζ Ιίϊ ⁿ ° L 2- ((^ RyRMSyR) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydro-furan-2yl) methoxy) -2 - ((2carboxybenzofuran-5- yl) methyl) malonic acid 89 О ΝΗ ₂ о% ОН ν 1 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -2- (4- (2,2,2trifluoroethoxy) benzyl) malonic

- 46 039042

acid 90 o nh ₂ A Un Ν ,, Χ DD / A Ο Μ. BUT F OH 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -2- (4 - (( E) -2carboxyvinyl) benzyl) malonic acid 91 o ΝΗ ₂ yyo Asi _Me o ₂ f ^ Y ^F 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2- chloro-9H-purin-9-yl) -4-fluoro-3- hydroxytetrahydrofuran-2- yl) methoxy) -2- (4- (methoxycarbonyl) benzyl) malonic acid 92 О NH ₂ Won U А Α ΑΪ УД Ο ^ _ο nA _n A _{c |} Q Μ ^{Η0 F} he 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2- chloro-9H-purin-9-yl) -4-fluoro-3- hydroxytetrahydrofuran-2- yl) methoxy) -2- (4- (carboxymethoxy) benzyl) malonic acid 93 A BUT '' F 2-benzyl-2- (((2R, 3R, 4S, 5R) -5- (2chloro-6-oxo-1H-purin-9 (6H) -yl) -4fluoro-3-hydroxytetrahydrofuran-2yl) methoxy) malonic acid 94 o NH ₂ 0. A ^{0H M} Y b <W kn ° ' ^F 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -2- (4- (5-methyl-1,3,4oxadiazol-2-yl) benzyl) malonic acid 95 o nh ₂ A DoH N ^ X _M XuDXX a ^{ff F} 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -2- ((2'-cyano- [1, Gbiphenyl] -4-yl) -methyl) malonic acid

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96 0 nh ₂ O 'F ^0H XY ° dchu ^ ^{N 4: 1} U _C T ^F 2- (({2R, 3R, 43.5R} -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) -2 - ((5- chlorobenzo [b] thiophen-3-yl) methyl) - malonic acid 97 0 NH ₂ O _v K ^0H N ^ X, food (T ^s «οΉ 2- (({2R _r 3R, 43 _r 5R} -5- (6-amino-2chlor-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (benzo [ d] thiazole-2ylmethyl) malonic acid 98 о nh ₂ о Koh n__К Tj (Ji KK ⁰ OK y ^N ο G 0 ^ / HO F NH / 2 - (((2R, 3R, 4S, 5Rj-5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2yl) methoxy) -2- (4- (methylcarbamoyl) benzyl) malonic acid 99 9 0 NH v> - Gn _HC j diethyl 2 - (((2R, 3S, 4R, 5R) -5- (6amino-2-chloro-9H-purin-9-yl) -3,4 dihydroxytetrahydrofuran-2yl) methoxy) -2-benzylmalonate one hundred 0 NH ₂ G / G Y / ° lx JTA, HOrC ^ ^{H0 0H} 2 - (((2R, 3S, 4R, 5Rj-5- (6-amino-2- chloro-9H-purin-9-yl) -3,4- dihydroxytetrahydrofuran-2yl) methoxy) -2- (4- carboxybenzyl) malonic acid 101 N HN 'J NH ₂ o. K ^N N-_D _m NG <'11 ^H0 but '' he (5) -2 - (((2R, 3S, 4R, 5R) -5- (6-amino2-chloro-9H-purin-9-yl) -3,4 dihydroxytetrahydrofuran-2yl) methoxy) -2- (1H- tetrazole-5yl) acetic acid

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102 N HN 'N NH ₂ О, A ^N ьС <Άϊ ^H0 θ - but''he (R) -2- (((2R, 3S _r 4RYR) -5- (6-amino2-chloro-9H-purin-9-yl) -3,4 dihydroxytetrahydrofuran-2yl) methoxy) -2- (1H-tetrazole- 5yl) acetic acid 103 n ⁿ > j YU nh ₂ HN- <W n_A _m 0Jr < ^z Td I ° A, oJ N ^ CI he Υ Ύ Ho '0H (5) -2 - (((2R, 3S, 4R, 5R) -5- (6-amino2-chloro-9H-purin-9-yl) -3,4 dihydroxytetrahydrofuran-2yl) methoxy) -3-phenyl-2 - (1Htetrazol-5-yl) propanoic acid 104 AA NHj, A _n O. rD 5 ί A θ “Λ, O AlAci he γ Ύ but Oh (R) -2- (((2R, 3S,. 4R, 5R ') -5- (6-amino 2-chloro-9H-purin-9-yl) -3,4- dihydroxytetrahydrofuran-2- yl) methoxy) -3-phenyl-2- (1Htetrazol-5-yl) propanoic acid 105 m - \ UU ^nh 2 Τ ° DL / OH Y / ho 'oh (5) -2 - (((2R, 3S, 4R, 5R ') -5- (6-amino2-methoxy-9H-purin-9-yl) -3,4dihydroxytetrahydrofuran-2- yl) methoxy) -3-phenyl-2- (1H- tetrazol-5-yl) propanoic acid 106 у ή (T a ^HN 4/0 A / < ^Z J 1 T ° uMe HO 0H (d) -2 - (((2R, 35,4R, 5R) -5- (6-amino2-methoxy-9H-purin-9-yl) -3,4dihydroxytetrahydrofuran-2- yl) methoxy) -3-phenyl-2- (ΎΗtetrazol-5-yl) propanoic acid 107 О nh ₂ О -OH | \ L Tx ^H °° \ o * a _n a _ci ο TI but 'bn OH

Representative compounds of formula (I) include compounds shown in table. 1B.

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IB Table

Conn. No. Compound 108 F J \, F about XX but? —Ί ϊ ιΤ HO ”F ^Ν γ ^Ν CI 109 Ο О ΚθΗ Μ 1 χΧ <XX ίΒ ° λ ^ ^ν ΒΒι HO F 110 ο ΝΗ ₂ O 'Kon Β <Β1 ^ ~ y ^Ο ^ - ^α Β X ^{Ηο <f F} F 111 Ο ΝΗ ₂ Ο Β ^Η W ('J jXl θ ^ Χ / ⁰ ' -! ¹ N ^{c |} В M. оHO 'F nh ₂ 113 nh ₂ N vX f J Y / ^N N ^ ci OH O-D O / M - X OH HO HO 114 nh ₂ N-v '·' in? he o-d O - \\ A ⁰ he HO - HO

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115 О NH ₂ О Don s ¢ 33 ЗУ ° D s О 0 = 3 ° ⁿ he 116 C1 ^ o / I A ¹ to I 0 AG T ^ \ r ¹ ° ° '^ ^z A ^H As in the first O-έ- 117 o NH ₂ O Don | \ L A 3 Ui J3 / ° AaX Ho O s - 03 ^ ^{but F} he 118 o / - NH ₂ O 3 ° N ^ 3> 3 (XZd ° 3Xv ^N ^ ^N ^ ⁰¹ O m 119 o νη ₂ O Hon N ^ 3> 3 (1 JN O ^ 3 120 О NH ₂ О 3θΗ N ^ 3> у <j? about m F

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122 About NH ₂ about. An n-_A _m 3 < ^z T ΐ ° ^ \ ^ ^Ν З ^ З ^ HCf F О 123 o NH ₂ o aon m A b (¢ 13 3γ ° ^, o o,? 0 M ^ 3 - / ^ HO F ^z n 124 o NH ₂ O ΆθΗ Ν -, - '3 ¢ 3 Ϊ / ^ 3 ° but F / ^ O n 125 nh ₂ 14 ,, ...., - 9, J ί 3 Ν _С | F ₃ CO OH? ^{with |} 33z33o \\ / G-- ^U he no 126 nh ₂ N - Ux J ί Λ ^Ν ν 'ci he od ^ 3338 / ^ c'-a3Z3 ^ o ⁷ \\ A ^{--- / Α υ} he but F 127 nh ₂ Ν A ^{N c |} OH O- ^ _o A-o-> A ^ A__ / ° θ ^Η l, but F

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128 nh ₂ he οΆ_ ^Cl cX ^: ^ he o 129 o NH ₂ o Won N_-L> X UI o XX OTs Λν ^ Ηό F 130 О NH ₂ О% ОН | \ k X> χχ < ^z l ί o ₂ n ^ ^{but f} 131 о NH ₂ о Voh Χχ <J 1 l / '/ hcj f 133 h Κ ^οΗ nzL, v 1J J X ° A- ° y ^{N s} ^ ^{C |} XX HO 'F 134 About S '^ Awy ^ - O uh-oh A <XT HO c XX Ηό 'F

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- 54 039042

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147 О NH ₂ О ΧθΕΐ m X Χχ < ^z J 1 XX θΛ, Ογ ^ ΝΧΐ О м F ОН 148 Ο ΝΗ ₂ Ο XoEt n .X XX < ^z JI XX ° XXy ^N N ^ CI Ο -χχ HO OH 149 o NH ₂ O Hon n X X7G < ^z Jl XX ° XX ^N N ^ CI Ο Ή NO OH 150 о νη ₂ А Х ^ОН «X W and ϊ χχ ^Μ χ XX? < ^F to Λ-Ν ^HO / X n Xa 151 o ΝΗ ₂ O Hon 1 \ kX N C I ^HO X ° (j ^but O 152 o NH ₂ O Hon X Π < ^Ζ Χ ΐ X / ° A / ° y N ^ CI \ O χΧ ^ ⁷ nA ^ην X A

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158 O ° 1 ? d 7 W. st'o JF y ω ^ ζ 159 0 νη ₂ a D ° ⁿ Η I // - Y Ο but 'N \ h ₂ n ^z ^ ~~' ^ 160 0 NH ₂ 0. D ° Η Ν -_D _{k |} BG <TD / iy ⁰ Ay D D D | HO V 3 r - ^ ^{F H0} 'O 161 О NH ₂ О VoEt Dx I <J ί О NO 162 О NH ₂ о Don m D W 1Т Ϊ * DD ° X / ^o D ⁿ ci о О An ^Hd 163 О NH ₂ О DoE1 N ^ Dx H < ^Z J 1 5D / ° ldu ^{N <<} ci 1J -M he

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164 О NH ₂ О ^ OEt me u u u u u u lb 'he 165 0 NH ₂ units of _it's units in <41 VT ^o yy ^N / Y. Oh y F OH 166 О NH ₂ о edon ν, unit y <L I H / ° y ° y Y ¹ 5 / H ₂ N - ^ - (- ⁷ OH 167 o NH ₂ O VoH m J- y < ^ζ 4ι Tu ° y ° y ^N Y ¹ 1 / m 'he 168 o nh ₂ o ed he m _ed u u / ° uu u। Oh -M he 169 o NH ₂ o food is _he eating at Chu's? Tu ° uu u। o ^ y ^p ~ - ⁷ but

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170 About NH ₂ about XoEt z. A 3 Oli 3X ° 3-O ^ 3 O o ^ A but 'o 171 o NH ₂ θ Hon / \ A y / 3 Ν 3 / ° \ 3 s ^H c1 O X- ^ 0 ^ 3 ^ but he 172 о nh ₂ о XoEt А ЗХ n3 | n Зз ° ЛХу no 173 o NH ₂ o 3 ^OEt Ν ^ 3κ A < ^z j Ϊ Д / yvy ^ νΑι but he 174 о nh ₂ ° l X ^0Н n3 _m А <j? fly uuu άα but 'bn 175 o ^ Z ^g XX ° ^ rX ° ° γΧχ °)

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182 ⁿ n ^HN V> N ojB HO '' q _H ΝγΝ Cl 183 ⁿ -n ^HN yN of / / O / o \ but; __ / γ | f HO OH Α, -Ν Cl 184 В B hn-4 / XX ° B В / Ο τ 'but γ | f ho' oh ^N y ^N Cl 185 fo oX <f ^ n / o; ^ ^N ..f but \ __ / γ jf HO- 'N ^ N O 186 O / ₀ nh ₂ Gb < ^0H σ M ° HO ⁴ F mixture of diastereomers 187 N ° \? ^Н2 Гв ^on < ^{/ N} jS X / ° B ° y ^N NO ⁴ 'F

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mixture of diastereomers 188 Mo X _p l '-A ”sL O M HO ⁴ F mixture of diastereomers 189 ⁿ fl l V Y-U-.T_ but? -1 1 II ⁿ ° £, _n ΝγΝ Cl mixture of diastereomers 190 F F ^ _X F lu _o / = N but? —II II NO bn ^Ν γ ^Ν Cl mixture of diastereomers 191 F ^ L / ⁿ A / ° y \ but F ^ F г '^^, ο) \ V ⁿ vAa / NH ₂ Т Η Htf _0H у Cl

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192 L? ^N Ay η ^{Ν ο} γνΥ Y * ^M \ A-XH ₂ but g — 1 G H but £ n ^Ν γ ^Ν Cl mixture of diastereomers 193 Y ^N Ay 'η A ^N ° y oA y ^ o / AT T ¥ - / HO ^V _F N ^ N Cl 194 y cA ^F y Τ ^Ν ΑΧ _ yN ^θ7 / Α 'y ^ but .. ¥ X Τ ¥ Ηό Un ΝγΝ Cl 195 ° Ύ ° ^ ⁿ ΐιΊ ΓΑ _Μ XX ν; J ¹ Γ nAy ¹ 'yN Α ^ οΆΤ α ^ν <ζ ο / Τ ¥ no bn ^N y ^N Cl

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196 οΧ У AJ 1 οο / χ у Χ'Α.Χ о? - ^ζ ϊ ¥ but he ^N y ^N Cl 197 ° χ ^{ΟΗ n} ίιΊ ^Ν η ¥ Χ ν ' ^ν j Χ <χνςχ ₂ but ι— / Τ ¥ but ^{n N} y ^N Cl 198 χΧ ^н О X τ Χγ> Χ _ΝΗ2 but \ ^/ Τ ¥ Η А ь _н Ν <γ.Ν Cl 199 F, - ^ Οχ-Έ ^н [I ¥ f n. _m ¥ X У J ^N | Ν'-χχ ' _n / - ΓΊ X \ AJ ^z 1 χ ^Ν \ Χ \ / ΝΗ ₂ ИО' 5 _H yN Cl

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200 I yOO ₂ H ⁿ ΓΊ ^ν μ YY ^Ν Y ^ Ο ^><Α, ΝΗ ₂ but? - ² G N NO `` he Cl 201 OH oU n V ^s , _N 'ν xy ^N ) Ϊ ^N Y / o x ^N ° X ^> Y ^/ ' X 'Y NO.-/ 1 II NO' he ^N y ^N Cl 202 l 0 νΛ J UlxSU no .Y4 I ¥ ^no no ^N y ^N Cl 203 l 0 Ν N Y nX J _K1 sYX o / X θχο '^ Υ Χ ^ν χΑ ^, νη ₂ but yy T G but _on p CI 204 0 Ν Ν XY nX j XoY ^ Xnn, BUT) -! 1 Ιί ': n ^ n ho _OH p Cl

Other compounds of the invention include

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or a pharmaceutically acceptable salt thereof.

Pharmaceuticals

In some embodiments, the present invention relates to a pharmaceutical preparation suitable for use in a human patient, comprising any of the compounds shown above (e.g., a compound of the invention such as a compound of formula (I)) and one or more pharmaceutically acceptable excipients. In some embodiments, pharmaceutical preparations can be used to treat or prevent a condition or disease described herein.

Any of the described compounds can be used in the manufacture of medicaments for the treatment of any diseases or conditions described herein.

Application methods

Provided herein are methods for inhibiting CD73 in a cell, comprising contacting the cell with a compound of the invention, such as a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the implementation of the contact with the cell is carried out in a subject in need thereof, and, thus, the disease or disorder mediated by adenosine is treated.

Also described herein are methods of treating a disease or disorder mediated by adenosine, comprising administering a compound of the invention, such as a compound of formula (I), or a pharmaceutically acceptable salt thereof.

Adenosine acts on various immune cells to induce immunosuppression, and the immunosuppressive effects of ectonucleotidases, which increase adenosine levels, are also associated with increased infection of mammalian cells with parasites, fungi, bacteria, and viruses. In addition to immunosuppressive effects, adenosine also plays a role in modulating the cardiovascular system (as a vasodilator and cardiac depressor), the central nervous system (CNS) (causing sedative, anxiolytic and antiepileptic effects), the respiratory system (causing bronchoconstriction), kidney (having biphasic action; causing vasoconstriction at low concentrations and vasodilation at high doses), fat cells (inhibiting lipolysis) and platelets (as an antiplatelet agent). In addition, adenosine also promotes fibrosis (excess matrix production) in various tissues. Therefore, improved treatment targeting CD73 will provide drugs for treating a wide range of conditions other than malignant neoplasm, including cerebral and cardiac ischemic disease, fibrosis, immune and inflammatory disorders (e.g., inflammatory bowel motility disorder), neurological, neurodegenerative and CNS races.

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In some embodiments, the adenosine mediated disease or disorder is selected from cerebral ischemic disease, malignant neoplasm, coronary heart disease, depression, fibrosis, immune disorder, inflammatory disorder (eg, inflammatory bowel motility disorder), neurological disorder or disease, neurodegenerative disorder, or diseases (for example, Parkinson's disease), disorders and diseases of the central nervous system, and sleep disorders.

The methods described herein can be used to treat a wide variety of cancers, including bladder cancer, bone cancer, brain cancer (including glioblastoma), breast cancer, heart cancer, cervical cancer, colon cancer, colorectal cancer, cancer esophagus, fibrosarcoma, stomach cancer, gastrointestinal cancer, head and neck cancer, Kaposi's sarcoma, kidney cancer (including renal cell adenocarcinoma), leukemia, liver cancer, lung cancer (including non-small cell lung cancer, small cell lung cancer, and mucoepidermoid cancer lung), lymphoma, melanoma, myeloma, ovarian cancer (including ovarian adenocarcinoma), pancreatic cancer, penile cancer, prostate cancer, testicular germ cell cancer, thymoma and thymic carcinoma.

In some embodiments, the subject suffers from a cancer selected from breast cancer, brain cancer, colon cancer, fibrosarcoma, kidney cancer, lung cancer, melanoma, ovarian cancer, and prostate cancer. In some embodiments, the subject is suffering from a cancer selected from breast cancer, colon cancer, fibrosarcoma, melanoma, ovarian cancer, and prostate cancer. In other embodiments, the subject is suffering from a cancer selected from brain cancer, breast cancer, kidney cancer, lung cancer, melanoma, and ovarian cancer. In yet other embodiments, the implementation of the subject suffers from breast cancer. In some embodiments, the breast cancer is breast adenocarcinoma. In some embodiments, the breast cancer is triple negative breast cancer.

In some embodiments, methods of treating or preventing cancer may be demonstrated by one or more responses, such as increased apoptosis, inhibition of tumor growth, reduction of tumor metastasis, inhibition of tumor metastasis, decrease in microvessel density, decrease in neovascularization, inhibition of tumor migration, tumor regression, and increase the survival of the subject.

In some embodiments, the adenosine mediated disease or disorder is a disease or disorder mediated by CD73 activity. In some embodiments, compounds of the invention, such as compounds of formula (I), can be used as inhibitors of CD73.

In some embodiments, the methods described herein treat or prevent cardiovascular disease using CD73 inhibitors. Mutant genes encoding CD73 lead to extensive calcification of the arteries of the lower extremities and small joint capsules, which is associated with an increased risk of cardiovascular disease (Hilaire et al., N. Engl. J. Med., 364 (5): 432-442 , 2011).

In some embodiments, the methods described herein treat or prevent cancer using CD73 inhibitors. Small interfering RNA CD73 and monoclonal antibodies against CD73 have shown significant effect in the treatment or prevention of malignant neoplasm (Antonioli et al., Nat. Rev. Cancer, 13: 842-857, 2013). There is a strong correlation between CD73 expression and the ability of cancer cells to migrate, penetrate and adhere to the extracellular matrix (ECM) (Antonioli 2013; Antonioli et al., Trends Cancer, 2 (2): 95-109, 2016).

In some embodiments, treatment or prevention of cancer with CD73 inhibitors may be demonstrated by one or more responses selected from activation, clonal expansion, and homing of tumor-specific T cells (Antonioli 2016). In other embodiments, the methods described herein increase the number of effector T lymphocytes (eg, cytolytic effector T lymphocytes).

Combined treatment.

In some embodiments, a method for treating or preventing cancer may include co-administering a CD39 inhibitor with one or more other chemotherapeutic agents. In one embodiment, the CD73 inhibitor is a compound of the invention, such as a compound of formula (I). Other chemotherapeutic agents may include CD73-specific monoclonal antibodies, which potentiate the action of other antibodies and drugs due to increased overall immune system activity (lower T-regulatory function and higher T-effector function, etc.) (Antonioli 2016).

In some embodiments, a method for treating or preventing cancer may comprise administering a compound of the invention together with one or more other chemotherapeutic agents.

Chemotherapeutic agents that can be co-administered with the compounds of the invention include the following: 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (acid blue 25), 1-amino-4- [4-hydroxyphenylamino] -9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1amino-4- [4-aminophenylamino] -9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1 - amino-4- [1-naphthylamino] -9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4- [4-fluoro-2-carboxyphenylamino] -9,10-dioxo-9,10- dihydroanthracene-2-sulfonate, 1-amino-4- [2-anthracetylamino] -9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, ABT-263, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastrozole, APCP , asparaginase, AZD5363, Bacillus Calmette-Guerin vaccine (BCG), bicalutamide, bleomycin, bortezomib, β-methylene-ADP (AOPCP), buserelin, busulfan, cabazitaxel, cabosantinib, campocein, capecitabil, cabozantinib, carmbothecin, capecitabil, carboplatin, carboperitin , chloroquine, cisplatin, cladibine, clodronate, cobimetinbine, colchicine, krizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demetoksiviridin, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gefitinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenaliprolidovidone, mega-taminophenolamide, leystroxol melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotan, mitoxantrone, MK-2206, mutamycin, N- (4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, nilazidolitamide, octodaparylitate , pazopanib, pemexetred, pentostatin, perifosin, PF-04691502, plikamycin, pomalidomide, porfimer, PPADS, pro carbazine, quercetin, raltitrexed, ramucirumab, reactive blue 2, rituximab, rolophilin, romidepsin, rucaparib, selumetinib, sirolimus, 2,4-dinitrobenzenesulfonate sodium, sorafenib, streptozocin, sunitinialox, teniniferos, testaribose, temparibosocin, sunitinialox , thalidomide, thioguanine, thiotepa, titanocene dichloride, tonapophylline, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, vinorelbine and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that can be co-administered with compounds of the invention include ABT-263, dexamethasone, 5-fluorouracil, PF-04691502, romidepsin, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that may be co-administered with compounds of the invention include 1-amino-4-phenylamino-9,10-dioxo-9,10 dihydroanthracene-2-sulfonate (acid blue 25), 1-amino-4 - [4-hydroxyphenylamino] -9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4- [4-aminophenylamino] -9,10-dioxo-9,10-dihydroanthracene-2sulfonate, 1-amino -4- [1-naphthylamino] -9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4- [4fluoro-2-carboxyphenylamino] -9,10-dioxo-9,10-dihydroanthracene -2-sulfonate, 1-amino-4- [2anthracenylamino] -9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, APCP, β-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N- (4sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, PPADS, quercetin, reagent blue 2, rolofilin sodium 2,4-dinitrobenzenesulfonate, sumarin and tonapophylline.

Many combination drugs have been developed for the treatment of malignant neoplasm. In some embodiments, compounds of the invention (eg, compounds of Formula (I)) may be co-administered with combination therapy. Examples of combination preparations with which the compounds of the invention can be administered are included in table. one.

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Table 1

An example of combinatorial therapy for cancer treatment

Name Therapeutic agents ABV doxorubicin, bleomycin, vinblastine ABVD doxorubicin, bleomycin, vinblastine, dacarbazine AC (mammary gland) doxorubicin, cyclophosphamide AS (sarcoma) doxorubicin, cisplatin AS (neuroblastoma) cyclophosphamide, doxorubicin ACE cyclophosphamide, doxorubicin, etoposide ACe cyclophosphamide, doxorubicin AD doxorubicin, dacarbazine AR doxorubicin, cisplatin ARAC-DNR cytarabine, daunorubicin B-CAVe bleomycin, lomustine, doxorubicin,

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vinblastine BCVPP carmustine, cyclophosphamide, vinblastine, procarbazine, prednisone BEACOPP bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, filgrastim BEP bleomycin, etoposide, cisplatin BIP bleomycin, cisplatin, ifosfamide, mesna BOMP bleomycin, vincristine, cisplatin, mitomycin CA cytarabine, asparaginase CABO cisplatin, methotrexate, bleomycin, vincristine CAE cyclophosphamide, doxorubicin, fluorouracil CAL-G cyclophosphamide, daunorubicin, vincristine, prednisone, asparaginase CAMP cyclophosphamide, doxorubicin, methotrexate, procarbazine CAP cyclophosphamide, doxorubicin, cisplatin CAV cyclophosphamide, doxorubicin, vincristine CAVE ADD CAV and etoposide CA-VP16 cyclophosphamide, doxorubicin, etoposide CC cyclophosphamide, carboplatin CDDP / VP-16 cisplatin, etoposide CEE cyclophosphamide, epirubicin, fluorouracil CEPP (B) cyclophosphamide, etoposide, prednisone, with or without / bleomycin CEV cyclophosphamide, etoposide, vincristine CF cisplatin, fluorouracil, or carboplatin fluorouracil CHAP cyclophosphamide or cyclophosphamide, altretamin, doxorubicin, cisplatin ChlVPP chlorambucil, vinblastine, procarbazine, prednisone CHOP cyclophosphamide, doxorubicin, vincristine,

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prednisone CHOP-BLEO bleomycin supplement to CHOP CISCA cyclophosphamide, doxorubicin, cisplatin CLD-BOMP bleomycin, cisplatin, vincristine, mitomycin CMF methotrexate, fluorouracil, cyclophosphamide CMFP cyclophosphamide, methotrexate, fluorouracil, prednisone CMFVP cyclophosphamide, methotrexate, fluorouracil, vincristine, prednisone CMV cisplatin, methotrexate, vinblastine CNF cyclophosphamide, mitoxantrone, fluorouracil CNOP cyclophosphamide, mitoxantrone, vincristine, prednisone COB cisplatin, vincristine, bleomycin CODE cisplatin, vincristine, doxorubicin, etoposide COMLA cyclophosphamide, vincristine, methotrexate, leucovorin, cytarabine COMP cyclophosphamide, vincristine, methotrexate, prednisone Cooper's scheme cyclophosphamide, methotrexate, fluorouracil, vincristine, prednisone COP cyclophosphamide, vincristine, prednisone COPE cyclophosphamide, vincristine, cisplatin, etoposide COPP cyclophosphamide, vincristine, procarbazine, prednisone SR (chronic lymphocytic leukemia) chlorambucil, prednisone SR (ovarian cancer) cyclophosphamide, cisplatin CVD cisplatin, vinblastine, dacarbazine CVI carboplatin, etoposide, ifosfamide, mesna CVP cyclophosphamide, vincristine, prednisone CVPP lomustine, procarbazine, prednisone

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CYVADIC cyclophosphamide, vincristine, doxorubicin, dacarbazine DA daunorubicin, cytarabine DAT daunorubicin, cytarabine, thioguanine DAV daunorubicin, cytarabine, etoposide DCT daunorubicin, cytarabine, thioguanine DHAP cisplatin, cytarabine, dexamethasone DI doxorubicin, ifosfamide DTIC / Tamoxifen dacarbazine, tamoxifen DVP daunorubicin, vincristine, prednisone EAP etoposide, doxorubicin, cisplatin EC etoposide, carboplatin EFP etoposide, fluorouracil, cisplatin ELF etoposide, leucovorin, fluorouracil EMA 8 6 mitoxantrone, etoposide, cytarabine EP etoposide, cisplatin EVA etoposide, vinblastine FAC fluorouracil, doxorubicin, cyclophosphamide FAM fluorouracil, doxorubicin, mitomycin FAMTX methotrexate, leucovorin, doxorubicin FAP fluorouracil, doxorubicin, cisplatin F-CL fluorouracil, leucovorin FEC fluorouracil, cyclophosphamide, epirubicin FED fluorouracil, etoposide, cisplatin FL flutamide, leuprolide FZ flutamide, goserelin acetate implant HDMTX methotrexate, leucovorin Hexa-CAF altretamine, cyclophosphamide, methotrexate, fluorouracil IDMTX / 6-MP methotrexate, mercaptopurine, leucovorin IE ifosfamide, etoposide, mesna IfoVP ifosfamide, etoposide, mesna I PA ifosfamide, cisplatin, doxorubicin M-2 vincristine, carmustine, cyclophosphamide,

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prednisone, melphalan methotrexate, leucovorin, dactinomycin, MAC-III cyclophosphamide methotrexate, doxorubicin, cyclophosphamide, MASS lomustine methotrexate, leucovorin, doxorubicin, MACOP-B cyclophosphamide, vincristine , bleomycin, prednisone mesna, doxorubicin, ifosfamide, MAID dacarbazine bleomycin, doxorubicin, cyclophosphamide, m-BACOD vincristine, dexamethasone, methotrexate, leucovorin MBC methotrexate, bleomycin, cisplatin MC mitoxantrone, cytarabine MF methotrexate, fluorouracil, leucovorin MICE ifosfamide, carboplatin, etoposide, mesna MINE mesna, ifosfamide, mitoxantrone, etoposide mini-BEAM carmustine, etoposide, cytarabine, melphalan bleomycin, vincristine, cisplatin, MOBP mitomycin MOP mechlorethamine, vincristine,: procarbazine mechlorethamine, vincristine, procarbazine, MOPP prednisone mechlorethamine, vincristine, procarbazine, MOPP / ABV prednisone, doxorubicin, bleomycin, vinblastine MP (plural myeloma) melphalan, prednisone MP (prostate cancer) mitoxantrone, prednisone MTX / 6-MO methotrexate, mercaptopurine MTX / 6-MP / VP methotrexate, mercaptopurine , vincristine, prednisone methotrexate, leucovorin, cisplatin, MTX-CDDPAdr doxorubicin

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MV (breast cancer glands) mitomycin, vinblastine MV (sharp myelocytic leukemia) mitoxantrone, etoposide M-VACMeTOTpeKcaT vinblastine, doxorubicin, cisplatin MVP Mitomycin vinblastine, cisplatin MVPP mechlorethamine, vinblastine, procarbazine, prednisone NFL mitoxantrone, fluorouracil, leucovorin NOVP mitoxantrone, vinblastine, vincristine OPA vincristine, prednisone, doxorubicin ORRA addition of procarbazine to OPA. RAS cisplatin, doxorubicin PAC-1 cisplatin, doxorubicin, cyclophosphamide PA-CI cisplatin, doxorubicin PCV lomustine, procarbazine, vincristine PFL cisplatin, fluorouracil, leucovorin RUS prednisone, vincristine, lomustine ProMACE prednisone, methotrexate, leucovorin, doxorubicin, cyclophosphamide, etoposide ProMACE / cytaBOM prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, leucovorin, cotrimoxazole PRoMACE / MOPP prednisone, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, procarbazine, methotrexate, leucovorin Pt / VM cisplatin, teniposide PVA prednisone, vincristine, asparaginase PVB cisplatin, vinblastine, bleomycin PVDA prednisone, vincristine, daunorubicin, asparaginase SME streptozocin, mitomycin, fluorouracil TAD mechlorethamine, doxorubicin, vinblastine,

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vincristine, bleomycin, etoposide, prednisone mmm methotrexate, cytarabine, hydrocortisone Toro / CTX cyclophosphamide, topotecan, mesna VAB-6 cyclophosphamide, dactinomycin, vinblastine, cisplatin, bleomycin VAC vincristine, dactinomycin, cyclophosphamide VACAdr vincristine, cyclophosphamide, doxorubicin, dactinomycin, vincristine VAD vincristine, doxorubicin, dexamethasone VATH vinblastine, doxorubicin, thiotepa, fluoxymesterone VBAP vincristine, carmustine, doxorubicin, prednisone VBCMP vincristine, carmustine, melphalan, cyclophosphamide, prednisone VC vinorelbine, cisplatin VCAP vincristine, cyclophosphamide, doxorubicin, prednisone VD vinorelbine, doxorubicin VelP vinblastine, cisplatin, ifosfamide, mesna VIP etoposide, cisplatin, ifosfamide, mesna VM mitomycin, vinblastine VMCP vincristine, melphalan, cyclophosphamide, prednisone VP etoposide, cisplatin V-TAD etoposide, thioguanine, daunorubicin, cytarabine 5 + 2 cytarabine, daunorubicin, mitoxantrone 7 + 3 cytarabine together with / daunorubicin or idarubicin or mitoxantrone methylprednisolone, vincristine, lomustine, "8 in 1" procarbazine, hydroxyurea, cisplatin, cytarabine, dacarbazine

In some embodiments, chemotherapeutic agents that may be co-administered with compounds of the invention, such as a compound of formula (I), include a CD39 inhibitor. CD39 or ectonucleoside triphosphate diphosphate 1 (E-NTPDase1 or ENTPD 1) is a membrane-bound enzyme that catalyzes the conversion of extracellular adenosine triphosphate (ATP) and / or ADP (adenosine diphosphate) to adenosine monophosphate (AMP). In one embodiment, the CD39 inhibitor is polyoxometalate-1 (POM-1).

In other embodiments, chemotherapeutic agents that may be co-administered with compounds of the invention, such as a compound of formula (I), include known CD73 inhibitors. In some embodiments, the CD73 inhibitor is an anthraquinone derivative (Baqi et al., J. Med. Chem., 53 (5): 2076-2086, 2010, incorporated herein by reference). In other embodiments, the CD73 inhibitor is a sulfonic acid derivative (Raza et al., Med. Chem., 8: 1133-1139, 2012, incorporated herein by reference). In still other embodiments, the CD73 inhibitor is selected from 1-amino-4-phenylamino9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (acid blue 25), 1-amino-4- [4-hydroxyphenylamino] 9.10 -dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4- [4-aminophenylamino] -9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4- [1-naphthylamino] -9,10-dioxo-9,10-dihydroanthracene-2sulfonate, 1-amino-4- [4-fluoro-2-carboxyphenylamino] -9,10-dioxo-9,10-dihydroanthracene-2- 76 039042 sulfonate, 1 -amino-4- [2-anthraceneamino] -9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, sodium

2,4-dinitrobenzenesulfonate, N- (4-sulfamoylphenylcarbamothioyl) pivalamide, APCP, β-methylene-ADP (AOPCP), PPADS, NF279, NF449, quercetin, reagent blue 2 and sumarin (Baqi 2010; Raza 2012).

In some embodiments, the combination of a compound of the invention, such as a compound of Formula (I), with a second CD73 inhibitor or CD39 inhibitor may have a synergistic effect in the treatment of cancer and other adenosine-mediated diseases or disorders. While not wishing to be bound by any theory, this synergy can be observed because CD39 and CD73 are often found on different cell types. The hypoxic tumor microenvironment also induces increased levels of CD39 and CD73.

In some embodiments, chemotherapeutic agents that can be co-administered with compounds of the invention, such as a compound of formula (I), include an adenosine receptor inhibitor. In other embodiments, the adenosine receptor inhibitor is selected from rolofilin, tonapophyllin, ATL-444, isstradephylline, MSX-3, preladenant, SCH-58261, SCH-412348, ScH-442416, ST-1535, VER-6623, VER-6947 VER-7835 , vipadenant and ZM-241385. In some embodiments, the adenosine receptor inhibitor targets the A _2A receptor as this subtype is predominantly expressed in most immune cells.

In other embodiments, chemotherapeutic agents that can be co-administered with compounds of the invention, such as a compound of formula (I), include a nucleoside drug. In some embodiments, the nucleoside drug is selected from gemcitabine, capecitabine, cytarabine, fludarabine, and cladribine.

In other embodiments, the combination therapy comprises a compound of the invention, such as a compound of formula (I), co-administered with an anthracycline. In other embodiments, the combination therapy comprises a compound of the invention, such as a compound of formula (I), co-administered with doxorubicin. Combination treatment with anti-CD73 antibody and doxorubicin has shown significant chemotherapeutic effect (Young et al., Cancer Discov., 4 (8): 1-10, 2014, incorporated herein by reference).

In some embodiments, the combination therapy comprises a compound of the invention, such as a compound of formula (I), co-administered with an A _2A receptor inhibitor and an anthracycline. In some embodiments, the anthracycline is doxorubicin. Combination treatment with anti-CD73 antibody, A _2A receptor inhibitor and doxorubicin has been shown to have an enhanced chemotherapeutic effect (Antonioli 2013).

In some embodiments, co-therapies of the invention include co-administration with other types of chemotherapeutic agents, such as immuno-oncological agents. Cancer cells often have specific cell surface antigens that can be recognized by the immune system. Thus, immuno-oncological agents such as monoclonal antibodies can selectively bind to cancer cell antigens and influence cell death. Other immuno-oncological agents can suppress tumor-mediated inhibition of a native immune response or otherwise activate an immune response and thus facilitate tumor recognition by the immune system. Typical antibody-based immuno-oncological agents include, but are not limited to, abagovomab, adekatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, blinatumomab, BMS-936559, catumaxomab, intellecturazura, induchuimabumabum, innitumabum, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, okaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, and tremelimumab. In some embodiments, the antibody-based immuno-oncological agents are selected from an anti-CD73 monoclonal antibody (mAb), an anti-CD39 mAb, an anti-PD-1 mAb, and an anti-CTLA4 mAb. Thus, in some embodiments, the methods of the invention comprise co-administering one or more immuno-oncological agents, such as those mentioned above.

In some embodiments, the combination therapy comprises a compound of the invention, such as a compound of formula (I), co-administered with an anti-PD-1 drug and an anti-CTLA4 drug. Combined treatment with anti-CD73 monoclonal antibodies (mAb), anti-PD-1 mAb and anti-CTLA4 mAb has shown significant chemotherapeutic effect (Young 2014; Antonioli 2013).

In some embodiments, a compound of the invention can be co-administered with non-chemical cancer treatments. In certain embodiments, a compound of the invention can be co-administered with radiation therapy. In some embodiments, a compound of the invention can be co-administered with surgery, thermal ablation, focused ultrasound therapy, cryotherapy, or any combination thereof.

In some embodiments, the compounds of the invention may be co-administered with one or more other compounds of the invention. In addition, such combinations can be co-administered with other therapeutic agents, such as other agents suitable for the treatment of cancer, immunological or neurological diseases, such as those mentioned above. In some embodiments, co-administration of one or more additional chemotherapeutic agents with a compound of the invention provides a synergistic effect. In some embodiments, the co-administration of one or more additional chemotherapeutic agents provides an additive effect.

Pharmaceutical compositions.

The compositions and methods of the present invention can be used to treat a subject in need thereof. In some embodiments, the subject is a mammal, such as a human, or a non-human mammal. When administered to a subject, such as a human, the composition or compound is preferably administered as a pharmaceutical composition containing, for example, a compound of the invention and a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline, or other solvents or carriers such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are intended for administration to humans, especially for invasive routes of administration (i.e., routes such as injection or implantation that bypass transport or diffusion across the epithelial barrier), the aqueous solution is pyrogen-free or substantially free contains pyrogens. For example, excipients can be selected to effect delayed release of an agent or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition may be in the form of a unit dose such as a tablet, capsule (including a coated particle capsule and a gelatin capsule), granule, lyophilisate for reconstitution, powder, solution, syrup, suppository, injection, or the like. The composition may also be present in a transdermal delivery system, such as a transdermal patch. The composition can also be present in a solution suitable for topical application, such as eye drops.

A pharmaceutically acceptable carrier may contain physiologically acceptable agents that act, for example, to stabilize, increase solubility, or increase absorption of a compound, such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose or dextrans, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The drug or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulative drug delivery system.

The pharmaceutical composition (preparation) can also be a liposome or other polymer matrix, which can include, for example, a compound of the invention. Liposomes, for example, which include phospholipids or other lipids, are non-toxic, physiologically acceptable and metabolizable carriers that are relatively easy to prepare and administer.

The expression pharmaceutically acceptable is used herein to denote those compounds, substances, compositions and / or unit dosage forms that are medically suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction or other problems or complications. , commensurate with a reasonable benefit / risk ratio.

The phrase “pharmaceutically acceptable carrier,” as used herein, means a pharmaceutically acceptable substance, composition, or carrier medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and harmless to the patient. Some examples of substances that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic sodium chloride solution; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

The pharmaceutical composition (preparation) can be administered to a subject by any of a number of modes of administration, including, for example, oral administration (e.g., infusion as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including coated particle capsules and gelatinous

- 78 039042 capsules), boluses, powders, granules, pastes for application on the tongue); absorption through the oral mucosa (eg, sublingual); anal, rectal, or vaginal (for example, as a pessary, cream, or foam); parenteral (including intramuscular, intravenous, subcutaneous, or intrathecal as, for example, a sterile solution or suspension); intranasal; intraperitoneal; subcutaneous; transdermal (eg, as a patch applied to the skin); and topical (eg, as a cream, ointment, or spray applied to the skin or as eye drops). The compound can also be formulated for inhalation. In some embodiments, the compound can be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable therefor can be found, for example, in US Patent Nos. 610973, 5763493, 5731000, 5541231, 5427798, 5358970 and 4172896, as well as in the patents cited therein.

The formulations can conveniently be presented in unit dosage form and can be prepared by any means well known in the pharmaceutical art. The amount of active ingredient that can be combined with a carrier material to produce a unit dosage form will vary depending on the subject being treated and the particular route of administration. The amount of active ingredient that can be combined with the carrier material to provide a unit dosage form is usually that amount of the compound that provides a therapeutic effect. Typically, out of one hundred percent, this amount will be from about 1 to about 99% of the active ingredient, preferably from about 5 to about 70%, most preferably from about 10 to about 30%.

Methods for preparing these compositions or compositions include the step of bringing into association an active compound, such as a compound of the invention, with a carrier and optionally one or more additional ingredients. Typically, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with liquid carriers or finely divided solid carriers, or both, and then shaping the product, if necessary.

Compositions of the invention suitable for oral administration may be in the form of capsules (including coated particle capsules and gelatin capsules), sachets, pills, tablets, lozenges (using a flavored base, usually sucrose and gum arabic or tragacanth), lyophilisates, powders , granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a lozenge (using an inert base such as gelatin and glycerin, or sucrose and gum arabic), and / or in the form of mouthwash and the like, each of which contains a predetermined amount of a compound of the present invention as an active ingredient. The compositions or compounds can also be administered as a bolus, electuary, or paste.

When preparing solid dosage forms for oral administration (capsules (including coated particle and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as citrate sodium or dicalcium phosphate and / or any of the following: (1) fillers or diluents such as starches, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) humectants such as glycerin; (4) disintegrants such as agaragar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) retarding dissolution agents such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents such as modified and unmodified cyclodextrins; and (11) colorants. In the case of capsules (including coated particle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also contain buffering agents. In addition, solid compositions of a similar type can be employed as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

A tablet can be made by compression or molding, optionally with one or more additional ingredients. Compressed tablets can be prepared using a binder (e.g. gelatin or hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactant, or dispersing agent. Molded tablets can be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Tablets and other solid dosage forms of pharmaceutical compositions such as dragees, capsules (including coated particle capsules and gelatin capsules), pills and granules can optionally be filled or prepared with coatings and shells such as enterosol

- 79 039042 Variable coatings and other coatings well known in the pharmaceutical field. In addition, they can be formulated to provide slow or controlled release of the active ingredient from them, using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by the administration of sterilizing agents in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately prior to use. Such compositions may optionally additionally contain opacifiers and may be compositions that release only the active (s) ingredient (s), or preferably in a certain part of the gastrointestinal tract, optionally in a delayed form. Examples of encapsulated compositions that can be used include polymeric substances and waxes. In addition, the active ingredient can be in microencapsulated form, if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, peanut, corn, wheat germ oil, olive, castor and sesame oils), glycerin, tetrahydrofuryl alcohol, polyethylene glycols and esters of fatty acids and sorbitan, and mixtures thereof.

In addition to inert diluents, compositions for oral administration may additionally contain adjuvants such as humectants, emulsifiers and suspending agents, sweeteners, flavors, colors, flavors and preservatives.

Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations of pharmaceutical compositions for rectal, vaginal or urethral administration can be presented in the form of suppositories, which can be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol, wax or salicylate for suppositories that are solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

Formulations of pharmaceutical compositions for oral administration may be presented as a mouthwash or oral spray or oral ointment.

Alternatively or additionally, the compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices can be particularly effective for delivery to the bladder, urethra, ureter, rectum, or intestine.

Formulations suitable for vaginal administration further include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be suitable.

Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and implants. The active ingredient can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffering agents or propellants as needed.

Ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids, talc and zinc oxide, or their mixtures.

Powders and sprays may contain, in addition to a compound provided herein, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or a mixture of these substances. Sprays may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

Transdermal patches have the additional advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be obtained by dissolving or dispensing a compound in an appropriate medium. Additionally, absorption enhancers can be used to increase the absorption of the compound through the skin. The rate of such inflow can be controlled by a speed-controlling membrane, or

- 80 039042 by dispersing the compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions, etc. are also contemplated to be within the scope of the present invention. Examples of ophthalmic formulations are described in US 2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and US Pat. No. 6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic formulations can have properties similar to those of tears, aqueous humor, or vitreous humor, or be compatible with such fluids. The preferred route of administration is topical administration (eg, topical administration such as eye drops or through an implant).

As used herein, the phrases parenteral and parenterally administered mean routes of administration other than enteral and local administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal , transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intraarticular injection and infusion.

Pharmaceutical compositions suitable for parenteral administration may contain one or more active compounds in combination with one or more pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders, which can be reconstituted with sterile injectable solutions or dispersions immediately prior to use. which may contain antioxidants, buffers, bacteriostatic agents, soluble substances that keep the preparation isotonic with the blood of the intended recipient, or suspending agents or thickening agents.

Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerin, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, the maintenance of the desired particle size in the case of dispersions, and the use of surfactants.

In addition, these carriers may contain adjuvants such as preservatives, humectants, emulsifiers and dispersing agents. Prevention of exposure to microorganisms can be achieved by the administration of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenolsorbic acid, and the like. It may also be desirable to incorporate isotonicity agents such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of an injectable pharmaceutical form can be achieved by the administration of agents that delay absorption, such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it is desirable to slow down the absorption of the drug by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with low water solubility. The rate of absorption of the drug further depends on the rate of dissolution, which, in turn, may depend on the size of the crystals and the crystalline form. Alternatively, absorption of a parenterally administered dosage form is slowed down by dissolving or suspending the drug in an oily vehicle.

Depot injection molds are made by forming microencapsulated matrices of the compounds of interest in biodegradable polymers such as polylactide polyglycolide. Depending on the ratio of drug to polymer, as well as the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Also receive preparations for injection depots, including the drug in liposomes, microemulsions, which are compatible with the tissue of the body.

For use in the methods of this invention, the active compounds can be taken alone or in the form of a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

Routes of administration can also be provided with rechargeable or biodegradable devices. In recent years, various in vivo slow release polymer devices have been developed and tested for controlled drug delivery, including protein biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and insoluble polymers, can be used to sustainably release a compound at a specific target site during implant formation.

Actual dosage levels of active ingredients in pharmaceutical compositions can be varied so as to obtain an amount of active ingredient that will be effective to achieve the desired therapeutic response in a particular patient, composition and route of administration.

- 81 039042 denia, no patient toxicity.

The selected dosage level will depend on many factors, including the activity of the particular compound or combination of compounds used or an ester, salt or amide thereof, route of administration, time of administration, rate of release of the particular compound (s), duration of treatment, other drugs, compounds and / or substances used in combination with the particular compound (s), age, sex, weight, condition, general health and previous medical history of the patient being treated, and similar factors well known in medicine.

A physician or veterinarian of ordinary skill in the art can readily determine and prescribe a therapeutically effective amount of the pharmaceutical composition required. For example, a physician or veterinarian may start dosing of the pharmaceutical composition or compound at levels lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By a therapeutically effective amount is meant a concentration of a compound sufficient to achieve the desired therapeutic effect. It will generally be understood that the effective amount of a compound will vary depending on the weight, sex, age, and medical history of the subject. Other factors that affect the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent administered with the compound of the invention. A large total dose can be delivered in multiple doses of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, incorporated herein by reference).

Typically, a suitable daily dose of active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest effective dose to produce a therapeutic effect. This effective dose usually depends on the factors described above.

If desired, an effective daily dose of the active compound can be administered as one, two, three, four, five, six or more subdoses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. In some embodiments, implementation of the present invention, the active compound can be administered two or three times a day. In preferred embodiments, the active compound will be administered once a day.

In some embodiments, the dosing is on a 3 + 3 regimen. The traditional 3 + 3 regimen does not require modeling of a dose-toxicity curve that goes beyond the classic cytotoxic drug assumption that toxicity increases with dose. This rule-based design works with cohorts of three patients; the first group is treated at an initial dose that is considered safe based on extrapolation from animal toxicological data, and the subsequent groups are treated at higher dose levels that have been fixed in advance. In some embodiments, the three doses of a compound of formula (I) range from about 100 to about 1000 mg orally, such as from about 200 to about 800 mg, such as from about 400 to about 700 mg, such as from about 100 to about 400 mg. , for example, from about 500 to about 1000 mg, and in addition, for example, from about 500 to about 600 mg. Dosing can be three times daily when taken without food, or twice daily when taken with food. In some embodiments, the three doses of a compound of formula (I) range from about 400 to about 800 mg, such as from about 400 to about 700 mg, such as from about 500 to about 800 mg, and further, for example, from about 500 to about 600 mg twice daily. In certain preferred embodiments, a dose greater than about 600 mg is administered twice daily.

If none of the three patients in the cohort experience dose-limiting toxicity, three more patients will receive treatment at the next higher dose level. However, if one of the first three patients experiences dose-limiting toxicity, three more patients will be treated at the same dose level. The dose escalation continues until at least two patients in a group of three to six patients experience dose-limiting toxicity (i.e.> about 33% of patients with dose-limiting toxicity at this dose level). The recommended dose for Phase II trials is usually defined as a dose level just below the toxic dose level.

In some embodiments, the dosing regimen can be from about 40 to about 100 mg / m ² , for example, from about 50 to about 80 mg / m ² , and further, for example, from about 70 to about 90 mg / m ² intravenously in within 3 weeks of a 4 week cycle.

In some embodiments, the compounds of the invention can be used alone or in conjunction with another type of therapeutic agent. As used herein, the expression co-administration refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., two compounds are simultaneously effective in

- 82 039042 subjects, which may involve a synergistic effect of the two compounds). For example, different therapeutic compounds can be administered either in the same composition or in a separate composition, either simultaneously or sequentially. In some embodiments, the various therapeutic compounds can be administered at intervals of 1 hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or weeks relative to each other. Thus, a subject who receives such treatment can benefit from the combined action of various therapeutic compounds.

In some embodiments, co-administration of compounds of the invention with one or more additional therapeutic agents (e.g., one or more additional chemotherapeutic agents) provides improved efficacy with respect to each individual administration of a compound of the invention (e.g., a compound of Formula I or IA) or one or more additional therapeutic agents. In some such embodiments, co-administration provides an additive effect, where the additive effect refers to the sum of each of the effects of individual administration of a compound of the invention and one or more additional therapeutic agents.

The present invention includes the use of the pharmaceutically acceptable salts of the present invention in the compositions and methods of the present invention. In some embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkyl ammonium salts. In some embodiments, contemplated salts of the invention include, but are not limited to, salts of L-arginine, benetamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino) ethanol, ethanolamine, ethylenediamine, N- methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4- (2-hydroxyethyl) morpholine, piperazine, potassium, 1- (2-hydroxyethyl) pyrrolidine, sodium, triethanolamine, tromethamine and zinc. In some embodiments, contemplated salts of the invention include, but are not limited to, salts of Na, Ca, K, Mg, Zn, or other metals.

The pharmaceutically acceptable acid addition salts can also exist as various solvates, for example with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such a solvate can be a crystallization solvent corresponding to the solvent in the preparation or crystallization, or random for such a solvent.

Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coatings, sweeteners, flavors and aromas, preservatives and antioxidants, may be present in the compositions.

Examples of pharmaceutically acceptable antioxidants are: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol and the like; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

General synthesis.

Compounds numbers 1-45 used in the general synthesis section below refer only to structures of the genus in this section and do not refer to compounds described in other sections of this application. The compounds described herein can be prepared by the methods depicted in the reaction schemes below.

The starting materials and reagents used in the preparation of these compounds are either available from a commercial supplier such as Aldrich Chemical Co., Bachem, etc., or may be prepared by methods well known in the art. The schemes are merely illustrative of some of the methods by which the compounds described herein can be synthesized and various modifications of these schemes can be made and will be offered by POSITA with reference to this disclosure. Starting materials and intermediates, as well as final reaction products, can be isolated and purified, if desired, using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like, and can be characterized using conventional means, including physical constants and spectral data.

Unless otherwise indicated, the reactions described herein proceed at atmospheric pressure in a temperature range from about -78 ° C to about 150 ° C.

Compounds of formula (I) having the structure

- 83 039042 where R ^u , R ^v , R ⁵ and R ^{9 are} defined in the Summary of the Invention can be synthesized as shown and described in Scheme 1 below.

Scheme 1

Removal of benzoyl groups in a compound of Formula 1 with a suitable base such as NH3 in an organic alcohol solvent such as MeOH or aq. LiOH, or aq. a NaOH solution followed by selective protection of the 5'-OH group with a tert-butyldiphenylsilyl group affords the compound of formula 2.

Compounds of Formula 1 are either commercially available or can be prepared by methods well known in the art. For example, ((2R, 3R, 4S, 5R) -3- (benzoyloxy) -5- (2,6dichloro-9H-purin-9-yl) -4-fluorotetrahydrofuran-2-yl) methylbenzoate and ((2R, 3R , 4S, 5R) -3- (benzoyloxy) -5 (2-amino-6-chloro-9H-purin-9-yl) -4-fluorotetraαhydrofuran-2-yl) methyl benzoate are commercially available. Compounds of formula 1 wherein R ^u is other than chlorine or amino and R ^v is other than chlorine can be prepared from ((2R, 3R, 4S, 5R) -3- (benzoyloxy) -5- (2, 6-dichloro-9H-purin-9-yl) -4fluorotetrahydrofuran-2-yl) methyl benzoate, as described in PCT Patent Publication Nos. WO 2015/164573 and WO 2017/120508.

Protection of the 3'-hydroxy group in compound 2 with a suitable hydroxy protecting group such as Boc followed by removal of the silyl group under conditions well known in the art such as TBAF in THF affords a compound of formula 4. Reacting compound 4 with a diazo reagent of formula 5 wherein R ⁹ is unsubstituted alkyl or benzyl, in the presence of a catalyst such as Rh ₂ (OAc) ₄ or CuOAc ₂ in a suitable organic solvent such as toluene, benzene, dichloromethane, dichloroethane and THF, gives a compound of formula 6 wherein R ⁵ is is hydrogen. Compound 6 can then be converted to a compound of formula (I) by removal of the Boc group under acid hydrolysis conditions followed by removal of the R ⁹ group under basic hydrolysis conditions, for example aq. LiOH or NaOH (when R ⁹ is alkyl), or by hydrolysis with Pd / C or Pd (OH) 2 / C (when R ⁹ is benzyl).

Alternatively, compound 6 can be reacted with a halide of the formula R ⁵ X, where X is halogen (preferably chlorine, bromine, iodine, tosylate, mesylate or triflate) and R ⁵ is as defined in the Summary of the Invention section other than hydrogen, under alkylation reaction conditions to give the corresponding compound of formula (I) wherein R ⁵ and R ⁹ are other than hydrogen, which can then be converted to the corresponding compound of formula (I) wherein R ⁹ is hydrogen as described above.

Compounds of formula (I) wherein Het is other than purine can be prepared by methods well known in the art. For example, compounds of formula (I) wherein a group of formula (i), (ii) or (vii) can be prepared from 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine, 4,6-dichloro- Spirazolo [3,4-d] pyrimidine and 4,6-dichloro-1H-imidazo [4,5-c] pyridine, respectively, synthetic

84 039042 by the methods described in PCT Patent Publication No. WO 2017/120508 and in Scheme 1 above.

Acting as described above, but replacing the compound of formula 1 with (2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-chloro-2- (hydroxymethyl) tetrahydrofuran -3-ol (prepared according to the methods described by Secrist, John A., III et al., Journal of Medicinal Chemistry, 31 (2), 405-10; 1988, and Anderson, Bruce G. et al., Organic Process Research & Development, 12 (6), 1229-1237; 2008), compounds of formula (I) can be prepared wherein R ^1a is chlorine, R ^1b and R ^2b are hydrogen and R ^2a is hydroxy and Het is 2-chloro-9H-nurin-6-amine. It will be apparent to those skilled in the art that analogs of such compounds, i. E. Het, other than 2-chloro-9Hpurin-6-amine, can also be prepared based on the description of the present application and methods known in the art.

Acting as described above, but replacing the compound of formula 1 with (2R, 3S, 4S, 5R) -2- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-5- (hydroxymethyl) tetrahydrofuran -3-ol (prepared according to the methods described by Ren, Hang et al., Beilstein Journal of Organic Chemistry, 11, 2509-2520; 2015, and Schinazi, Raymond F. et al., Heterocyclic Communications, 21 (5) , 315-327; 2015), compounds of formula (I) can be prepared wherein R ^1a is hydroxy, R ^1b and R ^2b are hydrogen and R ^2a is fluorine and Het is 2-chloro-9H-purine -6-amine. It will be apparent to those skilled in the art that analogs of such compounds, i. E. Het, other than 2-chloro-9H-purine-6amine, can also be prepared based on the description of the present application and methods known in the art.

Acting as described above, but replacing the compound of Formula 1 with ((2R, 3R, 4R, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -3,4-difluorotetrahydrofuran-2-yl ) methanol (prepared according to the methods described by Schinazi, Raymond F. et al., Heterocyclic Communications, 21 (5), 315-327; 2015, and Sivets, Grigorii G. et al., Nucleosides, Nucleotides & Nucleic Acids, 28 (5-7), 519-536; 2009), compounds of formula (I) can be prepared wherein R ^1b is fluorine, R ^1a and R ^2a are hydrogen and R ^2b is fluorine and Het is 2 -chloro-9H-purin-6-amine. It will be apparent to those skilled in the art that analogs of such compounds, i. E. Het, other than 2-chloro-9H-purine-6amine, can also be prepared based on the description of the present application and methods known in the art.

Acting as described above, but replacing the compound of formula 1 with (2R, 3S, 4R, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -2- (hydroxymethyl) -3-methyltetrahydrofuran- 3,4-diol (prepared according to the methods described by Franchetti, Palmarisa, et al., J. Med. Chem., 48 (15), 4983-4989, 2005) or (2R, 3S, 4R, 5R) - 5- (6-amino-2-chloro-9H-purin-9-yl) -3-ethynyl-2- (hydroxymethyl) tetrahydrofuran-3,4-diol (prepared according to the methods described by Hulpia, Fabian et al. , Bioorganic & Medicinal Chemistry Letters, 26 (8), 1970-1972; 2016), compounds of formula (I) can be prepared wherein R ^1a and R2a are hydroxy, R ^1b is hydrogen and R ^2b is methyl or ethynyl accordingly, a Het is 2-chloro-9H-purin-6-amine. It will be apparent to those skilled in the art that analogs of such compounds, i. E. Het, other than 2-chloro-9H-purin-6-amine, can also be prepared based on the description of the present application and methods known in the art.

Compounds of formula (I) having the structure

where R ^1a is halogen, alkyl, alkynyl, alkenyl or cyano, R ^1b is halogen or hydroxy, or R ^1a and R ^1b are fluoro, Het is a ring of formula (iii) where Rs is hydrogen and R ^u and R ^v are as defined in the Summary of the Invention, and R ⁵ and R ⁹ are as defined in the Summary of the Invention can be synthesized by operating as shown in Scheme 2 below.

- 85 039042

R ^u

Scheme 2

R ^u

K ^1a = alkyl, alkenyl alkynyl or cyano and R ^lb = OH or halogen; or R ^la and R ^lb are F

BocO 'R ^1b

R ^lb '= KpoMe R ^lb 9

R ^lb 'is OBos when R ^lb = OH

R ^u is M (Boc) 2, where R ^u is NH2

n1ya ¹ 'd ^1a = alkyl, alkenyl, alkynyl or cyano

R ^lb = OH or halogen; or

Ria _and Rib represent F

Compounds of formula (I) wherein R ^1a is halogen, alkyl, alkynyl, alkenyl or cyano, R ^1b is halogen or hydroxy, or R ^1a and R ^1b are fluoro, Het is a ring of formula (iii) where R ^s is hydrogen, and R ^u and R ^v are as defined in the Summary of the Invention, and R ⁵ and R ⁹ are as defined in the Summary of the Invention, can be prepared from compounds of Formula 7 as shown in Scheme 2 above. operating under the reaction conditions shown in Scheme 1 above.

Compounds of Formula 1 are either commercially available or can be prepared by methods known in the art. For example, a compound of Formula 7 (2R, 3R, 4R, 5R) -2- (6-amino2-chloro-9H-purin-9-yl) -5- (hydroxymethyl) -3-methyltetrahydrofuran-3,4-diol is commercially available or can be obtained in accordance with the method described by Caballero, Gerado et al., Helvetica Chimica Acta, 85 (5), 1284-1294; 2002 and Li, Nan-Sheng et al., J. Org. Chem., 74 (5), 2227-2230, 2009). (2R, 3R, 4R, 5R) -2- (6-amino-2-chloro-9H-purin-9-yl) -3-ethynyl-5- (hydroxymethyl) tetrahydrofuran-3,4-diol can be prepared in according to the method described by Nadler, Andre and Diedrerichsen, Ulf., European Journal of Organic Chemistry, 9, 1544-1549; 2008. (2R, 3R, 4R, 5R) -2- (6-amino-2-chloro-9H-nurin-9-yl) 5- (hydroxymethyl) -3-vinyltetrahydrofuran-3,4-diol can be obtained in according to the method described by Blatt, Lawrence M. et al., US Patent Application Publication No. 20150366888, and Carroll, Steven S. et al., PCT International Application Publication No. WO 2004000858. (2R, 3R, 4R, 5R) -2 - (6-amino-2-chloro9H-purin-9-yl) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-3-carbonitrile can be prepared according to the method described by Ohtawa, Masaki et al., J . Med. Chem 50 (9) 2007-2009; 2007.

(2R, 3R, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-2- (hydroxymethyl) -4-methyltetrahydrofuran-3-ol is commercially available ... (2R, 3R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -2 ((benzoyloxy) methyl) -4,4-difluorotetrahydrofuran-3-ylbenzoate can be obtained by reacting ((2R, 3R) -3- (benzoyloxy) -4,4-difluoro-5-iodo-tetrahydrofuran-2-yl) methyl benzoate and 2-chloroadenine under the Vorbrueggen reaction conditions [(i) (CH ₃ Si) ₂ NH, (NH ₄ ) ₂ SO ₄ or Me ₃ SiN = CMeOSiMe ₃ , (ii) TMSOTf, reflux] according to the method described by Vorbrueggen, Helmut & Ruh Polenz, Carmen, Organic Reactions, 55, 2000, and Beigelman, Leonid, et al., US patent application, publication No. US 2013/0165400, followed by the removal of benzoyl groups, resulting in the compound (2R, 3R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -2 - ((benzoyloxy) methyl) -4,4-difluorotetrahydrofuran-3yl benzoate as described below.

Compounds of formula (I) wherein Het is other than purine can be prepared from commercially available starting materials as shown in Scheme 1 above.

Compounds of formula (I) having the structure

where R ^1a is alkyl, alkynyl, vinyl or cyano, Het is a ring of formula (iii) where R ^s is hydrogen and R ^u and R ^v are as defined in the Summary of the Invention and R ⁵ and R ⁹ have the meanings defined in the Summary of the Invention can be synthesized by proceeding as illustrated and described in an illustrative example in Scheme 3 below.

- 86 039042

Scheme 3

Selective protection of the 4 ', 5'-diol in the compound of formula 12 with 1,3-dichloro-1,1,3,3 tetraisopropyldisiloxane and subsequent acylation of the 2'-OH in compound 13 with a suitable reagent such as 1,1'- thiocarbonyldiimidazole, O-phenylchlorothioformate or methyl chlorooxoacetate gives a compound of Formula 14. Compound 14 is converted to a compound of Formula 15 wherein R ^1b is hydrogen by deoxygenation with 2'-OH. The deoxygenation reaction is carried out by heating 14 in the presence of Bu ₃ SnH and AIBN at a high temperature, for example by boiling toluene. Protection of the amino group in compound 15 followed by removal of the silyl protecting group affords a compound of formula 16, which is then converted to a compound of formula (I) as shown in Scheme 1 above.

A compound of formula (I) in which R ^1a is ethynyl can be converted to a corresponding compound of formula (I) in which R ^1a is vinyl by reduction of the ethynyl group in the presence of a Lindlar catalyst in the presence of hydrogen.

Compounds of formula 12 such as (2R, 3R, 4R, 5R) -2- (6-amino-2-chloro-9H-purin-9-yl) -5 (hydroxymethyl) -3-methyltetrahydrofuran-3,4-diol are commercially available. (2R, 3R, 4R, 5R) 2- (6-amino-2-chloro-9H-purin-9-yl) -5- (hydroxymethyl) -3-vinyltetrahydrofuran-3,4-diol can be prepared according to the method described by Blatt, Lawrence M. et al., US Patent Application Publication No. 20150366888; or Carroll, Steven S. et al., PCT International Application Publication No. 2004000858; and (2R, 3R, 4R, 5R) -2- (6-amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxy-5- (hydroxylmethyl) tetrahydrofuran-3-carbonitrile can be obtained according to the method described by Ohtawa, Masaki et al., J. Med. Chem 50 (9) 2007-2009; 2007.

Compounds of formula (I) having the structure

where R ^1a is alkyl, alkynyl, vinyl or cyano, R ^1b is hydroxy or halogen; or R ^1a and R ^1b are fluoro; Het is a ring of formula (iii) and R ^u , R ^v , R ⁵ and R ⁹ are as defined in the Summary of the Invention section can be synthesized by proceeding as illustrated and described in an illustrative example in Scheme 4 below.

- 87 039042

Scheme 4

Selective protection of the primary alcohol in compound 17 with a silyl protecting group such as TBDPSCl followed by acylation and removal of 3'-OH leads to compound 18 as shown in Scheme 3 above, resulting in a compound of formula 20. Treatment of compound 20 with Boc ₂ O followed by removal of the silyl group yields a compound of Formula 21 which is then converted to a compound of Formula (I) as shown in Scheme 1 above. A compound of formula (I) where R ^1a is ethynyl can be converted to the corresponding compound of formula (I) where R ^1a is vinyl by reduction of the ethynyl group in the presence of a Lindlar catalyst in the presence of hydrogen.

Compounds of Formula 17 are either commercially available or can be prepared by methods known in the art. For example, (2R, 3R, 4R, 5R) -2- (6-amino-2-chloro-9H-purin-9-yl) 5- (hydroxymethyl) -3-methyltetrahydrofuran-3,4-diol is commercially available. (2R, 3R, 4R, 5R) 2- (6-amino-2-chloro-9H-nurin-9-yl) -5- (hydroxymethyl) -3-vinyltetrahydrofuran-3,4-diol can be prepared according to the method described by Blatt, Lawrence M. et al. in US Patent Application Publication No. 20150366888, or Carroll, Steven S. et al., PCT International Application Publication No. WO2004000858; and (2R, 3R, 4R, 5R) -2- (6-amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-3-carbonitrile can be obtained according to the method described by Ohtawa, Masaki et al., J. Med. Chem 50 (9) 2007-2009; 2007.

Compounds of formula (I) having the structure

where R ^1a is hydrogen or alkyl, R ^1b is hydroxy or halogen; R ^2a is azido or NH2 and R ^2b is hydrogen, R ³ is hydrogen, Het is a ring of formula (iii), R ^u , R ^v , R ⁵ and R ⁹ are as defined in the Summary of the Invention, can be synthesized by proceeding as illustrated and described in the exemplary example in Scheme 5 below.

- 88 039042

Scheme 5

Compound 23 was synthesized first by converting the 3'-OH group in compound 22 to a ketone using a suitable oxidizing agent such as Dess-Martin periodinane, Swern's reagent, Moffett's reagent, PDC or SO ₃ pyridine, followed by reacting the keto group with a suitable reducing agent such as sodium borohydride. Compound 22 can be prepared according to the method described in Koole, LH et al., Acta Chemica Scandinavica, 43, 665-669, 1989. The 3'-OH group in compound 23 is then converted to the corresponding azide of compound 24, converting first 3'-OH into a suitable leaving group such as mesylate, tosylate or triflate under reaction conditions well known in the art, followed by replacement of the leaving group with sodium azide.

After protecting the 6-amino group in compound 24 with a suitable protecting group such as tert-butoxycarbonyl, the 4-methoxytrityl group is selectively removed with an acid such as TFA to give compound 25. Compound 25 is then converted to a compound of formula 27 as shown in diagram 1 above. Sequential removal of TBDMS and Boc groups in compound 27 is achieved by treatment with TBAF, then treatment with TFA to obtain a compound of formula (I), where R ^2a is azido and R ⁹ is an alkyl group, which can then be converted to the corresponding compound of formula (I) where R ⁹ is hydrogen, as shown in Scheme 1 above. Compounds of formula (I) where R ^2a is azido can also be converted to the corresponding compound of formula (I) where R ^2a is amino under suitable reduction conditions such as H ₂ , Pd / C, Pd (OH ) ₂ / C or Lindlar catalyst.

Compounds of formula (I) having the structure

where R ^1a represents azido or NH ₂ ; Het is a ring of formula (iii) and R ^u , R ^v , R ⁵ and R ⁹ are as defined in the Summary of the Invention can be synthesized by proceeding as illustrated and exemplified in Scheme 6 below.

- 89 039042

Scheme 6

Compound 28 is first converted to compound 30 according to the method described in Scheme 5 above. Compound 28 can be prepared according to the method described in Secrist, John A., III et al., Journal of Medicinal Chemistry, 31 (2), 405-10; 1988 Compound 31 was prepared from 30 via a 4-step process. the bis-silyl protecting group on the 3 ', 5'-diol of compound 30 is first removed by treatment with TBAF and then the primary alcohol is protected as the TBDPS ester. Subsequent protection of the 3'-OH and 6-NH ₂ groups with Boc ₂ O and then removal of the TBDPS ester with TBAF affords compound 31. Compound 31 is converted to a compound of formula (I) as shown in Schemes 1 and 5 above.

Compounds of formula (I) having the structure

but 'where R ^1a is azido or NH2, Het is a ring of formula (iii) where R ^s is hydrogen and R ^u , R ^v , R ⁵ and R ⁹ are as defined in the Summary of the invention can be synthesized acting as illustrated and described in the illustrative example in diagram 7 below.

Scheme 7

R ¹³ = N ₃ or NHi

Compounds of formula (I) as shown above are prepared from compound 32 by converting it first to compound 35 as shown in Scheme 7. Compound 35 is then converted to a compound of formula (I) under the following reaction conditions shown in Scheme 1. Compound 32 can be obtained according to the method described in the work of Koole, LH et al., Acta Chemica Scandinavica, 43, 665-669, 1989.

Acting as shown in Scheme 7 above, but replacing compound 32 with compounds (2R, 3R, 4R, 5R) -5 (6-amino-2-chloro-9H-purin-9-yl) -4 - ((tert- butyldimethylsilyl) oxy) -2 - (((4-methoxyphenyl) diphenyl- 90 039042 / nh ₂

Ph) = / n ^ A ^ph A ¢ 13 ⁰ ~ \ ^ Oy ^N NI methoxy) methyl) tetrahydrofuran-3-ol, ^H0 'and (2R, 3R, 4S, 5R) -5- (6-amino-2- chloro-9H-purin-9-yl) OMe

ΛΛ nh ₂

Pn) = ^ < ^ζ 3ϊ

4-fluoro-2 - (((4-methoxyphenyl) diphenylmethoxy) methyl) tetrahydrofuran-3-ol, ^{Hti F} - can be synthesized, respectively, compounds of formula (I), where

where R ⁵ has the meanings defined in the Summary of the Invention section.

(2R, 3R, 4R, 5R) -5- (6-Amino-2-chloro-9H-purin-9-yl) -4 - ((tert-butyldimethylsulyl) oxy) -2 - (((4methoxyphenyl) diphenylmethoxy) methyl) tetrahydrofuran-3-ol and (2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9Hpurin-9-yl) -4-fluoro-2 - (((4-methoxyphenyl) diphenylmethoxy ) methyl) tetrahydrofuran-3-ol can be prepared according to the known method described in Koole, L.H. et al, Acta Chemica Scandinavica, 43, 665-669, 1989.

Compounds of formula (I) having the structure

R ^{2b <} R ^1b where R ^1a and R ^2a , or R ^1a and R ^2b , or R ^1b and R ^2b , or R ^1a , R ^2a , R ^1b and R ^2b are fluorine, Het is a ring of formula (iii) and R ^u , R ^v , R ⁵ and R ⁹ have the meanings defined in the Summary section can be synthesized by operating as illustrated and described in an illustrative example in Scheme 8 below.

Scheme 8

Treatment of compound 36 with 2-chloro-6H-purine-6-amine according to the method described in Sari, Ozkan. et al., Tetrahedron Letters, 58 (7), 642-644; 2017 gives compound 37. Protection of the amino group with tert-butoxycarbonyl followed by removal of the benzyl group gives the primary alcohol compound 39, which is converted to the compound of formula (I) as shown in Scheme 1 above.

Compounds of formula (I) having the structure

- 91 039042 where R ^2a is alkyl, alkynyl or cyano, Het is a ring of formula (iii) where R ^s is hydrogen and R ^u and R ^v and R ⁵ are as defined in the Summary

invention can be synthesized by proceeding as illustrated and described in an illustrative example in Scheme 9 below.

Scheme 9

R ^2a = Me: ethynyl or CN

Selective protection of the primary alcohol in the compound of Formula 40 with a suitable protecting group such as tributyldiphenylsilyl followed by treatment of the resulting silyl compound with Boc ₂ O under the reaction conditions described above affords the compound of Formula 41. Deoxygenation of 3'-hydroxy under the conditions described in Scheme 4 above gives a compound of Formula 42 which is then converted to a compound of Formula (I) as shown in Scheme 1 above.

The compound of Formula 40 can be prepared by methods well known in the art. (2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -2- (hydroximethyl) -3-methylmetrahydrofuran-3,4-diol can be prepared according to with the method described in Franchetti, Palmarisa, et al., J. Med. Chem., 48 (15), 4983-4989, 2005). (2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3-ethynyl-2 (hydroxymethyl) tetrahydrofuran-3,4-diol can be prepared according to with the method described in Hulpia, Fabian et al., Bioorganic & Medicinal Chemistry Letters, 26 (8), 1970-1972; 2016.

(2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxy-2- (hydroxymethyl) tetrahydrofuran-3-carbonitrile can be obtained from (2R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4 - ((tert-butyldimethylsilyl) -oxy) -2 - (((tert-butyldimethylsilyl) oxy) methyl ) dihydrofuran-3 (2H) -one and NaCN according to a similar method described by Camarasa, Maria Jose et al., Journal of Medicinal Chemistry, 32 (8), 1732-8; 1989, or from 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine according to the method described by Ohtawa, Masaki et al., J. Med. Chem., 50 (9), 2007-2010, 2007.

Compound of formula (I)

where R ^1a is hydrogen and R ^1b is hydroxyl, or R ^1a is fluoro and R ^1b is hydrogen, R ³ is alkyl or aralkyl, Het is a ring of formula (iii) where R ^s is hydrogen, and R ^u , R ^v , R ⁵ and R ⁹ , as defined in the Summary section, can be synthesized as shown and described in Scheme 10 below.

- 92 039042

Scheme 10

BUT 'A ω

R ^1a = H and R ^1b = OH; OR

R ^1a = F And R ^1b = H; and

R ³ = alkyl or aralkyl

Conversion of the primary alcohol group in the compound of Formula 43 with a suitable oxidizing agent such as Dess-Martin periodinane, Swern's reagent, Moffett's reagent or PDC gives the aldehyde compound of Formula 44. Compound 44 is reacted with lithium or a Grignard reagent of formula R ³ Li or R ³ MgX where R ³ is alkyl or aralkyl and X is halogen, under conditions well known in the art, to provide a compound of Formula 45. Compound 45 is then converted to a compound of Formula (I) as shown in Scheme 1 above.

The above compound numbers refer exclusively to the class structures in the above general synthesis section and not to compounds described elsewhere in the application.

Synthetic examples

Example 1. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) malonic acid

Stage 1.

To a solution of 2-chloro-2'-arabinofluoro-2'-deoxyadenosine (3.00 g, 9.9 mmol) in DMF (10 ml) at 0 ° C was added imidazole (1.68 g, 24.7 mmol) and then dropwise TBDPSCl (3.00 ml, 11.7 mmol). The reaction mixture was allowed to warm to room temperature and then stirred for 8 h, then quenched with H2O (50 ml) and extracted with EtOAc (3x50 ml). The combined organic layer was further washed with H2O (2x100 ml), brine, dried over Na ₂ SO ₄ and concentrated. The resin was purified by silica gel column chromatography (0-20% EtOAc in hexane) to give (2R, 3R, 4S, 5R)) - 5- (6-amino-2-chloro-9H-purin-9-yl) -2- (((tert-butyldiphenylsilane) oxy) methyl) -4fluorotetrahydrofuran-3-ol (4.10 g).

Stage 2.

To a solution of (2R, 3R, 4S, 5R)) - 5- (6-amino-2-chloro-9H-purin-9-yl) -2 - (((tert-butyldiphenylsulyl) oxy) methyl) -4-fluorotetrahydrofuran -3-ol (4.10 g, 7.56 mmol) in DMF (10 ml), Et ₃ N (3.48 ml, 25.0 mmol), 4-DMAP (150 mg, 1.2 mmol) and Boc ₂ O (5.20 g, 23.8 mmol). The reaction mixture was stirred for 16 h, then diluted with EtOAc (200 ml) and H ₂ O (100 ml). The organic layer was separated, washed with H ₂ O (2x100 ml), brine, dried over Na ₂ SO ₄ and concentrated. The resin was purified by silica gel column chromatography (0-20% EtOAc in hexane) to give N6, N6-bis- (tert-butoxycarbonyl) -5'-O- (tert-butylduphenylsilyl) -2'-arabinofluoro-2 '

- 93 039042 deoxy-3'-O- (tert-butoxycarbonyl) -2-chloroadenosine (5.58 g).

Stage 3.

N6, N6-bis- (tert-butoxycarbonyl) -5'-O- (tert-butyldiphenylsilyl) -2'-arabinofluoro-2'-deoxy-3'-O (tert-butoxycarbonyl) -2-chloradenosine (5.58 d, 6, 6 mmol) was dissolved in THF (10 ml) at 0 ° C and then a solution of TBAF (10 ml, 10 mmol, 1M in THF) was added dropwise. The reaction mixture was stirred at a temperature from 0 ° C to room temperature for 2.5 h, then evaporated to dryness. The resin was purified by silica gel column chromatography (0-20% EtOAc in hexane) to give N6, N6-bis- (tert-butoxycarbonyl) -5'-O- (tert-butyldiphenylsilyl) -2'-arabinofluoro-2'-deoxy- 3'-O (tert-butoxycarbonyl) -2-chloro-adenosine-fluoro-2'-deoxy-3'-O- (tert-butoxycarbonyl) -2-chloro-adenosine (3.15 g).

Stage 4.

To a solution of N6, N6-bis- (tert-butoxycarbonyl) -2'-fluoro-2'-deoxy-3'-O- (tert-butoxycarbonyl) -2chloro-adenosine (800 mg, 1.32 mmol) in argon atmosphere in toluene (2 ml), diethyl 2 diazomalonate (321 mg, 1.72 mmol) and Rh ₂ (OAc) ₄ (59 mg, 0.13 mmol) were added. The resulting mixture was stirred at 95 ° C for 2 h, then allowed to cool to room temperature. Volatile organic products were removed under reduced pressure. The resulting crude product was purified by silica gel column chromatography (0-20% EtOAc in hexane) to give diethyl 2 - (((2R, 3R, 4S, 5R) 5- (6- (N- (tert-butoxycarbonyl) (tert- butoxycarbonyl) amino) -2-chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate as foam (770 mg).

Stage 5.

To a solution of diethyl 2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro-9H-purin-9-yl ) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate (300 mg, 0.394 mmol) in CH ₂ Cl ₂ (2 ml) at 0 ° C, TFA (3 ml ). The resulting mixture was allowed to warm to room temperature and stirred for 2 hours, then concentrated under reduced pressure to give crude diethyl 2 - (((2R, 3R, 4S, 5R)) - 5- (6-amino-2-chloro- 9Hpurin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) malonate.

Stage 6.

To a solution of crude diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2-yl) methoxy ) malonate (0.394 mmol) in THF (2 ml) and H ₂ O (2 ml), LiOH monohydrate (200 mg) was added at room temperature. The resulting mixture was stirred overnight, then cooled to 0 ° C and acidified to pH ~ 6 1N. HCl solution (aq.) and concentrated under reduced pressure. The crude residue was purified by preparative reverse phase HPLC to give 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3- hydroxytetrahydrofuran-2yl) methoxy) malonic acid as a white solid.

¹ H NMR (D ₂ O, 300 MHz) δ 8.47 (d, J = 1.8 Hz, 1H), 6.46 (dd, J = 4.4, 13.1 Hz, 1H), 5, 27 (t, J = 8.5 Hz, 1H), 4.60-4.72 (m, 2H), 4.15 (q, J = 4.6 Hz, 1H), 3.86-4.03 (m, 2H); LC / MS [M + H] = 406.

Example 2. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2-benzylmalonic acid

aq. LiOH, THF

Stage 1.

To a solution of diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6- (N- [tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro-9H-purin-9-yl ) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate (170 mg, 0.223 mmol) in DMF (2 ml) at 25 ° C Cs ₂ CO ₃ (145 mg , 0.446 mmol). The reaction mixture was stirred for 30 min and then BnBr (53 μl, 0.446 mmol) was added. The reaction mixture was stirred for 3.5 h, then diluted with H ₂ O (20 ml) and extracted with EtOAc (3x30 ml). The combined organic layer was then washed with H2O (2x40 ml), brine, dried over Na ₂ SO ₄ and concentrated. The resulting crude product was purified by silica gel column chromatography (0-16% EtOAc in hexane) to give diethyl 2 - (((2R, 3R, 4S, 5R)) 5- (6- (N- (tert-butoxycarbonyl) (tert -butoxycarbonyl) amino) -2-chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluoro-tetrahydrofuran-2-yl) methoxy) -2-benzylmalonate as a foam.

- 94 039042

Stage 2.

To a solution of diethyl 2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro-9H-purin-9-yl ) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) -2benzylmalonate (200 mg, 0.235 mmol) in CH ₂ Cl ₂ (2 ml) at 0 ° C, TFA (2 ml). The resulting mixture was stirred at room temperature for 2.5 h, then concentrated under reduced pressure to give diethyl 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purine -9-yl) -4fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2-benzylmalonate.

Stage 3.

To a solution of crude 2 - (((2R, 3R, 4S, 5R)) - 5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxitetrahydrofuran-2-yl) methoxy) -2-benzylmalonate in THF (2 ml) and H2O (2 ml) at 0 ° C, LiOH monohydrate (150 mg) was added. The resulting mixture was stirred at room temperature overnight, then cooled to 0 ° C and acidified to pH ~ 6 1N. HCl solution (aq.) and concentrated under reduced pressure. The crude residue was purified by preparative reverse phase HPLC to give 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3- hydroxytetrahydrofuran-2yl) methoxy) -2-benzylmalonic acid as a white solid.

1H NMR (D ₂ O, 300 MHz) δ 8.27 (br s, 1H), 8.16 (s, 1H), 7.11 (br s, 5H), 6.35 (dd, J = 4.3, 13.5 Hz, 1H), 5.17-5.36 (m, 1H), 4.53-4.56 (m, 1H), 4.18-4.28 (m, 1H) , 3.70-3.85 (m, 2H); 3.24 (s, 2H);

LC / MS [M + H] = 496.

Example 3. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-carboxybenzyl) malonic acid

Acting as described in example 2 above, but replacing benzyl bromide with methyl 4 (bromomethyl) benzoate, 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purine -9-yl) -4-fluoro-3-hydroxitetrahydrofuran-2-yl) methoxy) -2- (4-carboxybenzyl) malonic acid as a white solid.

¹ H NMR (CD3OD, 300 MHz) δ 8.33 (d, J = 2 Hz, 1H), 7.78-7.81 (d, J = 8.3 Hz, 2H), 7.38-7, 41 (d, J = 8.3 Hz, 2H), 6.41-6.47 (dd, J = 4.5, 13.6 Hz, 1H), 5.07-5.28 (dt, J = 4.1, 52 Hz, 1H), 4.64-4.73 (dt, J = 4.2, 18.0 Hz, 1H), 4.15-4.19 (q, J = 4.6 Hz , 1H), 3.93-4.10 (m, 2H), 3.42-3.55 (m, 2H);

LC / MS [M-H] = 538.

Example 4. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((6-chloropyridin-3-yl) methyl) malonic acid

Operating as described in Example 2 above but substituting 5- (bromomethyl) -2chloropyridine for benzyl bromide gave the title compound as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.27 (s, 1H), 8.24 (d, J = 2.5 Hz, 1H), 7.74 (dd, J = 2.3, 8.4 Hz , 1H), 7.22 (d, J = 8.3 Hz, 2H), 6.43 (dd, J = 4.3, 13.7 Hz, 1H), 5.15 (dt, J = 4, 8, 51.7 Hz, 1H), 4.60-4.70 (m, 1H), 4.15-4.18 (m, 1H), 3.97-4.09 (m, 2H), 3 , 35-3.42 (m, 2H);

LC / MS [M + H] = 531.

Example 7. Synthesis of 2 - (((2R, 3R, 4R, 5R) -5- (6-amino-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 -benzylmalonic acid

- 95 039042

aq. LiOH, THF

2 - (((2R, 3R, 4R, 5R) -5- (6-Amino-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2benzylmalonic acid was prepared starting from diethyl-2 - (((2R, 3R, 4R, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -9H-purin-9-yl) -3 - ((tert- butoxycarbonyl) oxy) -4fluorotetrahydrofuran-2-yl) methoxy) malonate according to the method of Example 2. The title compound was obtained as a white solid.

LC / MS [M + H] = 4 62.

Examples 8a, 8b, 8c and 8d. Synthesis of ((R) -1 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2-yl) methoxy) -2-ethoxy-2-oxoethyl) phosphonic acid, ((S) -1 (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl ) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2ethoxy-2-oxoethyl) phosphonic acid, ((R) -1 - (((2R, 3R, 4S, 5R) -5- (6- ((tert-butoxycarbonyl) amino) -2chloro-9H-nurin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2-ethoxy-2-oxoethyl) phosphonic acid and ((S) -1 - (((2R, 3R, 4S, 5R) -5- (6 - ((tert-butoxycarbonyl) amino) -2-chloro-9H-purin-9-yl) -4fluoro-3-hydroxytetrahydrofuran-2- yl) methoxy) -2-ethoxy-2-oxoethyl) phosphonic acid

TMSBr, MeCN

Stage 1.

To a solution of N6, N6-bis- (tert-butoxycarbonyl) -2'-arabinofluoro-2'-deoxy-3'-O- (tert-butoxycarbonyl) -2-chloro-adenosine (512 mg, 0.85 mmol) in toluene (5 ml) under argon was added ethyl 2 diazo-2- (diethoxyphosphoryl) acetate (37 mg, 1.10 mmol) and Rh ₂ (OAc) ₄ (37 mg, 0.08 mmol). The resulting mixture was stirred at 95 ° C for 3 h, then allowed to cool to room temperature. Volatile organic products were removed under reduced pressure. The resulting crude product was purified by silica gel column chromatography (5-100% EtOAc in hexane) to give ethyl 2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert -butoxycarbonyl) amino) -2-chloro-9H-purin9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) -2- (diethoxyphosphoryl) acetate (557 mg) c the form of a mixture of diastereomers.

Stage 2.

To a solution of ethyl 2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2chloro-9H-purin-9-yl) - 3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) -2 (diethoxyphosphoryl) acetate (345 mg, 0.42 mmol) in MeCN (6 ml) at -20 ° C was added according to drops of TMSBr (441 ml, 3.34 mmol). The resulting mixture was stirred at -20 to 0 ° C for 26 h, then quenched with H2O (4 ml). The resulting mixture was stirred at a temperature

- 96 039042

0 ° C for 20 h, then quenched with NH4OH (6 ml) and concentrated under reduced pressure. The crude residue was purified by preparative reverse phase HPLC to give the title compounds as white solids.

((R) -1 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2yl) methoxy ) -2-ethoxy-2-oxoethyl) phosphonic acid (diastereomer 1):

1H NMR (CD ₃ OD, 300 MHz) δ 8.54 (br s, 1H), 6.42 (dd, J = 4.1, 10.1 Hz, 1H), 5.09-5.31 ( m, 1H), 4.554.74 (m, 1H), 4.37-4.53 (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.10-4.20 (m, 1H), 3.84-4.01 (m, 2H), 1.28 (t, J = 6.9 Hz, 3H); LC / MS [M + H] = 470.

((S) -1 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2yl) methoxy ) -2-ethoxy-2-oxoethyl) phosphonic acid (diastereomer 2):

1H NMR (CD3OD, 300 MHz) δ 8.52 (br s, 1H), 6.42 (dd, J = 4.6, 12.9 Hz, 1H), 5.21 (dt, J = 4, 6, 52.3 Hz, 1H), 4.72 (dt, J = 4.9, 13.1 Hz, 1H), 4.45 (d, J = 18.4 Hz, 1H), 4.27 ( q, J = 7.1 Hz, 2H), 4.10-4.20 (m, 1H), 3.854.01 (m, 2H), 1.29 (t, J = 7.0 Hz, 3H); LC / MS [M + H] = 470.

((R) -1 - (((2R, 3R, 4S, 5R) -5- (6 - ((tert-butoxycarbonyl) amino) -2-chloro-9H-purin-9-yl) -4-fluoro- 3hydroxytetrahydrofuran-2-yl) methoxy) -2-ethoxy-2-oxoethyl) phosphonic acid (NHBoc diastereomer 1):

1H NMR (CD ₃ OD, 300 MHz) δ 8.93 (brs, 1H), 8.46 (brs, 1H), 6.56 (m, 1H), 5.07-5.32 ( m, 1H), 4.65-4.74 (m, 1H), 4.40 (d, J = 23 Hz, 1H), 4.27 (q, J = 6.9 Hz, 2H), 4, 11-4.20 (m, 1H), 3.85-4.05 (m, 2H), 1.59 (br s, 9H), 1.26-1.35 (m, 3H); LC / MS [M + H] = 571.

((S) -1 - (((2R, 3R, 4S, 5R) -5- (6 - ((tert-butoxycarbonyl) amino) -2-chloro-9H-purin-9-yl) -4-fluoro- 3hydroxytetrahydrofuran-2-yl) methoxy) -2-ethoxy-2-oxoethyl) phosphonic acid (NHBoc diastereomer 1):

1H NMR (CD ₃ OD, 300 MHz) δ 8.95 (brs, 1H), 8.46 (brs, 1H), 6.53 (m, 1H), 5.15-5.39 ( m, 1H), 4.65-4.74 (m, 1H), 4.40 (m, 1H), 4.17-4.42 (m, 2H), 4.11-4.17 (m, 1H), 3.85-3.95 (m, 2H), 1.59 (brs, 9H), 1.26-1.35 (m, 3H); LC / MS [M + H] = 571.

Example 10. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-cyanobenzyl) malonic acid

By operating as described in Example 2 above, but replacing benzyl bromide with 4- (bromomethyl) benzonitrile, the title compound was obtained.

1H NMR (CD3OD, 300 MHz) δ 8.27 (s, 1H), 7.48 (s, 4H), 6.43-6.46 (m, 1H), 5.09-5.26 (m, 1H), 4.63-4.69 (m, 1H), 3.97-4.17 (m, 3H), 3.42-3.49 (m, 2H); LC / MS [M + H] = 521.

Example 11. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (3-cyanobenzyl) malonic acid

CN

Operating as described in Example 2 above but substituting 3- (bromomethyl) benzonitrile for benzyl bromide gave the title compound as a white solid.

1H NMR (CD ₃ OD, 300 MHz) δ 8.27 (s, 1H), 7.67 (br s, 1H), 7.57-7.60 (d, J = 8 Hz, 1H), 7 , 46-7.49 (d, J = 8 Hz, 1H), 7.30-7.35 (t, J = 8 Hz, 1H), 6.43-6.49 (dd, J = 4.13 Hz, 1H), 5.08-5.28 (dt, J = 4.50 Hz, 1H), 4.62-4.71 (dt, J = 4.17 Hz, 1H), 4.17-4 , 21 (q, J = 4 Hz, 1H), 4.00-4.12 (m, 2H), 3.40-3.52 (m, 2H); LC / MS [M + H] = 521.

Example 12. Synthesis of diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (trifluoromethoxy) benzyl) malonate

Operating as described in Example 2 above, but substituting 1- (bromomethyl) -4-97 039042 (trifluoromethoxy) benzene for benzyl bromide, the title compound was isolated as a white solid.

1H NMR (CDCl ₃ , 300 MHz) δ 8.13 (br s, 1H), 7.25-7.28 (d, J = 9 Hz, 2H), 7.09-7.12 (d, J = 8 Hz, 1H), 6.43-6.50 (dd, J = 4.16 Hz, 1H), 6.10 (br s, NH2), 5.05-5.24 (dt, J = 3.52 Hz, 1H), 4.68-4.77 (dt, J = 5.19 Hz, 1H), 4.22-4.28 (m, 4H), 3.98-4.10 (m , 3H), 3.41 (brs, 2H), 1.25-1.30 (dd, J = 1.7Hz, 6H); LC / MS [M + H] = 636.

Example 13 Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (trifluoromethoxy) benzyl) malonic acid, (R) -2 (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purine-9- yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -3ethoxy-3-oxo-2- (4- (trifluoromethoxy) benzyl) propanoic acid and (S) -2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -3-ethoxy-3-oxo-2- (4 - (trifluoromethoxy) benzyl) propanoic acid

2 - (((2R, 3R, 4S, 5R) -5- (6-Amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2yl) methoxy) -2- ( 4- (trifluoromethoxy) benzyl) malonic acid was obtained starting from diethyl 2 (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro -3-hydroxytetrahydrofuran-2-yl) methoxy) -2 (4- (trifluoromethoxy) benzyl) malonate by alkaline hydrolysis with aq. LiOH in THF according to the method described in Example 2 as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.38 (s, 1H), 7.37-7.34 (d, J = 8 Hz, 2H), 7.07-7.09 (d, J = 8 Hz , 2H), 6.396.46 (dd, J = 4.15 Hz, 1H), 5.05-5.25 (dt, J = 4.52 Hz, 1H), 4.63-4.80 (m, 1H), 4.15-4.20 (m, 1H), 3.91-3.99 (m, 2H), 3.37 (br s, 2H); LC / MS [M + H] = 580.

A pair of diastereomers of monoethyl ester (R) -2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9Hpurin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2 -yl) methoxy) -3-ethoxy-3-oxo-2- (4- (trifluoromethoxy) benzyl) propanoic acid and (S) -2 - (((2R, 3R, 4S, 5R) -5- (6- amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -3-ethoxy-3-oxo-2- (4- (trifluoromethoxy) benzyl) propanoic acid was prepared by partial hydrolysis of the compound of Example 12. The title compounds were purified by reverse phase HPLC and isolated as white solids.

Polar diastereomer 1: 1H NMR (CD3OD, 300 MHz) δ 8.30 (s, 1H), 7.36-7.38 (d, J = 8 Hz, 2H), 7.057.08 (d, J = 8 Hz , 2H), 6.40-6.46 (dd, J = 4.14 Hz, 1H), 5.08-5.27 (dt, J = 4.52 Hz, 1H), 4.63-4, 78 (m, 1H), 4.15-4.26 (m, 3H), 3.99-4.06 (m, 2H), 3.42-3.44 (m, 2H), 1.22- 1.27 (t, J = 7 Hz, 3H); LC / MS [M + H] = 608.

Less polar diastereomer 2: 1H NMR (CD ₃ OD, 300 MHz) δ 8.37 (s, 1H), 7.35-7.38 (d, J = 8 Hz, 2H), 7.05-7.08 (d, J = 8 Hz, 2H), 6.42-6.48 (dd, J = 4.14 Hz, 1H), 5.10-5.30 (dt, J = 4.52 Hz, 1H) , 4.64-4.71 (m, 1H), 4.15-4.25 (m, 3H), 4.02-4.04 (d, J = 4 Hz, 2H), 3.44 (s , 2H), 1.22-1.25 (t, J = 7 Hz, 3H); LC / MS [M + H] = 608.

Example 14. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (hydroxymethyl) benzyl) malonic acid

Stage 1.

To a solution of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-formylbenzyl) malonic acid (200 mg, 0.23 mmol), obtained from diethyl 2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl ) (tert-butoxycarbonyl) amino) -2-chloro-9H-purin9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate and 4- (bromomethyl) benzaldehyde in according to the method described in example 2, in EtOH at 0 ° C was added NaBH ₄ (11 mg, 0.2 9 mmol). The resulting mixture was stirred for 15 min, then quenched with 1N. HCl solution (aq.). The organic volatiles were removed under reduced pressure and aq.

- 98 039042 layer was extracted with EtOAc. The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The crude residue was purified by silica gel column chromatography (0-20%

EtOAc in hexane) to give the corresponding benzyl alcohol.

Stages 2-3.

Benzyl alcohol from the last stage was converted into 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9Hpurin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl ) methoxy) -2- (4- (hydroxymethyl) benzyl) malonic acid according to the method described in Example 2. The title compound was obtained as a white solid.

¹ H NMR (CD3OD, 300 MHz) δ 8.29 (s, 1H), 7.26-7.29 (d, J = 8 Hz, 2H), 7.14-7.29 (d, J = 8 Hz, 2H), 6.406.46 (dd, J = 4.13 Hz, 1H), 5.08-5.28 (dt, J = 4.52 Hz, 1H), 4.63-4.72 (dt , J = 4.18 Hz, 1H), 4.49 (s, 2H), 4.14-4.18 (q, J = 4 Hz, 1H), 3.96-4.08 (m, 2H) , 3.33-3.42 (m, 2H); LC / MS [M + H] = 526.

Example 16. Synthesis of 2 - (((2R, 3R, 4S, 5R) - ((1H-tetrazol-5-yl) methyl) -2 - (((2R, 3R, 4S, 5R) -5- (6- amino-2chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) malonic acid

Stage 1.

To a solution of diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro-9H-purun-9-ul ) -3 - ((tert-butoxycarbonyl) oxu) -4-fluorotetrahydrofuran-2-ul) methoxy) -2 (cyanomethyl) malonate (103 mg, 0.129 mmol), synthesized according to example 15, in toluene (5 ml) in portions azidotrimethylsilane (234 μl, 1.8 mmol) was added over 3 days, followed by bis (tributyltin) oxide (20 μl, 0.0386 mmol), the reaction mixture was heated at 75 ° C for three days, then concentrated under reduced pressure ... The crude product was purified by silica gel column chromatography (0-4% MeOH in DCM) to give diethyl 2 - (((2R, 3R, 4S, 5R) -5 (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl ) amino) -2-chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) -2- (1H-tetrazol-5-ylmethyl) malonata.

Stage 2.

Duetul-2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxukarbonyl) amino) -2-chloro9H-purin-9-yl) -3- ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) -2- (1H-tetrazol5-ylmethyl) malonate was converted to the title compound as a white solid by proceeding as described in Example 2 above.

1H NMR (CD3OD, 300 MHz) δ 8.58 (s, 1H), 6.44-6.50 (dd, J = 4.14 Hz, 1H), 5.09-5.29 (dt, J = 4.52 Hz, 1H), 4.59-4.68 (dt, J = 4.17 Hz, 1H), 4.19-4.22 (q, J = 5 Hz, 1H), 4.10- 4.12 (m, 2H); 3.83 (s, 2H); LC / MS [M + H] = 488.

Example 17 Synthesis of 2- (3- (1H-tetrazol-5-yl) benzyl) -2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-azido-9H-purine9- yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) malonic acid, 2 - (((2R, 3R, 4S, 5R) -5- (6amino-2-azido-9H-purin-9-yl ) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (3-cyanobenzyl) malonic acid and 2 - (((2R, 3R, 4S, 5R) -5- (2-azido-6- ((tert-butoxycarbonyl) amino) -9H-purin-9-yl) -4fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (3-cyanobenzyl) malonic acid

Stage 1.

A mixture of duetul-2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluoro-tetrahydrofuran-2-yl) methoxy) -2- (3cyanobenzyl) malonate (230 mg, 0.26 mmol) (prepared as described in example 2 above by reacting diethyl 2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro-9Hpurin-9-yl) -3 - (( tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate with 3-99 039042 (bromomethyl) benzonitrile), NaN ₃ (26 mg, 0.39 mmol) and NH4CI (18 mg, 0.34 mmol ) in DMF (1.5 ml) was heated at 100 ° C for 5 h, then allowed to cool to room temperature. The crude reaction mixture was diluted with EtOAc and water. The aqueous layer was then extracted with (2x) EtOAc. The combined organic layer was washed with brine, dried (MgSO ₄ ) and concentrated. The crude product was purified by reverse phase HPLC to give diethyl 2- (3- (1H-tetrazol5-yl) benzyl) -2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert -butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-azido9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluoro-tetrahydrofuran-2-yl) methoxy) malonate and diethyl-2 - (((2R, 3R, 4S, 5R)) - 5- (2-azido-6 - ((tert-butoxycarbonyl) amino) -9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) - 4-fluorotetrahydrofuran-2-yl) methoxy) -2- (3-cyanobenzyl) malonate.

Stage 2.

Diethyl-2- (3- (1 H-tetrazol-5-yl) benzyl) -2 - (((2R, 3R, 4S, 5 R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl ) amino) -2-azido-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate and diethyl-2 - (((2R, 3R , 4S, 5R) -5- (2-azido-6 - ((tert-butoxycarbonyl) amino) 9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl ) methoxy) -2- (3-cyanobenzyl) malonate was further converted to the corresponding title compounds according to the method described in Example 2.

2 - (((2R, 3R, 4S, 5R) -5- (6-Amino-2-azido-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2yl) methoxy) -2- ( 3-cyanobenzyl) malonic acid:

¹ H NMR (CD3OD, 300 MHz) δ 8.66 (s, 1H), 7.66 (s, 1H), 7.56-7.59 (d, J = 8 Hz, 1H), 7.46- 7.48 (d, J = 7 Hz, 1H), 7.33-7.35 (t, J = 7 Hz, 1H), 6.52-6.57 (dd, J = 5.11 Hz, 1H ), 5.17-5.38 (dt, J = 5.52 Hz, 1H), 4.64-4.75 (dt, J = 4.17 Hz, 1H), 4.21-4.25 ( m, 1H), 3.97-4.16 (m, 2H), 3.41-3.54 (m, 2H); LC / MS [M + H] = 528.

2 - (((2R, 3R, 4S, 5R) -5- (2-Azido-6 - ((tert-butoxycarbonyl) amino) -9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2-yl ) methoxy) -2- (3-cyanobenzyl) malonic acid:

¹ H NMR (CD3OD, 300 MHz) δ 8.72 (s, 1H), 7.67 (s, 1H), 7.56-7.59 (d, J = 8 Hz, 1H), 7.46- 7.49 (d, J = 8 Hz, 1H), 7.31-7.36 (t, J = 8 Hz, 1H), 6.57-6.62 (dd, J = 4.13 Hz, 1H ), 5.16-5.36 (dt, J = 4.52 Hz, 1H), 4.63-4.87 (dt, J = 4.17 Hz, 1H), 4.22-4.25 ( m, 1H), 4.00-4.14 (m, 2H), 3.41-3.53 (m, 2H), 1.60 (s, 9H); LC / MS [M + H] = 628.

2- (3- (1H-Tetrazol-5-yl) benzyl) -2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-azido-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2-yl) methoxy) malonic acid:

1H NMR (CD ₃ OD, 300 MHz) δ 8.19 (br s, 1H), 7.99 (br s, 1H), 7.77-7.79 (d, J = 8 Hz, 1H) , 7.497.52 (d, J = 8 Hz, 1H), 7.36-7.41 (t, J = 8 Hz, 1H), 6.32-6.38 (dd, J = 5.13 Hz, 1H), 5.05-5.25 (dt, J = 4.52 Hz, 1H), 4.66-4.75 (dt, J = 4.18 Hz, 1H), 4.17-4.22 (m, 1H), 3.98-4.14 (m, 2H), 3.45-3.57 (m, 2H); LC / MS [M + H] = 564.

Example 18 Synthesis of 2 - (((2S, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3-azido-4-hydroxytetrahydrofuran-2-yl) methoxy) -2-benzylmalonic acid and 2 - (((2S, 3S, 4R, 5R) -3-amino-5- (6-amino-2chloro-9H-purin-9-yl) -4-hydroxytetrahydrofuran-2- yl) methoxy) -2-benzylmalonic acid

NH ₂ Ph 1] NK, 1- Pyridine, CgO ₃ ph CT 1 Ac ₂ O, DCM Y ^h --------------- ^Ph H (3 'OTBDMS NBoc ₂ x Ph L CJ | U ⁵ diluted TFA, DCM Αφ Ng '' OTBDMS E ^ C- ^ COzEt θ Rh ₂ (OAc) ₄ , toluene N ₂ j 0 NBoc ₂ c Q Coi 7. BnBr, cs ₂ co ₃ 0 M Ui dmph _ H EY O ^ oA '^ nUi ------- IO / W CJ Ng' OTBDMS 10. (ί) ΤΦΧ DCM (ii) aq. LiOH, THF 0 nh ₂ ^ X ^ OMe NH ₂ ^ х> ЭМе _N h ₂ LJ Nv ^ _X 2- NaBH ₄ Ph Г T N-Js О 'OTBDMS HO' OTBDMS 3. Tf ₂ 0,4-DMAP Pyridine, DCM ^ x-OMe NBoc ₂ ^ γ · ^ΟΜβ NH ₂ J hX ,, 4. (i) NaNj , DMF Ph ί Γ nX ,, J (ii ) Boc ₂ 0,4-DMAP <J Y ^A θ ^ χ ^ Ο ^^ Ν ^ ΟΙ Ng t) TBDMS TfO '''' OTBDMS I ΝΒΰ ^ O NBoc ₂ OEt 8 Cat. Lindlar ^ “OEt N ^ G. _M у \ PI Hz, EtOAc 7 — Ά to II I ° ^ V.Oy ^N '^ N ^ ⁴ CI * θ ^ ΚοΧ ^ Ν ^ ΟΙ M Ohm Ng' OTBDMS HjN '' OTBDMS 9. (i) TFA DCM ( ii) aq. LiOH, THF 0 nh ₂

- 100 039042

Stage 1.

To a stirred suspension of chromium trioxide (2.59 g, 25.9 mmol) in CH ₂ Cl ₂ (60 ml) was added pyridine (4.19 ml, 51.8 mmol) dropwise and then acetic anhydride (2.45 ml, 25.9 mmol). This brown slurry was left stirring at room temperature for 10 minutes. To this mixture was added a solution of (2R, 3R, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4 - ((tert-butyldimethylsilyl) oxy) -2 - (((4 -methoxyphenyl) diphenylmethoxy) methyl) tetrahydrofuran-3-ol (synthesized from 2-chloroadenosine according to the method described in Koole, LH et al., Acta Chemica Scandinavica, 43, 665-669, 1989) (5.95 g , 8.64 mmol) in CH ₂ Cl ₂ (36 ml). The resulting mixture was stirred at room temperature for 18 h, then passed through a short silica pad using EtOAc as eluent. The filtrate was washed with EDTA (2x100 ml) and brine (100 ml). The organic layer was separated and concentrated. The resin was purified by silica gel column chromatography to give (2R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4 - ((tert-butyldimethylsilyl) oxy) -2 - ((( 4-methoxyphenyl) diphenylmethoxy) methyl) dihydrofuran-3 (2H) -one (4.19 g, 71% yield).

Stage 2.

A solution of (2R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4 - ((tert-butyldimethylsilyl) oxy) -2 - (((4methoxyphenyl) diphenylmethoxy) methyl ) dihydrofuran-3 (2H) -one (4.19 g, 6.11 mmol) in a mixture of EtOH (42 ml) and water (2.1 ml) was stirred for 20 min at a temperature of -5 ° C, then borohydride was added sodium (324 mg, 8.55 mmol). The reaction mixture was stirred for 5 h, then carefully quenched with 1N. aq. HCl until a pH of 5 is reached. The reaction mixture was separated with EtOAc (100 ml). The organic layer was separated and washed with water (3x50 ml), brine, dried (MgSO ₄ ) and concentrated. The crude residue was purified by silica gel column chromatography to give (2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4 - ((tert-butyldimethylsilyl) oxy) - 2 - (((4methoxyphenyl) diphenylmethoxy) methyl) tetrahydrofuran-3-ol (2.19 g, 52% yield).

Stage 3.

To a solution of (2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4 - ((tert-butyldimethylsilyl) oxy) -2 (((4-methoxyphenyl ) diphenylmethoxy) methyl) tetrahydrofuran-3-ol (2.19 g, 3.18 mmol) in CH ₂ Cl ₂ (33 ml) at 0 ° C under argon was added pyridine (2.3 ml, 28.6 mmol ) and 4dimethylaminopyridine (1.13 g, 9.22 mmol). The reaction mixture was stirred for 15 min then Tf ₂ O (0.803 mL, 4.77 mmol) was added. The reaction mixture was stirred at 0 ° C for 15 min, then it was allowed to warm to room temperature and then stirred for 4 h. The reaction mixture was quenched by the addition of water (22 ml). The organic layer was separated, dried (MgSO ₄ ) and concentrated. The crude residue was purified by silica gel column chromatography to give (2R, 3R, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4 - ((tert-butyldimethylsilyl) oxy) - 2 - (((4-methoxyphenyl) diphenylmethoxy) methyl) tetrahydrofuran-3-yl trifluoromethanesulfonate (2.00 g, 76% yield).

Stage 4.

To a solution of (2R, 3R, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4 - ((tert-butyldimethylsilyl) oxy) -2 (((4-methoxyphenyl ) diphenylmethoxy) methyl) tetrahydrofuran-3-yl trifluoromethanesulfonate (1.65 g, 2.01 mmol) in DMF (33 ml) at 0 ° C, sodium azide (1.31 g, 20.1 mmol) was carefully added. The reaction mixture was allowed to warm to room temperature and stirred for 6 h, then it was separated with EtOAc (100 ml). The organic layer was separated, washed with water (2x22 ml), brine, dried over MgSO ₄ and concentrated. _{Boc 2} O (1.70 g, 7.64 mmol) and 4-DMAP (24 mg, 0.20 mmol) were added to the crude oil in THF (5 ml). The reaction mixture was stirred under argon for 13 h, then concentrated and the crude residue was purified by SiO ₂ column chromatography to give tert-butyl (tert-butoxycarbonyl) (9 - ((2R, 3R, 4R, 5S) -4-azido- 3 - ((tert-butyldimethylsilyl) oxy) -5 - (((4-methoxyphenyl) diphenylmethoxy) methyl) tetrahydrofuran-2-yl) -2-chloro9H-purin-6-yl) carbamate (1.19 g, 65% going beyond 2 stages).

Stage 5.

To a solution of tert-butyl- (tert-butoxycarbonyl) (9 - ((2R, 3R, 4R, 5S) -4-azido-3 - ((tert-butyldimethylsilyl) oxy) -5 - (((4-methoxyphenyl) diphenylmethoxy ) methyl) tetrahydrofuran-2-yl) -2-chloro-9Hpurin-6-yl) carbamate (1.19 g, 1.30 mmol) in DCM (30 ml) in an argon atmosphere at room temperature was added dropwise trifluoroacetic acid ( 0.483 ml, 6.50 mmol). The reaction mixture was stirred for 7 hours, then concentrated. The crude residue was purified by SiO ₂ column chromatography to give tert-butyl- (tert-butoxycarbonyl) (9 - ((2R, 3R, 4R, 5S) -4-azido-3 - ((tert-butyldimethylsilyl) oxy) -5- (hydroxymethyl ) tetrahydrofuran-2-yl) -2-chloro-9H-purin-6-yl) carbamate (548 mg, 69% yield).

Stage 6.

A mixture of tert-butyl- (tert-butoxycarbonyl) (9 - ((2R, 3R, 4R, 5S) -4-azido-3 - ((tert-butyldimethylsilyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-2-yl) -2-chloro-9H-purin-6-yl) carbamate (385 mg, 0.60 mmol) and diethyl 2-diazomalonate (145 mg, 0.78 mmol) were placed in a 25 ml round bottom flask and subjected to azeotropic distillation with toluene. The resulting oil was dissolved in toluene (3.9 ml) and then rhodium (II) acetate dimer (27 mg, 0.06) mmol was added under argon atmosphere.

The reaction mixture was heated at 75 ° C for 3 h, then concentrated. The crude residue was purified by SiO ₂ column chromatography to give diethyl 2 - (((2S, 3R, 4R, 5R) -3-azido-5 (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) - 2-chloro-9H-purin-9-yl) -4 - ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) methoxy) malonate (234 mg, 48% yield).

Stage 7.

To a solution of diethyl 2 - (((2S, 3R, 4R, 5R) -3-azido-5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro-9H-purine -9-yl) -4 - ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2yl) methoxy) malonate (234 mg, 0.29 mmol) in DMF (2.3 ml) at 0 ° C oven-dried carbonate was added cesium (191 mg, 0.59 mmol). The resulting suspension was stirred for 30 min and then benzyl bromide (70 μL, 0.59 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 14 h, then it was partitioned between EtOAc (25 ml) and water (22 ml). The organic layer was separated and washed with water (22 ml), brine, dried over magnesium sulfate and concentrated. The crude residue was purified by SiO ₂ column chromatography to give diethyl 2 - (((2S, 3R, 4R, 5R) -3-azido-5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2 -chloro-9H-purin-9-yl) -4 - ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2yl) methoxy) -2-benzylmalonate (100 mg, 38% yield).

Stage 8.

A solution of diethyl-2 - (((2S, 3R, 4R, 5R) -3-azido-5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro-9H-purine- 9-yl) -4 - ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) methoxy) -2benzylmalonate (100 mg, 0.11 mmol) in EtOAc (2.0 ml), purged with argon gas three times and then added Lindlar catalyst (15 mg, 15 wt%) under an argon pad. The reaction mixture was then purged (three times) and stirred under a pressure of H2 at 1 ATM for 18 h. The reaction mixture was filtered through celite and washed with DCM (10 ml). The filtrate was concentrated to give diethyl 2 (((2S, 3R, 4R, 5R) -3-amino-5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro-9Hpurine- 9-yl) -4 - ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) methoxy) -2-benzylmalonate (92 mg, 94% yield), which was used in the next step without further purification.

Stage 9.

To a solution of diethyl 2 - (((2S, 3R, 4R, 5R) -3-amino-5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro-9H-purine -9-yl) -4 - ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2yl) methoxy) -2-benzylmalonate (92 mg, 0.11 mmol) in a mixture of DCM (2.3 ml) and water (92 μl) was added dropwise TFA (0.92 ml). The reaction mixture was stirred for 16 h, then evaporated to dryness and azeotroped twice with acetonitrile. The resulting oil was treated with THF (1.5 ml) and 4M NaOH (106 μl, 0.42 mmol) was added at room temperature. The reaction mixture was stirred for 10 h, then concentrated to dryness. The crude residue was purified by reverse phase HPLC to give 2 - (((2S, 3S, 4R, 5R) -3-amino-5- (6-amino-2-chloro-9H-purin-9-yl) -4-hydroxytetrahydrofuran -2yl) methoxy) -2-benzylmalonic acid.

1H NMR (CD3OD, 300 MHz) δ 8.35 (s, 1H), 7.10-7.77 (m, 5H), 6.45-6.52 (dd, J = 4.10 Hz, 1H) , 5.18-5.39 (dt, J = 4.5, 52 Hz, 1H), 4.65-4.73 (dt, J = 5.17 Hz, 1H), 4.21-4.24 (m, 1H), 3.95-4.18 (m, 2H), 3.45-3.59 (m, 2H); LC / MS [M + H] = 493.

Stage 10.

2 - (((2S, 3S, 4R, 5R) -5- (6-Amino-2-chloro-9H-purin-9-yl) -3-azido-4-hydroxytetrahydrofuran-2yl) methoxy) malonic acid was prepared starting from from diethyl 2 - (((2S, 3R, 4R, 5R) -3-azido-5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro-9H-purine-9- yl) -4 - ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) methoxy) malonate under the same deprotection conditions described in step 9.

1H NMR (CD3OD, 300 MHz) δ 8.87 (br s, 1H), 6.03 (d, J = 6.4 Hz, 1H), 5.17-5.21 (t, J = 5, 6 Hz, 1H), 4.61 (brs, 1h), 4.50 (brs, 1H), 4.20 (brs, 1H), 3.81-3.91 (q, J = 0 Hz, 2H); LC / MS [M + H] = 429.

Example 19 Synthesis of 2 - (((2R, 3S, 4R, 5R) -4-amino-5- (6-amino-2-chloro-9H-purin-9-yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) -2-benzylmalonic acid

- 102 039042

Boc ₂ 0,4-DMAP Ε1 ₃ Ν, ΤΓΦ

6.ΤΒΑΓ, ΤΓΦ

9. Lindlar catalyst H ₂ , EtOAc

Stage 1.

To a cooled (-70 ° C) solution of oxalyl chloride (4.18 ml, 48.78 mmol) in dry dichloromethane (100 ml) under argon was added dropwise a solution of dry DMSO (7.1 ml, 99.44 mmol) in dichloromethane (18 ml). After stirring for 30 min for 30 min, a solution of (6aR, 8R, 9R, 9aS) -8- (6-amino-2-chloro-9H-purin-9-yl) -2,2,4 was added dropwise, 4-teraisopropylterahydro-6H-furo [3,2-f [1,3,5,2,4] trioxadisilocin-9-ol (10.21 g, 18.76 mmol) synthesized from 2-chloroadenosine according to the method described in Secrist, John A., III et al .; (Journal of Medicinal Chemistry, 31, 405-10, 1988); and Chen, Robert HK (US Pat. No. 5,208,327) in a mixture of dichloromethane and THF (46 ml, 1: 1 / v: v) and then triethylamine (16 ml, 114.44 mmol) was added via syringe. The cooling bath was removed and the mixture was stirred at room temperature for 1.5 h, then chloroform (190 ml) and water (650 ml) were added and the pH of the mixture was brought to neutral with 2N HCl. aq. HCl solution. The organic layer was separated and the aqueous phase was then extracted with chloroform (2x190 ml). The combined organic phase was dried (MgSO ₄ ) and filtered through a thin pad of celite. The filtrate was concentrated to give (6aR, 8R, 9aR) -8- (6-amino-2-chloro-9H-purin-9-yl) -2,2,4,4-tetraisopropyldihydro-6Hfuro [3,2-f] [1,3,5,2,4] trioxadisilocin-9 (6aH) -one as a solid (8.37 g) which was used in the next step without further purification.

Stage 2.

Glacial acetic acid (19.3 ml, 337 mmol) was added dropwise to a suspension of NaBH ₄ (2.51 g, 66.4 mmol) in dry THF (130 ml) under argon at 0 ° C. The reaction mixture was stirred for 1.5 h and then a solution of (6aR, 8R, 9aR) -8- (6-amino-2-chloro-9Hpurin-9-yl) -2,2,4,4-tetraisopropyldihydro -6H-furo [3,2-f] [1,3,5,2,4] trioxadisilocin-9 (6aH) -one (3 g, 5.53 mmol) in tetrahydrofuran (30 ml). The mixture was stirred for 4 h at 0 ° C. Organic volatiles were removed under reduced pressure and the residue was separated with EtOAc (115 ml) and saturated aqueous sodium bicarbonate solution (115 ml). The organic phase was separated and the aqueous layer was then extracted with EtOAc (2x100 ml). The combined organic phase was dried (MgSO ₄ ), filtered and concentrated to give (6aR, 8R, 9R, 9aS) -8- (6-amino-2-chloro-9H-purine-9ul) -2,2,4,4- tetraisopropyltetrahydro-6H-furo [3,2-f] [1,3,5,2,4] trioxadisilocin-9-ol as foam (2.69 g).

Stage 3.

To a solution of (6aR, 8R, 9R, 9aS) -8- (6-amino-2-chloro-9H-purin-9-yl) -2,2,4,4-tetraisopropyltetrahydro6H-furo [3,2-f] [1,3,5,2,4] trioxadisilocin-9-ol (2.297 g, 4.22 mmol) in anhydrous dichloromethane (90 ml) under argon, pyridine (3.1 ml, 38 mmol) and 4-dimethylaminopyridine were added (1.5 g, 12.24 mmol). The mixture was cooled to 0 ° C and stirred for 15 min and then trifluoromethanesulfonic anhydride (1.1 ml, 6.33 mmol) was added dropwise. After stirring for 5 minutes, the cooling bath was removed and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with cold water (90 ml). The organic phase was separated and then the aqueous phase was extracted with DCM (2x80 ml).

The combined organic phase was dried (MgSO ₄ ), filtered and concentrated. The crude residue was purified by silica gel column chromatography (25-85% EtOAc in hexane) to give

- 103 039042 (6aR, 8R, 9S, 9aR) -8- (6-amino-2-chloro-9H-purin-9-yl) -2,2,4,4-tetraisopropyltetrahydro-6H-furo [3,2 -f]

[1,3,5,2,4] -trioxadisilocin-9-yl trifluoromethanesulfonate as a white solid (1.9 g).

Stage 4.

To a solution of (6aR, 8R, 9S, 9aR) -8- (6-amino-2-chloro-9H-purin-9-yl) -2,2,4,4-tetraisopropyltetrahydro6H-furo [3,2-f] [1,3,5,2,4] trioxadisilocin-9-yl trifluoromethanesulfonate (1.9 g, 2.8 mmol) in anhydrous DMF (12 ml) under argon was added sodium azide (1.83 g, 28.1 mmol ). The mixture was stirred for 24 h, then it was separated with EtOAc (120 ml) and brine (120 ml). The organic phase was separated and then the aqueous phase was extracted with EtOAc (2x100 ml). The combined organic phase was dried (MgSO ₄ ), filtered and concentrated to give 9 - ((6aR, 8R, 9R, 9aS) 9-azido-2,2,4,4-tetraisopropyltetrahydro-6H-furo [3,2-f] [1,3,5,2,4] trioxadisilocin-8-yl) -2-chloro-9Hpurin-6-amine as a solid (1.48 g).

Stage 5.

To a solution of 9 - ((6aR, 8R, 9R, 9aS) -9-azido-2,2,4,4-tetraisopropyltetrahydro-6H-furo [3,2-f] [1,3,5,2,4] trioxadisilocin-8-yl) -2-chloro-9H-purin-6-amine (1.48 g, 2.59 mmol) in anhydrous THF (31 ml) under argon was added 4-dimethylaminopyridine (153 mg, 1.25 mmol) and then di-tert-butyl dicarbonate (1.2 g, 5.5 mmol). The mixture was stirred at room temperature for 16 h, then it was separated with EtOAc (40 ml) and brine (60 ml). The organic phase was separated and then the aqueous phase was extracted with EtOAc (2x40 ml). The combined organic phase was dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by silica gel column chromatography (15% EtOAc in hexane) to give tert-butyl- (tert-butoxycarbonyl) (9 ((6aR, 8R, 9R, 9aS) -9-azido-2,2,4,4- tetraisopropyltetrahydro-6H-furo [3,2-f] [1,3,5,2,4] trioxadisilocin8-yl) -2-chloro-9H-purin-6-yl) dicarbamate as a viscous oil (1.857 g).

Stage 6.

To a solution of tert-butyl- (tert-butoxycarbonyl) (9 - ((6aR, 8R, 9R, 9aS) -9-azido-2,2,4,4-tetraisopropyltetrahydro-6H-furo [3,2-f] [ 1,3,5,2,4] trioxadisilocin-8-yl) -2-chloro-9H-purin-6-yl) dicarbamate (1.85 g, 2.41 mmol) in anhydrous THF (13 ml) under atmosphere argon at 0 ° C was added dropwise a solution of tetrabutylammonium fluoride (6.3 ml, 1.0 M in THF, 6.3 mmol). The reaction mixture in the flask was stirred overnight at 6 ° C, then it was separated with EtOAc (50 ml) and brine (50 ml). The organic phase was separated and then the aqueous phase was extracted with EtOAc (2x40 ml). The combined organic phase was dried (MgSO4), filtered and concentrated. The crude product was purified by silica gel column chromatography (55% EtOAc in hexane) to give tert-butyl- (tert-butoxycarbonyl) (9 - ((2R, 3R, 4S, 5R) -3-azido-4-hydroxy-5- ( hydroxymethyl) tetrahydrofuran-2-yl) -2-chloro-9H-purin-6-yl) carbamate as a solid (1.117 g).

Stage 7.

To a solution of tert-butyl- (tert-butoxycarbonyl) (9 - ((2R, 3R, 4S, 5R) -3-azido-4-hydroxy-5 (hydroxymethyl) tetrahydrofuran-2-yl) -2-chloro-9H- purin-6-yl) carbamate (408 mg, 0.77 mmol) and Rh ₂ (OAc) ₄ (14 mg, 0.04 mmol) in dry toluene (2 ml) in an argon atmosphere at room temperature, diethyl-2- diazomalonate (173 mg, 0.93 mmol). The resulting mixture was stirred at 75 ° C for 3 h, then allowed to cool to room temperature. The reaction mixture was then separated with EtOAc (20 ml) and brine (20 ml). The organic phase was separated and then the aqueous phase was extracted with EtOAc (2x20 ml). The combined organic phases were dried (MgSO4), filtered and concentrated. The resin was purified on preparative thin layer chromatography plates eluting with 60% EtOAc in hexane to give diethyl 2 - (((2R, 3S, 4R, 5R) -4azido-5- (6- (K- (tert-butoxycarbonyl) (tert -butoxycarbonyl) amino) -2-chloro-9H-purin-9-yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) malonate as a viscous oil (167 mg).

Stage 8.

To a solution of diethyl 2 - (((2R, 3S, 4R, 5R) -4-azido-5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro-9H-purine -9-yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) malonate (167 mg, 0.24 mmol) in dry DMF (1.5 ml) under argon, cesium carbonate (119 mg, 0.37 mmol) was added and then benzyl bromide (44 mg, 0.26 mmol). _{Additional Cs 2} CO ₃ (60 mg) and BnBr (40 mg) were added to the reaction mixture over 1.5 h and stirred for an additional 1 h. The reaction mixture was then separated with EtOAc (20 ml) and brine ( 20 ml). The organic phase was separated and then the aqueous phase was extracted with EtOAc (2x20 ml). The combined organic phase was dried (MgSO4), filtered and concentrated. The resin was purified by preparative thin layer chromatography (eluting with 40% EtOAc in hexane) to give diethyl 2 - (((2R, 3S, 4R, 5R) -4-azido-5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl ) amino) -2-chloro-9H-purin-9-yl) -3-hydroxytetrahydrofuran-2yl) methoxy) -2-benzylmalonate as a viscous oil.

Stage 9.

To a solution of diethyl 2 - (((2R, 3S, 4R, 5R) -4-azido-5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro-9H-purine -9-yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) -2-benzylmalonate (101 mg, 0.13 mmol) in ethanol (4 ml), Lindlar catalyst (25 mg) was added and then stirred under

104 039042 at 1 ATM H2 pressure for 18 hours. The reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was concentrated to give diethyl 2 - (((2R, 3S, 4R, 5R) -4-azido5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro- 9H-nurin-9-yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) -2-benzylmalonate (100 mg).

Stage 10.

To a solution of dietul-2 - (((2R, 3S, 4R, 5R) -4-azido-5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro-9H-purun -9-ul) -3-hydroxytetrahydrofuran-2-yl) methoxy) -2-benzylmalonate (100 mg, 0.13 mmol) in THF (1.5 ml) and water (0.75 ml), lithium hydroxide monohydrate ( 65 mg, 1.56 mmol). The substance was vigorously stirred for 5 h at room temperature and then stirred for 66 h at 6 ° C, then cooled to 0 ° C and 1N. aq. HCl solution (1.7 ml). The reaction mixture was concentrated to give an off-white powder (66 mg). This material was then treated with a solution of trifluoroacetic acid in dichloromethane (1.5 ml, 1: 1 / v: v) and stirred for 1 h, then concentrated. The residue was taken up in dichloromethane (5x5 ml) and concentrated each time. The crude product was purified by reverse phase HPLC to give 2 - (((2R, 3S, 4R, 5R) -4-amino-5- (6-amino-2-chloro-9H-purin-9-yl) -3-hydroxytetrahydrofuran -2yl) methoxy) -2-benzylmalonic acid (18 mg) as a solid.

¹ H NMR (CD3OD, 300 MHz) δ 8.29 (s, 1H), 7.26-7.16 (m, 5H), 6.36 (d, J = 9 Hz, 1H), 4.6 ( d, J = 5 Hz, 1H), 4.53-4.47 (m, 1H), 4.43 (br s, 1H), 4.01 (dd, J = 2.11 Hz, 1H), 3.80 (dd, J = 2.10 Hz, 2H); 3.46 (br s, 2H); LC / MS [M + H] = 493.

Example 21. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (4- (benzylamino) -1H-benzo [d] imidazol-1-yl) -4-fluoro-3hydroxytetrahydrofuran-2-yl) methoxy) -2- (3-carboxybenzyl) malonic acid

By operating as described in Example 2 above, but substituting methyl 3 (bromomethyl) benzoate for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.31 (s, 1H), 7.99 (s, 1H), 7.81-7.84 (d, J = 7 Hz, 1H), 7.52-7 , 55 (d, J = 7 Hz, 1H), 7.25-7.30 (t, J = 8 Hz, 1H), 6.40-6.46 (dd, J = 4.13 Hz, 1H) , 5.07-5.27 (dt, J = 4.52 Hz, 1H), 4.66-4.73 (dt, J = 5.17 Hz, 1H), 4.16-4.20 (m , 1H), 3.99-4.11 (m, 2H), 3.40-3.55 (m, 2H); LC / MS [M + H] = 540.

Example 22. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-nurin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (3-fluorobenzyl) malonic acid

F

By operating as described in Example 2 above, but substituting 3-fluorobenzyl bromide for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.33 (s, 1H), 7.03-7.18 (m, 3H), 6.81-6.82 (m, 1H), 6.41-6, 47 (dd, J = 4.13 Hz, 1H), 5.09-5.29 (dt, J = 4.52 Hz, 1H), 4.65-4.74 (dt, J = 5.18 Hz , 1H), 4.15-4.19 (q, J = 4 Hz, 1H), 3.96-4.10 (m, 2H), 3.36-3.46 (m, 2H); LC / MS [M + H] = 514.

Example 23. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-fluorobenzyl) malonic acid

By operating as described in Example 2 above, but substituting 4-fluorobenzyl bromide for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.33 (s, 1H), 7.26-7.30 (m, 2H), 6.81-6.87 (t, J = 9 Hz, 2H), 6 , 41-6.47 (dd, J = 4.13 Hz, 1H), 5.09-5.29 (dt, J = 4.52 Hz, 1H), 4.65-4.74 (dt, J = 5.18 Hz, 1H), 4.14-4.20 (m, 1H), 3.95-4.09 (m, 2H), 3.33-3.45 (m, 2H); LC / MS [M + H] = 514.

Example 24. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-πurin-9-yl) -4-fluoro-3-hydroxy

- 105 039042 tetrahydrofuran-2-yl) methoxy) -2- (3-methoxybenzyl) malonic acid

ОМе

By operating as described in Example 2 above, but substituting 3-methoxybenzyl bromide for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.41 (s, 1H), 7.01-7.06 (t, J = 7 Hz, 1H), 6.83-6.85 (m, 2H), 6 , 64-6.66 (d, J = 8 Hz, 1H), 6.42-6.48 (dd, J = 4.11 Hz, 1H), 5.11-5.31 (dt, J = 4 , 52 Hz, 1H), 4.67-4.74 (dt, J = 5.18 Hz, 1H), 4.164.20 (m, 1H), 3.94-4.10 (m, 2H), 3 , 60 (d, J = 1 Hz, 3H), 3.31-3.44 (m, 2H); LC / MS [M + H] = 526.

Example 25. Synthesis of 2- (3- (1H-tetrazol-5-yl) benzyl) -2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purine9- yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) malonic acid

n = n _N 'N

Stage 1.

To a solution of diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6- (N- [tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro-9H-purin-9-yl ) -3 - ((tert-butoxycarbonyl) oxy) -4-fluoro-tetrahydrofuran-2-yl) methoxy) -2- (3cyanobenzyl) malonate obtained from diethyl 2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2- yl) methoxy) malonate with 3- (bromomethyl) benzonitrile according to the method of example 2, (380 mg, 0.43 mmol) in toluene (8 ml), azidotrimethylsilane (350 μl, 2.64 mmol) and bis (tributyltin) oxide (66 μl, 0.13 mmol). The reaction mixture was then heated at 75 ° C for four days, then concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0-4% MeOH in DCM) to give diethyl 2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) -2- chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluoro-tetrahydrofuran-2-yl) methoxy) -2- (3-1H-tetrazol-5-ylbenzyl) malonate.

Stage 2.

Diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) -2-chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl ) oxy) -4-fluoro-tetrahydrofuran-2-yl) methoxy) -2- (3-1H-tetrazol-5-ylbenzyl) malonate was then converted to the title compound as described in Example 2 above.

1H NMR (CD3OD, 300 MHz) δ 8.26 (s, 1H), 7.99 (s, 1H), 7.77-7.79 (d, J = 7Hz, 1H), 7.47-7 , 50 (d, J = 8 Hz, 1H), 7.38 (t, J = 7 Hz, 1H), 6.35-6.46 (m, 1H), 5.06-5.27 (m, 1H), 4.66-4.80 (m, 1H), 4.20-4.21 (m, 1H), 4.00-4.17 (m, 2H), 3.44-3.62 ( m, 2H); LC / MS [M + H] = 564.

Example 26. Synthesis of 2- (4- (1H-tetrazol-5-yl) benzyl) -2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purine9- yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) malonic acid

The title compound was prepared as described in Example 25 above by substituting 4- (bromomethyl) benzonitrile for 3 (bromomethyl) benzonitrile, and the title compound was obtained as a white solid.

1H NMR (CD ₃ OD, 300 MHz) δ 8.27 (s, 1H), 7.79-7.82 (d, J = 8 Hz, 2H), 7.50-7.52 (d, J = 8 Hz, 2H), 6.426.47 (dd, J = 4.13 Hz, 1H), 5.09-5.29 (dt, J = 4.53 Hz, 1H), 4.65-4.74 ( dt, J = 4.17 Hz, 1H), 4.18-4.21 (m, 1H), 3.984.14 (m, 2H), 3.46-3.58 (m, 2H); LC / MS [M + H] = 564.

Example 27. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (benzyloxy) benzyl) malonic acid

- 106 039042

By operating as described in Example 2 above, but substituting 1- (benzyloxy) -4 (chloromethyl) benzene for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD ₃ OD, 300 MHz) δ 8.33 (s, 1H), 7.27-7.35 (m, 5H), 7.17-7.20 (d, J = 8 Hz, 2H) , 6.72-6.75 (d, J = 9 Hz, 2H), 6.40-6.46 (dd, J = 5.12 Hz, 1H), 5.10-5.29 (dt, J = 4.52 Hz, 1H), 4.89 (s, 2H), 4.66-4.75 (dt, J = 5.18 Hz, 1H), 4.15-4.17 (m, 1H) , 3.93-4.08 (m, 2H), 3.30-3.41 (dd, J = 5.14 Hz, 2H); LC / MS [M + H] = 602.

Example 28. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-hydroxybenzyl) malonic acid

To a solution of (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran2-yl) methoxy) -2- ( 4- (benzyloxy) benzyl) malonic acid (example 27) (280 mg) in EtOAc (10 ml) was added Pd / C (50 mg, 10 wt%). The resulting mixture was stirred under a pressure of H ₂ in 1 ATM for 1.5 h, then filtered. The filtrate was concentrated to give the title compound as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.33-8.34 (d, J = 2 Hz, 1H), 7.09-7.12 (d, J = 9 Hz, 2H), 6.58-6 , 61 (d, J = 8 Hz, 2H), 6.40-6.46 (dd, J = 4.14 Hz, 1H), 5.05-5.27 (dt, J = 4.52 Hz, 1H), 4.63-4.71 (dt, J = 4.33 Hz, 1H), 4.14-4.18 (q, J = 5 Hz, 1H), 3.96-4.00 (m , 2H), 3.46 (br s, 2H); LC / MS [M + H] = 512.

Example 29. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (3-hydroxybenzyl) malonic acid

By operating as described in Examples 2 and 28 above, but substituting 1- (benzyloxy) -3 (chloromethyl) benzene for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD ₃ OD, 300 MHz) δ 8.37 (s, 1H), 6.94-6.99 (t, J = 8 Hz, 1H), 6.76-6.78 (m, 2H) , 6.56-6.59 (d, J = 8 Hz, 1H), 6.41-6.46 (dd, J = 3.12 Hz, 1H), 5.08-5.27 (dt, J = 4.52 Hz, 1H), 4.66-4.73 (m, 1H), 4.11-4.20 (m, 1H), 3.92-4.07 (m, 2H), 3, 35 (m, 2H); LC / MS [M + H] = 512.

Example 30. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-carboxy-2-fluorobenzyl) malonic acid

By operating as described in Example 2 above, but substituting methyl 4- (bromomethyl) -3fluorobenzoate for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.25 (s, 1H), 7.51-7.60 (m, 3H), 6.38-6.44 (dd, J = 4.14 Hz, 1H) , 5.05-5.25 (dt, J = 5.52 Hz, 1H), 4.62-4.70 (m, 1H), 4.12-4.16 (m, 1H), 3.95 -4.05 (m, 2H), 3.54 (br s, 2H); LC / MS [M + H] = 558.

Example 31. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-carboxy-3-fluorobenzyl) malonic acid

- 107 039042

By operating as described in Example 2 above, but substituting methyl 4- (bromomethyl) -2fluorobenzoate for benzyl bromide, the title compound was obtained as a white solid.

¹ H NMR (CD3OD, 300 MHz) δ 8.32 (brs, 1H), 7.69-7.74 (t, J = 8 Hz, 1H), 7.12-7.16 (m, 2H ), 6.41-6.47 (dd, J = 5.14 Hz, 1H), 5.06-5.28 (dt, J = 5.52 Hz, 1H), 4.65-4.73 ( m, 1H), 4.14-4.19 (m, 1H), 3.92-4.04 (m, 2H), 3.44 (br s, 2H); LC / MS [M + H] = 558.

Example 32. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((5- (trifluoromethyl) furan-2-yl) methyl) malonic acid

By operating as described in Example 2 above, but substituting 2- (bromomethyl) -5 (trifluoromethyl) furan for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.38 (s, 1H), 6.78-6.79 (m, 4H), 6.39-6.45 (m, 2H), 5.06-5, 26 (dt, J = 4.53 Hz, 1H), 4.62-4.71 (dt, J = 4.17 Hz, 1H), 4.13-4.16 (m, 1H), 3.97 -4.00 (m, 2H), 3.58 (br s, 2H); LC / MS [M + H] = 554.

Example 33. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((6- (trifluoromethyl) pyridin-3-yl) methyl) malonic acid

By operating as described in Example 2 above, but substituting 5- (bromomethyl) -2 (trifluoromethyl) pyridine for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD ₃ OD, 300 MHz) δ 8.60 (br s, 1H), 8.37 (s, 1H), 7.89 (d, J = 9 Hz, 1H), 7.60 (d , J = 8 Hz, 1H), 6.51-6.59 (dd, J = 2.22 Hz, 1H), 5.08-5.27 (dt, J = 4.53 Hz, 1H), 4 , 62-4.71 (dt, J = 5.17 Hz, 1H), 4.21-4.24 (m, 1H), 3.96-4.17 (m, 2H), 3.45-3 , 59 (q, J = 15 Hz, 2H); LC / MS [M + H] = 565.

Example 34. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2-yl) methoxy) -2- (3-fluoro-4- (trifluoromethyl) benzyl) malonic acid

By operating as described in Example 2 above, but substituting 4- (bromomethyl) -2-fluoro-1 (trifluoromethyl) benzene for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.76 (s, 1H), 7.27-7.49 (m, 3H), 6.51-6.56 (dd, J = 4.10 Hz, 1H) , 5.18-5.39 (dt, J = 5.52 Hz, 1H), 4.62-4.71 (dt, J = 5.17 Hz, 1H), 4.21-4.24 (m , 1H), 3.96-4.17 (m, 2H), 3.45-3.59 (q, J = 15Hz, 2H); LC / MS [M + H] = 582.

Example 35. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((3-phenylisoxazol-5-yl) methyl) malonic acid

- 108 039042

NH ₂ o Voh bk A.

H W mV \ _ /

Β ^Η0 ' ^F o

By operating as described in Example 2 above, but substituting 5- (bromomethyl) -3-phenylisoxazole for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.96 (s, 1H), 7.40-7.80 (m, 5H), 6.51-6.56 (dd, J = 4.10 Hz, 1H) , 6.29 (s, 1H), 5.18-5.39 (dt, J = 5.52 Hz, 1H), 4.60-4.69 (dt, J = 5.17 Hz, 1H), 4.21-4.24 (m, 1H), 3.98-4.19 (m, 2H), 3.453.59 (q, J = 15Hz, 2H); LC / MS [M + H] = 563.

Example 36. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-nurin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((1-benzyl-1 H-pyrazol-4-yl) methyl) malonic acid about mn ₂

About VoH A ъG edv

In dd

U BUT 'F gu

By operating as described in Example 2 above, but substituting 1-benzyl-4- (bromomethyl) -1Hpyrazole for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.45 (s, 1H), 7.56 (s, 1H), 7.414 (s, 1H), 7.17-7.23 (m, 3H), 7.00 -7.03 (m, 2H), 6.39-6.45 (dd, J = 4.12 Hz, 1H), 5.10-5.31 (m, 3H), 4.65-4.75 (dt, J = 5.18 Hz, 1H), 4.14-4.17 (q, J = 5 Hz, 1H), 3.93-4.02 (m, 2H), 3.30-3, 36 (m, 2H); LC / MS [M + H] = 576.

Example 37. Synthesis of 2 - ((1H-nyrazol-4-yl) methyl) -2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purine-9yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) malonic acid

2 - ((1H-Pyrazol-4-yl) methyl) -2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4 -fluoro-3hydroxytetrahydrofuran-2-yl) methoxy) malonic acid was prepared according to example 36 (200 mg) by debenzylation with Pd / C (50 mg, 10 wt%) in a mixture of EtOH (0.5 ml) and EtOAc (5 ml) under a pressure of H2 in 1 atm. After 1 hour, the catalyst was filtered off and the filtrate was concentrated to give the title compound as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.46 (s, 1H), 7.55 (s, 2H), 6.44-6.49 (dd, J = 5.12 Hz, 1H), 5.12 -5.31 (dt, J = 4.53 Hz, 1H), 4.68-4.74 (dt, J = 5.13 Hz, 1H), 4.17-4.22 (q, J = 5 Hz, 1H), 3.96-4.03 (m, 2H), 3.36 (br s, 2H); LC / MS [M + H] = 486.

Example 38. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((2-carboxythiazol-5-yl) methyl) malonic acid

By operating as described in Example 2 above, but substituting methyl 4- (bromomethyl) thiazole 2-carboxylate for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.38 (d, J = 2 Hz, 1H), 7.37-7.59 (d, J = 4 Hz, 1H), 6.41-6.48 (m , 1H), 5.055.25 (dt, J = 3.52 Hz, 1H), 4.65-4.74 (m, 1H), 4.22-4.24 (m, 1H), 3.98 ( br s, 2H), 3.66 (br s, 2H); LC / MS [M + H] = 548.

Example 39. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((2-carboxythiazol-4-yl) methyl) malonic acid

- 109 039042

By operating as described in Example 2 above, but substituting methyl 5- (bromomethyl) thiazole 2-carboxylate for benzyl bromide, the title compound was obtained as a white solid.

¹ H NMR (CD3OD, 300 MHz) δ 8.48 (br s, 1H), 7.64 (br s, 1H), 6.41-6.44 (dd, J = 5.8 Hz, 1H ), 5.14-5.33 (dt, J = 4.52 Hz, 1H), 4.73-4.79 (m, 1H), 4.01-4.04 (m, 1H), 3, 70-3.79 (m, 2H), 3.73 (br s, 2H); LC / MS [M + H] = 547.

Example 40. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((5-carboxy-1-methyl-1 H-pyrazol-3-yl) methyl) malonic acid

By operating as described in Example 2 above, but substituting ethyl 5- (bromomethyl) -1-methyl 1H-pyrazole-3-carboxylate for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD ₃ OD, 300 MHz) δ 8.90 (brs, 1H), 6.51-6.56 (dd, J = 4.10 Hz, 1H), 6.35 (s, 1H) , 5.19-5.40 (dt, J = 4.7, 52 Hz, 1H), 4.61-4.70 (dt, J = 5.17 Hz, 1H), 4.21-4.24 (m, 1H), 3.96-4.17 (m, 2H), 3.93 (s, 3H), 3.453.59 (q, J = 15Hz, 2H); LC / MS [M + H] = 543.

Example 41. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((3-carboxyisoxazol-5-yl) methyl) malonic acid

By operating as described in the example above but substituting ethyl 5 (bromomethyl) isoxazole-3-carboxylate for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.98 (br s, 1H), 6.51-6.56 (dd, J = 4.10 Hz, 1H), 6.39 (s, 1H), 5 , 18-5.39 (dt, J = 5.52 Hz, 1H), 4.62-4.71 (dt, J = 5.17 Hz, 1H), 4.21-4.25 (m, 1H ), 3.97-4.17 (m, 2H), 3.43-3.56 (q, J = 15Hz, 2H); LC / MS [M + H] = 531.

Example 42. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-cyano-3-fluorobenzyl) malonic acid

By operating as described in Example 2 above, but substituting 4- (bromomethyl) -2 fluorobenzonitrile for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.35 (br s, 1H), 7.04-7.57 (m, 3H), 6.48-6.54 (dd, J = 4.10 Hz, 1H), 5.18-5.39 (dt, J = 5.52 Hz, 1H), 4.65-4.75 (dt, J = 5.17 Hz, 1H), 4.21-4.24 (m, 1H), 3.94-4.18 (m, 2H), 3.45-3.60 (m, 2H); LC / MS [M + H] = 539.

Example 43. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((5-carboxythiophen-3-yl) methyl) malonic acid

- 110 039042

By operating as described in Example 2 above, but substituting ethyl 4- (bromomethyl) thiophene 2-carboxylate for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.40 (br s, 1H), 7.73 (s, 1H), 7.50 (s, 1H), 6.44-6.49 (dd, J = 3.11 Hz, 1H), 5.03-5.30 (m, 1H), 4.65-4.75 (m, 1H), 4.15-4.23 (m, 1H), 3.96 -4.10 (m, 2H), 3.39-3.53 (m, 2H); LC / MS [M + H] = 546.

Example 44. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((5-carboxythiophen-2-yl) methyl) malonic acid

By operating as described in Example 2 above, but substituting ethyl 5- (bromomethyl) thiophene 2-carboxylate for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.36 (s, 1H), 7.52-7.53 (d, J = 4 Hz, 1H), 6.99-7.00 (d, J = 4 Hz , 1H), 6.416.47 (dd, J = 4.14 Hz, 1H), 5.07-5.26 (dt, J = 3.48 Hz, 1H), 4.68-4.76 (dt, J = 4.18 Hz, 1H), 4.18-4.21 (m, 1H), 4.014.11 (m, 2H), 3.66 (s, 2H); LC / MS [M + H] = 546.

Example 45. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (carboxymethyl) benzyl) malonic acid

By operating as described in the example above, but substituting ethyl 2- (4 (bromomethyl) phenyl) acetate for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.32 (br s, 1H), 7.24-7.26 (d, J = 8 Hz, 2H), 7.08-7.10 (d, J = 8 Hz, 2H), 6.40-6.46 (dd, J = 4.13 Hz, 1H), 5.07-5.27 (dt, J = 4.53 Hz, 1H), 4.63- 4.72 (dt, J = 4.18 Hz, 1H), 4.15-4.20 (m, 1H), 3.95-4.06 (m, 2H), 3.44-3.54 ( m, 2H), 3.40 (br s, 2H); LC / MS [M + H] = 554.

Example 46. Synthesis of 2 - ([1,1'-biphenyl] -4-ylmethyl) -2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purine- 9yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) malonic acid, (R) -2 - ([1,1'-biphenyl] -4ylmethyl) -2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-πurin-9-yl) -4-fluoro-3-hydroxymetrahydrofuran-2yl) methoxy) -3-methoxy-3-oxopropanoic acid, (S) -2 - ([1,1'-biphenyl] -4-ylmethyl) -2 - (((2R, 3R, 4S, 5R) -5 (6-amino-2-chloro-9H-purun-9-yl) -4 -fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -3-methoxy-3oxopropanoic acid, (R) -2 - ([1,1'-biphenyl] -4-ylmethyl) -2 - (((2R, 3R , 4S, 5R) -5- (6-amino-2-chloro-9Hpurin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -3-ethoxy-3-oxopropanoic acid and (S ) -2 - ([1,1'-biphenyl] -4-ylmethyl) -2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-nurin-9- yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -3-ethoxy-3-oxopropanoic acid

- 111 039042

Stage 1.

Diethyl 2 - ([1,1'-biphenyl] -4-ylmethyl) -2 - (((2R, 3R, 4S, 5R) -5- (6-N- (bis- (tert-butoxycarbonyl) amino) 2-chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate (200 mg, 0.22 mmol) obtained by alkylation of N6, N6 -bis- (tert-butoxycarbonyl) -2'-αrabinofluoro-2'deoxy-3'-O- (tert-butoxycarbonyl) -2-chloroadenosine 4-phenylbenzyl bromide in accordance with the method described in example 2 was dissolved in DCM (5 ml) and then TFA (1.5 ml) was added at room temperature. The resulting mixture was stirred for 7 hours, then concentrated. The residue was taken up again in DCM (3x5 ml) and concentrated under reduced pressure each time to remove excess TFA to give diethyl 2 - ([1,1'-biphenyl] -4-ylmethyl) -2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4- fluorotetrahydrofuran-2-yl) methoxy) malonate.

Stage 2.

To a solution of diethyl-2 - ([1,1'-biphenyl] -4-ylmethyl) -2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert -butoxycarbonyl) amino) -2-chloro-9H-purin-9-yl) -3 - ((tert-butoxyαcarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate (0.22 mmol) in MeOH mixture (2 ml), THF (2 ml) and H ₂ O (2 ml) were added LiOH-H ₂ O (90 mg, 2.15 mmol). The resulting mixture was stirred at room temperature for 5 hours, then volatile organic products were removed under reduced pressure. The residue was again dissolved in H ₂ O (2 ml) and acidified with 1N. aq. HCl solution to pH 5, then concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC to give the title compounds as white solids.

2 - ([1,1'-Biphenyl] -4-ylmethyl) -2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2-yl) methoxy) malonic acid:

1H NMR (CD ₃ OD, 300 MHz) δ 8.34 (brs, 1H), 7.27-7.46 (m, 9H), 6.41-6.46 (dd, J = 5, 12 Hz, 1H), 5.09-5.30 (dt, J = 4.52 Hz, 1H), 4.68-4.77 (dt, J = 4.18 Hz, 1H), 4.15-4 , 19 (m, 1H), 3.97-4.12 (m, 2H), 3.43-3.52 (m, 2H); LC / MS [M + H] = 572.

2 - ([1,1'-Biphenyl] -4-ylmethyl) -2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2-yl) methoxy) -3-methoxy-3-oxopropanoic acid (methyl diastereomer 1):

1H NMR (CD3OD, 300 MHz) δ 8.31 (brs, 1H), 7.26-7.48 (m, 9H), 6.42-6.47 (dd, J = 5, 12Hz, 1H), 5.10-5.31 (dt, J = 4.52 Hz, 1H), 4.67-4.77 (dt, J = 5.18 Hz, 1H), 4.15-4.19 (m, 1H), 3.98-4.10 (m, 2H), 3.78 (s, 3H), 3.40-3.52 (m, 2H); LC / MS [M + H] = 586.

2 - ([1,1'-Biphenyl] -4-ylmethyl) -2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2-yl) methoxy) -3-methoxy-3-oxopropanoic acid (methyl diastereomer 2):

1H NMR (CD3OD, 300 MHz) δ 8.31 (brs, 1H), 7.25-7.47 (m, 9H), 6.40-6.46 (dd, J = 4, 12Hz, 1H), 5.10-5.30 (dt, J = 4.53 Hz, 1H), 4.66-4.76 (dt, J = 5.18 Hz, 1H), 4.08-4.17 (m, 2H), 3.92-3.96 (m, 1H), 3.79 (s, 3H), 3.40-3.52 (m, 2H); LC / MS [M + H] = 586.

2 - ([1,1'-Biphenyl] -4-ylmethyl) -2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2-yl) methoxy) -3-ethoxy-3-oxopropanoic acid (ethyl diastereomer 1):

1H NMR (CD3OD, 300 MHz) δ 8.33 (br s, 1H), 7.26-7.48 (m, 9H), 6.44-6.49 (dd, J = 5.8 Hz, 1H), 5.115.31 (dt, J = 4.53 Hz, 1H), 4.71-4.77 (m, 1H), 4.17-4.25 (m, 3H), 4.00-4 09 (m, 2H), 3.44 (br s, 2H), 1.241.28 (t, J = 7 Hz, 3H); LC / MS [M + H] = 600.

2 - ([1,1'-Biphenyl] -4-ylmethyl) -2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2-yl) methoxy) -3-ethoxy-3-oxopropanoic acid (ethyl diastereomer 2):

1H NMR (CD3OD, 300 MHz) δ 8.31 (brs, 1H), 7.25-7.47 (m, 9H), 6.40-6.46 (dd, J = 5, 12Hz, 1H), 5.10-5.30 (dt, J = 4.52 Hz, 1H), 4.68-4.77 (dt, J = 5.18 Hz, 1H), 4.22-4.29 (q, J = 7 Hz, 2H), 4.10-4.19 (m, 2H), 3.93-3.98 (m, 1H), 3.40-3.53 (m, 2H), 1.25-1.30 (t, J = 7 Hz, 3H); LC / MS [M + H] = 600.

Example 47. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (3-chloro-4-methoxybenzyl) malonic acid

By operating as described in Example 2 above, but substituting 4- (bromomethyl) -2-chloro-1methoxybenzene for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.34 (br s, 1H), 7.27-7.28 (d, J = 2 Hz, 1H), 7.27-7.28 (dd, J = 2.8 Hz, 1H), 6.77-6.80 (d, J = 8 Hz, 1H), 6.43-6.48 (dd, J = 4.11 Hz, 1H), 5.11- 5.31 (dt, J = 4.52 Hz, 1H), 4.69-4.83 (dt, J = 5.17 Hz, 1H), 4.15-4.20 (m, 1H), 3 , 93-4.10 (m, 2H), 3.75 (s, 3H), 3.27-3.34 (m, 2H); LC / MS [M + H] = 560.

- 112 039042

Example 48. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-sulfamoylbenzyl) malonic acid

H ₂ n '7

By operating as described in Example 2 above, but substituting 4 (bromomethyl) benzenesulfonamide for benzyl bromide, the title compound was obtained as a white solid.

¹ H NMR (CD3OD, 300 MHz) δ 8.27 (s, 1H), 7.70-7.73 (d, J = 8 Hz, 2H), 7.47-7.49 (d, J = 8 Hz, 2H), 6.406.46 (dd, J = 4, 14 Hz, 1H), 5.07-5.27 (dt, J = 4.52 Hz, 1H), 4.62-4.70 (dt , J = 5.17 Hz, 1H), 4.16-4.20 (q, J = 5 Hz, 1H), 3.99-4.10 (m, 2H), 3.34-3.52 ( m, 2H); LC / MS [M + H] = 575.

Example 49. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-chloro-2-fluorobenzyl) malonic acid

By operating as described in Example 2 above, but substituting 4-chloro-2-fluorobenzyl bromide for benzyl bromide, the title compound was obtained as a white solid.

[M + H] = 548.

Example 50. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4 - ((2-carboxyethyl) carbamoyl) benzyl) malonic acid

OMe he

Diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro9H-purin-9-yl) -3- ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) -2- (4 - ((3-methoxy3-oxopropyl) carbamoyl) benzyl) malonate was obtained as described in example 2 above, but replacing benzyl bromide on methyl 3- (4- (bromomethyl) benzamido) propanoate. The title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.25 (s, 1H), 7.59-7.62 (d, J = 8 Hz, 2H), 7.37-7.40 (d, J = 8 Hz , 1H), 6.406.46 (dd, J = 5.14 Hz, 1H), 5.07-5.27 (dt, J = 4.52 Hz, 1H), 4.62-4.71 (dt, J = 4.18Hz, 1H), 4.14-4.19 (m, 1H), 3.97-4.10 (m, 2H), 3.57-3.62 (t, J = 7Hz , 2H), 3.42-3.52 (m, 2H), 2.59-2.64 (t, J = 7 Hz, 3H); LC / MS [M + H] = 611.

Example 51. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((2-carboxybenzofuran-5-yl) methyl) malonic acid

but

By operating as described in Example 2 above, but substituting methyl 5 (bromomethyl) benzofuran-2-carboxylate for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.21 (s, 1H), 7.64-7.67 (d, J = 9 Hz, 2H), 7.59 (s, 1H), 7.39-7 , 42 (dd, J = 1.9 Hz, 1H), 7.14 (s, 1H), 6.45-6.49 (dd, J = 7.7 Hz, 1H), 5.16-5, 38 (dt, J = 6.53 Hz, 1H), 4.75-4.85 (m, 1H), 4.184.25 (m, 2H), 3.88-3.93 (dd, J = 3, 10 Hz, 2H), 3.45-3.64 (m, 2H); LC / MS [M + H] = 580.

Example 52. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (2,2,2-trifluoroethoxy) benzyl) malonic acid

- 113 039042

By operating as described in Example 2 above, but substituting 1- (bromomethyl) -4- (2,2,2trifluoroethoxy) benzene for benzyl bromide, the title compound was obtained as a white solid.

that.

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.31 (s, 1H), 7.23-7.26 (d, J = 9 Hz, 2H), 6.76-6.79 (d, J = 8 Hz, 2H), 6.406.46 (dd, J = 4.13 Hz, 1H), 5.08-5.28 (dt, J = 4.52 Hz, 1H), 4.65-4.73 (dt, J = 4.17 Hz, 1H), 4.33-4.43 (m, 2H), 4.14-4.19 (m, 1H), 3.95-4.08 (m, 2H ), 3.32-3.42 (m, 2H); LC / MS [M + H] = 594.

Example 53. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (carboxymethoxy) benzyl) malonic acid

he

Stage 1.

Diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2yl) methoxy) -2 - (4- (cyanomethoxy) benzyl) malonate was prepared according to the method described in example 2 above, but replacing benzyl bromide with 2- (4- (bromomethyl) phenoxy) acetonitrile.

Stage 2.

Diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2yl) methoxy) -2 - (4- (cyanomethoxy) benzyl) malonate was then hydrolyzed to the corresponding acid by treatment with aq. LiOH in THF. The title compound was obtained as a white solid.

¹ H NMR (CD3OD, 300 MHz) δ 8.31 (s, 1H), 7.20-7.23 (d, J = 8 Hz, 2H), 6.71-6.74 (d, J = 8 Hz, 2H), 6.406.46 (dd, J = 4.13 Hz, 1H), 5.07-5.27 (dt, J = 4.52 Hz, 1H), 4.65-4.73 (m , 1H), 4.55 (s, 2H), 4.13-4.18 (m, 1H), 3.95-4.05 (m, 2H), 3.35-3.42 (m, 2H ); LC / MS [M + H] = 570.

Example 54. Synthesis of 2-benzyl-2 - (((2R, 3R, 4S, 5R) -5- (2-chloro-6-hydroxy-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2- yl) methoxy) malonic acid

Stage 1.

To a solution of ((2R, 3R, 4S, 5R) -3- (benzoyloxy) -5- (2,6-dichloro-9H-purin-9-yl) -4-fluorotetrahydrofuran2-yl) methyl benzoate (2.00 g, 3.77 mmol) in DMF was added K ₂ CO ₃ (625 mg, 4.52 mmol) and 1-pentanol (655 μL, 6.03 mmol). The resulting mixture was stirred at 40 ° C for 2 h, then allowed to cool to room temperature and diluted with EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO ₄ ) and concentrated. This crude product was dissolved in MeOH (20 ml) and cooled to 0 ° C. To this mixture was added a solution of NH ₃ in MeOH (19 ml, 2.0 M in MeOH). The reaction mixture was stirred at 0 ° C to room temperature for 18 h, then concentrated under reduced pressure. The crude product was purified by SiO ₂ column chromatography (0-5% MeOH in DCM) to give ((2R, 3R, 4S, 5R) -5- (2-chloro-6 (pentyloxy) -9H-purin-9-yl) -4-fluoro-2- (hydroxymethyl) tetrahydrofuran-3-ol.

- 114 039042

Stages 2-4.

(2R, 3R, 4S, 5R) -5- (2-chloro-6- (pentyloxy) -9H-purin-9-yl) -4-fluoro-2- (hydroxymethyl) tetrahydrofuran-3-ol was then converted to diethyl -2 - (((2R, 3R, 4S, 5R) -3 - ((tert-butoxycarbonyl) oxy) -5- (2chlor-6- (pentyloxy) -9H-purin-9-yl) -4-fluorotetrahydrofuran- 2-yl) methoxy) malonate according to the method described in Example 1.

Stage 5.

To a solution of diethyl 2 - (((2R, 3R, 4S, 5R) -3 - ((tert-butoxycarbonyl) oxy) -5- (2-chloro-6- (pentyloxy) -9Hpurin-9-yl) -4 α-fluorotetrahydrofuran-2-yl) methoxy) malonate (210 mg, 0.29 mmol) in DCM (4 ml) was added TFA (2.0 ml) at room temperature. The reaction mixture was then stirred for 8 hours, then concentrated under reduced pressure. The residue was redissolved in DCM (2x5 ml) and concentrated again. The crude product was dissolved in a mixture of THF (3 ml) and water (3 ml) and then LiOH-H ₂ O (139 mg) was added. The reaction mixture was then stirred at room temperature for 48 hours, then concentrated under reduced pressure. The residue was redissolved in water (2 ml) and acidified to pH 6 with 1N. aq. HCl solution, then concentrated. The crude residue was purified by reverse phase HPLC to give the title compound as a white solid.

¹ H NMR (CD3OD, 300 MHz) δ 8.25 (s, 1H), 7.16-7.30 (m, 5H), 6.38-6.45 (dd, J = 4.15Hz, 1H ), 5.05-5.25 (dt, J = 4.52 Hz, 1H), 4.59-4.68 (dt, J = 5.17 Hz, 1H), 4.15-4.19 ( q, J = 5 Hz, 1H), 3.96-4.05 (m, 2H), 3.40 (br s, 2H); LC / MS [M + H] = 497.

Example 55. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (5-methyl-1,3,4-oxadiazol-2-yl) benzyl) malonic acid

By operating as described in Example 2 above, but substituting 2- (4- (bromomethyl) phenyl) -5methyl-1,3,4-oxadiazole for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.26 (s, 1H), 7.66-7.69 (d, J = 8 Hz, 2H), 7.37-7.39 (d, J = 8 Hz , 2H), 6.426.47 (dd, J = 5.9 Hz, 1H), 5.14-5.33 (dt, J = 4.53 Hz, 1H), 4.62-4.70 (dt, J = 5.19Hz, 1H), 4.15-4.20 (m, 2H), 3.92-3.96 (m, 1H), 3.32-3.52 (q, J = 15Hz , 2H), 2.61 (s, 3H); LC / MS [M + H] = 578.

Example 56. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((2'-cyano- [1,1'-biphenyl] -4-yl) methyl) malonic acid

By operating as described in Example 2 above, but substituting 4 '- (bromomethyl) - [1,1'biphenyl] -2-carbonitrile for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.41 (d, J = 1 Hz, 1H), 7.70-7.73 (dd, J = 1.8 Hz, 1H), 7.55-7.58 (dd, J = 1.8 Hz, 1H), 7.29-7.49 (m, 6H), 6.41-6.46 (dd, J = 5.8 Hz, 1H), 5.12- 5.33 (dt, J = 5.53 Hz, 1H), 4.69-4.79 (dt, J = 5.18 Hz, 1H), 4.10-4.21 (m, 2H), 3 , 98-4.02 (m, 1H), 3.47-3.59 (m, 2H); LC / MS [M + H] = 597.

Example 57. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((5-chlorobenzo [b] thiophen-3-yl) methyl) malonic acid

By operating as described in Example 2 above, but substituting 3- (bromomethyl) -5chlorobenzo [b] thiophene for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.43 (s, 1H), 7.80 (s, 1H), 7.48-7.53 (m, 2H), 6.99-7.02 (d, J = 8 Hz, 1H), 6.44-6.49 (dd, J = 5, 10 Hz, 1H), 5.16-5.34 (m, 1H), 4.72-4.82 (dt , J = 6, 18 Hz, 1H), 4.12-4.20 (m, 2H), 3.94-3.98

- 115 039042 (m, 1H), 3.57-3.71 (m, 2H); LC / MS [M + H] = 586.

Example 58. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purun-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (benzo [d] thiazol-2-ylmethyl) malonic acid

By operating as described in Example 2 above, but substituting 2 (bromomethyl) benzo [b] thiazole for benzyl bromide, the title compound was obtained as a white solid.

¹ H NMR (CD3OD, 300 MHz) δ 8.35 (s, 1H), 7.80-7.86 (m, 2H), 7.28-7.41 (m, 2H), 6.37-6 , 42 (dd, J = 4.5, 13 Hz, 1H), 5.08-5.11 (dt, J = 4.52 Hz, 1H), 4.72-4.81 (dt, J = 4 , 17 Hz, 1H), 4.08-4.19 (m, 3H), 3.99 (s, 2H); LC / MS [M + H] = 553.

Example 59. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purun-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (methylcarbamoyl) benzyl) malonic acid

By operating as described in Example 2 above, but substituting 4- (bromomethyl) -Nmethylbenzamide for benzyl bromide, the title compound was obtained as a white solid.

¹ H NMR (CD3OD, 300 MHz) δ 8.26 (s, 1H), 7.59-7.62 (d, J = 8 Hz, 2H), 7.37-7.40 (d, J = 8 Hz, 2H), 6.406.46 (dd, J = 4.13 Hz, 1H), 5.07-5.27 (dt, J = 4.52 Hz, 1H), 4.62-4.71 (dt , J = 5.18 Hz, 1H), 4.17-4.18 (q, J = 4 Hz, 3H), 3.97-4.10 (m, 2H), 3.42-3.52 ( m, 2H); LC / MS [M + H] = 553.

Example 60. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (methoxycarbonyl) benzyl) malonic acid

TFU, dkhm

Stage 1.

Dubenzyl-2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro9H-purin-9-yl) -3- ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate was prepared by operating as described in Example 1 above, using dibenzyldiazomalonate instead of diethyldiazomalonate.

Stage 2.

Acting as described in Example 2 above, but using methyl 4- (bromomethyl) benzoate instead of benzyl bromide and then removing the Boc groups by treatment with TFA, we obtained dubenzyl-2 - (((2R, 3R, 4S, 5R) -5- (6amino -2-chloro-9H-nurin-9-yl) -4-fluoro-3-hydroxytetragudrofurαn-2-yl) methoxy) -2- (4- (methoxycarbonyl) benzyl) malonate.

Stages 3-4.

The title compound was obtained as a white solid from dibenzyl-2 (((2R, 3R, 4S, 5R)) - 5- (6-amino-2-chloro-9H-purun-9-yl) -4- fluoro-3-hydroxy-tetrahydrofuran-2-yl) methoxy) 2- (4- (methoxycarbonyl) benzyl) malonate according to the method described in example 28.

¹ H NMR (CD3OD, 300 MHz) δ 8.27 (s, 1H), 7.69-7.71 (d, J = 8 Hz, 2H), 7.36-7.38 (d, J = 8 Hz, 2H), 6.426.47 (dd, J = 5.11 Hz, 1H), 5.11-5.31 (dt, J = 5.53 Hz, 1H), 4.68-4.77 (dt , J = 5.18 Hz, 1H), 3.94-4.18 (m, 3H), 3.42-3.55 (m, 2H), 3.42-3.52 (m, 2H); LC / MS [M + H] = 554.

Example 61. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purun-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4 - ((E) -2-carboxyvinyl) benzyl) malonic acid

- 116 039042

Acting as described in example 2 above, but replacing benzyl bromide with methyl-3- (4-

he bromomethyl) cinnamate, the title compound was obtained as a white solid.

LC / MS [M + H] = 566.

Example 62. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (2-carboxyethyl) benzyl) malonic acid

OH he

The title compound was prepared from 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4 - ((E) -2-carboxyvinyl) benzyl) malonic acid (example 58) by reduction of the olefin bond with Pd / C in EtOH under a pressure of H ₂ in 1 atm. The title compound was obtained as a white solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.38 (s, 1H), 8.30 (br s, 1H), 7.00-7.24 (m, 5H), 6.38-6 , 41 (dd, J = 4, 10 Hz, 1H), 5.07-5.26 (dt, J = 4.7, 52 Hz, 1H), 3.98-4.16 (m, 4H), 3.98-4.20 (m, 2H), 3.32-3.36 (m, 4H), 2.52-2.85 (m, 5H); LC / MS [M + H] = 534.2.

Example 63. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (3-phenoxybenzyl) malonic acid

Operating as described in Example 2 above but substituting 3- (phenoxy) benzyl bromide for benzyl bromide gave the title compound and isolated as a white solid.

1H NMR (CD ₃ OD, 300 MHz) δ 8.38 (brs, 1H), 7.02-7.22 (m, 6H), 6.70-6.81 (m, 3H), 6, 37-6.41 (dd, J = 4.3, 13 Hz, 1H), 5.07-5.25 (m, 1H), 4.62-4.67 (m, 1H), 3.93- 4.18 (m, 3H); 3.24 (m, 2H); LC / MS [M + H] = 589.

Example 64. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (3- (trifluoromethoxy) benzyl) malonic acid

Operating as described in Example 2 above but substituting 3trifluoromethoxybenzyl bromide for benzyl bromide gave the title compound and isolated as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.34 (br s, 1H), 7.20-7.29 (m, 3H), 7.01-7.04 (d, 1H), 6.42- 6.48 (dd, J = 4.13 Hz, 1H), 5.08-5.28 (dt, J = 4.7, 52 Hz, 1H), 4.62-4.71 (dt, J = 5.17 Hz, 1H), 4.15-4.19 (m, 1H), 3.98-4.10 (m, 2H), 3.44-3.45 (m, 2H); LC / MS [M + H] = 580.8.

Example 65. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (3- (trifluoromethyl) benzyl) malonic acid

- 117 039042

Operating as described in Example 2 above but substituting 3trifluoromethylbenzyl bromide for benzyl bromide gave the title compound and isolated as a white solid.

¹ H NMR (CD3OD, 300 MHz) δ 8.96 (br s, 1H), 7.37-7.59 (m, 4H), 6.51-6.56 (dd, J = 4, 10 Hz , 1H), 5.18-5.39 (dt, J = 4.7, 52 Hz, 1H), 4.62-4.71 (dt, J = 5, 17 Hz, 1H), 4.21- 4.24 (m, 1H), 3.96-4.17 (m, 2H), 3.45-3.59 (q, J = 15Hz, 2H); LC / MS [M + H] = 564.8.

Example 66. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (naphthalen-2-ylmethyl) malonic acid

Bg

Operating as described in Example 2 above but substituting naphthalene-2ylmethyl bromide for benzyl bromide gave the title compound and isolated as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.29 (br s, 1H), 7.60-7.72 (m, 3H), 7.51-7.53 (d, J = 8 Hz, 1H) , 7.367.39 (d, J = 8 Hz, 1H), 7.19-7.30 (m, 2H), 6.40-6.45 (dd, J = 4.7, 10.6 Hz, 1H ), 5.10-5.30 (dt, J = 4.3, 53 Hz, 1H), 4.71-4.77 (m, 1H), 4.09-4.20 (m, 1H), 3.91-4.12 (m, 2H), 3.49-3.62 (q, J = 11 Hz, 2H); LC / MS [M + H] = 546.9.

Example 67. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (trifluoromethyl) benzyl) malonic acid

Bg

Operating as described in Example 2 above but substituting 4trifluoromethylbenzyl bromide for benzyl bromide gave the title compound and isolated as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.31 (d, J = 1.6 Hz, 1H), 7.41-7.49 (m, 4H), 6.40-6.46 (dd, J = 4.3, 13.4 Hz, 1H), 5.08-5.29 (dt, J = 4.0, 52 Hz, 1H), 4.63-4.88 (dt, J = 3.9, 17.5 Hz, 1H), 4.15-4.19 (m, 1H), 3.99-4.10 (m, 2H), 3.49 (m, 2H); LC / MS [M + H] = 564.8.

Example 68. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (methylsulfonyl) benzyl) malonic acid

Operating as described in Example 2 above but substituting 4methylsulfonylbenzyl bromide for benzyl bromide gave the title compound and isolated as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.28 (d, J = 1 Hz, 1H), 7.55-7.75 (dd, J = 8.3, 50 Hz, 2H), 6.40-6 , 46 (dd, J = 4.6, 13.3 Hz, 1H), 5.08-5.26 (dt, J = 4.1, 52 Hz, 1H), 4.63-4.68 (dt , J = 4.9, 17.6 Hz, 1H), 4.15-4.19 (m, 1H), 3.99-4.10 (m, 2H), 3.52-3.53 (m , 2H), 3.03 (s, 3H); LC / MS [M + H] = 574.9.

Example 69. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (3- (dimethylcarbamoyl) benzyl) malonic acid

Operating as described in Example 2 above but substituting 3- (bromomethyl) -N, N-dimethylbenzamide for benzyl bromide gave the title compound and isolated as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.42 (br s, 1H), 7.20-7.41 (m, 4H), 6.41-6.47 (dd, J = 4.4, 13 , 3 Hz, 1H),

- 118 039042

5.08-5.28 (dt, J = 4.52 Hz, 1H), 4.59-4.68 (dt, J = 4.3, 17.6 Hz, 1H), 4.14-4, 19 (q, J = 5 Hz, 1H), 4.02-4.05 (m,

2H), 3.52-3.53 (m, 2H), 3.00 (s, 3H), 2.92 (s, 3H); LC / MS [M + H] = 568.

Example 70. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (thiophen-3-ylmethyl) malonic acid

Operating as described in Example 2 above but substituting 3- (bromomethyl) thiophene for benzyl bromide gave the title compound and isolated as a white solid.

Ή NMR (CD3OD, 300 MHz) δ 8.38 (br s, 1H), 7.19-7.22 (m, 2H), 7.02-7.04 (m, 1H), 6.40- 6.46 (dd, J = 4.3, 13.4 Hz, 1H), 5.07-5.27 (dt, J = 3.9, 9, 52 Hz, 1H), 4.60-4, 66 (m, 1H), 4.15-4.19 (q, J = 5 Hz, 1H), 3.943.99 (m, 2H), 3.45 (br s, 2H); LC / MS [M + H] = 503.

Example 71. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (3-aminobenzyl) malonic acid

Bg

Operating as described in Example 2 above but replacing benzyl bromide with tert-butyl (3 (bromomethyl) phenyl) carbamate gave the title compound and isolated as a white solid.

Ή NMR (CD3OD, 300 MHz) δ 8.33 (brs, 1H), 7.09-7.25 (brs, 4H), 6.39-6.44 (d, J = 15 Hz, 1H), 5.06-5.24 (m, 1H), 4.18-4.28 (d, J = 18.4 Hz, 1H), 4.20 (br s, 1H), 3.90 (br s, 2H), 3.39 (s, 2H); LC / MS [M + H] = 512.

Example 72. Synthesis of 2-benzyl-2 - (((2R, 3R, 4S, 5R) -5- (6- (benzylamino) -2-chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran- 2-yl) methoxy) malonic acid

Stage 1.

To a solution of diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6- (benzyl (tert-butoxycarbonyl) amino) -2-chloro-9H-purin9-yl) -3 - ((tert- butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate (130 mg, 0.173 mmol) in DMF (2 ml) at 25 ° C was added Cs ₂ CO ₃ (113 mg, 0.346 mmol). The reaction mixture was stirred for 30 min and then benzyl bromide (41 μl, 0.346 mmol) was added. The reaction mixture was stirred for 3.5 h, then diluted with H ₂ O (15 ml) and extracted with EtOAc. The combined organic layer was then washed with H 2 O, brine, dried over Na ₂ SO ₄ and concentrated. The resulting crude product was purified by silica gel column chromatography (020% EtOAc in hexane) to give diethyl 2-benzyl-2 - (((2R, 3R, 4S, 5R) -5- (6- (benzyl (tert-butoxycarbonyl) amino) - 2-chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate as a foam.

Diethyl 2-benzyl-2 - (((2R, 3R, 4S, 5R) -5- (6- (benzyl- (tert-butoxycarbonyl) amino) -2-chloro-9H-purine-9yl) -3- ( (tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate was converted to the title compound according to the method described in Example 2.

¹ H NMR (CD3OD, 300 MHz) δ 8.23 (br s, 1H), 7.23-7.42 (m, 10H), 6.36-6.45 (dd, J = 2.6, 22.6 Hz, 1H), 4.96-5.14 (dd, J = 2.4, 50 Hz, 1H), 4.74-4.80 (m, 3H), 4.16-4.19 (m, 1H), 3.73-3.88 (m, 2H), 3.35-3.40 (m, 2H); LC / MS [M + H] = 587.

Example 73. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-hydroxybutyl) malonic acid

- 119 039042

OTBS he

By operating as described in Example 2 above, but substituting (4-bromobutoxy) (t-butyl) dimethylsilane for benzyl bromide, the title compound was obtained as a white solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.50-8.54 (m, 1H), 6.41-6.47 (dd, J = 4.6, 12.7 Hz, 1H), 5 , 17-5.36 (dt, J = 4.3, 52 Hz, 1H), 4.18-4.28 (dt, J = 4.2, 17.3 Hz, 1H), 4.08-4 , 17 (m, 2H), 3.70-3.90 (m, 2H), 3.52 (t, J = 6.3 Hz, 1H), 2.12-2.18 (m, 2H), 1.35-1.72 (m, 4H); LC / MS [M + H] = 479.

Example 74. Synthesis of 1 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) ethane-1, 1,2-tricarboxylic acid

By operating as described in Example 2 above, but substituting ethyl 2-bromoacetate for benzyl bromide, the title compound was obtained as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.78 (br s, 1H), 6.44-6.49 (dd, J = 4.6, 11.8 Hz, 1H), 5.12-5, 32 (dt, J = 4.5, 52 Hz, 1H), 4.67-4.76 (m, 1H), 4.13-4.18 (q, J = 4.7 Hz, 1H), 3 , 93-3.99 (m, 2H); 3.23 (s, 2H); LC / MS [M + H] = 464.

Example 75. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (4- (benzylamino) -1H-benzo [d] imidazol-1-yl) -4-fluoro-3hydroxytetrahydrofuran-2-yl) methoxy) malonic acid

Stage 1.

Suspension of N6, N6-bis-Boc-5'-O-m-tert-butyldiphenylsilyl-3'-O-Boc-2-chloro-adenosine (1.00 g, 1.19 mol) in a mixture of tert-BuOH and H ₂ O (8 ml, 1: 1 / v: v) was refluxed for 13 h, then allowed to cool to room temperature and concentrated. The crude residue was purified by silica gel column chromatography (5-20% EtOAc in hexane) to give tert-butyl- (9 ((2R, 3S, 4R, 5R) -4 - ((tert-butoxycarbonyl) oxy) -5 - (( (tert-butyldiphenylsilyl) oxy) methyl) -3-fluorotetrahydrofuran-2-yl) -2-chloro-9H-purin-6-yl) carbamate.

Stage 2.

To a solution of tert-butyl- (9 - ((2R, 3S, 4R, 5R) -4 - ((tert-butoxycarbonyl) oxy) -5 - (((tert-butyldiphenylsilyl) oxy) methyl) -3-fluortetrahydrofuran-2 -yl) -2-chloro-9H-purin-6-yl) carbamate (500 mg, 0.67 mmol) in MeCN (4 ml) DBU (201 μl, 1.35 mmol) was added at room temperature and then BnBr was added (119 μl, 0.996 mmol). The reaction mixture was stirred for 3 h, then diluted with EtOAc (10 ml) and H2O (10 ml). The organic layer was separated, washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude residue was purified by silica gel column chromatography (0-15% EtOAc in hexane) to give tert-butylbenzyl- (9 - ((2R, 3S, 4R, 5R) -4 - ((tert-butoxycarbonyl) oxy) -5 - ((( tert-butyldiphenylsilyl) oxy) methyl) -3-fluorotetrahydrofuran-2-yl) -2-chloro9H-purin-6-yl) carbamate.

Stage 3.

To a solution of tert-butylbenzyl- (9 - ((2R, 3S, 4R, 5R) -4 - ((tert-butyloxycarbonyl) oxy) -5 - (((tert-butyldiphenylsilyl) oxy) methyl) -3-fluorometrahydrofuran-2-yl ) -2-chloro-9H-purin-6-yl) carbamate (545 mg, 0.655 mmol) was dissolved in THF (1 ml) at 0 ° C and then the solution was added dropwise

- 120 039042

TBAF (1 ml, 0.982 mmol, 1M in THF). The reaction mixture was stirred at a temperature from 0 ° C to room temperature for 2.5 h, then evaporated to dryness. The resin was purified by silica gel column chromatography (0-20% EtOAc in hexane) to give tert-butylbenzyl- (9 - ((2R, 3S, 4R, 5R) -4 ((tert-butoxycarbonyl) oxy) -3-fluoro-5 - (hydroxymethyl) tetrahydrofuran-2-yl) -2-chloro-9H-purine-6yl) carbamate.

Stage 4.

To a solution of tert-butylbenzyl- (9 - ((2R, 3S, 4R, 5R) -4 - ((tert-butoxycarbonyl) oxy) -3-fluoro-5 (hydroxymethyl) tetrahydrofuran-2-yl) -2-chloro- 9H-purin-6-yl) carbamate (300 mg, 0.505 mmol) in toluene (3 ml) under argon, diethyl 2-diazomalonate (122 mg, 0.657 mmol) and Rh ₂ (OAc) ₄ (22 mg, 0.051 mmol). The resulting mixture was stirred at 80 ° C for 2.5 h, then allowed to cool to room temperature. Volatile organic products were removed under reduced pressure. The resulting crude product was purified by silica gel column chromatography (0-25% EtOAc in hexane) to give diethyl 2 - (((2R, 3R, 4S, 5R) -5- (6- (benzyl (tert-butoxycarbonyl) amino) - 2chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate.

Stage 5.

To a solution of diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6- (benzyl- (tert-butoxycarbonyl) amino) -2-chloro-9H-purin9-yl) -3 - ((tert α-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate (200 mg, 0.27 mmol) in CH ₂ Cl ₂ (2 ml) was added TFA (3 ml) at 0 ° C. The resulting mixture was warmed to room temperature and stirred for 2 hours, then concentrated under reduced pressure to give crude diethyl 2 - (((2R, 3R, 4S, 5R) -5- (6- (benzylamino) -2-chloro- 9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2-yl) methoxy) malonate as a TFA salt, which was used in the next step without further purification.

Stage 6.

To a solution of the crude salt with TFA diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6- (benzylamino) -2-chloro-9H-purin-9-yl) 4-fluoro-3-hydroxytetrahydrofuran -2-yl) methoxy) malonate (0.27 mmol) in THF (3 ml) and H2O (1 ml) was added LiOH monohydrate (50 mg) at room temperature. The resulting mixture was stirred overnight, then cooled to 0 ° C and acidified to pH ~ 6 with 1N. aq. HCl solution and concentrated under reduced pressure. The crude residue was purified by preparative reverse phase HPLC to give 2 - (((2R, 3R, 4S, 5R) -5- (4- (benzylamino) -1H-benzo [d] imidazol-1-yl) -4-fluoro-3-hydroxytetrahydrofuran- 2-yl) methoxy) malonic acid as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.40 (br s, 1H), 7.26-7.42 (m, 5H), 6.40-6.47 (dd, J = 4.5, 13 , 8 Hz, 1H), 5.07-5.28 (dt, J = 3.9, 52 Hz, 1H), 4.77 (br s, 2H), 4.62-4.70 (m, 2H), 4.13-4.16 (q, J = 5 Hz, 1H), 3.90-3.98 (m, 2H); LC / MS [M + H] = 497.

Example 76. Synthesis of ((R) -1 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran -2-yl) methoxy) -2- (methylamino) -2-oxoethyl) phosphonic acid and ((S) -1 (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro- 9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 (methylamino) -2-oxoethyl) phosphonic acid

MeNH ₂ , HATU DIEA

Stage 1.

To a solution of a diastereomeric mixture (1: 1 ratio) methyl-2 - (((2R, 3R, 4S, 5R) -5- (N6, N6-bis-Boc-2

- 121 039042 chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) -2 (dimethoxyphosphoryl) acetate (0.352 mmol) in THF (4 ml ) at room temperature was added 1N. aq. LiOH solution (0.7 ml). The resulting mixture was stirred for 75 min, then cooled to 0 ° C and acidified to pH ~ 6 with 1N. aq. HCl solution and concentrated under reduced pressure to obtain a crude diastereomeric mixture 2 - (((2R, 3R, 4S, 5R) -5- (N6, N6-6uc-Boc-2chloro-9H-purin-9-yl) -3- ((tert-butoxycarbonyl) oxy) -4-fluoro-tetrahydrofuran-2-yl) methoxy) -2 (dimethoxyphosphoryl) acetic acid (280 mg), which was used in the next step without further purification.

Stage 2.

To the above solution of crude diastereomeric mixture 2 - (((2R, 3R, 4S, 5R) -5- (N6, N6-6uc-Boc2-chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) hydroxy) -4-fluorotetrahydrofuran-2-yl) methoxy) -2 (dimethoxyphosphoryl) acetic acid (140 mg, 0.182 mmol) in dry DCM (10 ml) methylamine hydrochloride (49 mg, 0.73 mmol) and HATU (140 mg, 0.364 mmol). To this mixture was added DIEA (0.22 ml, 1.3 mmol) and the reaction mixture was stirred overnight. Additional amounts of methylamine (25 mg), HATU (140 mg) and DIEA (0.22 ml) were added and the mixture was stirred for 20 h, then quenched with water (25 ml). The organic layer was separated and the aqueous was extracted with DCM (3x25 ml). The combined organic phases were dried and the crude product was purified by preparative TLC (60% ethyl acetate / hexane) to give methyl 2 - (((2R, 3R, 4S, 5R) -5- (N6, N6-bis-Boc-2-chloro -9H-purin-9-yl) -3 ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) -2- (diethoxyphosphoryl) acetamide (66 mg) as a mixture of diastereomers (ratio 1: 1 ).

Stage 3.

Diastereomeric mixture methyl-2 - (((2R, 3R, 4S, 5R) -5- (N6, N6-bis-Boc-2-chloro-9H-purin-9-yl) -3 ((tert-butoxycarbonyl) oxy ) -4-fluorotetrahydrofuran-2-yl) methoxy) -2- (diethoxyphosphoryl) acetamide was transformed into a diastereomeric mixture ((R) -1 - (((2R, 3R, 4S, 5R) -5- (6-amino-2 -chloro-9H-purin-9-yl) -4fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (methylamino) -2-oxoethyl) phosphonic acid and ((S) 1 - (((2R, 3R , 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) 2- (methylamino) -2-oxoethyl) phosphonic acid as a solid (1: 1 ratio) according to the method of examples 8a and 8b.

1H NMR (CD ₃ OD, 300 MHz) for a mixture of diastereomers (1: 1 ratio): δ 8.63-8.91 (m, 1H), 6.51 (d, 1H, diastereomeric), 5.11-5 , 40 (m, 1H), 4.18-4.70 (m, 3H), 4.01 (br s, 2H), 2.78 (br d, 3H); LC / MS [M + H] = 456.

Example 77. Synthesis of 2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methoxy) -2- (4-carboxybenzyl) malonic acid

NS? Bn BocC? * OVos VosS? OVos

2 - (((2R, 3S, 4R, 5R) -5- (6-Amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran-2yl) methoxy) -2- (4- carboxybenzyl) malonic acid was prepared according to the method described in examples 1 and 2. Isolated as a white solid.

¹ H NMR (CD3OD, 300 MHz) δ 8.42 (br s, 1H), 7.79-7.82 (d, J = 8.2 Hz, 2H), 7.34-7.37 (d , J = 8.2 Hz, 2H), 6.02-6.04 (d, J = 6.2 Hz, 1H), 4.74-4.78 (m, 1H), 4.30-4, 35 (m, 2H), 3.80-4.04 (ddd, J = 3, 10, 59 Hz, 2H), 3.52 (br s, 2H); LC / MS [M + H] = 538.

Example 78. Synthesis of 1 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methoxy) ethane-1,1,2-tricarboxylic acid o

Boc '' OVos Boc 't) Boc NO' bn

1 - (((2R, 3S, 4R, 5R) -5- (6-Amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran-2- 122 039042 yl) methoxy) ethane- 1,1,2-tricarboxylic acid was prepared according to the method described in example 2. Isolated as a white solid.

1H NMR (D2O, 300 MHz) δ 8.49 (br s, 1H), 5.95-5.96 (d, J = 1 Hz, 1H), 4.60-4.49 (m, 1H) , 4.30-4.34 (m, 2H), 3.61-3.68 (m, 2H), 2.92-2.94 (m, 2H); LC / MS [M-H] = 462.

Example 79. Synthesis of (S) -2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran-2- yl) methoxy) -2- (1H-tetrazol-5-yl) acetic acid and (R) -2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2chloro-9H-purine- 9-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methoxy) -2- (1H-tetrazol-5-yl) acetic acid slots

Stage 1.

To a solution of 2-chloro-2 ', 3'-O-isopropylideneadenosine (7.66 g, 22.4 mmol) in DMF (70 ml) at 0 ° C in an argon atmosphere was added imidazole ) and then TBDMSCl (4.033 g, 26.89 mmol), which was added in 4 equal portions over 30 min. The reaction mixture was stirred for 2 h at 0 ° C and then allowed to warm to room temperature and stirred for 18 h. The solvent was removed on a rotary evaporator and the residue was quenched with H2O (150 ml) and extracted with EtOAc (3x150 ml). The combined organic layer was then washed with H2O (100 ml), brine (100 ml), dried over Na ₂ SO ₄ and concentrated to give 9 - ((3aR, 4R, 6R, 6aR) -6 (((tert-butyldimethylsilyl) hydroxy) methyl) -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) -2-chloro-9Hpurin-6-amine (10.78 g) as a white solid ...

Stage 2.

To a solution of 9 - ((3aR, 4R, 6R, 6aR) -6 - (((tert-butyldimethylsilyl) oxy) methyl) -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4- yl) -2-chloro-9H-purin-6-amine (10.2 g, 22.37 mmol) in dry DMF (150 ml) was added Et ₃ N (6.8 ml, 48.42 mmol) and 4- DMAP (273 mg, 2.24 mmol). The mixture was cooled to 0 ° C. under argon and then a solution of Boc ₂ O (10.36 g, 47.45 mmol) in dry DMF (5 ml) was added dropwise. The reaction mixture was stirred for 1 h at 0 ° C and then at room temperature for 18 h. The solvent was then removed on a rotary evaporator and the residue was purified by silica gel column chromatography (22-40% EtOAc in hexane) to give K6, K6- bis-Boc-5'-Otret-butyldimethylsilyl-2'-3'-O-isopropylidene-2-chloro-adenosine (10.36 g) as a solid.

Stage 3.

N6, N6-bis-Boc-5'-O-tert-butyldimethylsilyl-2'-3'-O-isopropylidene-2-chloro-adenosine (9.66 g, 14.72 mmol) was dissolved in dry THF (80 ml ) and to this mixture was added dropwise a solution of TBAF (22.1 ml, 22.1 mmol, 1M in THF). The reaction mixture was stirred for 18 h, then evaporated to dryness. The residue was purified by silica gel column chromatography (33-70% EtOAc in hexane) to give K6, K6-bis-Boc-2'-3'O-isopropylidene-2-chloro-adenosine (7.18 g) as a solid.

Stage 4.

Ethyl cyanodiazoacetate (770 mg, 5, 35 mmol) and air was sucked out of the flask and it was again filled with argon. _{Rh 2} (OAc) ₄ (41 mg, 0.09 mmol) was added, and again the flask was sucked off and filled with argon. The resulting mixture was stirred at 90 ° C for 1.5 h and then overnight at room temperature. Added additional amounts of ethyl cyanoacetate (200

- 123 039042 mg, 1.44 mmol) and Rh ₂ (OAc) ₄ (41 mg, 0.09 mmol) and the mixture was heated at 90 ° C for another 4 h, then allowed to cool to room temperature. The crude mixture was purified by silica gel column chromatography (10-70% EtOAc in hexane) to give ethyl 2 - (((3aR, 4R, 6R, 6aR) -6- (N6, N6-bis-Boc2-chloro-9H-purine -9-yl) -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methoxy) -2-cyanoacetate (1.22 g) as a mixture of diastereomers (ratio 1: 1 ).

Stage 5.

To a solution of a diastereomeric mixture of ethyl 2 - (((3aR, 4R, 6R, 6aR) -6- (N6, N6-bis-Boc-2-chloro-9H-purine-9yl) -2,2-dimethyltetrahydrofuro [3, 4-d] [1,3] dioxol-4-yl) methoxy) -2-cyanoacetate (211 mg, 0.323 mmol) in dry toluene (2 ml) was added azidotrimethylsilane (90 μl, 0.65 mmol) and bis (tributyltin ) oxide (58 mg, 0.097 mmol). The resulting mixture was stirred at 90 ° C for 4 hours. Additional azidotrimethylsilane (90 μL, 0.65 mmol) and bis (tributyltin) oxide (20 mg, 0.033 mmol) were added and the mixture was stirred at 90 ° C for 24 h. The resulting material was concentrated under reduced pressure, and the residue was purified by preparative TLC on silica gel (1% MeOH in EtOAc) to give ethyl 2 - (((3aR, 4R, 6R, 6aR) -6- (N6, N6-bis-Boc -2-chloro-9H-purin-9-yl) -2,2dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methoxy) -2- (1H-tetrazol-5-yl) acetate (80 mg) as a mixture of diastereomers as a solid (1: 1 ratio).

Stage 6.

To a solution of a diastereomeric mixture of ethyl 2 - (((3aR, 4R, 6R, 6aR) -6- (N6, N6-bis-Boc-2-chloro-9H-purine-9yl) -2,2-dimethyltetrahydrofuro [3, 4-d] [1,3] dioxol-4-yl) methoxy) -2- (1H-tetrazol-5-yl) acetate (80 mg, 0.115 mmol) in THF (1 ml) at room temperature was added 1N. aq. NaOH solution (0.29 ml, 0.29 mmol). The resulting mixture was stirred for 30 min, then acidified to pH ~ 6 with 1N. aq. HCl solution and concentrated under reduced pressure to give 2 - (((3aR, 4R, 6R, 6aR) -6- (N6, N6bis-Boc-2-chloro-9H-purin-9-yl) -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methoxy) -2- (1H-tetrazol-5-yl) acetic acid as a diastereomeric mixture (1: 1 ratio). This crude product was used in the next step without further purification.

Stage 7. To a solution of diastereomeric mixture 2 - (((3aR, 4R, 6R, 6aR) -6- (N6, N6-bis-Boc-2-chloro-9Hpurin-9-yl) -2,2-dimethyltetrahydrofuro [3 , 4-d] [1,3] dioxol-4-yl) methoxy) -2- (1H-tetrazol-5-yl) acetic acid (0.115 mmol) in CH2C12 (0.5 ml) was added TFA (0.5 ml) and H2O (2 drops). The resulting mixture was stirred for 4 hours and then concentrated under reduced pressure. The crude residue was purified by preparative reverse phase HPLC to obtain a mixture of diastereomers (S) -2 - (((2R, 3S, 4R, 5R) 5- (6-amino-2-chloro-9H-purin-9-yl) -3 , 4-dihydroxytetrahydrofuran-2-yl) methoxy) -2- (1H-tetrazol-5-yl) acetic acid and (R) -2 - (((2R, 3S, 4R, 5R) -5- (6-amino -2-chloro-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methoxy) -2- (1H-tetrazol-5-yl) acetic acid (25 mg) as a solid (ratio 1: 1).

1H NMR (CD3OD, 300 MHz) for a mixture of diastereomers (1: 1 ratio) according to example 78 δ 9.27 (d, 1H, diastereomeric), 6.07-6.13 (m, 1H), 5.66-5 , 69 (m, 1H), 4.61-4.70 (m, 1H), 4.36-4.55 (m, 1H), 4.36-4.33 (m, 1H), 3.93 -4.20 (m, 1H), 3.79-3.87 (m, 1H); LC / MS [M + H] = 428.

Example 80. Synthesis of (S) -2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran-2- yl) methoxy) -3-phenyl-2- (1H-tetrazol-5-yl) propanoic acid, (R) -2 - (((2R, 3S, 4R, 5R) -5- (6amino-2-chloro- 9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methoxy) -3-phenyl-2- (1H-tetrazol-5yl) propanoic acid, (S) -2 - (((2R, 3S , 4R, 5R) -5- (6-amino-2-methoxy-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methoxy) -3-phenyl-2- (1H-tetrazole- 5-yl) propanoic acid and (R) -2 (((2R, 3S, 4R, 5R) -5- (6-amino-2-methoxy-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran- 2-yl) methoxy) -3phenyl-2- (1H-tetrazol-5-yl) propanoic acid

- 124 039042

Stage 1.

To a solution of a diastereomeric mixture of ethyl 2 - (((3aR, 4R, 6R, 6aR) -6- (N6, N6-bis-Boc-2-chloro-9H-purine-9yl) -2,2-dimethyltetrahydrofuro [3, 4 ^] [1,3] dioxol-4-yl) methoxy) -2-cyanoacetate (1.09 g, 1.67 mmol) in DMF (7.5 ml) at 25 ° C, Cs ₂ CO ₃ ( 816 mg, 2.504 mmol) and BnBr (0.22 ml, 1.837 mmol). The reaction mixture was stirred for 2 h. Dilute brine (25 ml) was added and the material was extracted with EtOAc (3x25 ml). The combined organic layer was then washed with saturated brine (25 ml), dried over Na ₂ SO ₄ and concentrated. The resulting crude product was purified by silica gel column chromatography (5-60% EtOAc in hexane) to give (S) ethyl 2 - (((3aR, 4R, 6R, 6aR) -6- (N6, N6-bis-Boc-2 -chloro-9H-purin-9-yl) -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methoxy) -2-cyano-3-phenylpropanoate and (R) - ethyl 2 - (((3aR, 4R, 6R, 6aR) -6- (N6, N6-bisBoc-2-chloro-9H-purin-9-yl) -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methoxy) -2-cyano-3-phenylpropanoate as a mixture of diastereomers (approx. 1: 1 ratio).

Stage 2.

To the above diastereomeric mixture of (S) -ethyl-2 - (((3aR, 4R, 6R, 6aR) -6- (N6, N6-bis-Boc-2-chloro9H-purin-9-yl) -2,2- dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methoxy) -2-cyαno-3-phenylpropanoate and (R) -ethyl-2 - (((3aR, 4R, 6R, 6aR) - 6- (N6, N6-bis-Boc-2-chloro-9H-purin-9-yl) -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methoxy) - 2-cyano-3-phenylpropanoate (817 mg, 1.099 mmol) in dry toluene (2 ml) was added azidotrimethylsilane (0.29 ml, 2.2 mmol) and bis (tributyltin) oxide (197 mg, 0.33 mmol). The resulting mixture was stirred at 80 ° C for 1 h. Additional amounts of azidotrimethylsilane (0.29 ml, 2.2 mmol) and bis (tributyltin) oxide (50 mg, 0.08 mmol) were added and the mixture was stirred at 80 ° C for 4.5 hours. An additional amount of azidotrimethylsilane (0.29 ml, 2.2 mmol) was added and the mixture was heated for an additional 2.5 hours. An additional amount of azidotrimethylsilane (3x0.29 ml, 3x2.2 mmol) was added and the mixture was stirred at 70-80 ° C for 44 h. The material was cooled to room temperature and the crude product was purified by preparative TLC on silica gel (1% MeOH in EtOAc) to give ethyl 2 (((3aR, 4R, 6R, 6aR ) -6- (6 - ((tert-butoxycarbonyl) amino) -2-chloro-9H-purin-9-yl) -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4- yl) methoxy) -3-phenyl-2- (1H-tetrazol-5-yl) propanoαta (754 mg, solid) as a mixture of diastereomers (approx. 1: 1 ratio).

Stage 3. To a solution of a diastereomeric mixture of ethyl-2 - (((3aR, 4R, 6R, 6aR) -6- (6 - ((tert-butoxycαcarbonyl) amino) -2-chloro-9H-purin-9-yl) - 2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methoxy) 3-phenyl-2- (1H-tetrazol-5-yl) propanoate (605 mg, 0.77 mmol) in CH ₂ Cl ₂ (4 ml) was added TFA (4 ml) and H ₂ O (4 drops). The resulting mixture was stirred for 2 hours and then concentrated under reduced pressure. To the residue was added CH ₂ Cl ₂ (10 ml) and the solvent was then concentrated (the cycle was repeated 5 times) to give ethyl 2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro- 9H-purin-9-yl) -3,4-dihydroxytetraαhydrofuran-2-yl) methoxy) -3-phenyl-2- (1H-tetrazol-5-yl) propanoate as a mixture of diastereomers (approx. 1: 1 ratio) ...

Stage 4.

To the above solution of a diastereomeric mixture of ethyl 2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9Hpurin-9-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methoxy ) -3-phenyl-2- (1H-tetrazol-5-yl) propanoate (420 mg, 0.77 mmol) in MeOH (5 ml) at room temperature was added 2N. aq. NaOH solution (1.9 ml, 3.9 mmol). The resulting mixture was heated to a temperature of 62 ° C and stirred for 16 hours.

- 125 039042 added another 2n. aq. NaOH solution (1.0 ml, 2.0 mmol). The mixture was heated to 70 ° C and stirred for 6 h. The mixture was cooled to room temperature and acidified to pH ~ 6 with 1N. aq. HCl solution and concentrated under reduced pressure. The crude residue was purified by preparative reverse phase HPLC to give two fractions. The first eluted fraction contained the diastereomeric mixture (S) -2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran- 2-yl) methoxy) -3-phenyl-2- (1H-tetrazol-5-yl) propanoic acid (example 80-a) and (R) -2 (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methoxy) -3phenyl-2- (1H-tetrazol-5-yl) propanoic acid (example 80- b) as a solid (approx. 1: 1 ratio). The second eluted fraction contained the diastereomeric mixture (S) -2 - (((2R, 3S, 4R, 5R) -5 (6-amino-2-methoxy-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran-2 -yl) methoxy) -3-phenyl-2- (1Htetrazol-5-yl) propanoic acid (example 80-d) and (R) -2 - (((2R, 3S, 4R, 5R) -5- (6 -amino-2-methoxy-9Hpurin-9-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methoxy) -3-phenyl-2- (1H-tetrazol-5-yl) propanoic acid (example 80-c) as a solid (approx. 1: 1 ratio).

1H NMR (CD3OD, 300 MHz) for a mixture of diastereomers (approx. 1: 1 ratio) for examples 80-a and 80-b δ 8.37 (d, 1H, diastereomeric), 7, 00-7.38 (m, 5H), 5.92-6.04 (m, 1H), 4.67-4.81 (m, 1H), 4.35-4.46 (m, 1H), 4.16-4.30 ( m, 1H), 3.93-4.20 (m, 2H), 3.86-3.98 (m, 1H), 3.60-3.81 (m, 2H); LC / MS [M + H] = 518.

¹ H NMR (CD3OD, 300 MHz) for a mixture of diastereomers (approx. 1: 1 ratio) for examples 80-c and 80-d δ 8.44 (d, 1H, diastereomeric), 7.02-7.25 (m , 5H), 5.97-6.05 (m, 1H), 4.71-4.83 (m, 1H), 4.37-4.51 (m, 1H), 4.21-4.32 (m, 1H), 4.12 (d, 3H, diastereomeric), 3.57-3.96 (m, 4H); LC / MS [M + H] = 514.

Example 82. Synthesis of 2-benzyl-2 - (((2R, 3R, 4S, 5R) -5- (2-chloro-6- (cyclopentylthio) -9H-purin-9-yl) -4fluoro-3-hydroxytetrahydrofuran- 2-yl) methoxy) malonic acid

TBDPSCI Imidazole DMF 0 ~ 25 ° C

EtOaC ^ COsEt KC (OAc). I T

Stage 1.

To 2,6-dichloro-9- (2-C-methyl-2,3,5-tri-O-benzoyl-β-D-ribofuranosyl) purine (3.0 g, 5.65 mmol, 1 eq.) in DMF (30 ml) was added K2CO3 (0.82 g, 5.93 mmol, 1.05 eq.). Cyclopentanethiol (582.55 mg, 5.70 mmol, 610 μl, 1.01 eq.) In DMF (40 ml) was added dropwise to the mixture at 35 ° C. over 30 min. The mixture was stirred at 35 ° C for 16 hours. LCMS indicated that starting material was consumed completely. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous NH ₄ Cl (50 ml), H2O (50 ml) and brine (50 ml). The organic layer was separated, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo. The crude mixture was purified using a Combi-flash system on silica gel (petroleum ether: ethyl acetate = 10: 1 to 3: 2) to give ((2R, 3R, 4S, 5R) -3- (benzoyloxy) -5- (2- chloro-6 (cyclopentylthio) -9H-purin-9-yl) -4-fluorotetrahydrofuran-2-yl) methyl benzoate (2.48 g, 73.5% yield) as a light yellow gum.

Stage 2.

A mixture of ((2R, 3R, 4S, 5R) -3- (benzoyloxy) -5- (2-chloro-6- (cyclopentylthio) -9H-nurin-9-yl) -4-fluorotetrahydrofuran-2-yl) methyl benzoate ( 2.28 g, 3.82 mmol, 1 eq.) In a saturated solution of NH3 in MeOH (65.06 mg, 3.82 mmol, 25 ml, 1 eq.) Was stirred at 0 ° C for 2 h and then at a temperature

- 126 039042

25 ° C for 16 h. The reaction mixture was concentrated in vacuo, the resulting gum was dissolved in ethyl acetate (30 ml). The solution was washed with saturated aqueous NH ₄ Cl (30 ml). The aqueous layer was extracted with ethyl acetate (3x10 ml). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give a light yellow gum. The crude resin was purified by silica gel column chromatography to give (2R, 3R, 4S, 5R)) - 5- (2-chloro-6- (cyclopentylthio) -9Hpurin-9-yl) -4-fluoro-2- (hydroxymethyl) tetrahydrofuran -3-ol (1.8 g, 88.7% yield) as a light yellow resin.

Stage 3.

To a solution of (2R, 3R, 4S, 5R) -5- (2-chloro-6- (cyclopentylthio) -9H-purin-9-yl) -4-fluoro-2- (hydroxymethyl) tetrahydrofuran-3-ol (1 , 34 g, 3.45 mmol, 1 eq.) And imidazole (563.04 mg, 8.27 mmol, 2.4 eq.) In DMF (13.4 ml) at 0 ° C was added TBDPSCl (1, 14 g, 4.14 mmol, 1.06 ml, 1.2 eq.) In DMF (6.7 ml). The reaction mixture was stirred at 20-25 ° C for 16 h. An additional amount of TBDPSCl (88 μL, 0.1 eq.) Was added to the reaction mixture and stirred at 2025 ° C for 3 h. The reaction mixture was quenched with H2O (70 ml). The aqueous phase was extracted with EtOAc (3x70 ml). The combined organic layer was washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (eluted with petroleum ether / EtOAc with a gradient of 1: 0-4: 1) to give (2R, 3R, 4S, 5R) -2 - (((tert-butyldiphenylsilyl) oxy) methyl) - 5- (2-chloro-6- (cyclopentylthio) -9Hpurin-9-yl) -4-fluorotetrahydrofuran-3-ol as a white solid.

Stage 4.

To a solution of ((2R, 3R, 4S, 5R) -2 - (((tert-butyldiphenylsilyl) oxy) methyl) -5- (2-chloro-6- (cyclopentylthio) -9H-purin-9-yl) -4 -fluorotetrahydrofuran-3-ol (1.28 g, 2.04 mmol, 1 eq.) and 4-DMAP (37.40 mg, 306.10 mmol, 0.15 eq.) in DMF (12 ml) dropwise _{Boc 2} O (668, V mg, 3.06 mmol, 1.5 eq.) and TEA (568.08 μl, 4.08 mmol, 2.0 eq.) were added at 0 ° C. The reaction mixture was stirred at 20-25 ° C for 1 h. The mixture was washed with H2O (50 ml). The aqueous phase was extracted with EtOAc (3x30 ml). The combined organic layer was washed with brine (100 ml), dried over Na2SO4, filtered and concentrated. Crude product purified by column chromatography on silica gel (eluted with petroleum ether / EtOAc gradient 1: 0-4: 1) to give tert-butyl ((2R, 3R, 4S, 5R) -2 - (((tert-butyldiphenylsilyl) oxy) methyl ) -5- (2-chloro-6- (cyclopentylthio) -9Hpurin-9-yl) -4-fluorotetrahydrofuran-3-yl) carbonate (1.4 g, 94% yield) as a white foam.

Stage 5.

To a solution of tert-butyl - ((2R, 3R, 4S, 5R) -2 - (((tert-butyldiphenylsilyl) oxy) methyl) -5- (2-chloro-6 (cyclopentylthio) -9H-purin-9-yl ) -4-fluorotetrahydrofuran-3-yl) carbonate (1.4 g, 1.92 mmol, 1 eq.) In THF (14 ml) was added dropwise at 0 ° C TBAF in THF (1M, 2.89 ml , 1.5 equiv.). The reaction mixture was stirred at 0 ° C for 1.5 h, then quenched with aq. NH4Cl (30 ml). The aqueous phase was extracted with EtOAc (3x30 ml). The combined organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography on silica gel (eluted with petroleum ether / EtOAc gradient 1: 0-4: 1) to give tert-butyl ((2R, 3R, 4S, 5R)) - 5- (2-chloro-6- (cyclopentylthio) -9H-purin-9-yl) -4fluoro-2- (hydroxymethyl) tetrahydrofuran-3-yl) carbonate as a white foam.

Stages 6-9.

2-Benzyl-2 - (((2R, 3R, 4S, 5R) -5- (2-chloro-6- (cyclopentylthio) -9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2- yl) methoxy) malonic acid was obtained starting from tert-butyl - ((2R, 3R, 4S, 5R) -5- (2-chloro6- (cyclopentylthio) -9H-purin-9-yl) -4-fluoro-2- (hydroxymethyl) tetrahydrofuran-3-yl) carbonate according to the method described in Example 2, the title compound was obtained and isolated as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.48 (s, 1H), 7.13-7.29 (m, 5H), 6.48-6.55 (dd, J = 3.63 Hz, J = 3.60 Hz, 1H), 5.10-5.30 (m, 1H), 4.63-4.72 (m, 1H), 4.31-4.36 (m, 1H), 4.16 -4.20 (m, 1H), 3.97-4.02 (m, 2H), 3.40 (s, 2H), 2.29-2.37 (m, 2H), 1.73-1 , 86 (m, 6H); LC / MS [M + H] = 581.1.

Example 83. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((2,2-difluorobenzo [d] [1,3] dioxol-5-yl) methyl) malonic acid

Operating as described in Example 2 above but replacing benzyl bromide with 5- (bromomethyl) -2,2 difluorobenzo [0] [1,3] dioxole gave the title compound and isolated as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.34 (s, 1H), 7.14 (s, 1H), 7.02-7.04 (d, J = 8.14 Hz, 1H), 6.90 -6.93 (d,

- 127 039042

J = 8.26 Hz, 1H), 6.44-6.49 (dd, J = 4.44 Hz, J = 4.29 Hz, 1H), 5.11-5.32 (dt = 4.3 , 52 Hz, 1H), 4.67-4.76 (m, 1H),

4.10-4.19 (m, 2H), 3.95-3.99 (m, 1H), 3.36-3.49 (q, J = 13.44 Hz, 2H); LC / MS [M + H] = 576.

Example 84. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-carbamoylbenzyl) malonic acid

nh ₂

Operating as described in Example 2 above but substituting 4- (bromomethyl) benzamide for benzyl bromide gave the title compound and isolated as a white solid.

¹ H NMR (CD3OD, 300 MHz) δ 8.27 (s, 1H), 7.67-7.70 (d, J = 8.02 Hz, 2H), 7.39-7.41 (d, J = 8.05 Hz, 2H), 6.39-6.45 (dd, J = 4.56, 14.31 Hz, 1H), 5.06-5.26 (t, J = 3.90, 53 Hz, 1H), 4.61-4.70 (dt, J = 4.10, 17 Hz, J = 4.11 Hz, 1H), 4.14-4.19 (m, 1H), 3.98 -4.09 (m, 2H); 3.47 (s, 2H); LC / MS [M + H] = 539.

Example 85. Synthesis of 2 - (((2S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-hydroxytetrahydrofuran2-yl) methoxy) -2- (4- carboxybenzyl) malonic acid

BtB0M5 bTBDMS o N (Boc) ₂

Stage 1.

To a solution of (2R, 3R, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4 - ((tert-butyldimethylsilyl) oxy) -2 (((4-methoxyphenyl ) diphenylmethoxy) methyl) tetrahydrofuran-3-ol (2 g, 2.91 mmol, 1 eq.) in dichloroethane (20 ml) was added di (imidazol-1-yl) methanethione (776.77 mg, 4.36 mmol, 1.5 eq.). The resulting mixture was heated to 70 ° C and stirred for 5 h, then concentrated to dryness. The resin was purified on a flash column (SiO ₂ , eluted with 40% EtOAc in petroleum ether) to give O ((2R, 3R, 4R, 5R) -5- (6-amino-2-chloro-9H-purine-9- yl) -4 - ((tert-butyldimethylsilyl) oxy) -2 - (((4-methoxyphenyl) diphenylmethoxy) methyl) tetrahydrofuran-3-yl) -S-imidazole-1-carbothioate (1.53 g, 66% - yield) in the form of a white solid.

Stage 2.

To a solution of O - ((2R, 3R, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4 - ((tert-butyldimethylsilyl) oxy) -2 - (( AIBN (67 , 05 mg, 408.30 μmol, 0.2 eq.). The reaction mixture was heated at 110 ° C and (n-Bu) ₃ SnH (891.31 mg, 3.06 mmol, 810.28 μL, 1.5 eq.) Was carefully added dropwise to the reaction mixture. The reaction mixture was stirred at 110 ° C for 1 h, then quenched with sat. aq. KF solution (3 ml) and the reaction mixture was concentrated to dryness. The reaction mixture was purified on a flash column (SiO ₂ , eluted with 30% EtOAc in petroleum ether) to give 9 - ((2R, 3R, 5S) -3 - ((tert-butyldimethylsilyl) oxy) -5 - (((4-methoxyphenyl ) diphenylmethoxy) methyl) tetrahydrofuran-2-yl) -2-chloro9H-purin-6-amine (969 mg, 71% yield) as a white solid.

Stage 3.

To a solution of 9 - ((2R, 3R, 5S) -3 - ((tert-butyldimethylsilyl) oxy) -5 - (((4-methoxyphenyl) diphenylmethoxy) methyl) tetrahydrofuran-2-yl) -2-chloro-9H- purine-6-amine (969 mg, 1.44 mmol, 1 eq.) in DMF (10 ml) was added TEA (583.40 mg, 5.77 mmol, 802.48 μl, 4 eq.), DMAP (35 , 22 mg, 288.27 μmol, 0.2 eq.) And Boc ₂ O (1.26 g, 5.77 mmol, 1.32 ml, 4 eq.). The resulting mixture was stirred at 25 ° C for 0.5 h, then diluted with H2O (50 ml), extracted with EtOAc (20 mlx4). The combined organic layers were washed with brine (30 ml x 2), dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The resin was purified by flash column chromatography (SiO2, eluted with 20% EtOAc in petroleum ether) to give the bis-N-Boc protected product (1.05 g, 83% yield) as a white solid.

Stage 4.

A solution of TFA (216.39 μl, 2.92 mmol, 1.5 eq.) In DCM (20 ml). The resulting mixture was stirred at 25 ° C for 1 h. An additional 100 mg of TFA was added to the reaction mixture and then stirred for 6 h at 25 ° C. The reaction was quenched with TEA (2 ml) and concentrated to dryness. The resin was purified by flash column chromatography (SiO ₂ , eluted with 20% EtOAc in petroleum ether) to give the desired alcohol (662 mg, 51% yield) as a white solid.

Stage 5.

To a solution of alcohol from the previous stage (680 mg, 1.13 mmol, 1 eq.) And Rh ₂ (OAc) ₄ (25.04 mg, 113.30 mmol, 0.05 eq.) In toluene (8 ml) a solution of diethyl 2-diazomalonate (274.20 mg, 1.47 mmol, 1.3 eq.) in toluene (3 ml) was added dropwise at 95 ° C under N2. The resulting mixture was stirred at 95 ° C for 5 h, then concentrated to dryness. The resin was purified by flash column chromatography (SiO2, eluted with 20% EtOAc in petroleum ether) to give diethyl 2 - (((2S, 4R, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert- butoxyl) amino-2-chloro-9H-purin-9-yl) -4 ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) methoxy) malonate (490 mg, 54% yield) as a light resin yellow color.

Stage 6.

To a solution of diethyl-2 - (((2S, 4R, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino-2-chloro-9Hpurin-9-yl) -4- ( (tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) methoxy) malonate (300 mg, 395.61 μmol, 1 eq.) in DMF (3 ml) at 25 ° C was added K2CO3 (109.35 mg, 791, 21 μmol, 2 eq.) After stirring for 30 min, methyl 4- (bromomethyl) benzoate (181.24 mg, 791.21 μmol, 2 eq.) Was added to the reaction mixture. The resulting mixture was stirred at 25 ° C. over 4 h to give a white slurry. LCMS indicated the reaction was complete. The reaction mixture was diluted with H 2 O (20 ml), extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (15 ml), dried over Na 2 SO 4, filtered and concentrated. The resin was purified on a flash column (SiO2, eluted with 20% EtOAc in petroleum ether) to give diethyl 2 - (((2S, 4R, 5R) -5- (6- (N- (tert-butoxycarbonyl) ( tert-butoxyl) amino) -2-chloro-9H-purine-9yl) -4 - ((tert-butyldimethylsilyl) oxy) tet rahydrofuran-2-yl) methoxy) -2- (4- (methoxycarbonyl) benzyl) malonate (199.3 mg, 55% yield, 99%) as a colorless gum.

Stage 7.

To a solution of diethyl-2 - (((2S, 4R, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro-9Hpurin-9-yl) -4- ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) methoxy) -2- (4- (methoxycarbonyl) benzyl) malonate (168 mg) in DCM (2 ml) a solution of TFA (2.5 ml) was added at room temperature ... The resulting mixture was stirred for 4 h, then H2O (1 ml) was added and the reaction mixture was further stirred for 4 h. The reaction mixture was concentrated and subjected to azeotropic distillation with DCM (3x10 ml) to give crude 2 - (((2S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-carboxybenzyl) malonic acid, which was used in the next step without additional purification ...

1H NMR (CD3OD, 300 MHz) δ 8.54 (s, 1H), 7.76-7.79 (d, J = 8.26 Hz, 2H), 7.32-7.34 (d, J = 7.99 Hz, 2H), 5.96 (s, 1H), 4.63-4.70 (m, 2H), 4.09-4.12 (d, J = 10.27 Hz, 1H), 3.76-3.80 (d, J = 10 Hz, 1H), 3.48 (s, 2H), 2.392.50 (m, 1H), 1.98-2.03 (m, 1H); LC / MS [M + H] = 522.

Example 86. Synthesis of 2 - (((2S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-hydroxytetrahydrofuran2-yl) methoxy) -2- (4- (benzyloxy) benzyl) malonic acid

- 129 039042

Operating as described in Example 85 above but substituting 1 (bromomethyl) -4- (phenylmethoxy) benzene for methyl 4- (bromomethyl) benzoate gave the title compound and isolated as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.51 (s, 1H), 7.26-7.37 (m, 5H), 7.12-7.14 (d, J = 8.56 Hz, 2H) , 6.71-6.74 (d, J = 8.53 Hz, 2H), 5.95 (s, 1H), 4.92 (s, 2H), 4.59-4.66 (m, 2H ), 4.09-4.13 (d, J = 10.42 Hz, 1H), 3.74-3.78 (d, J = 11.23 Hz, 1H), 3.37-3.43 ( m, 2H), 2.40-2.49 (m, 1H), 1.96-2.03 (m, 1H); LC / MS [M + H] = 584.

Example 87. Synthesis of 2 - (((2R, 3R, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxy-4methyltetrahydrofuran-2- yl) methoxy) -2- (4-carboxybenzyl) malonic acid o MH ₂ ° '^ ^he

Oh XX

0 ^ / ^ HO 'F OH

Operating as described in Example 2 above but substituting 4- (bromomethyl) benzamide for benzyl bromide gave the title compound and isolated as a white solid.

¹ H NMR (CD3OD, 300 MHz) δ 8.45 (s, 1H), 7.69-7.72 (d, J = 8.11 Hz, 2H), 7.35-7.37 (d, J = 8.08 Hz, 2H), 6.21-6.26 (d, J = 16.42 Hz, 1H), 4.44-4.56 (dd, J = 9.34, 24.5 Hz, 1H), 4.21-4.27 (m, 2H), 3.94-3.97 (d, J = 8.71 Hz, 1H), 3.46-3.60 (q, J = 13, 99 Hz, 2H), 1.08-1.15 (d, J = 22.18 Hz, 3H); LC / MS [M + H] = 554.

Example 88 Synthesis of 2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-nurin-9-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methoxy) -2- (2H-tetrazol-5-yl) -3- (thiophen-3-yl) propanoic acid

Operating as described in Example 80 above but substituting 3- (bromomethyl) thiophene for benzyl bromide gave the title compound and isolated as a solid mixture of diastereomers (approx. 3: 2 ratio).

1H NMR (CD3OD, 300 MHz) for mixture of diastereomers (approx. 3: 2 ratio).

Minor isomer: δ 8.42 (br s, 1H), 7.25-7.20 (m, 1H), 7.08 (br s, 1H), 6.81 (d, J = 4.92 Hz, 1H), 6.01 (d, J = 5.64 Hz, 1H), 4.80 (t, J = 5.25 Hz, 1H), 4.43 (t, J = 4.25 Hz, 1H), 4.31-4.22 (m, 1H), 4.0-3.88 (m, 1H), 3.82-3.68 (m, 3H); LC / MS [M + H] = 524.

Major isomer: δ 8.39 (br s, 1H), 7.18-7.14 (m, 1H), 7.08 (br s, 1H), 6.78 (d, J = 4.95 Hz, 1H), 5.98 (d, J = 5.37 Hz, 1H), 4.73 (t, J = 5.15 Hz, 1H), 4.36 (t, J = 4.31 Hz, 1H), 4.31-4.22 (m, 1H), 4.0-3.88 (m, 1H), 3.82-3.68 (m, 3H); LC / MS [M + H] = 524.

Example 89. Synthesis of 2-benzyl-2 - (((2R, 3R, 4S, 5R) -5- (2-chloro-6- (pentylthio) -9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran- 2-yl) methoxy) -3-ethoxy-3-oxopropanoic acid

- 130 039042

Operating as described in Example 82 above but substituting pentane-1-thiol for cyclopentanethiol gave the title compound and isolated as a white solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.48-8.53 (t, J = 8.16 Hz, 1H), 7.14-7.26 (m, 5H), 6.49-6 , 55 (m, 1H), 5.105.32 (m, 1H), 4.65-4.73 (m, 1H), 4.17-4.23 (m, 3H), 3.99-4.05 (m, 2H), 3.31-3.40 (m, 4H), 1.76-1.86 (m, 2H), 1.20-1.54 (m, 7H), 0.93-0 , 98 (t, J = 6.9 Hz, 3H); LC / MS [M + H] = 611.

Example 90. Synthesis of 2-benzyl-2 - (((2R, 3R, 4S, 5R) -5- (2-chloro-6- (pentylthio) -9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran- 2-yl) methoxy) malonic acid

Proceeding as described in Example 2 above, treatment with diethyl-2-benzyl-2 - (((2R, 3R, 4S, 5R) -3 - ((tert-butoxycarbonyl) oxy) -5- (2-chloro-6- (pentylthio ) -9H-purin-9-yl) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate, aq. 2-benzyl-2 - (((2R, 3R, 4S, 5R) 5- (2-chloro-6- (pentylthio) -9H-purin-9-yl) -4-fluoro -3-hydroxytetrahydrofuran-2-yl) methoxy) malonic acid, the title compound was isolated as a white solid.

¹ H NMR (CD3OD, 300 MHz) δ 8.51 (s, 1H), 7.14-7.31 (m, 5H), 6.48-6.54 (dd, J = 4.20, 4, 35 Hz, 1H), 5.105.30 (dt, J = 3.86, 52 Hz, 1H), 4.64-4.73 (dt, J = 4.68, 17.94 Hz, 1H), 4, 15-4.21 (m, 1H), 3.99-4.06 (m, 2H), 3.313.40 (m, 4H), 1.81-1.95 (m, 2H), 1.36- 1.54 (m, 4H), 0.90-0.98 (m, 3H); LC / MS [M + H] = 583.

Example 91. Synthesis of 2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-nurin-9-yl) -3,4-dihydroxytetrahydrofurαn-2-yl) methoxy) -2- (2H-tetrazol-5-yl) -3- (4- (trifluoromethyl) phenyl) propanoic acid

but he

By operating as described in Example 80 above, but substituting 4 (trifluoromethyl) benzyl bromide for benzyl bromide, the title compound was obtained and isolated as a solid mixture of diastereomers (approx. 1: 1 ratio).

¹ H NMR (CD3OD, 300 MHz) for mixture of diastereomers (approx. 1: 1 ratio).

Isomer 1: δ 8.39 (brs, 1H), 7.52-7.43 (m, 2H), 7.38-7.25 (m, 2H), 6.03-5.94 (m , 1H), 4.80 (t, J = 4.75

- 131 039042

Hz, 1H), 4.48-4.38 (m, 1H), 4.32-4.21 (m, 1H), 4.05-3.68 (m, 4H).

Isomer 2: δ 8.36 (br s, 1H), 7.52-7.43 (m, 2H), 7.38-7.25 (m, 2H), 6.03-5.94 (m , 1H), 4.71 (t, J = 4.61 Hz, 1H), 4.48-4.38 (m, 1H), 4.32-4.21 (m, 1H), 4.05- 3.68 (m, 4H); LC / MS [M + H] = 586.

Example 92. Synthesis of 2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methoxy) -3- (pyridin-3-yl) -2- (1H-tetrazol-5-yl) propanoic acid

But he

Operating as described in Example 80 above but substituting 3- (bromomethyl) pyridine hydrobromide for benzyl bromide gave the title compound and isolated as a solid mixture of diastereomers (approx. 1: 1 ratio).

¹ H NMR (CD3OD, 300 MHz) for a mixture of diastereomers (approx. 1: 1 ratio): δ 8.62-8.69 (m, 2H), 8.31-8.09 (m, 2H), 7, 73-7.60 (m, 1H), 5.90-5.83 (m, 1H), 4.45-4.12 (m, 2H), 3.88-3.50 (m, 5H); LC / MS [M + H] = 519.

Example 93. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-chloro-3- (trifluoromethoxy) benzyl) malonic acid

Operating as described in Example 2 above but substituting 4-chloro-3 (trifluoromethoxy) benzyl bromide for benzyl bromide gave the title compound and isolated as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.31 (br s, 1H), 7.28-7.37 (m, 4H) 6.42-6.48 (dd, J = 4, 10 Hz, 1H ), 5.09-5.26 (dt, J = 4.7, 52 Hz, 1H), 4.64-4.70 (dt, J = 5.17 Hz, 1H), 4.18 (br. s, 1H), 4.03 (br s, 2H), 3.41 (br s, 2H); LC / MS [M + H] = 614.1.

Example 94. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-chloro-2,6-difluorobenzyl) malonic acid

Operating as described in Example 2 above but substituting 4-chloro-2,6-difluorobenzyl bromide for benzyl bromide gave the title compound and isolated as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.18 (d, J = 11.6 Hz, 1H), 6.88-6.96 (m, 2H), 6.33-6.39 (dd, J = 4.10 Hz, 1H), 5.04-5.23 (dt, J = 4.7, 52 Hz, 1H), 4.55-4.65 (dt, J = 5.17 Hz, 1H), 4.25-4.31 (m, 2H), 3.93 (brs, 1H), 3.433.59 (q, J = 15Hz, 2H); LC / MS [M + H] = 566.1.

Example 95. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (2-fluorobenzyl) malonic acid

Operating as described in Example 2 above but substituting 2-fluorobenzyl bromide for benzyl bromide gave the title compound and isolated as a white solid.

1H NMR (CD3OD, 300 MHz) δ 8.28 (s, 1H), 7.38-7.43 (m, 1H), 7.18-7.20 (m, 2H), 6.96-7, 03 (m, 1H), 6.376.44 (dd, J = 4, 10 Hz, 1H), 5.04-5.24 (dt, J = 4.7, 52 Hz, 1H), 4.61-4 , 67 (dt, J = 5.17 Hz, 1H), 4.13-4.15 (m, 1H), 3.98 (br s, 2H), 3.48 (s, 2H); LC / MS [M + H] = 514.1.

Example 96. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (3,4-dichlorobenzyl) malonic acid

- 132 039042

Operating as described in Example 2 above but substituting 3,4-dichlorobenzyl bromide for benzyl bromide gave the title compound and isolated as a white solid.

1H NMR (CD ₃ OD, 300 MHz) δ 8.32 (s, 1H), 7.43 (brs, 1H), 7.15-7.28 (m, 2H), 6.42-6, 48 (dd, J = 4, 10 Hz, 1H), 5.09-5.29 (dt, J = 4.7, 52 Hz, 1H), 4.65-4.73 (dt, J = 5, 17 Hz, 1H), 4.13-4.22 (m, 1H), 3.97-4.05 (m, 2H), 3.50 (s, 2H): LC / MS [M + H] = 564.1.

Example 97. Synthesis of 1-benzyl-3- (2-morpholunoethyl) -2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin9-yl) -4- fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (3- (trifluoromethoxy) benzyl) malonate

Stage 1.

Under an argon gas atmosphere, monobenzylmalonate (1.78 g, 9.17 mmol) was dissolved in anhydrous DMF (11 mL) and cooled in a 0 ° C bath. Potassium carbonate (317 mg, 2.29 mmol, 0.25 eq.) Was added and left stirring for 5 min, then 4- (2-chloroethyl) morpholine (3.58 g, 19.3 mmol, 2.1 eq.). The resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was diluted with EtOAc (50 ml) and washed with water (2x40 ml) and brine (60 ml). The organic layer was concentrated and purified by silica gel column chromatography to give benzyl (2-morpholinoethyl) malonate (1.57 g, 55% yield).

Stage 2.

Under an argon gas atmosphere, a solution of benzyl- (2-morpholinoethyl) malonate (1.57 g, 5.11 mmol) was dissolved in acetonitrile (16 ml) and triethylamine (1.42 ml, 10.22 mmol, 2.0 eq.) and cooled in a -10 ° C bath for 15 minutes. A solution of 4acetamidobenzenesulfonyl azide (1.84 g, 7.67 mmol, 1.5 eq.) In acetonitrile (16 ml) was added at a rate of 4 ml / min. The reaction was monitored by TLC and completed within 4 hours. The reaction mixture was concentrated and purified by silica gel column chromatography to give 1-benzyl-3- (2-morpholinoethyl) -2-diazomalonate (844 mg, 50% yield).

Stage 3.

(2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) amino) -2-chloro-9H-purine-9yl) -4-fluoro-2- (hydroxymethyl ) tetrahydrofuran-3-yl-tert-butyl carbonate (1.27 g, 2.11 mmol) and 1-benzyl

- 133 039042

3- (2-morpholinoethyl) -2-diazomalonate (844 mg, 2.53 mmol, 1.2 eq.) Was placed in a 25 ml round bottom flask and subjected to azeotropic distillation with toluene. The resulting oil was dissolved in toluene (13 ml) under argon gas. To the solution was added rhodium (II) acetate dimer (140 mg, 0.32 mmol, 0.15 eq.) And the resulting mixture was heated at 75 ° C for 3 h until the reaction was complete. The reaction mixture was concentrated to an oil and purified by silica gel column chromatography to give 1-benzyl-3- (2-morpholinoethyl) -2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert- butoxycarbonyl) (tert-butoxycarbonyl) -2-chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate (441 mg, 19% - exit).

Stage 4.

1-Benzyl-3- (2-morpholinoethyl) -2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) -2-chloro-9H -purin-9-yl) -3 - ((t-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate (441 mg, 0.485 mmol) was dissolved in DMF (6.6 ml) and cooled in water To this solution was added oven-dried cesium carbonate (316 mg, 0.970 mmol, 2.0 eq.) and the resulting suspension was stirred for 30 minutes To this suspension was added dropwise 1 (bromomethyl) -3- (trifluoromethoxy) benzene (157 μl, 0.970 mmol, 2.0 eq.) The reaction mixture was allowed to warm to room temperature and held for 14 h. The reaction mixture was diluted with ethyl acetate (50 ml) and washed twice with water (40 ml), brine , dried over magnesium sulfate and concentrated. Purified by silica gel column chromatography to give 1benzyl-3- (2-morpholinoethyl) -2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert- butoxycarbonyl) (tert-butoxycarbonyl) 2-chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) - 4-fluorotetrahydrofuran-2-yl) methoxy) -2- (3 (trifluoromethoxy) benzyl) malonate (480 mg, 91% yield).

Stage 5.

1-Benzyl-3- (2-morpholinoethyl) -2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxycarbonyl) -2-chloro-9H -purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) -2 (3- (trifluoromethoxy) benzyl) malonate (480 mg, 0.440 mmol) was dissolved in DCM (6.0 ml), then TFA (500 μl) was added dropwise. The reaction mixture was stirred for 16 h and the progress of the reaction was monitored by LC / MS. After completion of the reaction, the reaction solution was concentrated to dryness. The crude product was purified by reverse phase HPLC with obtaining the desired 1-benzyl-3- (2morpholinoethyl) -2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro- 3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (3- (trifluoromethoxy) benzyl) malonate LC / MS [M + H] = 783.3.

Example 98. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -3- (2-morpholinoethoxy) -3-oxo-2- (3- (trifluoromethoxy) benzyl) propanoic acid

Stage 1.

1-Benzyl-3- (2-morpholinoethyl) -2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro- 3hydroxytetrahydrofuran-2-yl) methoxy) -2- (3- (trifluoromethoxy) benzyl) malonate (248 mg, 0.32 mmol) dissolved at room temperature in EtOAc (2.5 ml) under an argon pad. Pd / C 10% (25 mg), placed in a round bottom flask and purged three times with argon gas. A hydrogen-filled balloon was attached to the round bottom flask and the flask was purged twice. The completion of the reaction was monitored by LC / MS. After completion of the reaction, the reaction flask was purged with argon gas. The reaction slurry was filtered through a pad of celite and washed twice with EtOAc (5.0 ml). The filtrate was concentrated and purified by reverse phase HPLC to give the desired 2 (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3- hydroxytetrahydrofuran-2-yl) methoxy) -3 (2-morpholinoethoxy) -3-oxo-2- (3- (trifluoromethoxy) benzyl) propanoic acid.

LC / MS [M + H] = 693.2.

Example 99. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (2,3,4-trifluorobenzyl) malonic acid

- 134 039042

Operating as described in Example 2 above but substituting 2,3,4-trifluorobenzyl bromide for benzyl bromide gave the title compound and isolated as a white solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.30 (brs, 1H), 7.15 (q, J = 6.63 Hz, 1H), 6.80 (q, J = 8.61 Hz, 1H), 6.42 (dd, J = 4.41, 12.97 Hz, 1H), 5.18 (td, J = 3.88, 52.34 Hz, 1H), 4.67 (td , J = 4.11, 17.65 Hz, 1H), 4.18-4.11 (m, 1H), 4.10-3.93 (m, 2H), 3.55-3.41 (m , 2H); LC / MS [M + H] = 550.

Example 100. Synthesis of 2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxy-3methyltetrahydrofuran-2-yl) methoxy) -2-benzylmalonic acid

Stage 1.

Imidazole (35 , 80 g, 525.78 mmol, 2.5 eq.) And TBDPSCl (69.37 g, 252.37 mmol, 64.83 ml, 1.2 eq.). The mixture was stirred at 25 ° C for 5 h, then quenched with H2O (1000 ml). The aqueous phase was extracted with EtOAc (3x250 ml). The combined organic layer was washed with brine (500 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness. The crude product was purified by silica gel flash chromatography to give the product (3aR, 5R, 6S, 6aR) -5 - (((tert-butyldiphenylsilyl) oxy) methyl) -2,2dimethyltetrahydrofuro [2,3-d] [1, 3] dioxol-6-ol (80 g, 88.7% yield) as a colorless syrup.

Stage 2.

To a solution of (3aR, 5R, 6S, 6aR) -5 - (((tert-butyldiphenylsilyl) oxy) methyl) -2,2-dimethyltetrahydrofuro [2,3-d] [1,3] dioxol-6-ol (80 g, 186.66 mmol, 1 eq.) in DCM (1000 ml) at 0 ° C, DMP (118.75 g, 279.99 mmol, 86.68 ml, 1.5 eq.) was added. The mixture was stirred at 25 ° C for 16 hours to give a white suspension. The mixture was quenched with saturated aq. a solution of Na ₂ S ₂ O ₃ (500 ml). The aqueous phase was extracted with DCM (2x500 ml). The combined organic layer was washed with brine (500 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude product was purified by silica gel column chromatography (0-17% EtOAc in petroleum ether) to give (3aR, 5R, 6aS) -5 - (((tert-butyldiphenylsilyl) oxy) methyl) -2,2-dimethyldihydrofuro [2,3d ] [1,3] dioxol-6 (3aH) -one (74.1 g, 93% yield) as a colorless gum.

Stage 3.

To a solution of (3aR, 5R, 6aS) -5 - (((tert-butyldiphenylsilyl) oxy) methyl) -2,2-dimethyldihydrofuro [2,3d] [1,3] dioxol-6 (3aH) -one (40, 8 g, 95.65 mmol, 1 eq.) In THF (400 ml) at 25 ° C under N2 atmosphere, MeMgBr (3M, 47.82 ml, 1.5 eq.) Was added. The mixture was stirred at 25 ° C for 1 h to obtain a brown suspension, then quenched with saturated aq. NH ₄ Cl solution (500 ml). The aqueous phase was extracted with EA (3x400 ml). The organic layer was washed with brine (500 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude product was purified by silica gel column chromatography (0-10% EtOAc in petroleum ether) to give (3aR, 5R, 6R, 6aR) -5 - (((tert-butyldiphenylsilyl) oxy) methyl) -2,2,6-trimethyltetrahydrofuro [2,3d] [1,3] dioxol-6-ol (41.77 g, 98.7% yield) as a colorless gum.

Stage 4.

To a solution of (3aR, 5R, 6R, 6aR) -5 - (((tert-butyldiphenylsilyl) oxy) methyl) -2,2,6-trimethyltetrahydrofuro [2,3-d] [1,3] dioxol-6-ol (15 g, 33.89 mmol, 1 eq.) In DCM (150 ml) and water (15 ml, 832.63 mmol, 24.57 eq.) TFA (150 ml, 2 , 03 mol, 59.78 eq.). The mixture was stirred at 20 ° C for 1 h, then quenched with saturated aq. a solution of 135 039042 pa NaHCO ₃ to pH 7. The aqueous phase was extracted with DCM (2x230 ml). The combined organic layer was washed with saturated brine (130 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness. The crude product was purified by flash column chromatography on silica gel (0-40% EtOAc in petroleum ether) to give (3R, 4S, 5R) -5 - (((tert-butyldiphenylsilyl) oxy) methyl) -4-methyltetrahydrofuran-2,3 , 4-triol in the form of a yellow resin.

Stage 5.

To a solution of (3R, 4S, 5R) -5 - (((tert-butyldiphenylsilyl) oxy) methyl) -4-methyltetrahydrofuran-2,3,4triol (8.23 g, 20.44 mmol, 1 eq.) In pyridine (80 ml) at 20 ° C was added 4-DMAP (7.49 g, 61.33 mmol, 3 eq.) And Ac ₂ O (19.15 ml, 204.44 mmol, 10 eq.). The mixture was stirred at 20 ° C for 16 h, then quenched with H2O (530 ml). The aqueous phase was extracted with EA (3x230 ml). The combined organic layer was washed with brine (240 ml), dried over Na2SO4, filtered and concentrated to dryness. The crude product was purified by silica gel column chromatography (0-50% EtOAc in petroleum ether) to give triacetate (3R, 4R, 5R) -5 - (((tert-butyldiphenylsilyl) oxy) methyl) -4-methyltetrahydrofuran-2,3,4- triyl (10.27 g, 95% yield) as a yellow gum.

Stage 6.

To a solution of (3R, 4R, 5R) -5 - (((tert-butyldiphenylsilyl) oxy) methyl) -4-methyltetrahydrofuran-2,3,4-triyl triacetate (10.27 g, 19.43 mmol, 1 eq. ) in MeCN (110 ml) at 0 ° C was added 2-chloro-9H-purin-6-amine (3.62 g, 21.37 mmol, 1.1 eq.), DBU (8.78 ml, 58 , 28 mmol, 3 eq.) And TMSOTf (17.55 ml, 97.13 mmol, 5 eq.). The mixture was stirred at 0 ° C for 0.5 h, then the mixture was stirred at 65 ° C for 1 h, then quenched with saturated aq. NaHCO ₃ solution (300 ml). The aqueous phase was extracted with EtOAc (2x220 ml). The combined organic layer was washed with brine (230 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude product was purified by flash column chromatography on silica gel (0100% EtOAc in petroleum ether) to give (2R, 3R, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -2 (((tert-butyldiphenylsilyl) oxy) methyl) -3-methyltetrahydrofuran-3,4-diyldiacetate (5.6 g, 28% yield) as a yellow solid.

Stage 7.

To a solution of (2R, 3R, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -2 - (((tert-butyldiphenylsilyl) oxy) methyl) -3-methyltetrahydrofuran- 3,4-diyldiacetate (5.1 g, 7.99 mmol, 1 eq.) In DMF (50 ml) at 20 ° C was added TeA (5.56 ml, 39.96 mmol, 5 eq.), 4 -DMAP (292.89 mg, 2.40 mmol, 0.3 eq.) And Boc ₂ O (8.72 g, 39.96 mmol, 5 eq.). The mixture was stirred at 20 ° C for 1 h to obtain a yellow suspension, quenched with H2O (250 ml). The aqueous phase was extracted with EA (3x230 ml). The combined organic layer was washed with brine (250 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude product was purified by flash column chromatography on silica gel (0-33% EtOAc in petroleum ether) to give (2R, 3R, 4R, 5R) -5- (6- (N (tert-butoxycarbonyl) (tert-butoxyl) amino 2-chloro-9H-purin-9-yl) -2 - (((tert-butyldiphenylsilyl) oxy) methyl) -3-methyltetrahydrofuran-3,4-diyldiacetate (5.59 g, 75% yield) as foam.

Stage 8.

To a solution of (2R, 3R, 4R, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino-2-chloro-9H-purin9-yl) -2 - (((tert- butyldiphenylsilyl) oxy) methyl) -3-methyltetrahydrofuran-3,4-diyldiacetate (5.59 g, 6.67 mmol, 1 eq.) in THF (60 ml) at 0 ° C was added TBAF (1M, in THF, 10.00 ml, 1.5 eq.) The reaction mixture was stirred at 0 ° C for 1 h, then diluted with H2O (150 ml). The aqueous phase was extracted with EA (3x130 ml). The combined organic layer was washed with brine ( 150 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel (0-33% EtOAc in petroleum ether) to give (2R, 3R, 4R, 5R) -5 - (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino-2-chloro-9Hpurin-9-yl) -2- (hydroxymethyl) -3-methyltetrahydrofuran-3,4-diyldiacetate (3.09 g , 77% yield) as a white foam.

Stage 9.

To a solution of (2R, 3R, 4R, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino-2-chloro-9H-purin9-yl) -2- (hydroxymethyl) -3 -methyltetrahydrofuran-3,4-diyldiacetate (680 mg, 1.13 mmol, 1 eq.) in toluene (5 ml) and Rh ₂ (OAc) ₄ (50.09 mg, 113.33 mmol, 0.1 eq. ) a solution of diethyl 2-diazopropanedioate (316.47 mg, 1.70 mmol, 1.5 eq.) in toluene (5 ml) was added at 20 ° C. The reaction mixture was heated at 95 ° C for 3 h, then allowed to cool to room temperature The reaction mixture was concentrated to dryness The crude product was purified by flash chromatography on silica gel (0-25% EtOAc in petroleum ether) to give diethyl 2 - (((2R, 3R, 4R, 5R) - 3,4-diacetoxy5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino-2-chloro-9H-purin-9-yl) -3-methyltetrahydrofuran2-yl) methoxy) malonate (585 mg, 59% yield) as white foam.

Stage 10.

To a solution of diethyl-2 - (((2R, 3R, 4R, 5R) -3,4-diacetoxy-5- (6- (N- (tert-butoxycarbonyl) (tert

- 136 039042 butoxyl) amino-2-chloro-9H-purin-9-yl) -3-methyltetrahydrofuran-2-yl) methoxy) malonate (535 mg, 705.65 μmol, 1 eq.) In DMF (5 ml) K ₂ CO ₃ (195.06 mg, 1.41 mmol, 2 eq.) was added and stirred at 20 ° C for 30 min, then bromomethylbenzene (167.62 μL, 1.41 mmol, 2 eq. .) and stirred at 20 ° C for 15.5 h. The reaction was quenched with H2O (10 ml). The aqueous phase was extracted with EtOAc (2x10 ml). The combined organic layer was washed with saturated brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude product was purified by flash chromatography on silica gel (0-25% EtOAc in petroleum ether) to give diethyl 2-benzyl-2 - (((2R, 3R, 4R, 5R) -3,4-diacetoxy-5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino-2-chloro-9H-purin-9-yl) -3-methyltetrahydrofuran-2-yl) methoxy) malonate as a colorless gum.

Stage 11.

To a solution of diethyl-2-benzyl-2 - (((2R, 3R, 4R, 5R) -3,4-diacetoxy-5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino-2- chloro-9H-purin-9-yl) -3-methyltetrahydrofuran-2-yl) methoxy) malonate (1.05 g, 1.24 mmol, 1 eq.) in DCM (10 ml) at 0 ° C TFA was added (1.5 ml) The mixture was stirred at 25 ° C for 16 h then quenched with saturated aqueous NaHCO ₃ until pH 7. The aqueous phase was extracted with DCM (2x50 ml) The combined organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness to give diethyl 2-benzyl-2 - (((2R, 3R, 4R, 5R) -3,4-diacetoxy-5- (6-amino -2-chloro-9H-purine-9yl) -3-methyltetrahydrofuran-2-yl) methoxy) malonate as foam, which was used directly in the next step without further purification.

Stage 12.

A mixture of diethyl 2-benzyl-2 - (((2R, 3R, 4R, 5R) -3,4-diacetoxy-5- (6-amino-2-chloro-9H-purin-9-yl) -3methyltetrahydrofuran-2 -yl) methoxy) malonate (736 mg, 1.14 mmol, 1 eq.) in MeOH saturated with NH3 (10 ml) was stirred at 10 ° C for 16 h, then the mixture was concentrated to dryness. The crude product was purified by flash column chromatography on silica gel (0-100% EtOAc in petroleum ether) to give diethyl 2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro- 9H-purin-9-yl) -3,4-dihydroxy-3-methyltetrahydrofuran-2-yl) methoxy) -2-benzylmalonate (448 mg, 67% yield) as a white solid.

Stage 13.

To a solution of diethyl-2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxy-3methyltetrahydrofuran-2-yl) methoxy) -2-benzylmalonate (150 mg, 265.96 μmol, 1 eq.) in EtOH (2 ml) at 10 ° C was added LiOH-H ₂ O (55.80 mg, 1.33 mmol, 5 eq. ) in H2O (0.5 ml). The mixture was stirred at 50 ° C for 4 h, then concentrated to dryness. The residue was dissolved in H2O (50 ml). The aqueous phase was extracted with EA (2x50 ml). The aqueous phase was brought to pH 2-3 with 1N. aq. HCl. The aqueous phase was extracted with EtOAc (3x50 ml). The combined organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness and then lyophilized to give 2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4 dihydroxy-3-methyltetrahydrofuran- 2-yl) methoxy) -2-benzylmalonic acid as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.77 (br s, 2H), 7.19 (br d, J = 6.53 Hz, 2H), 7.037 , 14 (m, 3H), 5.80 (d, J = 8.03 Hz, 1H), 4.42 (d, J = 8.03 Hz, 1H), 4.00 (m, 1H), 3 , 60-3.73 (m, 2H), 3.22-3.40 (m, 2H), 1.11 (s, 3H); LC / MS [M + H] = 508.0.

Example 101. Synthesis of 2 - (((2S, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluorotetrahydrofuran-2yl) methoxy) -2-benzylmalonic acid

- 137 039042

Stage 1.

To a mixture of (2R, 3R, 4S, 5R)) - 5- (6-amino-2-chloro-9H-purin-9-yl) -2 - (((tert-butyldiphenylsilyl) oxy) methyl) -4-fluorotetrahydrofuran -3-ol (2.6 g, 4.80 mmol, 1 eq.) In MeCN (20 ml) at 0 ° C was added TCDI (1.28 g, 7.19 mmol, 1.5 eq.) / the mixture was stirred at 25 ° C for 17 hours. More TCDI (1.28 g, 7.19 mmol, 1.5 eq.) was added to the above mixture and the mixture was stirred at 25 ° C for 5 hours. The mixture was partitioned between EtOAc (100 ml) and water (80 ml), the aqueous phase was extracted with EtOAc (3x40 ml), the combined extracts were washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give crude product which was purified by flash column chromatography on silica gel (17-33% EtOAc in petroleum ether) to give O - ((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9Hpurine -9-yl) -2 - (((tert-butyldiphenylsilyl) oxy) methyl) -4-fluorotetrahydrofuran-3-yl) 1H-imidazole-1carbothioate (2.3 g, 59% yield) as c the breakwaters are light yellow.

Stage 2.

To a mixture O - ((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -2 - (((tert-butyldiphenylsilyl) oxy) methyl) -4 -fluorotetrahydrofuran-3-yl) 1H-imidazole-1-carbothioate (300 mg, 459.97 μmol, 1 eq.) in toluene (5 ml) under N2 atmosphere, AIBN (15.11 mg, 91.99 μmol, 0 , 2 eq.), The mixture was heated to a temperature of 110 ° C, and (n-Bu) 3SnH (182.56 μl, 689.96 µmol, 1.5 eq.) Was added to the above mixture dropwise in an atmosphere of N2. The mixture was stirred at 110 ° C, then the mixture was quenched with saturated KF solution (20 ml), partitioned between EtOAc (100 ml) and water (10 ml), the organic phase was washed with saturated brine (2x50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (0-40% EtOAc in petroleum ether) to give 9 - ((2R, 3S, 5S) -5 (((tert -butyldiphenylsilyl) oxy) methyl) -3-fluorotetrahydrofuran-2-yl) -2-chloro-9H-purin-6-amine in the form of a white powder.

Stage 3.

To a mixture of 9 - ((2R, 3S, 5S) -5 - (((tert-butyldiphenylsilyl) oxy) methyl) -3-fluorotetrahydrofuran-2-yl) -2chloro-9H-nurin-6-amine (1.20 g , 2.28 mmol, 1 eq.) In DMF (10 ml), Boc ₂ O (1.10 g, 5.02 mmol, 2.2 eq.), DMAP (83.60 mg, 684.31 mmol, 0.3 eq.) And TEA (793.73 μl, 5.70 mmol, 2.5 eq.). The mixture was stirred at 25 ° C under N2 for 0.5 h, then the mixture was partitioned between EtOAc (100 ml) and water (50 ml), the aqueous phase was extracted with EtOAc (30 mlx4) and the combined extracts were washed with water (100 mlx2) , brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude bis-N-Boc protected product (1.8 g) as a yellow gum which was used directly in the next step without cleaning.

Stage 4.

TBAF (1M, 3.47 ml, 1.5 eq.), the mixture was stirred at 0 ° C for 0.5 h, then the reaction mixture was quenched with cold water (50 ml), then extracted with EtOAc (3x80 ml), the combined extracts were washed with cold water (2x80 ml), saturated saline solution (80 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by flash chromatography on silica gel (0-60% EtOAc in petroleum ether) to give the desired alcohol v

- 138 039042 in the form of a yellow oil.

Stage 5.

To a mixture of the alcohol product from the previous step (850 mg, 1.74 mmol, 1 eq.) In toluene (10 ml) was added Rh ₂ (OAc) ₄ (77.00 mg, 174.21 mmol, 0.1 eq.) and diethyl 2-diazomalonate (421.62 mg, 2.26 mmol, 1.3 eq.). The mixture was stirred at 115 ° C under N2 for 1 h, then the mixture was cooled to room temperature and partitioned between EtOAc (100 ml) and water (20 ml), the organic phase was washed with water (20 ml), brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (0-60% EtOAc in petroleum ether) to give diethyl 2 - ((( 2S, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro-9H-purin-9yl) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate 8 (480 mg, 41% yield) as a light yellow oil.

Stages 6-8.

Proceeding as described in Example 2 above gave the title compound and isolated as a white solid.

LC / MS [M + H] = 480.3.

Example 102. Synthesis of 2 - (((2S, 3R, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3-azido-4-hydroxytetrahydrofuran-2-yl) methoxy) -2-benzylmalonic acid

Proceeding as described in Example 18 above gave the title compound and isolated as a white solid.

1H NMR (CD ₃ OD, 400 MHz): δ 8.20 (s, 1H), 7.03-7.20 (m, 2H), 7.05 (dd, J = 5.1, 1.6 Hz , 3H), 5.82 (d, J = 4.5 Hz, 1H), 4.76-4.78 (m, 1H), 4.48 (br d, J = 6.3 Hz, 1H) , 4.25 (t, J = 5.9 Hz, 1H), 3.88 (d, J = 4.3 Hz, 2H), 3.29 (d, J = 5.5 Hz, 2H); LC / MS [M + H] = 519.4.

Example 103. Synthesis of 2 - (((2S, 3R, 4R, 5R) -3-amino-5- (6-amino-2-chloro-9H-purin-9-yl) -4-hydroxytetrahydrofuran-2-yl) methoxy) -2-benzylmalonic acid

Stage 1.

In a colorless solution of diethyl-2 - (((2S, 3R, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3-azido-4hydroxytetrahydrofuran-2-yl) methoxy ) -2-benzylmalonate (100 mg, 173.92 µmol, 1 eq.) In pyridine (2 ml) was added PPh ₃ (72.99 mg, 278.27 µmol, 1.6 eq.). The colorless solution was stirred at 25 ° C for 1 h. NH4OH (0.40 mL, 2.91 mmol, 16.72 eq.) Was added to the colorless solution. The colorless solution was stirred at 25 ° C for 16 h, then concentrated to give crude diethyl 2 - (((2S, 3R, 4R, 5R) -3-amino-5- (6-amino-2-chloro-9H -purin-9-yl) -4-hydroxytetrahydrofuran-2-yl) methoxy) -2-benzylmalonate (190 mg) as a colorless gum, which was used directly in the next step.

Stage 2.

Into a colorless solution of crude diethyl-2 - (((2S, 3R, 4R, 5R) -3-amino-5- (6-amino-2-chloro-9H-purin-9yl) -4-hydroxytetrahydrofuran-2-yl) methoxy) -2-benzylmalonate (190 mg, 173.05 μmol, 1 eq.) in THF (3 ml) was added LiOH (1M, 1.73 ml, 10 eq.). The colorless solution was stirred at 25 ° C for

- 139 039042 for 16 h, then diluted with water (2 ml) and extracted with ethyl acetate (3x2 ml). 1N was added to the aqueous layer. aq. HCl until pH 6. The aqueous layer was extracted with ethyl acetate (3x2 ml). The aqueous layer was freeze-dried to give a white solid (190 mg). This crude product was suspended in 10 ml of THF and filtered. The filtrate was concentrated to give a crude product, which was purified by reverse phase HPLC to give 2 - (((2S, 3R, 4R, 5R) -3-amino5- (6-amino-2-chloro-9H-purin-9-yl) -4-hydroxytetrahydrofuran-2-yl) methoxy) -2-benzylmalonic acid as a white solid.

¹ H NMR (CD3OD, 400 MHz): δ 8.32 (br s, 1H), 7.15 (br s, 5H), 5.93 (br s, 1H), 4.50-4, 60 (m, 2H), 4.02-4.10 (m, 1H), 3.89 (br s, 1H), 3.78 (br d, J = 10.0 Hz, 1H), 3 , 18-3.27 (m, 2H); LC / MS [M + H] = 493.4.

Example 104. Synthesis of 2 - (((2R, 3S, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-azido-3hydroxytetrahydrofuran-2-yl) methoxy) -2-benzylmalonic acid

Proceeding as described in Example 18 above gave the title compound and isolated as a white solid.

¹ H NMR (CD3OD, 400 MHz): δ 8.43 (s, 1H), 7.20-7.30 (m, 2H), 7.05-7.11 (m, 3H), 6.39 ( d, J = 6.53 Hz,

1H), 4.60 (t, J = 7.53 Hz, 1H), 4.45-4.50 (m, 1H), 4.06-4.14 (m, 2H), 3.89-4 01 (m, 1H), 3.33-3.49 (m, 2H);

LC / MS [M + H] = 518.9.

Example 105. Synthesis of 2 - (((2R, 3S, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3-fluoro-4-hydroxytetrahydrofuran-2-yl) methoxy) -2-benzylmalonic acid

nsg btvsmv

Tf ₂ O, DMAP

DXM o's, 1 h

AsOMa DMF

25C, 16 h

Vos ₂ O, TEM, DMAP

DMF 0-25 ° C, 1H

- 140 039042

Stage 1.

To a solution of (2R, 3R, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4 - ((tert-butyldimethylsilyl) oxy) -2 (((4-methoxyphenyl ) diphenylmethoxy) methyl) tetrahydrofuran-3-ol (10 g, 14.53 mmol, 1 eq.) in DCM (100 ml) at 0 ° C was added 4-DMAP (5.32 g, 43.59 mmol, 3 eq.) and Tf ₂ O (2.88 ml, 17.43 mmol, 1.2 eq.). The mixture was stirred at 0 ° C for 1 h, then quenched with H2O (500 ml). The aqueous phase was extracted with DCM (2x340 ml). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude product was purified by flash chromatography on silica gel (0-60% EtOAc in petroleum ether) to afford the triflate derivative (9.62 g, 80.7% yield) as a white foam.

Stage 2.

To a solution of the triflate derivative from the previous step (6.6 g, 8.05 mmol, 1 eq.) In DMF (70 ml) at 25 ° C was added AcONa (6.60 g, 80.45 mmol, 10 eq.) ... The mixture was stirred at 25 ° C for 16 h, then the mixture was diluted with H2O (250 ml). The aqueous phase was extracted with EA (2x200 ml). The combined organic layer was washed with brine (250 ml), dried over Na2SO4 and filtered. The filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to afford the acetate derivative (4.35 g, 74% yield) as a foam.

Stage 3.

To a mixture of the acetate derivative from the previous step (4.35 g, 5.96 mmol, 1 eq.) In DMF (40 ml) at 0 ° C was added TEA (3.01 g, 29.78 mmol, 4.15 ml , 5 eq.), 4-DMAP (218.30 mg, 1.79 mmol, 0.3 eq.) And tert-butoxycarbonyl-tert-butyl carbonate (6.50 g, 29.78 mmol, 5 eq.). The mixture was stirred at 25 ° C for 1 h, diluted with H2O (250 ml). The aqueous phase was extracted with EtOAc (3x240 ml). The combined organic layer was washed with brine (250 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel (0-20% EtOAc in petroleum ether) to give the bis-NBoc derivative (4.4 g, 64% yield) as a foam.

Stage 4.

To a solution of the bis-N-Boc-derivative from the previous step (4.4 g, 4.73 mmol, 1 eq.) In MeOH (150 ml) at 20 ° C were added TEA (150 ml) and H2O (50 ml) ... The mixture was stirred at 20 ° C for 1 h, then H2O (120 ml) was added to the reaction mixture. The aqueous phase was extracted with EtOAc (3x120 ml). The combined organic layer was washed with saturated brine (130 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel (0-20% EtOAc in petroleum ether) to afford the alcohol derivative (3.59 g, 84% yield) as a white foam.

Stage 5.

Pyridine (1.5 ml, 18.58 mmol, 10.39 eq.) and the alcohol derivative from the previous step (1.59 g, 1.79 mmol, 1 eq.) in DCM (20 ml). The mixture was stirred at 20 ° C for 3 h, then the mixture was diluted with H2O (130 ml). The aqueous phase was extracted with DCM (3x120 ml). The combined organic layer was washed with brine (130 ml), dried over Na2SO4 and filtered. The filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel (020% EtOAc in petroleum ether) to afford the fluoride derivative (344 mg, 22% yield) as a yellow foam.

Stage 6.

To a solution of the fluoride derivative from the previous step (344 mg, 386.30 μmol, 1 eq.) In DCM (3 ml) at a temperature of 0 ° C was added TFA (150 μl) in DCM (3 ml). The mixture was stirred at 0 ° C for 5 min, then TEA was added to the reaction mixture to reach pH 7, then the mixture was concentrated to dryness. The crude product was purified by flash chromatography on silica gel (0-25% EtOAc in petroleum ether) to give the primary alcohol derivative (226 mg, 68% yield) as a yellow solid.

Stages 7-11.

Proceeding as described in Example 1 above gave the title compound and isolated as a white solid.

1H NMR (DMSO-d ₆ , 400 MHz): δ 8.46 (brs, 1H), 7.84 (brs, 2H), 7.13-7.25 (m, 5H), 5, 94 (br d, J = 6.63 Hz, 1H), 5.85 (d, J = 8.00 Hz, 1H), 4.94-5.17 (m, 1H), 4.77-4 , 91 (m, 1H), 4.37-4.48 (m, 1H), 3.66 (brs, 2H), 3.21 (brs, 2H); LC / MS [M + H] = 495.9.

Example 106. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-chloro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2-benzylmalonic acid

- 141 039042

Stage 1.

To a solution of (6aR, 8R, 9R, 9aR) -8- (6-amino-2-chloro-9H-purin-9-yl) -2,2,4,4-tetraisopropyltetrahydro6H-furo [3,2-f] [1,3,5,2,4] trioxadisilocin-9-yl trifluoromethanesulfonate (5 g, 7.39 mmol, 1 eq.) In DMF (60 ml) was added LiCl (1.57 g, 36.97 mmol, 5 eq. .). The colorless solution was stirred at 25 ° C for 16 h, then it was poured into 100 ml of water and extracted twice with ethyl acetate (100 ml). The organic product was washed with water (200 ml), brine (200 ml), dried with Na ₂ SO ₄ and concentrated. The crude product was purified using a Combi-flash system (20 g silica gel, ethyl acetate in petroleum ether 20-60%) to give 2-chloro-9 - ((6aR, 8R, 9S, 9aR) -9-chloro2,2,4, 4-tetraisopropyltetrahydro-6H-furo [3,2-f] [1,3,5,2,4] trioxadisilocin-8-yl) -9H-purin-6-amine (2.85 g, 69% yield ) as a white solid.

Stage 2.

Into a colorless solution of 2-chloro-9 - ((6aR, 8R, 9S, 9aR) -9-chloro-2,2,4,4-tetraisopropyltetrahydro-6Hfuro [3,2-f] [1,3,5,2 , 4] trioxadisilocin-8-yl) -9H-purin-6-amine (2.80 g, 4.98 mmol, 1 eq.) In DMF (35 ml) was added 4-DMAP (121.60 mg, 995, 31 μmol, 0.2 eq.), TEA (3.02 g, 29.86 mmol, 4.16 ml, 6 eq.) And (Boc) ₂ О (5.43 g, 24.88 mmol, 5, 72 ml, 5 eq.). The yellow solution was stirred at 25 ° C for 1 h.

The reaction mixture was diluted with water (60 ml) and was extracted with ethyl acetate (60 ml) twice. The combined organic products were washed with water (100 ml), brine (100 ml), dried with Na ₂ SO ₄ and filtered. The filtrate was concentrated to give the crude product (4.2 g) as a yellow gum. The crude product was purified using a Combi-flash system (20 g silica gel that was treated with TEA, ethyl acetate in petroleum ether 10-25%) to give the bis-N-Boc derivative (3.35 g, 85, 95% yield) as a white solid.

Stage 3.

TBAF (1M, 17.57 ml, 4 eq.). The solution was stirred at 0 ° C for 1 hour. The reaction mixture was diluted with ice water (50 ml) and extracted twice with ethyl acetate (50 ml). The organic product was washed with water (100 ml), brine (100 ml), dried with Na ₂ SO ₄ and filtered. The filtrate was concentrated to give a crude product. The crude product was purified using a Combi-flash system (12 g silica gel treated with TEA, ethyl acetate in petroleum ether 30-80%) to give the 3,5-diol derivative (1.95 g, 81% yield) as a white solid.

Stage 4.

Rh ₂ (OAc) ₄ (247.17 mg, 559.23 μmol , 0.15 equiv.). The green suspension was heated to 50 ° C under N2. Diethyl 2-diazomalonate (902.27 mg, 4.85 mmol, 1.3 eq.) Was added to the suspension. The green suspension was stirred at 50 ° C for 36 hours. The reaction mixture was diluted with water (20 ml) and extracted twice with ethyl acetate (20 ml). The organic product was washed with brine (40 ml), dried with Na ₂ SO ₄ and filtered. The filtrate was concentrated to give the crude product (3.2 g) as a purple gum. The crude product was purified using a Combi-flash system (20 g silica gel treated with TEA, ethyl acetate in petroleum ether 20-70%) to give diethyl 2 - (((2R, 3R, 4S, 5R) -5- (6 - (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro-9H-purin-9-yl) -4-chloro-3-hydroxytetrahydrofuran-2yl) methoxy) malonate (1060 mg, 40% yield ) in the form of a yellow resin.

- 142 039042

Stage 5.

To a yellow solution of diethyl-2 - (((2R, 3R, 4S, 5R)) - 5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro-9H-purine-9- yl) -4-chloro-3-hydroxytetrahydrofuran-2-yl) methoxy) mαlonate (1.25 g, 1.84 mmol, 1 eq.) in DMF (15 ml) was added K ₂ CO ₃ (509.22 mg, 3.68 mmol, 2 eq.). The yellow suspension was stirred at 25 ° C for 0.5 h. Bromomethylbenzene (378.11 mg, 2.21 mmol, 262.57 μL, 1.2 eq.) Was added to the yellow suspension. The yellow suspension was stirred at 25 ° C for 16 hours. An additional amount of K2CO3 (500 mg) was added and the yellow suspension was stirred at 25 ° C for another 6 hours. The yellow suspension was diluted with water (20 ml) twice and extracted with ethyl acetate. (20 ml). The organic product was washed with water (40 ml), brine (40 ml), dried with Na ₂ SO ₄ and filtered. The filtrate was concentrated to give the crude product (2.6 g) as a yellow gum. The crude product was purified using a Combi-flash system (20 g silica gel, ethyl acetate in petroleum ether 15-40%) to give diethyl 2-benzyl-2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2chloro-9H-purin-9-yl) -4-chloro-3-hydroxytetrahydrofuran-2-yl) methoxy) mαlonate (855 mg, 59% yield) as a white solid.

Stage 6.

In a colorless solution of diethyl 2-benzyl-2 - (((2R, 3R, 4S, 5R)) - 5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro-9H-purine -9-yl) -4-chloro-3-hydroxytetrahydrofuran-2-yl) methoxy) malonate (400 mg, 520.40 μmol, 1 eq.) In DCM (6.7 ml) at 0 ° C, TFA ( 1.54 g, 13.51 mmol, 1 ml, 25.95 eq.). The yellow solution was stirred at 25 ° C for 5 h. The reaction mixture was diluted with saturated aq. NaHCO3 solution (20 ml) and extracted three times with ethyl acetate (20 ml). The organic product was washed with saturated brine (50 ml), dried with Na ₂ SO ₄ and filtered. The filtrate was concentrated to give the crude product (330 mg) as a yellow gum. The crude product was purified using a Combi-flash system (4 g silica gel, ethyl acetate in petroleum ether 30-80%) to give 290 mg of a colorless gum. The resin was freeze-dried to give diethyl 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-chloro-3hydroxytetrahydrofuran-2- yl) methoxy) -2-benzylmalonate (260 mg, 81.6% yield) as a white solid.

Stage 7.

To a solution of diethyl-2 - (((2R, 3R, 4S, 5R)) - 5- (6-amino-2-chloro-9H-purin-9-yl) -4-chloro-3-hydroxytetrahydrofuran-2-yl ) methoxy) -2-benzylmalonate (110 mg, 193.52 μmol, 1 eq.) in EtOH (4 ml), LiOH (1M, 1.94 ml, 10 eq.) was added. The reaction mixture was stirred at 25 ° C for 8 hours. 2N. HCl (aq.) To reach pH 5 and the mixture was extracted with EtOAc (4x5 ml). The combined organic products were dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated. The crude product was purified by preparative reverse phase HPLC and freeze-dried to give 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4- chloro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2-benzylmalonic acid (22.0 mg, 22% yield) as a white powder.

¹ H NMR (DMSO-d6, 400 MHz): δ, 41 (s, 1H), 7.85 (brs, 2H), 7.16-7.22 (m, 2H), 7.10-7 , 15 (m, 3H),

6.41 (d, J = 6.3 Hz, 1H), 6.16 (br s, 1H), 4.75-4.83 (m, 1H), 4.54 (br t, J = 7.5 Hz, 1H), 3.97 (m, 1H), 3.91 (m, 2H), 3.24 (s, 2H); LC / MS [M + H] = 512.4.

Example 107. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (4-amino-2-chloro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -4fluoro-3- hydroxytetrahydrofuran-2-yl) methoxy) -2-benzylmalonic acid

Stage 1.

HBr (6.56 g, 28.36 mmol, 4.4 ml, 35% purity in AcOH, 3.29 equiv.). The solution was stirred at 25 ° C for 16 h. The pH of the reaction mixture was adjusted to 8 with saturated NaHCO ₃ (aq.), Then extracted with EtOAc (50 ml × 3). The combined organics were washed with brine (50 ml x 2). The solution was dried with Na ₂ SO ₄ and filtered. The filtrate was concentrated to give the bromide derivative (3.59 g, crude) as a yellow oil.

Stage 2.

To a solution of compound ((2R, 3R, 4S, 5R) -3- (benzoyloxy) -5-bromo-4-fluorotetrahydrofuran-2yl) methyl benzoate (1.91 g, 10.18 mmol, 1.2 eq.) In anhydrous MeCN (100 ml) at 0 ° C was added NaH (407.12 mg, 10.18 mmol, 60% purity, 1.2 eq.). The reaction mixture was then stirred for 20 minutes. A solution of 2,4-dichloro-7H-pyrrolo [2,3d] pyrimidine compound (3.59 g, 8.48 mmol, 1 eq.) In MeCN (20 ml) was added dropwise over 10 min. The mixture was stirred at 25 ° C for 1.5 h, then quenched with water (30 ml) and extracted with EtOAc (50 ml × 3). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a yellow foam residue. The crude product was purified by column chromatography on a 40 g silica gel column (eluted with 10-70% EtOAc in petroleum ether) to give ((2R, 3R, 4S, 5R)) - 3- (benzoyloxy) -5- (2,4- dichloro-7H-pyrrolo [2,3d] pyrimidin-7-yl) -4-fluorotetrahydrofuran-2-yl) methyl benzoate (3.8 g, 84% yield) as a white foam.

Stage 3.

To a solution of NH ₃ in THF (40 ml) was added the dichloro derivative of the product from the previous step (2 g, 3.77 mmol, 1 eq.). The reaction mixture was stirred at 25 ° C for 16 h in an autoclave. The reaction mixture was concentrated to give a mixture of (2R, 3R, 4S, 5R) -5- (4-amino-2-chloro-7Hpyrrolo [2,3-d] pyrimidin-7-yl) -2 - ((benzoyloxy) methyl) -4-fluorotetrahydrofuran-3-ylbenzoate and (2R, 3R, 4S, 5R) -5- (4-amino-2-chloro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2- ( (benzoyloxy) methyl) -4fluorotetrahydrofuran-3-ylbenzoate (2.2 g) as a white solid. This crude mixture was used directly in the next step without further purification.

Stage 4.

To a solution of the mixture (2R, 3R, 4S, 5R) -5- (4-amino-2-chloro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2 ((benzoyloxy) methyl) -4 -fluorotetrahydrofuran-3-yl benzoate and (2R, 3R, 4S, 5R) -5- (4-amino-2-chloro-7Hpyrrolo [2,3-d] pyrimidin-7-yl) -2 - ((benzoyloxy) methyl ) -4-fluorotetrahydrofuran-3-ylbenzoate (6.60 g, 16.22 mmol, 1 eq.) In MeOH (100 ml) under N2, CH ₃ ONa / MeOH (1.5M, 108.16 ml, 10 eq.). The reaction mixture was stirred at 25 ° C for 1 hour. The pH of the reaction mixture was adjusted to 5 ~ 6 with 2N. HCl (water), extracted with EtOAc (150 mlx4). The organic phase was collected and washed with brine (30 ml x 3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated to give a residue (5.5 g) as a yellow oil. The crude product was purified using a 40 g silica gel Combi-flash system (eluted with 25-70% EtOAc in petroleum ether) to give (2R, 3R, 4S, 5R) -5- (4-amino-2-chloro-7H- pyrrolo [2,3-d] pyrimidin-7-yl) -4-fluoro-2 (hydroxymethyl) tetrahydrofuran-3-ol (2.45 g, yield: 46%) as a white solid.

Stages 5-11.

Proceeding as described in Example 1 above gave the title compound and isolated as a white solid.

1H NMR (DMSO-de, 400 MHz,) δ 13.49 (brs, 2H), 7.58 (brs, 2H), 7.24-7.30 (m, 1H), 7.13 -7.24 (m, 5H), 6.59 (d, J = 3.76 Hz, 1H), 6.43 (dd, J = 16.69, 4.14 Hz, 1H), 5.95 ( br s, 1H), 5.00-5.19 (m, 1H), 4.42 (br d, J = 18.07 Hz, 1H), 3.95 (m, 1H), 3.78 (br s, 2H), 3.21 (br s, 2H); LC / MS [M + H] = 494.9.

Example 108. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (4-amino-2-chloro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -4fluoro-3- hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-carboxybenzyl) malonic acid

Acting as described in example 2 above, but replacing diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro- 9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4- 144 039042 fluorotetrahydrofuran-2-yl) methoxy) malonate on diethyl 2 - (((2R, 3R, 4S, 5R) - 5- (4-N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -3 - ((tert-butoxycarbonyl) oxy ) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate gave the title compound and isolated as a white solid.

'H NMR (DMSO-f, 400 MHz): δ 12.30-14.28 (br s, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.57 (br. s, 2H), 7.35 (d, J = 8.4 Hz, 2H)), 7.21-7.30 (m, 1H), 6.59 (d, J = 4.0 Hz, 1H) , 6.44 (dd, J = 16.4, 4.0 Hz, 1H), 5.97 (br s, 1H), 5.00-5.23 (m, 1H), 4.42 (m , 1H), 3.92-4.01 (m, 1H), 3.84 (br d, J = 4.4 Hz, 2H), 3.24 (s, 2H); LC / MS [M + H] = 538.9.

Example 109. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (4-amino-6-chloro-1H-pyrazolo [3,4-d] pyrimidin-1-yl) -4fluoro-3- hydroxytetrahydrofuran-2-yl) methoxy) -2-benzylmalonic acid

Stage 1.

In a mixture of 3,5-di-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl bromide (5 g, 10.77 mmol, 1 eq.) And 4,6-dichloro-1H-pyrazolo [3 , 4-d] pyrimidine (2.24 g, 11.84 mmol, 1.1 eq.) In anhydrous MeCN (80 ml) at 0 ° C, DBU (4.92 g, 32.30 mmol, 4, 87 ml, 3 eq.). The mixture was stirred at 0 ° C for 5 min and then TMSOTf (10.77 g, 48.45 mmol, 8.75 mL, 4.5 eq.) Was added dropwise. The mixture was stirred at 0 ° C for 30 min and then stirred at 70 ° C for 17 h, then the mixture was cooled to room temperature and diluted with EtAOc (200 ml) and the organic layer was washed with saturated NaHCO ₃ solution (100 ml), saturated saline solution (100 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (0-17% ethyl acetate in petroleum ether) to give ((2R, 3R, 4S, 5R) ) -3 (benzoyloxy) -5- (4,6-dichloro-1H-pyrazolo [3,4-d] pyrimidin-1-yl) -4-fluorotetrahydrofuran-2-yl) methyl benzoate (3 g, 51.7% output) in the form of a colorless oil.

Stage 2.

MeOH saturated with NH3 (188.21 μmol, 30 ml) was added to the product from the previous step (2.5 g, 4.71 mmol, 1 eq.). The mixture was stirred at 25 ° C for 17 h, then the mixture was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (0-80% ethyl acetate in petroleum ether) to give (2R, 3R, 4S , 5R) -5- (4-amino-6-chloro-1H-pyrazolo [3,4-d] pyrimidin-1-yl) -4-fluoro-2- (hydroxymethyl) tetrahydrofuran-3-ol as a white powder colors.

Stage 3.

TBDPSCl (582.16 μL, 2.27 mmol) and imidazole (403.53 mg, 5.93 mmol, 2.5 eq.). The mixture was stirred at 25 ° C for 17 h, then the mixture was partitioned between water (50 ml) and EA (80 ml), the aqueous phase was extracted with EA (3x30 ml), the combined extracts were washed with water (2x80 ml), brine ( 80 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (0-75% ethyl acetate in petroleum ether) to give (2R, 3R, 4S, 5R )) - 5 (4-amino-6-chloro-1H-pyrazolo [3,4-d] pyrimidin-1-yl) -2 - (((tert-butyldiphenylsilyl) oxy) methyl) -4fluorotetrahydrofuran-3-ol in the form of a white powder.

Stage 4.

To a mixture of the product from the previous step (1.32 g, 2.44 mmol, 1 eq.) In DMF (10 ml) was added TEA (1.23 g, 12.18 mmol, 1.69 ml, 5 eq.), 4-DMAP (89.25 mg, 730.53 μmol, 0.3 eq.) And tert-butoxycarbonyl tert-butyl carbonate (2.66 g, 12.18 mmol, 2.80 ml, 5 eq.). The mixture was stirred at 20 ° C for 2 h, then the mixture was partitioned between EA (50 ml) and water (50 ml), the aqueous phase was extracted with EA (15 ml × 3) and the combined extracts were washed with water (50 ml × 2), brine

- 145 039042 (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The resin was purified by flash chromatography on silica gel (0-14% ethyl acetate in petroleum ether) to give the tri-Boc protected product (1 g, 47% yield) as a colorless oil.

Stage 5.

To a mixture of the tri-Boc-protected product from the previous step (900 mg, 1.07 mmol, 1 eq.) In MeOH (10 ml) at 25 ° C was added NH4F (158.27 mg, 4.27 mmol, 4 eq. .). The mixture was stirred at 25 ° C for 15 h, then the mixture was quenched with cold water (40 ml), extracted with EA (50 ml × 3), the combined extracts were washed with water (50 ml × 2), brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The resin was purified by flash chromatography on silica gel (0-25% ethyl acetate in petroleum ether) to afford the primary alcohol derivative (470 mg, 70% yield) as a foam.

Stage 6.

To a mixture of the primary alcohol derivative from the previous step (360 mg, 596.00 μmol, 1 eq.) In toluene (5 ml) was added Rh ₂ (OAc) ₄ (26.34 mg, 59.60 μmol, 0.1 eq. ), the mixture was stirred at 95 ° C, and then diethyl 2-diazomalonate (166.43 mg, 894.00 μmol, 1.5 eq.) in toluene (2 ml) was added dropwise to the above mixture. The mixture was stirred at 95 ° C under N2 for 3 hours to give a green mixture. The mixture was cooled to room temperature and concentrated under reduced pressure to give a crude product, which was purified by flash chromatography on silica gel (0-20% ethyl acetate in petroleum ether) to give diethyl 2 (((2R, 3R, 4S, 5R) -5- (4 - ((N- (tert-butoxycarbonyl) (mpet-butoxyl) amino) -6-chloro-1H-pyrazolo [3,4d] pyrimidin-1-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) memoxy) malonate (330 mg, 68% yield) as a white oil.

Stages 7-9.

Acting as described in example 2 above, but replacing diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tertbumoxycarbonyl) (mret-butoxyl) amino) -2-chloro- 9H-purin-9-yl) -3 - ((trem-butoxycarbonyl) oxy) -4-fluortetrahydrofuran-2-yl) methoxy) malonate on diethyl 2 - (((2R, 3R, 4S, 5R) -5- (4 - ((N- (m-butoxycarbonyl) (m-butoxyl) amino) -6-chloro-1H-pyrazolo [3,4-d] pyrimidin-1-yl) -3 - ((tert-butoxycarbonyl) oxy ) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate gave the title compound and isolated as a white solid.

LC / MS [M + H] = 496.1.

Example 110. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-nurin-9-yl) -4-fluoro-3-hydroxyhemrahydrofuran-2-yl) methoxy) -2- (4-nitrobenzyl) malonic acid

Oh nh ₂

О V ОН o ₂ n ^ ^{but <f}

Operating as described in Example 2 above but substituting 4-nitrobenzyl bromide for benzyl bromide gave the title compound and isolated as a white solid.

¹ H NMR (CD3OD, 400 MHz) δ 8.23 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H) , 6.43 (dd, J = 12.0, 4.80 Hz, 1H), 5.08-5.26 (m, 1H), 4.62-4.74 (m, 1H), 4.13 -4.19 (m, 1H), 3.95-4.11 (m, 2H), 3.45-3.57 (m, 2H); LC / MS [M + H] = 541.3.

Example 111. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-aminobenzyl) malonic acid

- 146 039042

Stage 1.

To a solution of diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) αmino) -2-chloro9H-purin-9-yl) - 3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) -2- (4-nitrobenzyl) malonate (8.16 g, 9.09 mmol, 1 eq.) In EtOH (100 ml ) was added PtO ₂ (310.86 mg, 1.37 mmol, 1.51e-1 eq.) in an atmosphere of H2 (15 psi). The mixture was stirred at 25 ° C for 4 h, then the mixture was filtered through a pad of celite. The filtrate was concentrated to dryness to give diethyl 2- (4-aminobenzyl) -2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) - 2chloro-9H-nurin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) mαlonαta (7.5 g) as an off-white foam.

Stage 2.

To a solution of the amine derivative from the previous step (1 g, 1.15 mmol, 1 eq.) In DCM (10 ml) at 0 ° C was added TFA (1.5 ml, 20.26 mmol, 17.57 eq.) ... The mixture was stirred at 25 ° C for 3 h, then the reaction mixture was washed with saturated aq. NaHCO ₃ solution to achieve pH 7. The aqueous phase was extracted with EtOAc (3x50 ml). The combined organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel (0-100% ethyl acetate in petroleum ether) to give diethyl 2 - (((2R, 3R, 4S, 5R) -5- (6-αmino-2-chloro-9H -purine-9yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-aminobenzyl) malonate (512 mg, 78% yield) as a yellow gum.

Stage 3.

To a solution of diethyl-2 - (((2R, 3R, 4S, 5R)) - 5- (6-amino-2-chloro-9H-nurin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl ) methoxy) -2- (4-aminobenzyl) malonate (512 mg, 903.05 μmol, 1 eq.) in EtOH (5 mL) at 25 ° C, LiOH (108.14 mg, 4.52 mmol, 5 eq.) in H2O (1 ml). The mixture was stirred at 50 ° C for 16 h, then the mixture was concentrated to dryness. The residue was dissolved in H ₂ O (50 ml). The aqueous phase was extracted with EtOAc (2x50 ml). The aqueous phase was brought to pH 2-3 with 1N. aq. HCl. The aqueous phase was lyophilized. The crude product was purified by preparative reverse phase HPLC to give 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3- hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-aminobenzyl) malonic acid (76.4 mg, 16% yield) as an off-white solid.

1H NMR (DMSO-J6, 400 MHz) δ 8.29 (d, J = 1.76 Hz, 1H), 7.88 (br s, 2H), 6.92 (d, J = 8.53 Hz , 2H), 6.50 (br d, J = 7.78 Hz, 2H), 6.34 (dd, J = 13.93, 4.64 Hz, 1H), 6.01 (br s, 1H), 5.14-5.31 (m, 1H), 4.51 (br d, J = 17.57 Hz, 1H), 3.97-4.02 (m, 1H), 3.80 (m, 2H), 3.07 (s, 2H); LC / MS [M + H] = 511.

Example 112. Synthesis of 2- (4-acetαmidobenzyl) -2 - (((2R, 3R, 4S, 5R) -5- (6-αmino-2-chloro-9H-πurin-9-yl) -4fluoro-3- hydroxytetrahydrofuran-2-yl) methoxy) malonic acid

TFA, DXM 0 ~ 25 ° C

T

Stage 1.

To a solution of diethyl 2- (4-aminobenzyl) -2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro-9H -purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2yl) methoxy) malonate (1.49 g, 1.72 mmol, 1 eq.) in AcOH (15 ml) at _{Ac 2} O (262.72 mg, 2.57 mmol, 241.03 μl, 1.5 eq.) was added at 25 ° C. The mixture was stirred at 70 ° C for 2 h, then the reaction was quenched with H ₂ O (100 ml). The aqueous phase was extracted with EA (3x50 ml). The combined organic layer was washed with brine (150 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to give diethyl 2- (4-acetamidobenzyl) -2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro -9H-nurin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4fluorotetrahydrofuran-2-yl) methoxy) malonate (2.35 g) as a yellow oil.

Stages 2-3.

Acting as described in example 2 above, from diethyl-2- (4-α-acetamidobenzyl) -2 - (((2R, 3R, 4S, 5R) -5- (6 (N- (tert-butoxycαarbonyl) (tert-butoxyl ) amino) -2-chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) ok-147 039042 si) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate to 2- (4-acetamidobenzyl ) -2 - (((2R, 3R, 4S, 5R) -5- (6amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) malonic acid obtained the title compound and isolated as a white solid.

Ή NMR (DMSO-d ₆ , 400 MHz,) δ 9.83 (s, 1H), 8.27 (d, J = 1.76 Hz, 1H), 7.88 (br s, 2H), 7 , 37 (d, J = 8.28 Hz, 2H), 7.12 (d, J = 8.53 Hz, 2H), 6.35 (dd, J = 13.43, 4.64 Hz, 1H) , 5.15-5.35 (m, 1H), 4.51 (m, 1H), 4.01 (q, J = 4.85 Hz, 1H), 3.88 (br d, J = 4 , 52 Hz, 2H), 3.20 (s, 2H), 1.99 (s, 3H); LC / MS [M + H] = 553.1.

Example 113. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-benzamidobenzyl) malonic acid

TFU, dkhm

Stage 1.

To a solution of diethyl-2- (4-aminobenzyl) -2 - (((2R, 3R, 4S, 5R)) - 5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro- 9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2yl) methoxy) malonate (1 g, 1.15 mmol, 1 eq.) In DCM (20 ml) at temperature 0 ° C was added TEA (240.72 μl, 1.73 mmol, 1.5 eq.) And BzCl (20.92 μl, 1.73 mmol, 1.5 eq.). The mixture was stirred at 25 ° C for 2 h, then the reaction mixture was diluted with H2O (130 ml). The aqueous phase was extracted with EtOAc (3x130 ml). The combined organic layer was washed with saturated brine (150 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness. The crude product was purified by silica gel flash chromatography (0-25% ethyl acetate in petroleum ether) to give diethyl 2- (4-benzamidobenzyl) -2 - (((2R, 3R, 4S, 5R) -5- (6 - (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) 2-chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) mαlonate (780 mg, 65% yield) as a yellow foam.

Stages 2-3.

Acting as described in Example 2 above, from diethyl 2- (4-benzamidobenzyl) -2 - (((2R, 3R, 4S, 5R) -5- (6 (N- (tert-butoxycarbonyl) (tert-butoxyl ) amino) -2-chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) malonate to 2 - (((2R, 3R, 4S , 5R) -5- (6-amino-2-chloro-9H-purine-9yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-benzamidobenzyl) malonic acid, the title compound and isolated as a white solid.

1H NMR (DMSO-d ₆ , 400 MHz,) δ 10.16 (s, 1H), 8.29 (d, J = 2.01 Hz, 1H), 7.90-7.94 (m, 2H) , 7.87 (br s, 2H), 7.49-7.61 (m, 5H), 7.20 (d, J = 8.78 Hz, 2H), 6.36 (dd, J = 13 , 55, 4.52 Hz, 1H), 5.16-5.36 (m, 1H), 4.53 (m, 1H), 3.98-4.06 (m, 1H), 3.91 ( broad d, J = 4.77 Hz, 2H), 3.24 (s, 2H); LC / MS [M + H] = 615.1.

Example 114. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (methylsulfonamido) benzyl) malonic acid

TFU, dxm 0-2 5C

Stage 1.

To a solution of diethyl-2- (4-aminobenzyl) -2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-148 039042 butoxyl) amino) -2 -chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2yl) methoxy) malonate (1.5 g, 1.73 mmol, 1 eq.) in DCM ( 20 ml) at 0 ° C, TEA (262.51 mg, 2.59 mmol, 361.09 μl, 1.5 eq.), DMAP (21.13 mg, 172.95 mmol, 0.1 eq.) Were added. ) and MsCl (401.58 μL, 5.19 mmol, 3 eq.). The mixture was stirred at 25 ° C for 2 h, then the mixture was quenched with H2O (50 ml). The aqueous phase was extracted with DCM (3x50 ml). The combined organic layer was washed with brine (50 ml), dried over Mg ₂ SO ₄ and filtered. The filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel (0-40% ethyl acetate in petroleum ether) to give dietuyl 2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl ) (tert-butoxyl) amino) -2-chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2yl) methoxy) -2- (4- (methylsulfonamido) benzyl) malonate (900 mg, 55% yield) as a white foam.

Stages 2-3. Acting as described in Example 2 above, from dietuyl-2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro-9H -purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4fluorotetrahydrofuran-2-yl) methoxy) -2- (4- (methylsulfonamido) benzyl) malonate up to 2 - (((2R, 3R, 4S , 5R) -5 (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (methylsulfonamido) benzyl) malonic acid gave the title compound and isolated as a white solid.

¹ H NMR (DMSO-d6, 400 MHz,) δ 9.60 (s, 1H), 8.26 (d, J = 1.51 Hz, 1H), 7.87 (br s, 2H), 7 , 18 (d, J = 8.53 Hz, 2H), 7.00 (d, J = 8.53 Hz, 2H), 6.35 (dd, J = 13.05, 4.77 Hz, 1H) , 5.17-5.34 (m, 1H), 4.52 (dt, J = 18.63, 4.99 Hz, 1H), 4.02 (m, 1H), 3.89 (br d , J = 4.27 Hz, 2H), 3.21 (s, 2H), 2.90 (s, 3H); LC / MS [M + H] = 589.

Example 115. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4 - ((ethoxycarbonyl) amino) benzyl) malonic acid

Stage 1.

To a solution of dietul-2- (4-aminobenzyl) -2 - (((2R, 3R, 4S, 5R)) - 5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro- 9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2yl) methoxy) malonate (1 g, 1.15 mmol, 1 eq.) In Py (20 ml) at temperature Ethyl chloroformate (164.64 μL, 1.73 mmol, 1.5 eq.) Was added at 0 ° C. The mixture was stirred at 25 ° C for 2 h, then the reaction was quenched with H2O (100 ml). The aqueous phase was extracted with EtOAc (2x50 ml). The combined organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel (0-20% ethyl acetate in petroleum ether) to give diethyl 2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) ( tert-butoxyl) amino) -2-chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4fluorotetrahydrofuran-2-yl) methoxy) -2- (4 - ((ethoxycarbonyl) amino ) benzyl) malonate (665 mg, 61% yield) as a white foam.

Stages 2-3.

Acting as described in Example 2 above, from diethyl 2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro-9H -purin-9-ul) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) -2- (4 - ((ethoxycarbonyl) amino) benzyl) malonate up to 2 - ((( 2R, 3R, 4S, 5R) -5- (6amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4 - ((ethoxycarbonyl ) amino) benzyl) malonic acid gave the title compound and isolated as a white solid.

1H NMR (DMSO-d6, 400 MHz,) δ 9.49 (s, 1H), 8.27 (d, J = 1.76 Hz, 1H), 7.87 (br s, 2H), 7, 25 (br d, J = 8.28 Hz, 2H), 7.11 (d, J = 8.53 Hz, 2H), 6.35 (dd, J = 13.55, 4.77 Hz, 1H ), 5.15-5.34 (m, 1H), 4.46-4.56 (m, 1H), 3.98-4.05 (m, 2H), 4.05-4.12 (q , J = 7.19 Hz, 2H), 3.18 (s, 2H), 1.20-1.24 (t, J = 7.2 Hz, 3H); LC / MS [M + H] = 583.1.

- 149 039042

Example 116. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (2-oxopiperidin-1-yl) benzyl) malonic acid

Stage 1.

To a solution of diethyl-2- (4-aminobenzyl) -2 - (((2R, 3R, 4S, 5R)) - 5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro- 9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2yl) methoxy) malonate (1 g, 1.15 mmol, 1 eq.) In THF (10 ml) at temperature 0 ° C was added TEA (240.72 μl, 1.73 mmol, 1.5 eq.) And 5-chlorovaleroyl chloride (178.74 μl, 1.38 mmol, 1.2 eq.). The mixture was stirred at 25 ° C for 2 h, then the mixture was quenched with H ₂ O (50 ml). The aqueous phase was extracted with DCM (2x50 ml). The combined organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel (0-25% ethyl acetate in petroleum ether) to give diethyl 2 - (((2R, 3R, 4S, 5R)) - 5- (6- (N- (tert- butoxycarbonyl) (tert-butoxyl) amino) -2-chloro-9H-purin-9-yl) -3 ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) -2- (4- ( 5-chloropentanamido) benzyl) malonate (789 mg, 69% yield) as a white foam.

Stage 2.

To a solution of diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro9H-purin-9-yl) - 3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2-yl) methoxy) -2- (4- (5chloropentanamido) benzyl) malonate (789 mg, 800.31 mmol, 1 eq.) In DMF (10 ml) at 25 ° C was added K ₂ CO ₃ (331.82 mg, 2.40 mmol, 3 eq.). The mixture was stirred at 60 ° C for 4 h, then the reaction was quenched with H2O (30 ml). The aqueous phase was extracted with EtOAc (3x20 ml). The combined organic layer was washed with brine (40 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel (0-33% ethyl acetate in petroleum ether) to give diethyl 2 - (((2R, 3R, 4S, 5R) -5- (6- (N (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (2-oxopiperidin-1-yl) benzyl) malonate (679 mg, 76% yield) as a yellow gum.

Stages 3-4.

Acting as described in Example 2 above, from diethyl 2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro-9H -purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2yl) methoxy) -2- (4- (2-oxopiperidin-1-yl) benzyl) malonate up to 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9Hpurin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (2-oxopiperidin-1-yl) benzyl) malonic acid gave the title compound and isolated as a white solid.

¹ H NMR (DMSO, 400 MHz) δ 14.32-12.09 (br s, 2H), 8.25 (d, J = 1.76 Hz, 1H), 7.88 (br s, 2H), 7.20 (d, J = 8.53 Hz, 2H), 7.01 (d, J = 8.28 Hz, 2H), 6.35 (dd, J = 12.55, 4.77 Hz, 1H), 5.17-5.35 (m, 1H), 4.53 (dt, J = 18.63, 4.99 Hz, 1H), 4.00 (br d, J = 3, 76 Hz, 1H), 3.87-3.92 (m, 2H), 3.44-3.49 (m, 2H), 3.26 (s, 2H), 2.312.37 (m, 2H), 1.74-1.84 (m, 4H); LC / MS [M + H] = 593.1.

- 150 039042

Example 117. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-iodobenzyl) malonic acid

Proceeding as described in Example 2 above, substituting 4-iodobenzyl bromide for benzyl bromide gave the title compound and isolated as a white solid.

1H NMR (DMSO-d ₆ , 400 MHz,) δ 8.24 (d, J = 2.01 Hz, 1H), 7.88 (br s, 2H), 7.49 (d, J = 8, 28 Hz, 2H), 7.01 (d, J = 8.28 Hz, 2H), 6.34 (dd, J = 13.18, 4.64 Hz, 1H), 5.16-5.34 ( m, 1H), 4.46-4.56 (m, 1H), 3.97-4.00 (m, 1H), 3.87 (br d, J = 4.52 Hz, 2H), 3 , 20 (s, 2H); LC / MS [M + H] = 621.9.

Example 118. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (2-methoxybenzamido) benzyl) malonic acid

Proceeding as described in Example 113 above, substituting 2methoxybenzoyl chloride for benzoyl chloride gave the title compound and isolated as a white solid.

1H NMR (DMSO-d ₆ , 400 MHz,) δ 10.02 (s, 1H), 8.30 (d, J = 1.25 Hz, 1H), 7.88 (br s, 2H), 7 , 61 (dd, J = 7.53, 1.51 Hz, 1H), 7.54 (br d, J = 8.53 Hz, 2H), 7.43-7.52 (m, 1H), 7.16 (br d, J = 7.28 Hz, 3H), 7.05 (t, J = 7.40 Hz, 1H), 6.35 (dd, J = 13.55, 4.52 Hz , 1H), 5.97-6.13 (m, 1H), 5.14-5.39 (m, 1H), 4.45-4.61 (m, 1H), 4.02 (q, J = 4.60 Hz, 1H), 3.88 (s, 3H), 3.79-3.87 (m, 2H), 3.14-3.22 (s, 2H); LC / MS [M + H] = 645.1.

Example 118. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (thiophene-2-carboxamido) benzyl) malonic acid

Proceeding as described in Example 113 above, substituting 2thiophenecarbonyl chloride for benzoyl chloride gave the title compound and isolated as a white solid.

1H NMR (CD3OD, 400 MHz,) δ 8.31 (d, J = 1.75 Hz, 1H), 7.84 (dd, J = 3.75, 1 Hz, 1H), 7.7 (dd, J = 5.1 Hz, 1H), 7.48 (d, J = 8.63 Hz, 2H), 7.28 (d, J = 8.63 Hz, 2H), 7.16 (dd, J = 5, 3.88 Hz, 1H), 6.43 (dd, J = 13.26, 4.38 Hz, 1H), 5.25-5.10 (m, 1H) 4.73-4.65 ( m, 1H), 4.17 (m, 1H), 4.09-3.95 (m, 2H), 3.4 (m, 2H); LC / MS [M + H] = 621.1.

- 151 039042

Example 119. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((2'-carboxy [1,1'-biphenyl] -4-yl) methyl) malonic acid and 2 (((2R, 3R, 4S, 5R) -5- (6-amino-2 -chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 ((2 '- (ethoxycarbonyl) - [1,1'-biphenyl] -4-yl) methyl) malonic acid

Stage 1.

To a solution of diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-iodobenzyl) malonate (300 mg, 442.58 μmol, 1 eq.), 2-ethoxycarbonylphenylboronic acid pinacol ester (146.65 mg, 531.09 μmol, 1.2 eq.) and K ₂ CO ₃ (183.50 mg, 1.33 mmol, 3 eq.) In 1,4-dioxane (3 ml) and H2O (1 ml) at a temperature of 20-25 ° C in an N2 atmosphere, Pd (dppf) Cl was added ₂ (324 mg, 442.58 μmol, 1 eq.). The reaction mixture was then heated at 80 ° C and stirred for 3 h. The reaction mixture was diluted with H ₂ O (15 ml), extracted with EtOAc (3x10 ml). The combined organic layer was washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by preparative TLC (50% ethyl acetate in petroleum ether) to give diethyl 2 - (((2R, 3R, 4S, 5R)) - 5- (6-amino-2-chloro-9H-purin-9-yl ) -4fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((2 '- (ethoxycarbonyl) - [1,1'-biphenyl] -4-yl) methyl) malonate (282 mg, 88% yield) in the form of a brownish resin.

Stage 2.

To a solution of diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((2 '- (ethoxycarbonyl) - [1,1'-biphenyl] -4-yl) methyl) malonate (100 mg, 142.83 μmol, 1 eq.) in THF (1 ml) at at a temperature of 20-25 ° C, LiOH-H ₂ O (44.95 mg, 1.07 mmol, 7.5 eq.) in H ₂ O (0.5 ml) was added. The reaction mixture was stirred at 50 ° C for 19 h, then cooled to room temperature. The reaction mixture was concentrated and the residue was diluted with H ₂ O (5 ml). The water was washed with EA (3x5 ml) and then acidified with 1N. aq. HCl until pH 2-3 is reached. The mixture was further extracted with EtOAc (3x5 ml). The combined organic layer was washed with brine (15 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 2 (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H -purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 ((2'-carboxy- [1,1'-biphenyl] -4-yl) methyl) malonic acid (52 , 2 mg, 56% yield) as a white solid.

¹ H NMR (CD ₃ OD, 400 MHz,) δ 8.38 (s, 1H), 7.73 (d, J = 7.78 Hz, 1H), 7.43-7.54 (m, 1H) , 7.35-7.43 (m, 1H), 7.31 (d, J = 8.03 Hz, 2H), 7.23 (br d, J = 7.53 Hz, 1H), 7, 15 (d, J = 8.03 Hz, 2H), 6.42 (dd, J = 13.18, 4.39 Hz, 1H), 5.06-5.28 (m, 1H), 4.69 (dt, J = 17.44, 4.33 Hz, 1H), 4.18 (m, 1H), 3.90-4.07 (m, 2H), 3.39-3.50 (m, 2H ); LC / MS [M + H] = 616.1.

Hydrolysis was carried out separately for 5 h at room temperature to give ethyl ether.

LC / MS [M + H] = 644.2.

Example 120. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((3'-carboxy [1,1'-biphenyl] -4-yl) methyl) malonic acid

- 152 039042

Operating as described in Example 119 above, replacing ethoxycarbonylphenylboronic acid pinacol 2-ester with 3-ethoxycarbonylphenylboronic acid pinacol ester gave the title compound and isolated as a white solid.

¹ H NMR (CD3OD, 400 MHz,) δ 8.31 (s, 1H), 8.15 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.67 (d , J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.36-7.44 (m, 4H), 6.43 (dd, J = 12, 4.8 Hz, 1H), 5.08-5.28 (m, 1H), 4.68-4.77 (m, 1H), 4.16-4.18 (m, 1H), 4.07 -4.11 (m, 1H), 3.98 (m, 1H), 3.40-3.52 (m, 2H); LC / MS [M + H] = 616, 1.

Example 121. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((4'-carboxy [1,1'-biphenyl] -4-yl) methyl) malonic acid o nh ₂

A T ^0H

О ^Н0 '

I /

ΗΟ-Μ ^ o

Operating as described in Example 119 above, substituting 4-ethoxycarbonylphenylboronic acid pinacol ester for 2ethoxycarbonylphenylboronic acid pinacol ester gave the title compound and isolated as a white solid.

¹ H NMR (CD3OD, 400 MHz,) δ 8.33 (s, 1H), 8.03 (m, J = 8.28 Hz, 2H), 7.56 (m, J = 8.28 Hz, 2H ), 7.36-7.45 (m, 4H), 6.42 (dd, J = 11.92, 4.64 Hz, 1H), 5.12-5.25 (m, 1H), 4, 73 (dt, J = 17.94, 4.58 Hz, 1H), 4.17 (m, 1H), 4.034.12 (m, 1H), 3.93-4.01 (m, 1H), 3 , 39-3.51 (m, 2H); LC / MS [M + H] = 616.0.

Example 122. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (pyridin-2-yl) benzyl) malonic acid

Operating as described in Example 119 above but replacing the pinacol ester of 2-ethoxycarbonylphenylboronic acid with 2- (tributylstannyl) pyridine gave the title compound and isolated as a white solid.

¹ H NMR (CD3OD, 400 MHz,) δ 8.58 (br d, J = 4.52 Hz, 1H), 8.34 (s, 1H), 7.99 (t, J = 6.96 Hz , 1H), 7.80 (d, J = 8.28 Hz, 1H), 7.71 (br d, J = 8.03 Hz, 2H), 7.41-7.56 (m, 3H) , 6.42 (dd, J = 12.55, 4.02 Hz, 1H), 4.975.30 (m, 1H), 4.60-4.75 (m, 1H), 4.17 (q, J = 4.35 Hz, 1H), 3.98-4.05 (m, 1H), 3.85-3.98 (m, 1H), 3.34-3.51 (m, 2H); LC / MS [M + H] = 573.1.

Example 123. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (pyridin-3-yl) benzyl) malonic acid

- 153 039042

Proceeding as described in Example 119 above, by replacing the pinacol ester of 2ethoxycarbonylphenylboronic acid with the pinacol ester of 3-pyridylboronic acid, the indicated

the title compound and isolated as a white solid.

¹ H NMR (DMSO-d ₆ , 400 MHz,) δ 8.84 (br s, 1H), 8.56 (br d, J = 4.00 Hz, 1H), 8.27 (d, J = 1.63 Hz, 1H), 8.01 (br d, J = 8.00 Hz, 1H), 7.87 (br s, 2H), 7.46-7.54 (m, 3H) , 7.34 (d, J = 8.13 Hz, 2H), 6.36 (dd, J = 13.13, 4.75 Hz, 1H), 6.06 (br s, 1H), 5, 17-5.36 (m, 1H), 4.49-4.60 (m, 1H), 4.03 (q, J = 4.92 Hz, 1H), 3.90 (br d, J = 4.38 Hz, 2H), 3.31 (s, 2H); LC / MS [M + H] = 573.

Example 124. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (pyridin-4-yl) benzyl) malonic acid

Proceeding as described in the example

119 above, substituting 4-pyridylboronic acid pinacol ester for 2 ethoxycarbonylphenylboronic acid pinacol ester gave the title compound and isolated as a white solid.

¹ H NMR (DMSO-J6, 400 MHz,) δ 8.64 (d, J = 6.02 Hz, 2H), 8.28 (d, J = 1.76 Hz, 1H), 7.88 (br s, 2H), 7.69 (br d, J = 4.77 Hz, 2H), 7.60 (d, J = 8.03 Hz, 2H), 7.36 (d, J = 8, 28 Hz, 2H), 6.36 (dd, J = 13.18, 4.64 Hz, 1H), 6.07 (brs, 1H), 5.14-5.38 (m, 1H), 4.55 (br d, J = 18.82 Hz, 1H), 4.00-4.03 (m, 1H), 3.90 (br s, 2H), 3.32 (br s, 2H); LC / MS [M + H] = 573.1.

Example 125. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (pyrimidin-5-yl) benzyl) malonic acid

Operating as described in Example 119 above, substituting 4-pyrimidinylboronic acid pinacol ester for 2ethoxycarbynylphenylboronic acid pinacol ester gave the title compound and isolated as a white solid.

1H NMR (DMSO-6, 400 MHz,) δ 9.16 (s, 1H), 9.08 (s, 2H), 8.28 (s, 1H), 7.86 (br s, 2H), 7.63 (br d, J = 8.00 Hz, 2H), 7.36 (br d, J = 7.88 Hz, 2H), 6.36 (br dd, J = 13.07, 4.57 Hz, 1H), 6.05 (br s, 1H), 5.14-5.37 (m, 1H), 4.55 (br d, J = 18.39 Hz, 1H), 4.03 (br d, J = 4.13 Hz, 1H), 3.86 (br s, 2H), 3.30 (s, 2H); LC / MS [M + H] = 574.1.

Example 126. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (5-methyl-1H-pyrazol-4-yl) benzyl) malonic acid

Operating as described in Example 119 above, substituting 5-methylpyrazole-4-boronic acid pinacol ester for 2 ethoxycarbonylphenylboronic acid pinacol ester gave the title compound and isolated as a white solid.

1H NMR (CD3OD, 400 MHz,) δ 8.38 (s, 1H), 7.61 (s, 1H), 7.27-7.37 (d, J = 8, 2H), 7.18-7 , 26 (d, J = 8, 2H), 6.42 (dd, J = 13.18, 4.39 Hz, 1H), 5.08-5.28 (m, 1H), 4.66-4 , 78 (m, 1H), 4.17 (br d, J = 4.77 Hz, 1H), 3.88-4.05 (m, 2H), 3.40 (s, 2H), 2, 32 (s, 3H); LC / MS [M + H] = 576.

Example 127. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (3, 5-dimethyl-1H-pyrazol-4-yl) benzyl) mαlonic acid

Operating as described in Example 119 above, replacing the pinacol ester of 2ethoxycarbonylphenylboronic acid with the pinacol ester of 3,5-dimethylpyrazole-4-boronic acid gave the title compound and isolated as a white solid.

¹ H NMR (CD3OD, 400 MHz,) δ 8.37 (d, J = 1.76 Hz, 1H), 7.34 (d, J = 8.03 Hz, 2H), 7.10 (d, J = 8.03 Hz, 2H), 6.41 (dd, J = 13.68, 4.39 Hz, 1H), 4.91-5.24 (m, 1H), 4.68 (br d, J = 18.32 Hz, 1H), 4.17 (br d, J = 4.27 Hz, 1H), 3.94-4.04 (m, 2H), 3.34-3.45 (m , 2H), 2.25 (s, 6H); LC / MS [M + H] = 589.9.

Example 128. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (3,5-dimethylisoxazol-4-yl) benzyl) malonic acid

N '

Operating as described in Example 119 above, replacing the pinacol ester of 2ethoxycarbonylphenylboronic acid with the pinacol ester of 3,5-dimethylisoxazole-4-boronic acid gave the title compound and isolated as a white solid.

1H NMR (CD3OD, 400 MHz) δ 8.33 (s, 1H), 7.39 (d, J = 7.38 Hz, 2H), 7.13 (d, J = 7.75 Hz, 2H) , 6.41 (dd, J = 13.45, 4.57 Hz, 1H), 5.01-5.25 (m, 1H), 4.67 (dt, J = 17.85, 4.14 Hz , 1H), 4.16 (br d, J = 4.75 Hz, 1H), 3.884.09 (m, 2H), 3.39-3.50 (m, 2H), 2.31 (s, 3H), 2.16 (s, 3H); LC / MS [M + H] = 591.

Example 129. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (thiophen-2-yl) benzyl) malonic acid

Operating as described in Example 119 above, substituting 2-thiophene-2-boronic acid pinacol ester for 2-ethoxycarbonylphenylboronic acid pinacol ester gave the title compound and isolated as a white solid.

1H NMR (DMSO-d ₆ , 400 MHz,) δ 8.30 (d, J = 1.75 Hz, 1H), 7.88 (br s, 2H), 7.51 (d, J = 5, 13 Hz, 1H), 7.40-7.47 (m, 3H), 7.24 (d, J = 8.25 Hz, 2H), 7.11 (dd, J = 5.00, 3.63 Hz, 1H), 6.36 (dd, J = 13.38, 4.63 Hz, 1H), 6.06 (brs, 1H), 5.17-5.37 (m, 1H), 4 , 55 (br d, J = 19.76 Hz, 1H), 3.99-4.06 (m, 1H), 3.88 (br s, 2H), 3.26 (s, 2H); LC / MS [M + H] = 578.

Example 130. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((4 '- (methylsulfonyl) - [1,1' -biphenyl] -4-yl) methyl) malonic acid

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Operating as described in Example 119 above, replacing the pinacol ester of 2ethoxycarbonylphenylboronic acid with the pinacol ester of 4- (methanesulfonylphenyl) boronic acid gave the title compound and isolated as a white solid.

1H NMR (CD3OD, 400 MHz) δ 8.27 (d, J = 1.50 Hz, 1H), 7.92-7.96 (m, 2H), 7.68-7.72 (m, 2H ), 7.41 (q, J = 8.42 Hz, 4H), 6.41 (dd, J = 11.26, 4.88 Hz, 1H), 5.11-5.25 (m, 1H) , 4.69-4.84 (m, 1H), 4.07-4.18 (m, 2H), 3.95 (dd, J = 10.32, 4.06 Hz, 1H), 3.40 -3.55 (m, 2H); 3.31 (s, 3H); LC / MS [M + H] = 650.1.

Example 131. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((4'-fluoro- [1,1'-biphenyl] -4-yl) methyl) malonic acid

Proceeding as described in the example

119 above, substituting 4-fluorophenylboronic acid pinacol ester for 2 ethoxycarbonylphenylboronic acid pinacol ester gave the title compound and isolated as a white solid.

1H NMR (CD ₃ OD, 400 MHz,) δ 8.34 (d, J = 1.00 Hz, 1H), 7.39-7.46 (m, 2H), 7.27-7.37 (m , 4H), 7.07 (t, J = 8.78 Hz, 2H), 6.42 (dd, J = 11.54, 4.77 Hz, 1H) 5.08-5.30 (m, 1H ), 4.73 (dt, J = 18.01, 4.93 Hz, 1H), 4.13-4.20 (m, 1H), 4.09 (br d, J = 10.29 Hz, 1H), 3.96 (dd, J = 10.04, 4.27 Hz, 1H), 3.38-3.51 (m, 2H); LC / MS [M + H] = 590.4.

Example 132. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (2-aminopyrimidin-5-yl) benzyl) malonic acid

Proceeding as described in the example

119 above, substituting 2-aminopyrimidine-5-boronic acid pinacol ester for 2-ethoxycarbonylphenylboronic acid pinacol ester gave the title compound and isolated as a white solid.

1H NMR (CD3OD, 400 MHz) δ 8.45 (s, 2H), 8.29 (s, 1H), 7.34 (q, J = 8.28 Hz, 4H), 6.41 (dd, J = 12.55, 4.52 Hz, 1H), 5.04-5.25 (m, 1H), 4.70 (dt, J = 17.82, 4.77 Hz, 1H), 4.16 (q, J = 4.43 Hz, 1H), 4.03 (br dd, J = 9.91, 3.39 Hz, 1H), 3.94 (dd, J = 9.66, 4.64 Hz, 1H), 3.33-3.49 (m, 2H); LC / MS [M + H] = 589.

Example 132. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 - ((2'-hydroxy [1,1'-biphenyl] -4-yl) methyl) malonic acid

Proceeding as described in the example

119 above, substituting 2-hydroxyphenylboronic acid pinacol ester for 2-ethoxycarbonylphenylboronic acid pinacol ester gave the title compound and isolated as a white solid.

¹ H NMR (DMSO-d6, 400 MHz,) δ 9.47 (s, 1H), 8.29 (s, 1H), 7.89 (brs, 2H), 7.35 (d, J = 8.28 Hz, 2H), 7.24 (d, J = 8.03 Hz, 2H), 7.08-7.17 (m, 2H), 6.91 (d, J = 7.53 Hz, 1H), 6.82-6.87 (m, 1H), 6.36 (dd, J = 13.80, 4.77

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Hz, 1H), 6.05 (brs, 1H), 5.16-5.37 (m, 1H), 4.51-4.62 (m, 1H), 4.00-4.03 ( m, 1H), 3.90 (m, 2H), 3.27 (s, 2H);

LC / MS [M + H] = 588.1.

Example 133. Synthesis of 2 - (((2R, 3S, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4-carboxybenzyl) malonic acid

Stage 1.

To a solution of (2R, 3S, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro-9H-purin9-yl) -4-fluoro-2- (((4-methoxyphenyl) diphenylmethoxy) methyl) tetrahydrofuran-3-yl-4-nitrobenzoate (930 mg, 1.01 mmol, 1 eq.) In DCM (5 ml) at 0 ° C, TFA (0.6 ml, 8.10 mmol, 8.06 eq.) in DCM (5 ml). The reaction mixture was stirred at 0 ° C for 0.1 h. The reaction mixture was podslushivaet with TEA until pH ~ 7 and then concentrated. The crude product was purified by silica gel column chromatography (elution with 0-33% EtOAc in petroleum ether) to give (2R, 3S, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino ) -2-chloro-9Hpurin-9-yl) -4-fluoro-2- (hydroxymethyl) tetrahydrofuran-3-yl-4-nitrobenzoate (480 mg, 66% yield) as a brownish foam.

Stage 2.

To a solution of the alcohol derivative from the previous stage (480 mg, 735.06 μmol, 1 eq.) And Rh ₂ (OAc) ₄ (32.49 mg, 73.51 μmol, 0.1 eq.) In toluene (4.8 ml) under N2 at 90 ° C was added diethyl 2-diazomalonate (246.31 mg, 1.32 mmol, 1.8 eq.) in toluene (2.4 ml). The reaction mixture was stirred at 90 ° C for 4 hours. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography (eluted with 0-30% EtOAc in petroleum ether) to give diethyl 2 - (((2R, 3S, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2chloro-9H-purin-9-yl) -4-fluoro-3 - ((4-nitrobenzoyl) oxy) tetrahydrofuran-2-yl) methoxy) malonate (250 mg, 39% yield) in the form of a brownish resin.

Stage 3.

To a solution of diethyl-2 - (((2R, 3S, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro9H-purin-9-yl) - 4-fluoro-3 - ((4-nitrobenzoyl) oxy) tetrahydrofuran-2-yl) methoxy) malonate (250 mg, 308.20 μmol, 1 eq.) And K2CO3 (85.19 mg, 616.40 μmol, 2 eq.) in DMF (2.5 ml) was stirred at 20-25 ° C for 1 h. Methyl (4-bromomethyl) benzoate (141.20 mg, 616.40 mmol, 2 eq.) was added to the reaction mixture. and stirred at 20-25 ° C for 16 hours. The reaction mixture was diluted with H2O (20 ml), extracted with EtAOc (3x10 ml). The combined organic layer was washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by preparative TLC (eluted with 33% EtOAc in petroleum ether) to give diethyl 2 - (((2R, 3S, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl ) amino) -2-chloro-9H-purin9-yl) -4-fluoro-3 - ((4-nitrobenzoyl) oxy) tetrahydrofuran-2-yl) methoxy) -2- (4- (methoxycarbonyl) benzyl) malonate ( 170 mg, 56% yield) as a colorless gum.

Stage 4.

To a solution of diethyl-2 - (((2R, 3S, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro9H-purin-9-yl) - 4-fluoro-3 - ((4-nitrobenzoyl) oxy) tetrahydrofuran-2-yl) methoxy) -2- (4- (methoxycarbonyl) benzyl) malonate (170 mg, 177.21 μmol, 1 eq.) In DCM ( 2 ml) at 0 ° C was added TFA (462.00 mg, 4.05 mmol, 0.3 ml, 22.86 eq.). The reaction mixture was stirred at 20-25 ° C for 1 hour. The reaction mixture was cooled to 0 ° C and basified with TEA until pH ~ 7 was reached. The mixture was then concentrated. The crude product was purified by preparative TLC (eluted with 50% EtOAc in petroleum ether) to give diethyl 2 - (((2R, 3S, 4S, 5R) -5- (6-amino-2chloro-9H-purin-9-yl) -4-fluoro-3 - ((4-nitrobenzoyl) oxy) tetrahydrofuran-2-yl) methoxy) -2- (4- (methoxycarbonyl) benzyl) malonate (125 mg, 93% yield) as a colorless gum.

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Stage 5.

To a solution of diethyl-2 - (((2R, 3S, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3 - ((4-nitrobenzoyl) oxy) tetrahydrofuran-2-yl) methoxy) -2- (4- (methoxycarbonyl) benzyl) malonate (125 mg, 164.67 μmol, 1 eq.) in THF (1.2 ml) in H2O (0.7 ml ) at a temperature of 20-25 ° C was added LiOH-H ₂ O (69.10 mg, 1.65 mmol, 10 eq.). The reaction mixture was stirred at 50 ° C for 2 h. The reaction mixture was quenched with H2O (20 ml) and concentrated. Aq. the layer was washed with EtOAc (3x15 ml) and then acidified with 1N. aq. HCl until pH 2-3 with the formation of a white solid. The mixture was filtered and the solid was collected and dried to give 2 - (((2R, 3S, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) 4-fluoro-3-hydroxytetrahydrofuran -2-yl) methoxy) -2- (4-carboxybenzyl) malonic acid (44.9 mg, 49% yield) as a white solid.

1H NMR (DMSO-d ₆ , 400 MHz,) δ 12.82 (br s, 2H), 8.29 (s, 1H), 7.89 (br s, 2H), 7.75 (d, J = 8.03 Hz, 2H), 7.28 (br d, J = 7.53 Hz, 2H), 6.34 (dd, J = 14.31, 4.52 Hz, 1H), 6, 06 (br s, 1H), 5.12-5.34 (m, 1H), 4.52 (br d, J = 18.07 Hz, 1H), 4.00 (br d, J = 4.77 Hz, 1H), 3.76 (br s, 2H), 3.23 (br s, 2H); LC / MS [M + H] = 540.

Example 134. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (2-oxopyrrolidin-1-yl) benzyl) malonic acid

Proceeding as described in Example 116 above, substituting 4-chlorobutyryl chloride for 5-chlorovaleroyl chloride gave the title compound and isolated as a white solid.

1H NMR (CD3OD, 400 MHz,) δ 8.26 (s, 1H), 7.32-7.39 (d, J = 8.4 Hz, 2H), 7.22-7.31 (d, J = 8.4 Hz, 2H), 6.42 (dd, J = 11.80, 4.77 Hz, 1H), 5.09-5.27 (m, 1H), 4.70 (br d, J = 17.32 Hz, 1H), 4.14 (br d, J = 5.02 Hz, 1H), 4.03-4.10 (m, 1H), 3.94 (m, 1H), 3.65-3.83 (m, 2H), 3.39 (br d, J = 9.03 Hz, 2H), 2.55 (t, J = 8.16 Hz, 2H), 2.07 -2.19 (m, 2H); LC / MS [M + H] = 579.

Example 135. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (1,1-dioxy-1,2-thiazinan-2-yl) benzyl) malonic acid

Operating as described in Example 116 above, substituting 4-chloro-1-butanesulfonyl chloride for 5-chlorovaleroyl chloride gave the title compound and isolated as a white solid.

¹ H NMR (CD3OD, 400 MHz,) δ 8.32 (s, 1H), 7.29 (d, J = 8.53 Hz, 2H), 7.11 (d, J = 8.28 Hz, 2H ), 6.41 (dd, J = 12.80, 4.52 Hz, 1H), 5.05-5.27 (m, 1H), 4.66 (dt, J = 18.01, 4.42 Hz, 1H), 4.15 (q, J = 4.35 Hz, 1H), 3.92-4.05 (m, 2H), 3.54-3.65 (m, 2H), 3.47 -3.49 (m, 2H), 3.13-3.27 (m, 2H), 2.21-2.29 (m, 2H), 1.78-1.88 (m, 2H); LC / MS [M + H] = 629.

Example 136. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (2-oxotetrahydropyrimidin-1 (2H) -yl) benzyl) malonic acid

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Stage 1.

To a mixture of diethyl-2- (4-aminobenzyl) -2 - (((2R, 3R, 4S, 5R) -5- (6- (N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -2-chloro-9H -purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-fluorotetrahydrofuran-2yl) methoxy) malonate (300 mg, 34 5 μmol, 1 eq.) in THF (3 ml) was added 1-chlorine -3-isocyanatopropane (53.8 mg, 449 μmol, 1.3 eq.). The mixture was stirred at 25 ° C for 17 h, then quenched with H ₂ O (10 ml). The aqueous phase was extracted with EA (2x20 ml). The combined organic layer was washed with saturated brine (10 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness and purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to afford the urea derivative (260 mg, 76% yield) as a colorless gum.

Stage 2.

To a mixture of the urea derivative isolated from the previous step (260 mg, 263 mmol, 1 eq.) In DMF (8 ml) was added Cs ₂ CO ₃ (343 mg, 1.05 mmol, 4 eq.). The mixture was stirred at 50 ° C for 2 h, then quenched with H2O (20 ml). The aqueous phase was extracted with EA (2x20 ml). The combined organic layer was washed with saturated brine (20 ml), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel (0-100% EtOAc in petroleum ether) to afford the cyclized urea derivative (150 mg, 58% yield) as a colorless gum.

Stage 3.

To a mixture of the cyclized urea derivative from the previous step (150 mg, 158 μmol, 1 eq.) In DCM (2 ml) was added TFA (882 μl, 11.9 mmol, 75.5 eq.). The mixture was stirred at 25 ° C for 3 h, then quenched with saturated aq. NaHCO ₃ solution (5 ml), then extracted with EA (2x30 ml). The combined extracts were washed with brine (2x10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The mixture was purified by preparative TLC (1% MeOH in EtOAc) to give diethyl 2 (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4- fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2 (4- (2-oxotetrahydropyrimidin-1 (2H) -yl) benzyl) mαlonate (60 mg, 58% yield) as a white solid.

Stage 4.

To a mixture of diethyl-2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (2-oxotetrahydropyrimidin-1 (2H) -yl) benzyl) malonate (90 mg, 138 μmol, 1 eq.) in THF (2 ml), LiOH-H ₂ O (84 mg, 2.00 mmol, 1 ml, 14.4 eq.). The mixture was stirred at 20 ° C for 17 h, then the mixture was partitioned between EtOAc (10 ml) and water (10 ml). The aqueous phase was brought to pH 2-3 with 2M aq. HCl solution. The aqueous phase was partitioned between EtOAc (40 ml) and brine (20 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a crude product. The mixture was lyophilized to give 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-methyl-9H-purin-9-yl) -4-fluoro-3hydroxytetrahydrofuran-2-yl) methoxy) -2- (4- (2-oxotetrahydropyrimidin-1 (2H) -yl) benzyl) malonic acid (51.2 mg, 59% yield) as a white powder.

Ή NMR (CD3OD, 400 MHz,) δ 8.37 (d, J = 1.25 Hz, 1H), 7.28 (d, J = 8.28 Hz, 2H), 7.05 (d, J = 8.53 Hz, 2H), 6.42 (dd, J = 12.05, 4.52 Hz, 1H), 5.08-5.31 (m, 1H), 4.58-4.73 (m , 1H), 4.11-4.18 (m, 1H), 3.92-4.06 (m, 2H), 3.53 (t, J = 5.65 Hz, 2H), 3.35- 3.46 (m, 2H), 3.47-3.33 (m, 2H), 1.90-2.04 (m, 2H); LC / MS [M + H] = 594.

Example 137. Synthesis of 2 - (((2S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-4-methyltetrahydrofuran-2-yl) methoxy) -2- (4-carboxybenzyl) malonic acid

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n-Vis5pN toluene

ОМе

Stage 1.

To a mixture of diethyl-2 - (((2R, 3R, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxy-4methyltetrahydrofuran-2- yl) methoxy) -2- (4- (methoxycarbonyl) benzyl) malonate (70 mg, 112.18 μmol, 1 eq.) in MeCN (2 ml) at 20 ° C was added TCDI (29.99 mg, 168, 27 μmol, 1.5 eq.). The mixture was stirred at 20 ° C for 17 hours. Additional TCDI (29.99 mg, 168.27 μmol, 1.5 eq.) Was added to the above mixture and the mixture was stirred at 20 ° C for 3 hours. The mixture was partitioned between EtOAc (20 ml) and water (10 ml), the aqueous phase was extracted with EtOAc (3x10 ml). The combined extracts were washed with brine (2x20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give diethyl 2 (((2R, 3R, 4R, 5R) -3 - ((1H-imidazole- 1-carbonothiol) okCi) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-4methyltetrahydrofuran-2-yl) methoxy) -2- (4- (methoxycarbonyl) benzyl) malonate (75 mg) as a yellow oil. The crude product was used in the next step without purification.

Stage 2.

A mixture of products isolated from the previous step (150 mg, 204.32 μmol, 1 eq.) And AIBN (3.36 mg, 20.43 μmol, 0.1 eq.) In toluene (5 ml) was heated at a temperature 110 ° C and then H-Bu ₃ SnH (89.20 mg, 306.48 µmol, 81.09 µl, 1.5 eq.) Was added to the above mixture. The mixture was stirred at 110 ° C for 0.5 h. The mixture was cooled to room temperature and quenched with saturated aq. KF solution (8 ml), extracted with EtOAc (3x15 ml), the combined extracts were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (0-60% EtOAc in petroleum ether) to give diethyl 2 - (((2S, 4R, 5R) -5- (6-amino-2-chloro9H-purin-9-yl) -4-fluoro- 4-methyltetrahydrofuran-2-yl) methoxy) -2- (4- (methoxycarbonyl) benzyl) malonate (65 mg, 104.77 μmol, 51.28% yield, 98% pure) as a white resin ...

Stage 3.

To a mixture of diethyl-2 - (((2S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-4-methyltetrahydrofuran2-yl) methoxy) -2 - (4- (methoxycarbonyl) benzyl) malonate (60 mg, 98.68 mmol, 1 eq.) In THF (2 ml) was added LiOH-H ₂ O (82.82 mg, 1.97 mmol, 20 eq.) in H2O (2 ml). The mixture was stirred at 25 ° C for 20.5 hours. The reaction mixture was brought to pH 2-3 with 2M aq. HCl, then extracted with EtOAc (3x50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a crude product that was purified by preparative reverse phase HPLC and lyophilized to give 2 - (((2S, 4R, 5R ) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-4methyltetrahydrofuran-2-yl) methoxy) -2- (4-carboxybenzyl) malonic acid (11.1 mg, 21% yield) as a white powder.

1H NMR (DMSO-d ₆ , 400 MHz,) δ 12.79 (br s, 1H), 8.52 (s, 1H), 7.87 (br s, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.11 (d, J = 16.8 Hz, 1H), 4.43-4.64 ( m, 1H), 3.94-4.05 (m, 1H), 3.81-3.88 (m, 1H), 3.35 (s, 2H), 2.32-2.37 (m, 2H), 1.07-1.18 (d, J = 22.0 Hz, 3H); LC / MS [M + H] = 538.

Example 138. Synthesis of 2 - (((2S, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-hydroxy-3methyltetrahydrofuran-2-yl) methoxy) -2-benzylmalonic acid

- 160 039042

Proceeding as described in Example 2 above gave the title compound and isolated as a white solid.

¹ H NMR (CD ₃ OD, 400 MHz,) δ 8.65 (s, 1H), 7.19-7.30 (m, 2H), 7.08-7.16 (m, 3H), 5, 97 (s, 1H), 4.29 (d, J = 4.52 Hz, 1H), 4.17 (d, J = 9.29 Hz, 2H), 3.73-3.84 (m, 1H ), 3.39-3.52 (m, 2H), 2.62 (m, 1H), 1.03 (d, J = 6.78 Hz, 3H); LC / MS [M + H] = 492.

Example 139. Synthesis of 2 - (((2S, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-hydroxy-3-methyltetrahydrofuran-2-yl) methoxy) -2-benzylmalonic acid

Proceeding as described in Example 2 above gave the title compound and isolated as a white solid.

1H NMR (CD3OD, 400 MHz) δ 8.34 (s, 1H), 7.19 (br d, J = 6.78 Hz, 2H), 6.99-7.09 (m, 3H), 5.78 (d, J = 7.28 Hz, 1H), 4.59 (m, 1H), 4.40 (br d, J = 8.53 Hz, 1H), 3.94 (br d , J = 9.03 Hz, 1H), 3.66-3.72 (m, 1H), 3.45-3.52 (m, 1H), 3.33-3.39 (m, 1H), 2.51-2.58 (m, 1H), 1.14 (d, J = 6.78 Hz, 3H); LC / MS [M + H] = 492.

Example 140. Synthesis of (S) -2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran-2- yl) methoxy) -2- (1H-tetrazol-5-yl) -3- (4- (trifluoromethoxy) phenyl) propanoic acid

Operating as described in Example 80 above but substituting 4 (trifluoromethoxy) benzyl bromide for benzyl bromide gave the title compound and isolated as a solid mixture of diastereomers (approx. 1: 1 ratio).

1H NMR (CD3OD, 300 MHz) for mixture of diastereomers (approx. 1: 1 ratio).

Isomer 1: δ 8.37 (br s, 1H), 7.19 (d, J = 8.35 Hz, 2H), 6.96 (d, J = 8.11 Hz, 2H), 5.99 (d, J = 5.79 Hz, 1H), 4.71 (t, J = 5.12 Hz, 1H), 4.40 (t, J = 4.37 Hz, 1H), 4.31-4 , 20 (m, 1H), 3.98-3.89 (m, 1H), 3.86-3.64 (m, 3H); LC / MS [M + H] = 602.

Isomer 2: δ 8.40 (br s, 1H), 7.19 (d, J = 8.35 Hz, 2H), 7.07 (d, J = 7.99 Hz, 2H), 5.98 (d, J = 5.67 Hz, 1H), 4.80 (t, J = 5.15 Hz, 1H), 4.45 (t, J = 4.17 Hz, 1H), 4.31-4 , 20 (m, 1H), 3.98-3.89 (m, 1H), 3.86-3.64 (m, 3H); LC / MS [M + H] = 602.

Example 141. Synthesis of 4- (2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran-2-yl ) methoxy) -2-carboxy-2- (1 H-tetrazol-5-yl) ethyl) benzoic acid

- 161 039042

VosO OVos but he nd he

By operating as described in Example 79 above, but replacing the tetra-Boc-protected alcohol derivative described in Example 77 for N6, N6-bis-Boc-2'-3'-O-isopropylidene-2-chloro-adenosine, the product was obtained Rh-catalyzed inclusion. Subsequent deprotection as described in Example 80 above but substituting methyl 4- (bromomethyl) benzoate for benzyl bromide gave the title compound and isolated as a solid diastereomeric mixture (approx. 3: 2 ratio).

'll NMR (CD ₃ OD, 300 MHz) for a mixture of diastereomers (approx. 3: 2 ratio).

Minor isomer: δ 8.35 (s, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.14 Hz, 2H), 5.98 (d , J = 5.1 Hz, 1H), 4.72 (t, J = 5.1 Hz, 1H), 4.41 (t, J = 4.29 Hz, 1H), 4.32-4.22 (m, 1H), 4.03-3.67 (m, 4H); LC / MS [M + H] = 562.

Major isomer: δ 8.38 (s, 1H), 7.70 (d, J = 8.23 Hz, 2H), 7.20 (d, J = 8.13 Hz, 2H), 6.01 (d , J = 5.34 Hz, 1H), 4.79 (t, J = 5.15 Hz, 1H), 4.46 (t, J = 4.38 Hz, 1H), 4.32-4.22 (m, 1H), 4.03-3.67 (m, 4H); LC / MS [M + H] = 562.

Example 142. Synthesis of 2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methoxy) -3- (4- (benzyloxy) phenyl) -2- (1H-tetrazol-5-yl) propanoic acid

but he

By operating in a manner similar to Example 80 above, but substituting 4 (benzyloxy) benzyl bromide for benzyl bromide, the title compound was obtained and isolated as a solid mixture of diastereomers (approx. 3: 2 ratio).

'H NMR (CD3OD, 300 MHz) for mixture of diastereomers (approx. Ratio 3: 2).

Minor isomer: δ 8.41 (br s, 1H), 7.41-7.21 (m, 5H), 7.01-6.91 (m, 2H), 6.83-6.62 (m , 2H), 6.01 (d, J = 5.25 Hz, 1H), 4.90-4.86 (br s, 2H), 4.76 (t, J = 4.89 Hz, 1H) , 4.49-4.44 (m, 1H), 4.30-4.25 (m, 1H), 4.0-3.85 (m, 1H), 3.79-3.51 (m, 2H), 3.26-3.15 (m, 1H); LC / MS [M + H] = 624.

Major isomer: δ 8.32 (br s, 1H), 7.41-7.21 (m, 5H), 7.01-6.91 (m, 2H), 6.83-6.62 (m , 2H), 5.97 (d, J = 5.16 Hz, 1H), 4.90-4.86 (br s, 2H), 4.69 (t, J = 4.74 Hz, 1H) , 4.49-4.44 (m, 1H), 4.30-4.25 (m, 1H), 4.0-3.85 (m, 1H), 3.79-3.51 (m, 2H), 3.26-3.15 (m, 1H); LC / MS [M + H] = 624.

Example 143. Synthesis of 2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran-2-yl) methoxy) -2- (1H-tetrazol-5-yl) -3- (3- (trifluoromethoxy) phenyl) propanoic acid

but he

Operating in a manner similar to Example 80 above but substituting 3 (trifluoromethoxy) benzyl bromide for benzyl bromide gave the title compound and isolated as a solid mixture of diastereomers (approx. 3: 2 ratio).

'H NMR (CD3OD, 300 MHz) for mixture of diastereomers (approx. Ratio 3: 2).

Minor isomer: δ 8.42 (br s, 1H), 7.35-6.94 (m, 4H), 6.01 (d, J = 5.16 Hz, 1H), 4.80-4, 75 (m,

- 162 039042

1H), 4.44 (t, J = 4.24 Hz, 1H), 4.32-4.22 (m, 1H), 3.99-3.87 (m, 1H), 3.83-3 , 67 (m, 3H); LC / MS [M + H] = 601.

Major isomer: δ 8.42 (br s, 1H), 7.35-6.94 (m, 4H), 5.98 (d, J = 4.92 Hz, 1H), 4.72 (t, J = 4.91 Hz, 1H), 4.40 (t, J = 4.47 Hz, 1H), 4.32-4.22 (m, 1H), 3.99-3.87 (m, 1H ), 3.83-3.67 (m, 3H); LC / MS [M + H] = 601.

Example 144. Synthesis of 2 - (((2R, 3R, 4S, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) -3-phenyl-2- (1 H-tetrazol-5-yl) propanoic acid

By operating in a manner similar to Example 80 above, but substituting 4 (benzyloxy) benzyl bromide for benzyl bromide, the title compound was obtained and isolated as a solid mixture of diastereomers (approx. 1: 1 ratio).

LC / MS [M + H] = 520.

Example 145. Synthesis of 4 '- (2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran-2- yl) methoxy) -2-carboxy-2- (2H-tetrazol-5-yl) ethyl) - [1,1'-biphenyl] -2-carboxylic acid with it, with

SEM-CI, DMF

K ₂ COz g EKDS ^ DU *> r ^N 'SEM

Stage 1.

To a solution of ethyl 1H-tetrazole-5-acetate (3 g, 19.21 mmol) in DMF (40 ml) in an argon atmosphere were added 2- (trimethylsilyl) ethoxymethyl chloride (4.1 ml, 23.05 mmol) and powdered carbonate potassium (5.31 g, 38.42 mmol). The reaction mixture was stirred overnight. Added brine (70 ml) and EtOAc (70 ml) and the mixture was shaken and the organic phase was separated. The aqueous phase was extracted with EtOAc (2x70 ml). The combined organic layer was washed sequentially with saturated brine (70 ml) and water (70 ml) and then dried over Na ₂ SO ₄ and concentrated. The resin was purified by silica gel column chromatography (15-48% EtOAc in hexane) to give ethyl 2- (2 - ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5-yl) acetate (2.379 g) in the form of a mobile oil of light yellow color.

Stage 2.

To a solution of ethyl 2- (2 - ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5-yl) acetate (2.379 g, 8.31 mmol) in dry acetonitrile (25 ml) under argon was added DBU (1.87 ml, 12.47 mmol) followed by 4-acetamidobenzenesulfonyl azide (2.395 g, 9.96 mmol), in 3 equal portions over 5 min. The reaction mixture was stirred for 3.5 h and then the solvent was removed (rotary evaporation). The resin was purified by silica gel column chromatography (20% EtOAc in hexane) to give ethyl 2-diazo 2- (2 - ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5-yl) acetate (2.316 g) in the form of a thick light orange oil.

Stages 4-6.

Acting similarly to that described in Example 77 above, but replacing diethyl 2-diazomalonate with ethyl 2 diazo-2- (2 - ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5-yl) acetate, and also replacing methyl 4- 163 039042 (bromomethyl) benzoate on methyl 4'-bromomethylbiphenyl-2-carboxylate gave the title compound and isolated as a solid mixture of diastereomers (approx. 1: 1 ratio).

1H NMR (CD3OD, 300 MHz) for mixture of diastereomers (approx. 1: 1 ratio).

Isomer 1: δ 8.52 (s, 1H), 7.77 (d, J = 6.18 Hz, 1H), 7.54-7.07 (m, 7H), 6.05 (d, J = 5.76 Hz, 1H), 4.82 (t, J = 5.34 Hz, 1H), 4.44-4.38 (m, 1H), 4.31-4.27 (m, 1H), 4.09-3.90 (m, 1H), 3.86-3.60 (m, 3H); LC / MS [M + H] = 638.

Isomer 2: δ 8.39 (s, 1H), 7.76 (d, J = 6.33 Hz, 1H), 7.54-7.07 (m, 7H), 5.99 (d, J = 5.61 Hz, 1H), 4.70 (t, J = 5.25 Hz, 1H), 4.42-4.38 (m, 1H), 4.28-4.23 (m, 1H), 4.09-3.90 (m, 1H), 3.86-3.60 (m, 3H); LC / MS [M + H] = 638.

Example 146. Synthesis of 4- (2 - (((2R, 3S, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxytetrahydrofuran-2-yl ) methoxy) -2-carboxy-2- (1H-tetrazol-5-yl) ethyl) thiophene-2-carboxylic acid

BUT HE

By operating in a manner similar to Example X10 above, but substituting methyl 4- (bromomethyl) thiophene-2-carboxylate for 3 (trifluoromethoxy) benzyl bromide, the title compound was obtained and isolated as a solid mixture of diastereomers (approx. 1: 1 ratio).

1H NMR (CD3OD, 300 MHz) for mixture of diastereomers (approx. 1: 1 ratio).

Isomer 1: δ 8.46 (s, 1H), 7.53 (brs, 1H), 7.38 (brs, 1H), 6.00 (d, J = 4.98 Hz, 1H) , 4.74 (t, J = 5.12 Hz, 1H), 4.44 (t, J = 4.25 Hz, 1H), 4.34-4.24 (m, 1H), 4.03- 3.90 (m, 1H); 3.83-3.69 (m, 3H); LC / MS [M + H] = 568.

Isomer 2: δ 8.49 (s, 1H), 7.58 (br s, 1H), 7.40 (br s, 1H), 6.04 (d, J = 5.37 Hz, 1H) , 4.81 (t, J = 5.12 Hz, 1H), 4.39 (t, J = 4.49 Hz, 1H), 4.34-4.24 (m, 1H), 4.03- 3.90 (m, 1H); 3.83-3.69 (m, 3H); LC / MS [M + H] = 568.

Example 147. Synthesis of 2 - (((2R, 3R, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4-dihydroxy-4methyltetrahydrofuran-2-yl) methoxy) -3-phenyl-2- (2H-tetrazol-5-yl) propanoic acid

1) ion, _{Н 2} о iso-PrOH, МеОН

2) TFA, DXM

but he

Acting as described in Example 145 above, but replacing tert-butyl- (tert-butoxycarbonyl) (9 ((2R, 3R, 4R, 5R) -3,4-bis ((tert-butoxycarbonyl) oxy) -5- ( hydroxymethyl) -3-methyltetrahydrofuran-2-yl) 2-chloro-9H-purin-6-yl) carbamate on tert-butyl- (tert-butoxycarbonyl) (9 - ((2R, 3R, 4R, 5R) -3, 4-bis ((tert-butoxycarbonyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-2-yl) -2-chloro-9H-purin-6-yl) carbamate, as well as replacing methyl 4'-bromomethylbiphenyl-2-carboxylate with benzyl bromide gave the title compound and isolated as a solid mixture of diastereomers (approx. 1: 1 ratio).

1H NMR (CD3OD, 300 MHz) for mixture of diastereomers (approx. 3: 2 ratio).

Minor Isomer: δ 8.47 (br s, 1H), 7.19-6.96 (m, 5H), 6.015 (br s, 1H), 4.33 (d, J = 9.07 Hz, 1H), 4.25-4.16 (m, 1H), 4.13-3.67 (m, 4H), 0.98 (br s, 3H); LC / MS [M + H] = 532.

Major isomer: δ 8.48 (br s, 1H), 7.19-6.96 (m, 5H), 6.04 (br s, 1H), 4.39 (d, J = 9.04 Hz, 1H), 4.25-4.16 (m, 1H), 4.13-3.67 (m, 4H), 0.98 (br s, 3H); LC / MS [M + H] = 532.

Examples 148a and 148b. Synthesis of 2 - (((2R, 3R, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4 dihydroxytetrahydrofuran-2-yl) methoxy) -3-phenyl- 2- (2H-tetrazol-5-yl) propanoic acid and 2 (((2R, 3R, 4R, 5R) -5- (6-amino-2-chloro-9H-purin-9-yl) -3,4 -dihydroxytetrahydrofuran-2-yl) methoxy) -2- (2 (tert-butyl) -2H-tetrazol-5-yl) -3-phenylpropanoic acid

- 164 039042

1) LiOH, H ₂ O iso-PrOH, MeOH

2) TFA, DXM

BUT HE

Stage 1.

To a solution of tert-butyl- (9 - ((2R, 3R, 4S, 5R) -4 - ((N- (tert-butoxycarbonyl) (tert-butoxyl) amino) -3 ((tert-butyldimethylsilyl) oxy) -5 - (hydroxymethyl) tetrahydrofurαn-2-yl) -2-chloro-9H-purin-6-yl) carbamate (622 mg, 0.868 mmol) in dry toluene (3 ml) ethyl 2-diazo-2- (2- ((2 (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5-yl) acetate (353 mg, 1.13 mmol) and the flask was sucked off and filled with argon again. Rh ₂ (OAc) ₄ (8 mg , 0.017 mmol) and the flask was sucked off again and backfilled with argon.The resulting mixture was stirred at 75 ° C for 2.5 h, then allowed to cool to room temperature.The crude mixture was purified by column chromatography on silica gel (5-55% EtOAc in hexane) to obtain a diastereomeric mixture of ethyl-2 (((2R, 3S, 4R, 5R) -5- (6- (N, N'-bis (tert-butoxycarbonyl) -2-chloro-9H-purine-9- yl) -3 - ((tert-butoxycarbonyl) oxy) -4 - ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) methoxy) -2- (2 - ((2- (trimethylsilyl) ethoxy) methyl) - 2H-tetrazol-5-yl) acetate (757 mg) as ma weak.

Stage 2.

To a solution of a diastereomeric mixture of ethyl-2 - (((2R, 3S, 4R, 5R) -5- (6- (N, N'-bis (tert-butoxycarbonyl) -2chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4 - ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) methoxy) -2- (2 - ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazole- 5-yl) acetate (757 mg, 0.756 mmol) in dry DMF (5 ml), Cs ₂ CO ₃ (1.23 g, 3.78 mmol) and BnBr (207 mg, 1.21 mmol) were added. The reaction mixture was stirred over 3 h. Diluted brine (25 ml) was added and the product was extracted with EtOAc (3x25 ml). The combined organic layer was then washed with brine (25 ml), dried over Na ₂ SO ₄ and concentrated. The resulting crude product was purified column chromatography on silica gel (5-60% EtOAc in hexane) to give ethyl 2 - (((2R, 3S, 4R, 5R) -5- (6- (N, N'-bis- (tert-butoxycαcarbonyl) - 2-chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4 - ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) methoxy) -3-phenyl-2- ( 2 - ((2 (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5-yl ) propanoate in the form of a mixture of diastereomers (approx. ratio 1: 1).

Stage 3.

Ethyl-2 - (((2R, 3S, 4R, 5R) -5- (6- (N, N'-bis- (tert-butoxycαcarbonyl) -2-chloro-9H-purin-9-yl) -3- ((tert-butoxycarbonyl) oxy) -4 - ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-2-yl) methoxy) -3-phenyl-2- (2 ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazole- 5-yl) propanoate (551 mg, 0.505 mmol) was dissolved in dry THF (8 ml) and a solution of TBAF (1.16 ml, 1.16 mmol, 1 M in THF) was added dropwise to this mixture. The reaction mixture was stirred for 1 h. , then it was evaporated to dryness.The residue was purified by column chromatography on silica gel (8-60% EtOAc in hexane) to give ethyl 2 - (((2R, 3R, 4R, 5R) -5- (6- (N, N'- bis- (tert-butoxycarbonyl) -2-chloro-9H-purin-9-yl) -3 - ((tert-butoxycarbonyl) oxy) -4-hydroxytetrahydrofuran2-yl) methoxy) -3-phenyl-2- (2 - (( 2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5-yl) propαnoate (169 mg) as a viscous clear oil.

Stages 4-5.

Acting similarly to that described in example 2 above, ethyl-2 - (((2R, 3R, 4R, 5R) -5- (6- (N, N'-bis- (tert-butoxycαcarbonyl) -2-chloro-9H-purine-9 -yl) -3 - ((tert-butoxycarbonyl) oxy) -4-hydroxytetrahydrofuran2-yl) methoxy) -3-phenyl-2- (2 - ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5 -yl) propαnoate was converted to the title diastereomeric compounds 148a and 148b and isolated as light brown solids.

¹ H NMR (CD ₃ OD, 300 MHz) for a mixture of diastereomers (approx. 1: 1 ratio) according to example X13a.

Isomer 1: δ 8.29 (brs, 1H), 7.22-7.16 (m, 2H), 7.15-7.05 (m, 2H), 7.03-6.98 (m , 1H), 5.98 (br s, 1H), 4.61-4.49 (m, 1H), 4.47 (br s, 1H), 4.27-4.18 (m, 1H ), 4.13-4.02 (m, 1H), 3.08 (dd, J = 8.29, 8.29 Hz, 1H), 3.74-3.55 (m, 2H); LC / MS [M + H] = 518.

- 165 039042

Isomer 2: δ 8.23 (brs, 1H), 7.22-7.16 (m, 2H), 7.15-7.05 (m, 2H), 7.03-6.98 (m , 1H), 5.95 (br s,

1H), 4.61-4.49 (m, 1H), 4.39 (brs, 1H), 4.27-4.18 (m, 1H), 4.13-4.02 (m, 1H), 3.95 (dd, J = 5.06, 9.44 Hz,

1h), 3.74-3.55 (m, 2H); LC / MS [M + H] = 518.

1H NMR (CD3OD, 300 MHz) for a mixture of diastereomers (approx. 1: 1 ratio) according to example X13K

Isomer 1: δ 8.25 (br s, 1H), 7.35-7.16 (m, 5H), 5.91 (br s, 1H), 4.46-4.36 (m, 2H ), 4.18-4.11 (m, 1H), 4.03-3.91 (m, 1H), 3.85-3.75 (m, 1H), 3.72-3.53 (m , 2H), 1.73 (s, 9H); LC / MS [M + H] = 574.

Isomer 2: δ 8.18 (br s, 1H), 7.35-7.16 (m, 5H), 5.90 (br s, 1H), 4.46-4.36 (m, 2H ), 4.18-4.11 (m, 1H), 4.03-3.91 (m, 1H), 3.85-3.75 (m, 1H), 3.72-3.53 (m , 2H), 1.72 (s, 9H); LC / MS [M + H] = 574.

Example 149. In vitro inhibition of the CD73 enzyme.

To measure the activity of soluble CD73 enzyme, recombinant CD73 was obtained from R&D Systems, cat. No. 5795-EN-010. Serial dilutions of test compounds were incubated with recombinant CD73 and AMP in reaction buffer (25 mM Tris HCl, pH 7.5, 5 mM MgCl ₂ , 50 mM NaCl, 0.25 mM DTT, 0.005% Triton X-100). The final reaction volume was 25 μl and the final concentrations of recombinant CD73 and AMP were 0.5 nM and 50 μM, respectively. The reaction was allowed to proceed for 30 minutes at room temperature, then 100 μl of malachite green (Cell Signaling Technology, Cat. # 12776) was added. After 5 min at room temperature, the absorbance was determined at 630 nm using a microplate spectrophotometer. The concentration of inorganic phosphate was determined using a standard phosphate curve. IC ₅₀ data are given in table. 3 below.

Table 3

Conn. No. Compound 1C ₅₀ (μM) 5 On nh _{h 2} O OH N ___% A HO ^H0 'F 13,089 6 , __, 0 \ _ /> 0 .o ⁴ - 0- ^ h.d ° £ ° Y - r o 0, 130 7 о νη ₂ В В О м ^{Н0 F} 0, 121

- 166 039042

eight o nh ₂ 3% 0.363 10 0 nh ₂ ° y> ^he / uL O m no 'ΐ 21, 63 thirteen 1 I ^- ° z \ = / \ __, o AA. A \ _ /> 0 _, o '-' O '7> z T ° AA ^z Az ⁴ J 0.403 15 f ₃ co UL y l Jx rJJ ^but NO F 0.308 sixteen ^p zS UL A ² T J1 no ^ y W ^Н0 HO F 0.257 17 Ig G r <71 Ty ⁰ 3 ° y ^{N but} Ao N ^but no 'F 0.699 twenty ΖΞ OA '° L - Y ^ \ ^O' r \ r Oh Ji 0 0.109

- 167 039042

21 0 ul ^H0 Ko H ^H0 HQ F 0.193 22 О о J K ^ 'o Г1кд 1 о о ¹ 0.521 23 R <xS νΙ ° ^ ° γ ^{Ν N} ^ ^{CI H0} Ko H ^H0 ho 'f 0.206 27 0 NH ₂ o Hon G UI ^H0 h ₂ n ^ho ' ^f 0.218 28 V 0 NH ° L M ^HN G ъГ (ΤΊ ^H0 LG ° V ^{N c} 'О M X ho' f 2, 648 50 0 NH ₂ 4 UoH N ^ .M G <TI ^H0 (° -ί o '' no: Xn \ / HN 7 \ (' ⁿ ' ^N ho 'f 1.911 34 CN О M r G ° Л ° Л ° у ^{N Cl H} °> 0 Ы ^H0 HO 'F 0.097

- 168 039042

35 0 nh ₂ Y unit / no f NC 0.531 36 О NH ₂ ° y units ⁿ honey ^ _m units <20 units units / but f 0CF ₃ 0.057 37 o nh ₂ O / he ν ___ / \ O <20 fl units u / but f OCF ₃ isomer 1 0.718 38 0 nh ₂ p. / he and ^ unit bb ' ^l unit but' f OCF ₃ isomer 2 0, 686 39 o nh ₂ a g-honey ,, unit unit but ί ^o- \ unit m ^ a unit Y / unit / but 'f / he 0.160 40 o nh ₂ 0 / he N ^. / unit <unit 1 ^but red ^ Ohm unit unit / but f NC 1,280 41 0 ΗΝ- / ₀ 4 / ό ^Η ho0 ^ q / OA ₃ // HO F NC 1,790

- 169039042

42 0 NH ₂ 0 Aon NA ^H0 (° Vv ^{nAnAc |} 3 m ^F OH 0, 119 43 о NH ₂ AA ^0H nA „, hn-ZA ^{0 f} V 1,040 44 0 NH ₂ γ3 ^{Η Η} ° ^ Χ XX _f AA ho 'f 0.273 47 о nh ₂ o, AoH N..AV <'Αϊ ^Ho f ° yAy ^N 3 УХ у / HO F F 0.343 49 o nh ₂ 0 Aon N- A 3 <31 ^H0 C3q ^{n nA} c у-У ho 'f' -o 0.839 32 nh ₂ nA «Λ VjJ ~ _f ^{n Cl H0} 13 ^{0H bH} О 0 0.199 51 nh ₂ flfS AA N '^' ^ CI _ho 33ho ^ o 1,870

- 170 039042

53 o nh ₂ VF ^0H N ^ F _rl bl < ^z ΓΪ F ^ OyFF nJU HO '' F N, / Г N'N 0.448 54 0 NH ₂ 0% OH NF f / ¢ 31 ISAi kJ HO 'F HnFn NN 0.220 55 HO '' hh, ^N y ^N Cl > 50 56 ZE o I \ ____ _s o ..., oc 0.168 57 1 \ A1F1> ^{O /.} Y s G about L Q 0, 142 58 0 nh ₂ A ΐ ^ ^0Η Ν_Λ- _Μ ъГ <f; h ^{0 ιθ Ν} ^ ^Cl _F XJ HO 'F O ^ O Η 0.038 59 o nh ₂ o F ° hn F FX ¢ 13 HO Jo-yo n ^ n3i ^l F 0.439

- 171 039042

60 nh ₂ vp ^ΗΟ Υ $ -ΟΗ he 0 0 0.051 61 5 V / у n V ^ _C | 4x / 0 0 2,246 63 o nh ₂ ° Χ \ ° ^{H H} “y o γ ^ ci NN HO '\ b 1,222 64 0 NH ₂ 0 VoH A X <χ Ϊ ^H0 yy ^ yXX HN-N HO 'F 0.860 65 0 nh ₂ O 'Aon N As ^Ho nA _n A _{c |} lyj ns / L ό 0.031 66 rj 7? - / o V. / \ ¹ XXr ° O o - X 0.13

- 172 039042

67 ο nh ₂ 0 Aon b < ^H0 RlAAA Ν = <HO 'F) = 0 HO 0, 602 68 0 nh ₂ a ⁿ <'L but jA) A but' F but - / O 0.322 73 nh ₂ ^Н0 А ° d A nT _n A _{c |} - Oh oh 8, 614 74 o nh ₂ C) AoH nA ^ b (< ^ζ 1α -τ OnoH 1.659 75 mn ₂ \ A e A / \ A _N Al ζγ ^ηο ύΑ ^δΗ о 0 0, 887 76 0 νη ₂ V ^0H Ta ^{Η0 ί Ο} Λ> Τ / - s HO 'F ° l he 0, 074 77 О NH ₂ о Aon a A b (< ^z J U ^{NT 0} 'A but' F Do no 0.255

- 173 039042

78 0 nh ₂ °, Y N_I, _M A fl ^H ° / o ^ _o nA _n A _{c |} Ts1 but 'f Io OH 0.086 79 o nh ₂ AA ^0H ν._Α _μ Ul I ^N / 1 ^{7 0 N} ^ ^N ^ ^CI HQ- 'F θ 0.029 80 Cl ^{F 4} / ° / = N HoA _o AQ-NfyiH ₂ Cl 0.044 81 0 _z nh ₂ bГ < ^? r C ⁰ I ^N ^ ci О M HO F if isomer 1 2.857 82 0 _z nh ₂ A Y ⁰ O <Il I / ⁰ lU ^L A | ^{Ohm H0 F} if isomer 2 3.433 83 nh ₂ know ³ / '' Ν Ν n ^ CI г ^Н0 У he he 0 0 6.443 84 0 νη ₂ O. 7.261

- 174 039042

isomer 1 84 o nh ₂ O Hon _Ν Χ RU ° Dx ° y | Oh hh but ' ^F and isomer 2 8.264 85 o nh ₂ X ^he Y ^but ί ° Vv ^νΛ “L noN 0.183 86 o% P, ---- k O gh O gC / \ ¹¹ X O O - o X 0.062 87 0 ΝΗ ₂ ^ ^he , ΚγΑ no'roDual, TSU NO '' F Ο ^ ΝΗ oHen 0.083 88 o νη ₂ p ^on <Y / ⁰ pp ^ Y ^A c1 8 ^{but <f n} ° A 0.238 89 T] O R /? O O xA, o o - ^ p ¥ Y s rl J 0.043

- 175 039042

91 0 NH2 0 ΑθΗ s Y AA a ° kq ⁿ aa MeO ₂ A ^ ^{H0 <} ' ^F 0.322 92 0 NH ₂ ° Y Y yy ° y ° y nVi ₀ AA OH 0.172 94 ¥ = n ° yN Ty-y. HO J— (G Τ BUT 'Wu ΝγΝ Cl 0, 906 95 A 1 ^N oU Α-Ά HO J— (\ T HO F ^Ν γ ^Ν Cl 0, 105 96 Ck A | A ^S HO-AT ~ -m ° VoA ° Ύ ^N .f, N n ₂ ^HO HO'A y. Cl 0.788 97 i ο ^Η οΛ <^ ο ^ nA у oy r ^N \ A < ^NH2 but? - (Г Г but У ^Ν γ ^Ν Cl 3.432

- 176 039042

98 Η ΟγΥ but Ж <\ Г but 'V ^Ν γ ^Ν Cl 0.512 107 o νη ₂ A Jong Y ^ Ж В B1 nВ oyBBi О XX 0. ^ 4 but he he 42.47 108 h ^HO _О X> о Ж ° у О ^ Ж NH ₂ but 0— (ί ΙΪ HO F Ν-γΝ Cl 0, 104 109 Ο VH O Chon M. U V V] nV o ^ _o nA _n A _{c |} Oh well; BUT 'F 0, 601 110 o nh ₂ o ^ Chon s ^ Ж B ^ Xzh ^H Y ° \ o ./^^ ' _N A' X 0.066 111 О NH ₂ ° Х ^Н <в Water ^ о ВЖ _{С |} O in O, s4 HO F nh ₂ 0.141

- 177 039042

113 nh ₂ n ^ A 1¾ J ^N Cl OH ° \ _ gaUU HO HO 0.161 114 nh ₂ nA. ij! he oA o 1 - ⁷ 1 JA g ° he HO HO 1,567 115 О NH ₂ О Hon N ^ A 3 7; ^o y ° y Va o 0 = 3 ° ^H OH 0.238 116 О NH ₂ О XoH Ν-, Λ ^3/3 ° γ ΝΛ Ν ^Λ _α А " 0.146 117 ο ΝΗ ₂ o. Hon fl А 3 ¢ 77 у ° ^{З ° у Ν Cl} О τχ- O.- _; ... HO F he 63, 9 118 o / - NH ₂ h Y ° ⁿ - = 7m s 7 UZy ° 3Ay ^N ^ ^N АА F > 200 119 ο νη ₂ О, Hon Ν- ^ Λ УУ ¢ 7 у УУу ^Ο 3Αγ ^Ν ^ ^{Ν <} ί Ο! O ^ A F 28.04

- 178 039042

120 О NH ₂ А ¥ he D / ° VV ¥ ^^ О М F 54.51 122 О NH ₂ a ¥ ^he nX _m Η Λ I ^ 4 ^ο ^ νΧν 4 ^ -ы ^ ^but ' ^F / V n Vp 0.032 123 О NH ₂ ° у ° ^н ? ¥ ⁿ / / '\ O, ^N Ο noН b-n ^{Μυ r z} H 0, 152 124 o nh ₂ Ο A ° ^H N- ^ X .. ¥ / ^l HO 'F V ° H 0.15 125 nh ₂ (Tf X ^nA ci F ₃ CO OH θ \ _. V Wv / ^F ciV \ 2 ^/ / ^{0 0H} HO 0.242 126 nh ₂ N- ^ D ·. 6 J 7 “A, OH O \ ^ci X \ ° / Vo 0 // —- / / ° OH (HO F 25,333 127 nh ₂ N-sA <4fb M ^Cl OH O \ / ^ _o X / ° Xv ^ ^F V 44 - Ρ V ° OH \ HO F 0.149

- 179 039042

128 nh ₂ xy Cl OH οΆ, ^Cl yGL ° G ° 'G- / _{c |} UGxy _0H he oh 0.258 129 o nh ₂ O _{h -} ON N ^ X A 9 D Ϊ DH AGA o GG Λν ^ ^{but f} 0.022 130 o go Z. DM = E ADo ₀ jG ⁰ Y G § A o iG o 0.240 131 (G go. ': Hey? Oh 0.098 133 o 3 ' ^x --- o. G ^h nG, Y < ^z J 1 y ' ⁰ U HO' F 0.742 134 / ° oGU «G \ G 0 -> 0 - ⁷ ΞΕ 0.087 135 About NH ₂ o _v Won GK U. GU! but / od ^ o nX _n A _{c |} h ₂ n ^ ^{ho <f} 0, 111

- 180 039042

136 o NH ₂ U ^he U Ρ I ^ζ Η 0, 110 139 νη ₂ N-Яы / θ У% 7 λ Ν Ν CI Ν оУ ^ΟΗ ΟΗ ° ^ 16,523 140 ο ΝΗ ₂ ο, I ^he U _m U <U? ьР edo / yy о Ср р-Р ^but 0.030 141 o nh ₂ k I ^OH U _m y <y? units / UU o Sr \ CW UYa ^ ^NO / A ^N I ^z 0.060 142 o NH ₂ H I ^OH n-Y ^, Y < ^z J ϊ Jy ° y ° yyy / ^ =: / ^HO 'N \ / R 0.067 143 o nh ₂ O / he U <U? PP ° y ° y ^N Us। Ur ^but 'N \ if 0.16

- 181 039042

144 О NH ₂ О А ОН N ...., ...- f A < ^z J 1 Зф А О ^ - ^f / ^ у but 0 F 0.065 145 O About uf δ-, Ο ιθ ° 3 O 0, 106 146 νη ₂ A A ^H νΑ ^ _μ A < ^z J 1 uo Y Ν Al but 0.181 149 o nh ₂ O O ^he N- ^ A A < ^z J j A ⁰ o / y ^N A Αι 0 -A but he 0.051 150 о nh ₂ А А ⁿ mA A < ^z J Ϊ фА ° А ° у ^N Ai о fl _If МеО И у / г _s y = " 0.016 151 o NH ₂ h A ⁿ nAym A < ^z J Ϊ ^H A AaOAAi know ° A) VJ-F OA ^ ⁷ but A 0.031

- 182 039042

152 o nh ₂ х З ^on NЛ ^^, Л 3/3 o-yo N Л Л | \ O 3 / ^ but hn A 0.034 153 o nh ₂ O / s X L 3! ^H X, '° l ^ - ^F / A ^ HO o.LZ X ^z o 0, 074 154 0 NH ₂ L ⁿ / 3 L '' 1,800 155 Nh 0 ₂ 0 X he fkF 1J Ϊ H ⁿ ° / "BP, Ν ^ α QX Vy ^but he ~ l ol 0.047 156 0 _{νη 2} Ον Hon N- ^ F Л < ^z Л1 / 3 ⁰ Λ / ¹ /! Αι / y X ^F / ^ - < ^but ^ -Y 0.086 157 0 νη ₂ 0 Hon n ^ .F L L; ⁰ 3χ ^{Ν N << c: l} li ' ⁷ ' ^{but <} о 1 N 0.034

- 183 039042

158 0 NH ₂ 0. Don nA A < ^Z J 1 Az AAAAci (λ A * ^f sZ ^ but 9D 0, 105 159 0 nh ₂ o Don s A. AA Ϊ ^H0 / AA / Ai PP ^f HO N \ 7 Z h ₂ n ⁿ 0.076 160 0 NH ₃ 0. Τ ^Η nAt, a ¢ 17 ¢ 7 / ° ~ \ _/ ° γ ^ι ΑΑι HO £ J) -7 / ЛА ^ ⁿ ° ^r o 0.012 162 о NH ₂ 9s У ^ОН Ν_Λ _Κ1 А Τϊ А to Yes о (Д уА jAj ^Н ° ' 0.054 165 o ΝΗ ₂ Aon ν ^ Α Τα ° λα _υ ^ν A Aon 8,926 166 o NH ₂ ° Z o ^ 7 ° λαα ^{ν ν <} Αι Aa ^η 2νΤα he > 10 167 o νη ₂ o Aon ν ^ _Α P < ^Ζ Χα ΤΑοΝ ^Λ νΑι o Mn > 40

- 184 039042

168 o NH ₂ О У ОН n Р,> А К ТА PP ° PpNP | Oh -M he 1,747 169 о NH ₂ о ron Р рр ТТ ⁿ О Р ^ no 0, 119 171 O NH ₂ o Ron P yA pp ^{n HO} ° P / O & op ^ but he 0, 114 174 о nh ₂ О Р ^ОН nP _m P <P1 D7 ° DAR ^L S | AA but 'bn <0.020 175 o nh ₂ o P ^he nP,> A to T? PA ^ ZZ / ^ Rl Y Kr ^ no 'O 0.018 176 νη about ₂ ° ·, P ^0H N ^ P _kl H ^<z J Ϊ ° nor po O Aj-f HO 'Ar 0.056

- 185 039042

177 o nh ₂ О Ι ^0Η Η <J ° лХ ^л Λι \ О M- ^{F but} HN J N 0.048 178 o nh ₂ 0 Won Α ^ο ΛΑ / ^Ν n ^A ci ^ho 0.016 179 o nh ₂ AI ^0H n ^ A _m AU Ϊ Z / ° ΛΑ, ^ν n ^ ci 0 Cy V-Zf nLy ^H0 ' 0, 009 180 0 NH ₂ a F ^OH n ^ A _m W <J 1 Α ° Αο _γ Α ^Λ _α ^7? OH > 100 181 0 NH ₂ X < ^z J 1 but / O ^ _o nA _n / A _{c |} HO £ J Vl-F ^Η0 0, 009 182 , ⁿ -n ^HN yN О ^H f _n / = N A HO `` o _H N ^ zN Cl > 50

- 186 039042

188 //) \ 1 θ <An A W yd “ЛА / Αα Ο Η. mixture of diastereomers 11.525 189 Н П 4 / Α 1 οΤχ ^ ο ^ μΠ у О ^ Д V * ^N x _< X _< NH ₂ but Τ — 1 ί Г no bn ^Ν γ ^Ν Cl mixture of diastereomers 0.227 190 fXf ^н ί], Ν. _Μ Ν _χ Ρ [Ν χ-τ ¹ ^ / ^ Ν ° / ο AV ⁿ \ A / ^nh 2 ho 2—1 1 If no bn ^Ν γ ^Ν Cl mixture of diastereomers 0.300 191 fXf Λϊ ^Ν 'ο ΑΝ ^Ο Α ο'Χ' yN ^ lMH; but .g-IT II Ηό θ _Η Ν <γΝ Cl 0, 130 192 Г _Мк no Τ T HO 6h ^N Y ^N Cl 1.178

- 187 039042

mixture of diastereomers 193 . = /, ¹ 0 ^ 0 ^N X 4 ^N \ Bm ^NH 2 o. Zh / 1 II - ⁷ HO `` ΝγΝ Cl > 50 194 MF ⁿ rS Λ T ^N n / = ^N H o '; ^ ^N ......... NH ₂ ho. · - ⁷ T II HO' OH ^N < ^N Cl 0.273 195 OB ^H II] nX T ° уЖ _о ^/ * Ж Ж о - ¹ T Η but 'bn ^N y ^N Cl > 50 197 ... ^N Г \ / X О ^Z i ° Z ⁴ ° ^X ^ fy ^N vB / ^NH2 but - ⁷ T ¥ NO n ^Ν γ ^Ν Cl 2.433 198 ^{o /} XX Λ О X / ^ / О Ж ° / о ¥ Χ ^Ν Χ \ _< ΝΗ ₂ but 1 - T ιΤ but 'he ^Ν γ ^Ν Cl 0.029

- 188 039042

199 n rG d t Y-oU NO G— ² T ¥ IO ' _0H N ^ N Cl 0, 118 200 201 202 203 204 Q γ with ₂ n ^Η J] D'M ¥ U G T about o M ° ^: / 'o'X V-nM. nh ₂ but J. 1 but ¥ 'he NoyN Cl OH fl ⁿ GT _ / = _^N ° Ko' ^x T \ -ν 1χΧΗ 1- ₂ but ^{July 1} but ¥ 'he ^Ν γ ^Ν Cl χ 0 Ν Ν ΧΚ νΜ J ΰ · ^; οχ but 1-4 Г ¥ ⁿ ° ny ^Ν γ ^Ν Cl л О ΜΧο / = Ν ° у Ο'Ά 'yN Mh, NH ₂ ho J – г T ¥ ho' 3H G ⁿ Cl Ν N JK о o- ° - ^N nh ₂ ho j— / Г ¥ but _he has Cl 0.053 0.386 > 50 1.107 7,847

Table 4, the IC50 data are as follows: A means <1 μM, B means 1-3 μM and C means> 3 μM.

- 189 039042

Table 4

Example 81. Biological activity of the described compounds in vitro.

The ability of the compounds to inhibit endogenous cell-associated activity of the CD73 enzyme has been demonstrated using SK-MEL-28 cells that express CD73 on their surface. The day before the experiment, 5000 cells per well were seeded in a 96-well plate. Cells were washed twice with 200 μl reaction buffer (20 mM HEPES, pH 7.4, 125 mM NaCl, 1 mM KCl, 2 mM MgCl ₂ , 10 mM glucose) to remove residual inorganic phosphate. After washing, assays contained serial dilutions of test compounds and 100 μM AMP in a total volume of 200 μl reaction buffer with a final DMSO concentration of <0.5%. After 30 min at room temperature, the supernatant was removed from the cells. To 25 μl of the supernatant was added a volume of 100 μl of malachite green (Cell Signaling Technology, Cat. # 12776). After 5 min at room temperature, the optical density at 630 nm was determined using a microplate spectrophotometer. The concentration of inorganic phosphate was determined using a phosphate standard curve to determine the IC ₅₀ . Table 5 shows IC ₅₀ data for representative compound numbers.

- 190 039042

Table 5

Conn. No. Compound 1C ₅₀ (μM) 6 сч __ / o J o / k q /// / = \ O O - ΞΕ 0.489 7 о nh ₂ 0, У ^0Н ν /,., unit о О м ^{but F} 0.257 eight o NH ₂ θ U ° ⁿ mU .. unit Πΐ pl O unit _C / ^N HO 'F 0.772 thirteen o nh ₂ o / he N ^ /. p <14 HO <Ο ^ οΝ- / _Ν / _α q11 HO 'f 1 2.19 15 F ₃ CO unit / / ^{</ Ν} Χλ ^but Nb ~ F 1.579 sixteen ^p zS. V / NH ₂ at <U Ηο ^ χθ units ^H0 BUT 'F 1.024 17 / Chad U ² G <J ϊ ed ° / ^ ^s U ¹ nP / o U ^no no 'F 1, 814

- 191 039042

twenty A P G ² G <3 ^H0 NO F 0.611 21 ° 7Y — XX ° UzOLx t ° J O ,, L ° ΑχΧ 2 - - ^ - 10 0.510 22 0 AL ν ^ Α _κι 7 3 ZyuYU ' ^but Ao Η ^H0 but' F 1, 135 23 ys y \ A ⁿ Am G O MOu ^{N but} Ao Η ^Η0 HO 'F 0.480 27 0 NH ₂ A Y ^he N ^ A _kl 3 < ^z О ^H0 £ 3α3 ^ ν3ι ГУ Yul Г = / HO F η ₂ ν 0, 886 50 0 ΝΗ ₂ p. Hon FK A Ο 31 ^but ί ° - \ ο3 ^L _{S |} An \ / ΗΝ _λ ? <- (' ⁿ ' ⁿ ho 'f 6.368 34 CN O u r Jl O ^but no 'F 0.153

- 192 039042

35 0 nh ₂ 0 VoH hl A AA! ^{H 0} AA OA HO F NO 0.261 36 o nh ₂ 1 A ^HN Am A <j Ϊ ^H ° (° Α ^ο γ ^ΑΝΪ7α Α Χί A HO F OCF ₃ 0, 197 37 o nh ₂ o Aon n ^ A _k1 \ Α A (Oq ^nA n ^A ci AA ho f ^OCF 3 isomer 1 0.598 38 O NH ₂ 0, A OH Α- Χ A AI ^n7ci о Xi HO F OCF ₃ isomer 2 1.485 39 0 NH ₂ 1 A ^H nA. AA ^H0 (° yoA'AtO! A Xi A / but f Ah 0.493 40 o nh ₂ o Aon hl A A ^<z Xa ^h ° X \ q ⁿ nA ₃ HO F NO 2.411 41 ⁰ 1 0 hAq-A 0 A OH N-.A Ka <fX h ° AAQ / ^{n Λ} Α AA HO F NO 4, 885

- 193 039042

42 0 NH ₂ % L ⁿ nX, l L ^but (ΧοΧΑ о И Ογ ^ ΗΟ F ОН 0, 887 43 0 NH ₂ ° v X ^H N ^ X _M l L ^H0 \ L if we-L ⁷ ^ ^F % d N ' 9, 921 44 0 NH ₂ % F ^0H nX HO _F X <HO 'F 1, 006 47 0 nh ₂ a L ⁿ nX _h L ¢ 13 ^H0 l ^ Vo / ^ N ^ CI fl l HO F F 0.669 49 o nh ₂ 0% OH N ^ X l ¢ 13 ^but / KhdLAL О У = У HO F '-o 2,382 32 nh ₂ CF ₃ / L1 ¢ 3; ^λ ν ^λ οι GJIa ^but lu- ° ⁿ '^ ⁿ 0 0 2,317 51 nh ₂ N Л> м ¢ 11 / X, N ^^ Xci jFv hoX) 4,344

- 194 039042

53 o nh ₂ ° h U ^{he n} A, A <T1 ^but pxo.zA, ⁿ JA / A N HO F Ν, II nn 2,598 54 0 NH ₂ A Kon nA, b < ^H ° ί. ° ~ A ^ - ° y ^{N Ν} An TA but 'F hnA NN 0.973 55 ho 3 - ^z Τ T HO 'y N ^ N Cl > 50 56 0 nh ₂ °. A n ^ A- A Ш ^H0 Pyyyj nAi HOΆ HO 'F 1,250 57 o nh ₂ AA ^H nA, Α Α Ϊ ^H0 [° WO AnA fA, y ύ TA ho '' f 0 ^ 0 Η 0, 1.250 58 0 NH ₂ h A ^H nAu A <A ^{n 0} J. ⁰ X ° y ^NN ^ ^{C |} _p JyJ HO '' F O ^ O Η 0, 853 59 0 NH ₂ о У oh n ^ _A А Ц ΐ ^Η θ <° - \ qN Aci M HO '' f У 6, 984

- 195 039042

60 nh ₂ F SU PnAi PjP ⁿ ° Pron bn 0 0 0.512 61 (T Г ² X Pa p P ^M * ° p & H 0 0 6, 974 63 o nh ₂ °, pOH nP p ^ Yp ^H0 / o ^ _o PA _{C |} NN but 'F b 2.006 64 0 NH ₂ 0 PoH [AP p PI ^H0 fpojPPi HN-N HO 'F 0.588 65 0 nh ₂ О PoH Ν P p UI HO pyopPPi fr 0 0 0.196 66 0 NH ₂ O Ron N ^ .P P ^ Yp ^H ° fp PPi C) noP OH 0.426

- 196 039042

67 0 nh ₂ C \ Don N-Λ HO ^ O ^ qN ^ nAi nA ho 'f Before HO 1.309 68 0 nh ₂ Ο _λ Don n ^ A A ^ Dd HO p-yo Ν ^Λ _Ν Α _α Dz but 'F HO - / 0 0.924 73 nh ₂ ho-A NA _w \ A <'j 1 AN 1D ^ r A ^H0 A ^bn O 0 1,243 74 o he o Don A _k1 a < ^Z 2O HCj 'F 2,557 75 nh ₂ £ A ^ n dA n ^ _n Aq | a>”A> o 0 0.990 76 0 nh ₂ ° v A ^H nA _ki A <A ^H ° (° γο, / ΑΑι D but '' F o D OH 0.305 77 0 NH ₂ ° x A ^H nA _h A < ^z J ΐ ^but TddA ^ sA- _; | As \ _ / A / but 'F To HO 1.331

- 197039042

78 at / χΖ ^ * X / Y o o τ 0.234 79 o νη ₂ 4 Y ° n nV, V <Y1 y / Λν _α Ο V V - HO 'F ο 0.162 80 α Yx ° ^{n F} Y / = ^Ν HO Xy-CyN, ku ⁿ 2 0 ί Ν ί, / Ν HO F Υ CI 0.177 81 0 _ζ ΝΗ ₂ ° ζ Χ ° ^ν Χμ V <ν у / ууХа Ο Μ ^ ν ^ HO 'F ο isomer 1 2.109 82 0 _ζ νη ₂ τ Χ ° nV VX ϊ yY ⁰ -yV ^N Vi Ο v z ^ v ^ ^but ' ^F o isomer 2 4, 122 83 nh ₂ HO-U ³ N ^ X _W us, ^H0 V-0H δΗ 0 0 5, 196 85 0 ΝΗ ₂ V Χ ^0Η Ν, Ι b << ^z Ta ^H0 y ° yo Νχχ Cl-φ ^{H0 F} 1,368

- 198 039042

86 0 NH ₂ 0 VoH [\ LI ^H0 । ° y ^about X ^l Ta fL o = s = o nh ₂ 0.626 87 NH 0 ₁ February T ^0H AU Ϊ ^H0 1. ⁰ A APC ⁷¹ IJ HO f Vm of Hon 0.549 88 o nh ₂ O Won N -__ X bl < ^Z X1 X HO <F ^h X 0.443 89 0 NH ₂ A ^H nA bl <III Hoy toi (I 14 pfo ⁷ ^ HO 'F F 0.070 92 O NH ₂ AA ^H NX A q 33 ° y / y ^N О Uch oy-o ^ HO 'F ОН 0.202 108 F aa ^f LI Ο ^HO A1 ° у оУ / A ⁿ x1 ^ nh ₂ ho 1— <1 il HO F ^N > y ^N Cl 0.246

- 199 039042

109 o sXX o Hon n X b < ^z D I XX ^o χ .. ^ 1.912 110 о nh ₂ О Уон м X Н U Ϊ уу Ar 7 ν'-a X ^{but F F} F 0.361 111 О NH ₂ h D ^on nB, H <X i Y / ° \ / λ ^Ν gg 'Cl Osl, ~ Nb' F nh ₂ 0.182 113 nh ₂ N._X f J Y V he oy o BoX ^ Uch y / X h ° he but no 0.161 114 nh ₂ cc he oH O HOOH / Dh h ° he but no 1,567 115 о νη ₂ О Уон Ν ^ .Χχ в <Дт ДД ° ХуВ N 'CI О хх о = (° ^Н he 0.872

- 200 039042

116 О NH ₂ О Ron | \ L Р р < ^z J ΐ nor ^ο ρ.- ^ο .Ρ О ΑΑ _Ο Ρ Ън Ιρ * 0.267 122 O fp About J 9 Г i ОРК ° about RA about R_ O 0.17 123 o NH ₂ o Ron m P Ap ^ ΑΑΪ ΑΑ ° p.o ^ P o. ° ДР Pv S ^ P ^ HO F ^Ζ Η 0.387 124 О ΝΗ ₂ О Ron R Ar K TA TA ^o r..o..r u / 8 8 \ ^ά - _Ν but F ro n 0.636 125 ΝΗ ₂ Ν- ^ Ρ J f / ^N nTdi F ₃ CO OH 9P_) _. P Ό.Ρ - .. Ρ Cl —- P ^ 3.O / 3: ¥ ϊ 3 — Pp ° OH HO 0.836

- 201 039042

127 nh ₂ f JA / Cl OH ox xoGG ^{4 F} T / ° he \ HO F 0.408 128 nh ₂ nGak, <'1 A ΝΜΌΙ OH ox. _c ^Cl c | GGMy_ _OH OH o 0.827 129 o NH ₂ O Mon hk A G < ^z Ju O £ J Μζ An ^ ^{ho f} 0.086 130 o NH ₂ o Mon nA. GJ < ^z J ΐ Gm ° G ° v ⁿⁿ G 'О O ₂ td ^HO ' ^F 1.045 131 o NH ₂ O Mon A G < ^z Ju ° A ^^ ^N ^ ^{N <iJxci} HO F 0.285 133 o S '^ X-X ^ -' 4 T-OH N .. „n G <G ϊ kJ HO 'F > 1

- 202 039042

134 O H Zones n3m L U 1 ^but £ XJ NO F 1.489 135 О МН ₂ О Hon X Л 31 η ₂ ν ^ ^H d ^f 0.272 136 ο ΝΗ ₂ О Hon Ν ^, Χ Л ¢ 33 Л / ° Л / ^{ν <} Χ 'о Л) ac 3n ^ ^{Hd f ζ} Η 1, 87 189 Η 14 χΥ but? - '1 Η io bn ^Ν γ ^Ν Cl mixture of diastereomers 0.597 190 fAf A? ^Ν Λ><о Λ = ^{Ν o} y ^ o ' ^z * X 3 ^N Gx ^NH2 ho ^z ? -1 1 II but 6h ^N y ^N Cl mixture of diastereomers 0.927

- 203 039042

191 F fAf ^h ill Άι 'A n, Γ 1 ^N > 7 n Z = N °' J oy y ^N ^ 3 but .X- / T II uo 'y Cl 0.215 192 7 “ ^N AZ О / = N _{Halano 3/1 II НО 6 Н} NyN Cl mixture of diastereomers 7.161 194 C ^{, FA 11 Ν} \ A _ο / = Ν Oyo'3 ^ 7 ^ν 3α ΝΗ ₂ no. '- / T II HO' he N <yN Cl 1.709 197 ° y ^{OH н} ill ^N H АА ^N i J | ^N UfA η / ^ ^Ν “'yo' ^ A X ^N \ 3v ^NH2 but / T ΙΪ no bn ^N y ^N Cl 2.433

- 204 039042

198 kA L 9 'but / - <T ¥ but he ^N y ^N Cl 0, 175 199 n A / d 1 «A / η / = Ν η A ο /. Ι- οΧ yN 1 ^ ΜΗ ₂ but A Υ if ^Η0 'όΗ ^Ν γ ^Ν CI 0, 665 200 Q γ с ₂ n ⁿ ή ^ν μ Α ¥ Ν? (LI] ^Ν X- - Ν ch X Ο ^ζ \ ^ο γ ¥ ζΧ ho. ³ - <Τ ¥ but he ^N y ^N Cl 0, 110 201 he X о X А ° γ θΑ HO / - <¥ ¥ but 'he ^N y ^N Cl 1, 822 203 ί 0 Ν Ν Υ- A Ο ^ο γΧοΆΤ but, a / 1 ¥ ^Η ° ΗΟ ^Ν Υ ^Ν CI 4.769

Table 6, the IC50 data are as follows: A means <1 μM, B means 1-3 μM and C means> 3 μM. ND means not disclosed.

Table 6

Compound 1C ₅₀ (μm) 0 0 Αοη _{νη 2} νΑμ <Τ ί Α ΗΓι Hu, ° - ΦΧΧ one Α but 'ΟΗ Η0 ₂ Υ one hundred

Incorporation by reference.

All publications and patents mentioned in this document are incorporated by reference in

- 205 039042 in their entirety, as if each individual publication or patent were expressly and separately indicated for inclusion by reference. If there is a discrepancy, then this application, including any definitions herein, will prevail.

Equivalents.

While specific embodiments of the subject matter have been discussed, the above description is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon consideration of this description and claims below. The full scope of the invention is to be determined by reference to the claims, in their entirety, of equivalents, and to the description in conjunction with such variations.

Claims (53)

1. Compound of formula (I) R ⁴ R ³ (I) or a pharmaceutically acceptable salt thereof, where X is O; Y represents O or S; Z represents NR ¹⁹ , O or S; Het is a purinyl ring or 5-methylpyrimidine-2,4-dione ring, where Het is optionally substituted with one or two substituents selected from halogen, CN, NO2, azido, hydroxy, C _1-6 alkoxy, C _1-6 αalkylthio, thioC _1-6 alkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, C _1-6 alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfonyl, phosphoryl, phosphate, phosphonate, phosphinate and C ₆ arylC _1-6 alkyl; R ^{1a is} selected from H, halogen, hydroxy, cyano, azido, amino, C _1-6 alkyl, hydroxy _{C 1-6} alkyl, amino-C _1-6 alkyl, —OC (O) —OC _1-6 alkyl, C _{1 -6} acyloxy, C _1-6 alkoxy, C _2-6 alkenyl and C _2-6 alkynyl α; and R ^{1b is} selected from H, halogen, C _1-6 alkyl, hydroxy-C _1-6 alkyl, amino-C _1-6 alkyl, C _2-6 α-alkenylα, and C _2-6 alkynyl; or R ^1a and R ^1b together with the carbon atom to which they are attached form C = CH ₂ or C = C (H) C _1-6 alkyl; R ^{2a is} selected from H, halogen, hydroxy, cyano, azido, amino, C _1-6 alkyl, hydroxy-C _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 acyloxy, -OC (O) -OC _{1 -6} alkyl, C _1-6 alkoxy, C _2-6 alkenyl, and C _2-6 alkynyl; R ^{2b is} selected from H, halogen, C _1-6 alkyl, hydroxy-C _1-6 alkyl, amino-C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl; or R ^2a and R ^2b together with the carbon atom to which they are attached form C = CH ₂ or C = C (H) C _1-6 alkyl; R ^{3 is} selected from H, C _1-6 alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkylC _1-6 alkyl, heterocyclyl, heterocyclyl _{C 1-6} alkyl, C ₆ aryl, C ₅ -C ₇ - arylC _1-6 alkyl, heteroaryl, heteroarylC _1-6 alkyl and - (CH2) C (O) OR ⁹ ; R ^{4 is} selected from heteroaryl, C _1-6 alkyl, -C (O) OR ⁹ , -C (O) NR ¹¹ R ¹² , -S (O) 2R ¹⁰ , -P (O) (OR ¹¹ ) (OR ¹² ) and -P (O) (OR ¹¹ ) (NR ¹³ R ¹⁵ ); R ^{5 is} selected from H, cyano, C _1-6 alkyl, C ₃ -C ₈ -cycloalkylC _1-6 alkyl, heterocyclylC _1-6 alkyl, C ₆ arylC _1-6 alkyl, heteroarylC _1-6 alkyl, and -C (O ) OR ⁹ ; R ^{6 is} selected from —C (O) OR ⁹ and —P (O) (OR ¹¹ ) (OR ¹² ); R ^{9 is} independently selected from H, C1-6alkyl, acyloxyC1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C8cycloalkyl, C3-C8cycloalkylC1-6alkyl, heterocyclyl, heterocyclylC1-6alkyl, C6aryl, C6arylC1-6alkyl, heteroaryl geteroarilS1-6alkila and - (CHR ¹³⁾ mZC (O) -R ^14; each R ^{10 is} independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, amino, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkyl _{C 1-6} alkyl, heterocyclyl, heterocyclyl _{C 1- 6} alkyl, C ₆ aryl, C ₆ arylC _1-6 alkyl, heteroaryl, and heteroarylC _1-6 alkyl; and each of R ¹¹ and R ^{12 is} independently selected from H, C1-6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylC1-6 alkyl, heterocyclyl, heterocyclylC1-6alkyl, C6aryl, C6arylC1-6alkyl, heteroaryl, heteroarylC1-6 alkyl and - (CHR ¹³ ) mZC (O) -R ¹⁴ ; or R ¹¹ and R ¹² together with the atoms to which they are attached form a 5-7 membered heterocyclyl; and each R ^{13 is} independently H or C _1-6 alkyl; each R ^{14 is} independently selected from C _1-6 alkyl, aminoC _1-6 alkyl, heterocyclyl, and heterocyclyl _{C 1-6} - 206 039042 alkyl; R ^{15 is} selected from C _1-6 alkyl, C ₆ arylC _1-6 alkyl, —C (R ¹⁶ ) (R ¹⁷ ) —C (O) OR ¹⁸ ; each of R ¹⁶ and R ^{17 is} selected from H, C _1-6 alkyl, aminoC _1-6 alkyl, hydroxyC _1-6 alkyl, mercaptoC _1-6 alkyl, sulfonylC _1-6 alkyl, C ₃ -C ₈ cycloalkyl, C ₆ aryl, C ₆ arylC _1-6 alkyl, heterocyclylC _1-6 alkyl, heteroarylC _1-6 alkyl and - (CH ₂ ) C (O) OR ⁹ ; R ^{18 is} selected from H, C _1-6 αalkyl, C _1-6 alkoxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, amido, C ₃ C ₈ cycloalkyl, C ₃ -C ₈ cycloalkyl _1-6 alkyl, heterocyclyl, heterocyclylC _1-6 alkyl, C ₆ aryl, C ₆ arylC _1-6 alkyl, heteroaryl, heteroarylC _1-6 alkyl; R ¹⁹ represents H or C _1-6 αalkyl; and m is 1 or 2; provided that a) either R ⁴ is tetrazolyl or R ⁵ is C ₆ arylC _1-6 alkyl or heteroarylC _1-6 alkyl, or both, and b) if R ^1a and R ^2a are each hydroxy, then R ^2b is C _1-6 αalkyl or C _2-6 alkynyl; where each heterocyclyl is a 3-10 membered ring having 1-4 heteroatoms selected from nitrogen, oxygen and sulfur; and each heteroaryl is a 5-7 membered aromatic ring having at least 1 heteroatom selected from nitrogen, oxygen and sulfur; where C _1-6 alkyl, C ₁ -C ₆ -alkylaminoC _1-6 alkyl, acylaminoC _1-6 alkyl, C _2-6 alkenyl, C _1-6 α alkoxy, C _1-6 alkoxy _{C 1-6} alkyl, C ₆ aryl , C ₆ arylC _1-6 alkyl, C ₆ aryloxy, C ₆ aryloxyC _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkylC _1-6 alkyl, heterocyclyl, heterocyclylC _1-6 alkyl, heterocyclylC _1-6 alkoxy , heteroaryl, geteroarilS1-6alkil, heteroaryloxy or geteroariloksiS1-6alkil optionally substituted with one or more substituents selected from halo, hydroxy, carboxyl, C _1-6 alkoxycarbonyl, formyl, acyl, thioester, thioacetate, thioformate, C _1-6 alkoxy, phosphoryl , phosphate, phosphonate, phosphinate, amino, amido, amidino, imino, cyano, nitro, azido, sulfhydryl, C _1-6 alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, C ₆ arylC _1-6 alkyl, C ₆ aryl and heteroaryl. 2. A compound according to claim 1, wherein R ^1a is selected from H, halogen, hydroxy, cyano, azido, amino, C _1-6 αlkila, hydroxyC _1-6 alkyl, amino-C _1-6 αlkila, C _1-6 acyloxy , C _1-6 α-alkoxy, C _2-6 alkenyl and C _2-6 alkynyl. 3. A compound according to claim 1, wherein R ^1a is fluoro. 4. A compound according to claim 1, wherein R ^1a is chlorine. 5. A compound according to claim 1, wherein R ^1a is hydroxy. 6. A compound according to claim 1, wherein R ^2a is selected from H, halogen, hydroxy, cyano, azido, amino, C _1-6 αlkila, hydroxyC _1-6 alkyl, amino-C _1-6 αlkila, C _1-6 acyloxy , C _1-6 α-alkoxy, C _2-6 alkenyl and C _2-6 alkynyl. 7. A compound according to any one of claims 1-6, wherein R ^2a is C _1-6 alkyl. 8. A compound according to any one of claims 1-6, wherein R ^2a is hydroxy. 9. A compound according to any one of claims 1-6, wherein R ^2a is ethynyl. 10. A compound according to any one of claims 1-9, wherein R ^2b is C _1-6 alkyl. 11. A compound according to claim 1, wherein R ^1a is fluoro and R ^1b is H. 12. A compound according to claim 1, wherein R ^1a is fluoro and R ^2a is hydroxy. 13. A compound according to claim 1 wherein R ^1a is chlorine and R ^2a is hydroxy. 14. A compound according to claim 1 wherein R ^1a is hydroxy and R ^2a is C _1-6 alkyl. 15. A compound according to claim 1, wherein R ^1a is hydroxy, R ^2a is hydroxy, and R ^2b is C _2-6 α-alkyl. 16. A compound according to claim 1 wherein R ^1a is hydroxy and R ^2a is C _2-6 alkynyl. 17. A compound according to any one of the preceding claims, wherein R ³ is H. 18. A compound according to any one of claims 1-16, wherein R ³ is unsubstituted C _1-6 alkyl. 19. A compound according to any one of claims 1-16, wherein R ³ is C _1-6 alkyl and the alkyl is unsubstituted or substituted with one or more substituents selected from halogen, CN, NO2, azido, hydroxy, C _1-6 alkoxy, C _1-6 alkylthio, thioC _1-6 alkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, C _1-6 alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate and phosphinate. 20. A compound according to claim 19, wherein the substituents are selected from halogen, CN, azido, C _1-6 alkoxy, carbonyl, amino, amido, and C _1-6 α-alkoxycarbonyl. 21. A compound according to any one of the preceding claims, wherein R ⁴ is heteroaryl. 22. A compound according to any one of the preceding claims, wherein R ⁴ is tetrazolyl. 23. A compound according to any one of the preceding claims, wherein R ^{4 is} selected from —C (O) OR ⁹ , —C (O) NR ⁿ R ¹² , —S (O) 2R ^10, and —P (O) (OR ¹¹ ) ( OR ¹² ). 24. A compound according to any one of the preceding claims, wherein R ⁴ is —C (O) OR ⁹ . 25. A compound according to any one of claims 1-20, wherein R ⁴ is C _1-6 alkyl. 26. A compound according to any one of claims 1 to 21, wherein R ⁴ is —C (O) NR ¹¹ R ¹² . 27. A compound according to any one of the preceding claims, wherein R ^{5 is} selected from C _1-6 α-alkyl, C ₃ -C ₈ - 207 039042 cycloalkylC1-balkyl, heterocyclylC _1-6 alkyl, SbarylC1-balkyl and heteroarylC _1-6 alkyl, and each is unsubstituted or substituted by one or more substituents selected from halogen, CN, NO2, azido, hydroxy, C _1-6 alkoxy, C _1-6 alkylthio, thioC _1-6 alkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, C _1-6 α alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, phosphinate, C ₃ -C ₈ -cycloalkyl, heterocyclyl, C ₆ arylC _1-6 alkyl and heteroarylC _1-6 alkyl. 28. A compound according to claim 27, wherein the substituents are selected from halogen, CN, azido, C _1-6 alkoxy, carbonyl, amino, amido, and C _1-6 α-alkoxycarbonyl. 29. A compound according to any one of the preceding claims, wherein R ^{5 is} selected from H, C _1-6 alkyl, C ₃ -C ₈ cycloalkylC _1-6 alkyl, heterocyclylC _1-6 alkyl, C ₆ arylC _1-6 alkyl, and heteroarylC _{1- 6} alkyl. 30. A compound according to any one of the preceding claims, wherein R ⁵ is H or C ₆ arylC _1-6 alkyl. 31. A compound according to any one of claims _{1 to} ^{29, wherein R 5} is C ₆ arylC 1-6 alkyl or heteroarylC _1-6 alkyl. 32. A compound according to claim 31, wherein R ⁵ is heteroarylC _1-6 alkyl, wherein the heteroaryl ring is selected from benzofuranyl, benzothienyl, benzothiazolyl, pyridyl, thienyl, furanyl, pyrazolyl, thiazolyl and oxazolyl and oxadiazolyl, each of which may be substituted or unsubstituted. 33. The connection according to any one of claims 31? 32, wherein R ⁵ is unsubstituted or substituted by one or more substituents selected from halogen, CN, OH, C _1-6 alkyl, C _2-6 alkenyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, C _1-6 α-alkoxy, haloC _1-6 alkoxy, C ₆ aryloxy, C ₆ arylC _1-6 alkyloxy, C _1-6 alkylsulfonyl, sulfonamido, amido, amino, hydroxycarbonyl, C _1-6 α-alkoxycarbonyl, heteroaryl, C6aryl, C6arylC1-6alkyl and heteroarylC1- 6alkyl. 34. A compound according to claim 33, wherein the substituents are selected from halogen, CN, haloC _1-6 alkyl, haloC _1-6 alkoxy, carboxy, C _1-6 alkoxycarbonyl, and C ₆ aryl. 35. A compound according to claim 33, wherein the substituents are selected from tetrazolyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl. 36. A compound according to claim 33, wherein R ⁵ is unsubstituted or substituted with one or more substituents selected from chlorine, trifluoromethyl, trifluoromethoxy, phenyloxy, dimethylamido, methylsulfonyl, CN, and carboxylic acid. 37. A compound according to any one of the preceding claims, wherein R ⁶ is —C (O) OR ⁹ . 38. A compound according to any one of the preceding claims, wherein R ⁹ is H, C _1-6 aalkyl, or amido. 39. A compound according to any one of the preceding claims, wherein R ⁹ is H, methyl or ethyl. 40. A compound according to any one of the preceding claims, wherein R ¹¹ and R ¹² are each H. 41. A compound according to any one of claims 1 to 39, wherein R ¹¹ and R ¹² are each C _1-6 alkyl. 42. A compound according to any one of claims 1 to 37, wherein each of R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 is} independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 α-alkyl, amido, C _3-8 cycloalkyl, C _3-8 cycloalkylC _1-6 alkyl, heterocyclyl, heterocyclylC _1-6 alkyl, C ₆ aryl, C ₆ arylC _1-6 alkyl, heteroaryl and heteroarylC _1-6 alkyl, and each is unsubstituted or substituted with one or more substituents selected from halogen, CN, NO ₂ , azido, hydroxy, C _1-6 alkoxy, C _1-6 alkylthio, thioC _1-6 alkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, C _{1- 6} α-alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate and phosphinate. 43. A compound according to claim 42, wherein the substituents on each of R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are selected from halogen, CN, azido, C _1-6 alkoxy, carbonyl, amino, amido, and C _1-6 α-alkoxycarbonyl. 44. A compound according to any one of the preceding claims, wherein X is O. 45. A compound according to any one of the preceding claims, wherein Y is O. 46. A compound according to any one of the preceding claims, wherein Z is O. 47. A compound according to any one of the preceding claims, wherein Het is unsubstituted or substituted with one or more substituents selected from halogen, CN, NO2, azido, hydroxy, C _1-6 α alkoxy, C _1-6 alkylthio, thioC _1-6 alkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, C _1-6 alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfonyl, phosphoryl, phosphate, phosphonate and phosphinate. 48. A compound according to claim 47, wherein the substituents are selected from halogen, CN, azido, C _1-6 alkoxy, carbonyl, amino, amido, and C _1-6 alkoxycarbonyl. 49. A compound according to any one of claims 1 to 46, wherein Het is - 208 039042 50. A compound according to claim 1, wherein Het is selected from 51. A compound according to claim 1, wherein Het is substituted with one or two substituents selected from halogen, C6arylC _1-6 alkyl, amino, azido, and hydroxy. 52. A compound according to claim 51, wherein Het is selected from 53. The connection according to claim 1, where