BR112021004435A2 - cd73 inhibitors and their pharmaceutical uses - Google Patents

Abstract

"CD73 INHIBITORS AND THEIR PHARMACEUTICAL USES". The present invention relates to CD73 inhibitory compounds (also known as ecto-5'-nucleotidase) are provided, as well as compositions and uses thereof for the treatment or prevention of diseases, disorders and conditions associated with or related to CD73, including disorders related to cancer and the immune system. CD73 inhibitory compounds include compounds having the structure shown in Formula I and pharmaceutically acceptable esters or salts thereof.

Description

Invention Patent Descriptive Report for "CD73 INHIBITORS AND THEIR PHARMACEUTICAL USES".

CROSS REFERENCE TO RELATED ORDERS

[001] This application claims the priority benefit of US Provisional Application No. 62/773,267, filed on November 30, 2018, and Chinese Patent Application No. 201811057145.X, filed on September 11, 2018, each of which is herein incorporated by reference in its entirety.

FIELD

[002] The present invention relates to compounds and compositions that inhibit CD73 (ecto-5-nucleotidase) and their uses to treat and/or prevent diseases, disorders and conditions associated with or related to CD73, including cancer-related disorders. and to the immune system.

BACKGROUND

[003] Ectonucleotidases are a group of etoenzymes located on the cell surface. Members of the ectonucleotidase family include ectonucleotide pyrophosphatase/phosphodiesterases (E-NPPs), ectonucleoside triphosphate diphosphohydrolases (E-NTPDases), ecto-5'-nucleotidase (eSNT, also known as CD73) and alkaline phosphatase ( AP). These enzymes hydrolyze a variety of extracellular nucleotides to nucleosides, including adenosine. Extracellular nucleotides are important signaling molecules that trigger cellular responses by acting on their respective receptors (eg, adenosine activates P1 receptors, and their nucleotides (ADP, ATP) activate P2 receptors. Adenosine 5'-monophosphate (AMP) is a major substrate of CD73 that is hydrolyzed to adenosine. Adenosine is present throughout the body and is an important regulator of purinergic cell signaling, vital for many physiological and pathophysiological processes.

[004] There are many data that implicate the enzymatic activity of CD73 in the promotion and metastasis of cancer. CD73 is up-regulated in many types of cancer cells and tumors, and its expression has been shown to be associated with tumor neovascularization, invasion, and metastasis. The hydrolytic cascade from extracellular ATP to adenosine is an important immunosuppressive regulatory pathway in the tumor microenvironment. Overexpression of CD73 impairs adaptive anti-tumor immune responses and enhances tumor growth and metastasis. Extracellular adenosine is also involved in the regulation of adaptive responses to hypoxia. Decreased eS5NT activity with monoclonal antibodies, siRNA, and small molecule inhibitors including AMPCP (adenosine [(a,B)-methylene]diphosphate) has been shown to attenuate tumor growth and metastasis (see, for example, Zhou et al. al., Oncol.Rep. 17 (2007): 1341-1346; Stagg and Smyth, Oncogene, 29 (2010): 5346-5358). Tumor growth is also impaired in CD73-deficient mice and it has been established that these effects are largely mediated by decreased adenosine production in these mice. CD73 inhibitors have been actively explored for their therapeutic potential against cancer (see, for example, M. al-Rashida et al., Eur. J. Med. Chem., 115 (2016): 484-494, and references cited therein).

[005] Tumor cells overcome antitumor responses in part through immunosuppressive mechanisms. There are several such modulatory immune mechanisms. Among them, adenosine is a key factor that can be generated by cancer and immune cells in the tumor microenvironment to suppress antitumor responses. The generation of adenosine from adenosine triphosphate (ATP) is catalyzed by two cell surface proteins, CD73 and CD39, and can be increased under metabolic stress, such as conditions of tumor hypoxia. Adenosine exerts its immunoreactive functions.

gulators through four adenosine receptors (ARs), called A1, A2A, AZB and A3, which are expressed in various cells of the immune system. Overexpression of adenosine-generating enzymes such as CD73 and ARs has been correlated with tumor progression in a multitude of cancers. Since ARs signaling increases tumor progression, their modulation also represents a promising therapeutic approach for cancer (MH Kazemi, et al., J. Cell. Physiol., 233 (2018): 2032-2057, and references cited there).

[006] As mentioned above, ectonucleotidases are enzymes located on the cell surface that regulate purinergic (and pyrimidinergic) signaling pathways. There are four distinct families of ectonucleotidases: ectonucleoside triphosphatiphoshydrolase (CD39), ectonucleotide pyrophosphatases/phosphodiesterases, alkaline phosphatases and ecto-5 -nucleotidase (eSNT, also known as CD73). CD73 is a di-Zn metallophosphatase anchored in glycophosphatidylinositol. CD73 catalyzes the dephosphorylation of extracellular adenosine monophosphate (AMP) to adenosine. This ectoenzymatic cascade together with CD39 generates adenosine from ATP. CD73-catalyzed conversion of AMP to adenosine is considered a major contributor to elevated levels of extracellular adenosine in the tumor microenvironment (Stagg, J. et al., Proc. Natl. Acad. Sci. USA: 107 (2010) : 1547- 1552). The expression of CD73 is directly up-regulated by hypoxia-inducible factor-1a, which explains the observed increase in extracellular adenosine in hypoxic malignant tumors. CD73 is also expressed by regulatory T cells (Tregs) and promotes Treg-mediated immunosuppression (Stagg J, et al., Cancer Res. 71 (2011): 2892-2900). In addition, CD73 is induced by the transformation of growth factor-B (TGF-B), tumor necrosis factor-a (TNF-a), hepatocyte growth factor (HGF), interleukin-6 (IL-

6), mitogen activated protein kinase (MAPK), signal transducers and activators of transcription 3 (STAT3), interleukin-2 (IL-2), retinoic acid, intwingless (WNT), epithelial to mesenchymal and mu- p53 tations. CD73 is overexpressed in several types of tumor and promotes the invasion, migration and adhesion of tumor cells. CD73 is also associated with immune tolerance and poor prognosis in cancer. CD73 is a promising target for anticancer drug development. In addition, CD73 inhibitors have potential for the treatment of other diseases mediated by adenosine and its receptors (Y.-P. Gong, et al., Expert Opin. Ther. Pat., 28 (2018): 167-171) .

The adenosine pathway is also known to be an important immunosuppressive component of many human tumors (for review, see, Whiteside, T.L., Expert Rev. Anticancer Ther., 17 (2017): 527-535). Adenosine and inosine emerge as critical points of immune control in cancer. The cooperation of adenosine and PGE2 pathways in the tumor microenvironment contributes to the suppression of antitumor immune effector cells. Targeting the adenosine pathway with pharmacological inhibitors or antibodies is, therefore, a promising therapeutic strategy in cancer.

[008] The blocking activities of ectonucleotidases or adenosine receptor signaling in preclinical in vivo studies were successful in inhibiting tumor growth and metastasis. Blockade of the adenosine pathway alone or in combination with other immunological therapies, including checkpoint inhibitors, is currently being implemented in phased clinical trials | initials for individuals with advanced malignant diseases.

[009] Small molecule inhibitors of CD73 have been reported. For example, Adams et al. (PCT International Application Publication No. WO 2017/098421) describes substituted benzothiadiazine derivatives which are inhibitors of CD73, their pharmaceutical compositions and their use in the treatment of cancer, precancerous syndromes and diseases associated with CD73 inhibition.

[0010] Debien et al. (PCT International Application Publication No. WOZ2017/120508; U.S. Patent Application Publication No. US2017/0267710) describe compounds that modulate the conversion of AMP to adenosine by 5'-nucleotidase, ecto, compositions containing the compounds, methods to synthesize the compounds, and the use of such compounds and compositions for the treatment and/or prevention of a variety of diseases which are mediated by 5'-nucleotidase, ecto.

[0011] Cacatian et al. (PCT International Application Publication No. WOZ2015/164573) describes purine derivatives and their pharmaceutical compositions which are inhibitors of CD73 and are useful in the treatment of cancer.

[0012] Chen et al. (PCT International Application Publication No. WO 2018/049145) describes the preparation of nucleotides as ectonucleotidase inhibitors and the use of the compounds in the treatment or prevention of cancer.

[0013] The contents of all documents and references herein cited are hereby incorporated by reference in their entirety.

SUMMARY

The present invention relates to compounds and compositions comprising the compounds that inhibit the activity of ecto-5'-nucleotidase (also known as e5NT, CD73, NTSE and SNT). Inhibition of the enzymatic activity of CD73 leads to inhibition or modulation of extracellular adenosine levels and, therefore, modulates the physiological environment of cells and tissues.

[0015] The present invention also relates to the use of such com-

stations and compositions for the treatment and/or prevention of diseases, disorders and conditions mediated, in whole or in part, by CD73. CD73 inhibitors have been associated with the treatment of many disorders, including cancer, fibrosis, neurological and neurodegenerative disorders (eg, depression and Parkinson's disease), ischemic brain and heart diseases, disorders related to the immune system, and disorders with an inflammatory component. In particular embodiments, the CD73 inhibitory compounds and compositions described herein can act to inhibit the immunosuppressive activity and/or the anti-inflammatory activity of CD73, and are useful as therapeutics or prophylactic therapies when such inhibition is desirable.

[0016] In a first broad aspect, compounds of Formula | and their pharmaceutically acceptable salts or esters:

RR

o) | NO OH R' (1) where W is oxygen, sulfur, nitrogen or a methylene group; X is a selected portion of phosphonyl (-P(=O)(OR)—), sulfonyl (-S(=O)>—) and carbonyl (-C(=O)—) fragment, where R is hydrogen, ester-forming group or protecting group; Y is selected from phosphonate (-PO3R>2), sulfonate (-SO3R) and carboxylate (-CO2R), where R is a hydrogen, an ester-forming group or a protecting group; R'! is a hydroxyl group or a hydrogen; R? is chlorine or hydrogen; and Rº and Rº are independently selected from hydrogen, alkyl group, alkenyl group and alkynyl group, where at least one of Rº and Rº has a carbon number from 11 to 30.

[0017] In one modality, R? and Rº are independently selected.

fused from hydrogen and a ring system, the ring system being a bicycle, tricycle, spiral ring, fused ring or bridged ring containing the carbocyclic (aromatic or non-aromatic) or heterocyclic ring system, and the system of ring being substituted or unsubstituted, provided that R? and Rº are not both hydrogen at the same time.

[0018] In another modality, R? is hydrogen or a lower alkyl (eg, C1-6) and R° is —C(=O)R$ or —C(=0)ORS, where R° is a C11-30 alkyl group, a C11- group 39 alkenyl or a C11-320 alkynyl group.

[0019] In some embodiments, Rº is hydrogen or a lower alkyl and Rº is —C(=O)Rº or —C(=0)ORS, where Rº is a ring system that is a bicycle, tricycle, spiral ring, fused ring or bridged ring containing the carbocyclic (aromatic or non-aromatic) or heterocyclic ring system, the carbocyclic or heterocyclic ring system being substituted or unsubstituted.

[0020] In one embodiment, compounds of Formula II and/or Formula III, and their pharmaceutically acceptable salts or esters, are provided:

RR RJ RA

O O vox" o S | nº vox" o S NOT OH R' (11), OH R' (11) where W, X, Y, Ri, Rô, and Rº are as defined above.

[0021] In another embodiment, compounds of Formula IV and their pharmaceutically acceptable salts or esters are provided:

RW R o < 1 NANA nz o NOR YOXx 7 o OH R' (IV) where X, Y, R1, R2, R6, and Rº are as defined above.

[0022] In yet another embodiment, compounds of Formulas V and/or VI, and pharmaceutically acceptable salts or esters thereof, are provided: Rê .Rº 3 - 4

AN RIR < 1 < 1

NA ÇA NANA O N o NC! YOXx the. YOXx the. OH R' (V), OH R' (VI) where X, Y, R 1 , R e and R° are as defined above.

[0023] In another modality, compounds of Formulas VII and/or VIII are provided, and their pharmaceutically acceptable salts or esters: R$ Rô

N NR

N 1 oo EO ; PQ C-O NOR RO A o.

OR oH R (VI), R$ Rô

N NR

N 1 99 EO , CC PR-O NOR ROMA o

OR OH R' (VII) where R is hydrogen, an ester-forming group or a protecting group; and R1, R2à, Rº and Rº are as defined above.

[0024] In yet another embodiment, compounds of Formulas IX and/or Xl, and pharmaceutically acceptable salts or esters thereof, are provided.

available:

RR

NR to A, RO OR OR > oH R (IX) where R is hydrogen, an ester-forming group or a protecting group; and R1, R2à, Rº and Rº are as defined above.

[0025] In one embodiment, R' is a hydroxyl group (ie, the carbohydrate moiety in the compound is a D-ribosyl moiety). In another modality, R' is hydrogen (ie, the carbohydrate moiety in the compound is a 2-deoxy-D-ribosyl moiety).

[0026] In another modality, R? is hydrogen. In yet another modality, R? is hydrogen and R' is a hydroxyl group (ie, the compound is an adenosine derivative). In another modality, R? is hydrogen and R' is hydrogen (ie, the compound is a derivative of deoxyadenosine). In yet another modality, R? is hydrogen and both R° and R° are not hydrogen (that is, the compound is an adenosine derivative or a deoxyadenosine derivative with substituent groups on the amino group of the adenine moiety). In another modality, R? is chlorine and the compound is a 2-chloro-D-adenosine derivative or a 2-chloro-D-deoxyadenosine derivative.

In some embodiments, R° is hydrogen or a lower alkyl (eg, C1-6), and R° is an alkyl, alkenyl, or alkynyl group having 11 to 30 carbon atoms (ie, a C11-group 30 alkyl, a C11-30 alkenyl group or a C11-30 alkynyl group). In some embodiments, R° is a hydrogen or lower alkyl and R° is a group containing an adamantyl moiety. R° can be, for example, substituted or unsubstituted 1-adamantyl, substituted or unsubstituted 2-adamantyl, substituted or unsubstituted 1-adamantylmethyl,

Substituted or unsubstituted 1-adamantylpropyl, substituted or unsubstituted 1-adamantylpropyl, or substituted or unsubstituted 1-adamantylbutyl. In some embodiments, R° is a hydrogen or lower alkyl and R° is a group containing a naphthyl moiety. R° can be, for example, substituted or unsubstituted a-naphthyl, substituted or unsubstituted B-naphthyl, substituted or unsubstituted a-naphthylmethyl, substituted or unsubstituted B-naphthylmethyl, substituted or unsubstituted naphthylethyl, naphthylpropyl substituted or unsubstituted; or substituted or unsubstituted naphthylbutyl.

[0028] In another modality, R? is hydrogen or a lower alkyl and R° is a substituent group containing a bicyclic, tricyclic or multicyclic ring system, where the ring system is fused, spiral, bridged or parallel, and where the ring system is carbocyclic , aliphatic, aromatic, heterocyclic or a combination thereof.

[0029] In another embodiment, Rº is hydrogen or a lower alkyl, and Rº is —C(=O)Rº or —C(=0)ORS*, where Rº is an alkyl group or an alkenyl group or an alkynyl group having 11 to 30 carbon atoms.

[0030] In some embodiments, Rº is hydrogen or a lower alkyl, and Rº is —C(=O)Rº or —C(=0)ORº, where Rº is a substituent group containing a bicyclic, tricyclic ring system or multicyclic, where the ring system is fused, spiral, bridged or parallel, and where the ring system is carbocyclic, aliphatic, aromatic, heterocyclic, or a combination thereof.

[0031] In one embodiment, Rº is a group containing an adamantyl moiety. In another embodiment, R° is a substituted or unsubstituted 1-adamantyl or 2-adamantyl. In yet another embodiment, R° is a substituted or unsubstituted 1-adamantylmethyl. In some embodiments, R° is 1-adamantylethyl, 1-adamantylpropyl, or 1-adamantylbutyl, where the adamantylbutyl moiety can be substituted or unsubstituted.

[0032] In another modality, Rº is a group containing the naphthyl portion. In another embodiment, R° is substituted or unsubstituted a-naphthyl or B-naphthyl. In another embodiment, R° is a-naphthylmethyl or B-naphthylmethyl, without or with additional substitution. In yet another embodiment, R° is selected from naphthyl, naphthylpropyl and naphthylbutyl, wherein the naphthyl portion may be unsubstituted or substituted.

[0033] In another embodiment, Rº and R$, together with the nitrogen to which they are attached, form a fused tricyclic ring system, such as, without limitation, a substituted or unsubstituted carbazolyl moiety.

In some embodiments, compounds of Table 1 and their pharmaceutically acceptable salts or esters are provided. Table 1. Structures of example compounds.

TO N. R and EO 1 To NANA, RL PB-O Ne HO TX on == oH OH

TC N. oo EO 2 brio

O OF

LO 3 NA RN eg O JR R-O NoNÃa dO OH Or =

OH OH

Boc.,-B o“ oc

AT

N 2 o EA

P NONE 4 Aero o o . Z

NNE LO

DO o o < 1 RT R-o No HOT A o

OH OH

OH OH +

AT

N eo O BP P-o NON a HOT Oo.

OH OH OH OH “O AT N

The 7 ê of the SS HO o.

OH OH

oh oh o

AT

N 1 go EO BL R-O Node DE! HOT A o

OH OH OH OH LAS

NEAR H ca 1

PR PO NON CI HOT NT o

OH OH OH OH N AT

N o 99 EO B Po NON hey

HOT AND THE O OH OH

OH OH o HN to ss. 1 ú 8 to S Leo HOT A Oo.

OH OH OH OH O

IN THE ? gs A A - N HoRRrom Node >CI

OH OH

OH OH . It is 138 NEN o Oo <€ | 2 and SA, in the "R o o o

OH OH OH OH DD HNOTN D

NEAR 14 N 8 SAA Pp P-O NON DCI HOT A o.

OH OH

oh oh o

ODAODADSAÔODÔU no “O 71 2 AA, Hoi ho

OH OH

OH OH n 16 HNT S e TO " 5 N ã npotho QN NA

OH OH OH OH

HNU A " O 2 UA uu TR N PA Horrrom nNode>eCI

OH OH

OH OH o iAH

H

O 1 18 2 8 AU, Ho Rs ho Oo.

OH OH OH OH ADAODÔADADÔADÔANNWOSADÔADÔADÔHA AT

N 1 19 2 of the SS HOTEL o

OH OH OH OH

LOCO To 1 oo ROOM RR-O NC HO VAL o

OH OH OH OH

TS 2 To 1 oo PR OPR-O NC HO IVA ROOM o

OH OH

OH OH Mr.

HN 22 NEN o o < 1 PQ R-O Na

HOT INE O OH OH

oh oh o to

To H

HNT O 23 NA 28, AA To 2 RP P-O NON CI

HO PC OH OH o

OH OH T

HN 24 N YN o o <A] AA BL P-O NON >ECI HO" OH OH o

OH OH

NA o Oo < |] À BL B-o NON DEI HOT. O

OH OH

OH OH gn IN ONO

NS eo EO 26 RA R-O N NO HO SR Oria

OH OH 27 x W

NEAR

N 1 o o EO Ho ARO N Cl OH OH =

OH OH x & mn

N H H 28 SN 7 oo ROOM PQ P-O NC HOT VAL o

OH OH

OH OH node 3 A und-o À 29 Do o o << 1 BR R-o NO HO A O.

OH OH

OH OH yu o N— Ao" A

HN

DO go SA A PQ OP-O NO HO IA o.

OH OH

OH OH 31 DO 7 oo AA ROR-O NC HOT IVA o.

OH OH

OH OH NH>

AT

N ga O 32 B NON CI no Ro o OH C >

OH OH

LAS m

NEAR

N ” 9 o EO — NON CI engine

oh OH OH

LAS NEAR n

N * 2 1 8 P-O NON CI MAN o

oh OH OH

LAS NEAR n

N ” and O So NON e! HOT o o

OH OH

LAS ny

NAS 36 N o Op CA uu TEA N ã

PPC NC HOW A o

OH OH OH OH

HN 37 NA o Oo < 1 x RU R-o NON HOT VA O.

OH OH OH OH CD N AT

N so e TO uu N Z PO P-O AT THE HOTEL o

OH OH OH OH H CX. O N YN ” E E, PQ R-O

OD HO OK on ==

OH OH

RS “the Q 8 of the S Nexus

HO OH on Co

oh oh o

HN TO AT

N “ga TT Pp Pp-O NON CI HO) o

OH OH

oh oh knot

LN HN AT

No ga TT Pp Pp-O NON CI HO) o

OH OH OH OH oh

HNO 43

EO o Oo Ho ARO v NO OH OH Co,

OH OH n 4 HN"

NS N o < 1 2 A AL BO R-O Node and HOTEL o

OH OH

oh oh o

O O ace O o o Cdx 2 O N Z HoRhrom Node

OR OH

OH OH q

N LO HN AT

N ás o o Ex uu TR N Ná Cl Ho hÃo O.

OH OH OH OH N SL HNON

NAN u go. of the BL po NON CI Ho o

oh oh

OH OH 48 SÃO go NAL " UR N Z Ho RX RO o N Cl

OH OH OH OH

| %

N 49 NES o O <1 À Bu B-o NONÉ>CI HOT AA o

OH OH OH OH

HO HoN yH HNSOo 50 o RN o o BL R-O NON HOT NA o

OH OH OH OH

O “ “O o Oo < |] A R-o NONa HOT o

OH OH OH OH AT NEAR H

N ” cs 1 PQ 8S-O NON CI HOT TA o

OH O OH OH

[0035] In some embodiments, a compound as described herein is provided, wherein the C, H, O, and N atoms in the compound are each independently selected from atoms of natural abundance and atoms enriched with isotopes . Examples of isotope-enriched atoms include, without limitation, 12C, *%C and *C for carbon; *H, 2H and -H for hydrogen; *ºO, "O and *ºO for oxygen; and **N and *ºN for nitrogen.

In a second broad aspect, pharmaceutical compositions are provided comprising a compound in the present document described, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier. In some embodiments, pharmaceutical compositions comprising a compound of any of the Formulas are provided. to IX, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier. In some embodiments, pharmaceutical compositions comprising a compound of any of Formulas are provided. to IX, or a pharmaceutically acceptable salt or ester thereof, wherein, in the compound, one of R$ and Rº is not hydrogen or a C1 to C10 alkyl, alkenyl or alkynyl group. In some embodiments, pharmaceutical compositions are provided comprising a compound shown in Table 1, or a pharmaceutically acceptable salt or ester and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier comprises a cream, an emulsion, a gel, a liposome or a nanoparticle.

In some embodiments, the pharmaceutically acceptable carrier further comprises at least one additional therapeutic agent, such as, without limitation, a chemotherapeutic agent, an immunomodulatory and/or inflammation modulating agent, an antihypercholesterolemic agent, or an agent anti-infective. In one embodiment, the at least one additional therapeutic agent is an immunological checkpoint inhibitor. Non-limiting examples of immunological checkpoint inhibitors include ipulimumab, nivolumab, and lambrolizumab.

[0038] In a third broad aspect, provided are compounds, compositions and methods of inhibiting the activity of CD73 in an individual in need thereof, comprising administering to the individual an effective amount of a compound and/or a com- pharmaceutical position in this document described.

In particular embodiments, the compounds described herein act to inhibit the immunosuppressive activity and/or the anti-inflammatory activity of CD73 and are useful as therapeutic or prophylactic therapy when such inhibition is desired. Unless otherwise indicated, when uses of the compounds of the present invention are described herein, it is to be understood that such compounds may be in the form of a composition (for example, a pharmaceutical composition). When used herein, the terms "CD73 inhibitor", "CD73 blocker", "adenosine by ecto-5'-nucleotidase inhibitor", "NTSE inhibitor", "TSN inhibitor" and all others terms accepted in the art are used interchangeably to refer to a compound capable of inhibiting, directly or indirectly, the CD73 receptor in an in vitro assay, an in vivo model and/or other assay means indicative of CD73 inhibition and potential therapeutic or prophylactic efficacy. The terms also refer to compounds that exhibit at least some therapeutic or prophylactic benefit in a human subject.

Although the compounds of the present invention are believed to have an effect by inhibiting CD73, a precise understanding of the underlying mechanism of action of the compounds is not necessary for the practice of the invention. For example, the compounds may also have an effect, at least in part, through modulation (eg, inhibition) of other components of the purinergic signaling pathway (eg, CD39). The purinergic signaling system consists of transporters, enzymes and receptors responsible for synthesizing, releasing

ration, action and extracellular inactivation of (mainly) ATP and its extracellular degradation product adenosine. As inhibition of CD73 results in decreased production of adenosine, CD73 inhibitors can be used for the treatment of diseases or disorders mediated by adenosine and its actions at adenosine receptors, including A1, A2A, A2B and A3 .

For the purposes of the present description, the purinergic signaling process can be described as comprising the following components. Purinergic receptors (P1, P2X and P2Y), a first component, are membrane receptors that mediate various physiological functions (eg, bowel smooth muscle relaxation) as a response to the release of ATP or adenosine ; in general, all cells have the ability to release nucleotides into the extracellular environment, often by regulated exocytosis. Nucleoside transporters (NTs), a second component, are membrane transport proteins that transport nucleoside substrates (eg, adenosine) across cell membranes; the extracellular concentration of adenosine can be regulated by NTs, possibly in the form of a feedback loop connecting the receptor signaling with the transporter function. As previously described, ectonucleotidases (CD73 and CD39) hydrolyze nucleotides released into the extracellular environment and comprise another component.

[0042] In some embodiments, methods are provided for treating or preventing cancer in an individual (e.g., a human), comprising administering to the individual a therapeutically effective amount of at least one CD73 inhibitory compound or composition in the this document described. In some embodiments of such methods, the subject is administered at least one CD73 inhibitory compound or composition in an amount effective to reverse, slow or halt the progression of CD73-mediated immunosuppression. In some modalities, CD73-mediated immunosuppression is mediated by an antigen-presenting cell (APC).

[0043] The type of cancer or tumor that can be treated or prevented using the compounds and compositions described herein is not intended to be particularly limited. Examples of cancers and tumors that can be treated or prevented using the compounds and compositions described herein include, but are not limited to: cancers of the prostate, colorectal, pancreas, cervix, stomach, endometrium, brain, liver , bladder, ovary, testis, head, neck, skin (including melanoma and basal carcinoma), mesothelial lining, white blood cells (including lymphoma and leukemia), esophagus, breast, muscle, connective tissue, lung (including lung carcinoma small cell and non-small cell carcinoma), adrenal gland, thyroid, kidney, bone, glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma, choriocarcinoma, cutaneous basal cell carcinoma and testicular seminoma. In some embodiments of the present invention, the cancer is melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, a brain tumor, lymphoma, sarcoma, breast cancer. ovary or Kaposi's sarcoma.

[0044] In some embodiments, methods are provided for treating an individual who receives a bone marrow transplant or peripheral blood stem cell transplant by administering a therapeutically effective amount of an inhibitory compound of CD73 or sufficient composition to increase the delayed-type hypersensitivity reaction to the tumor antigen, delaying post-transplant malignancy relapse time, increases post-transplant relapse-free survival time, and/or increases survival long-term post-transplantation.

[0045] In certain embodiments, methods are provided for treating or preventing an infectious disorder (eg, a viral infection) in an individual (eg, a human) comprising administering to the individual a therapeutically effective amount of at least a CD73 inhibitory compound or composition provided herein in . In some modalities, the infectious disorder is a viral infection (eg, a chronic viral infection), a bacterial infection, a fungal infection, or a parasitic infection. In certain embodiments, the viral infection is the human immunodeficiency virus or cytomegalovirus.

[0046] In still other embodiments, methods are provided to treat and/or prevent diseases, disorders and conditions related to the immune system; diseases with an inflammatory component; as well as disorders associated with the preceding ones; with at least one CD73 inhibitory compound or composition provided herein.

[0047] Other diseases, disorders, and conditions that may be treated or prevented, in whole or in part, by inhibiting the activity of CD73 are candidate indications for the CD73 inhibitory compounds and compositions provided herein.

In some embodiments, the use of the CD73 inhibitory compounds and compositions herein described in combination with one or more additional agents is further provided. The one or more additional agents may have some CD73 modulating activity and/or they may function through distinct mechanisms of action. In some modalities, such agents comprise radiation (eg, localized radiotherapy or whole-body radiotherapy) and/or other treatment modalities of a non-pharmacological nature. When combination therapy is used, the inhibitor(s)

CD73(s) and an additional agent(s) may be in the form of a single composition or multiple compositions, and the treatment modalities may be administered simultaneously, sequentially, or via some other regimen. By way of example, in some embodiments, a treatment regimen is provided in which a radiation phase is followed by a chemotherapeutic phase. A combination therapy can have an additive or synergistic effect.

[0049] In some embodiments, the use of a CD73 inhibitory compound or composition described herein in combination with bone marrow transplantation, peripheral blood stem cell transplantation, or other types of transfusion therapy is provided. - plant.

In particular embodiments, the use of the inhibitors of CD73 function described herein in combination with immunological checkpoint inhibitors is provided. Blocking immunological checkpoints, which results in the amplification of antigen-specific T cell responses, has been shown to be a promising approach in human cancer therapy. Non-limiting examples of immunological checkpoints (ligands and receptors), some of which are selectively up-regulated in various types of tumor cells, which are candidates for blockade include PD1 (programmed cell death protein 1); PDL1 (PD1 linker); BTLA (B and T lymphocyte attenuator); CTLA4 (antigen 4 associated with cytotoxic T lymphocytes); TIM3 (T cell membrane protein 3); LAG3 (lymphocyte activation gene 3), A2aR (A2a adenosine receptor A2aR); and killing inhibitory receptors. Non-limiting examples of immunological checkpoint inhibitors include ipulimumab, nivolumab and lambrolizumab.

In other embodiments, methods are provided for treating cancer in an individual, comprising administering to the individual a therapeutically effective amount of at least one CD73 inhibitory compound or composition thereof and at least one agent chemotherapeutic agents, such agents including but not limited to alkylating agents (eg, nitrogen mustards such as chlorambucil, cyclophosphamide, isofamide, mechlorethamine, melphalan and uracil mustard; aziridines such as thiotepa; methanesulfonate esters such as methanesulfonate busulfan; nucleoside analogues (eg, gemcitabine); nitroso ureas such as carmustine, and lomustine, and streptozocin; topoisomerase 1 inhibitors (eg, irinotecan); platinum complexes such as cisplatin and carboplatin; bioreductive alkylators , such as mitomycin, procarbazine, dacarbazine and altretamine); DNA strand breaking agents (eg, bleomycin); topoisomerase II inhibitors (for example ansacrine, dactinomycin, daunorubicin, idarubicin, mitoxantrone, doxorubicin, etoposide and teniposide); DNA minor groove binding agents (eg, plicamidine); antimetabolites (eg, folate antagonists such as methotrexate and trimetrexate; pyrimidine antagonists such as fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytarabine, and floxuridine; purine antagonists such as mercaptopurine, 6-thioguanine, fludarabine, pentostatin; asparginase; and ribonucleotide reductase inhibitors; such as hydroxyurea); tubulin interactive agents (for example, vincristine, estramustine, vinblastine, docetaxel, epothilone derivatives and paclitaxel); hormonal agents (eg, estrogens; conjugated estrogens; ethinyl estradiol; diethylstilbesterol; chlorotrianisene; idenestrol; progestins such as hydroxyprogesterone caproate and medroxyprogesterone and megestrol; and androgens such as co-, testosterone, propionate of testosterone, fluoxymesterone and methyl-testosterone); adrenal corticosteroids (eg, prednisone, dexamethasone, methylprednisolone, and prednisolone); leuteinizing hormone-releasing agents or gonadotropin-releasing hormone antagonists (eg, leuprolide acetate and goserelin acetate); and anti-hormonal antigens (eg, tamoxifen, anti-androgenic agents such as flutamide; and anti-adrenal agents such as mitotane and aminoglutethimide). The use of CD73 inhibitors in combination with other agents known in the art (eg, arsenic trioxide) and other chemotherapeutic agents that may be developed in the future is also provided.

[0052] In some established modalities for cancer treatment methods, administration of a therapeutically effective amount of a CD73 inhibitor in combination with at least one chemotherapeutic agent results in a cancer survival rate greater than the cancer survival rate observed by administering either agent alone. In other established modalities for cancer treatment methods, administration of a therapeutically effective amount of a CD73 inhibitor in combination with at least one chemotherapeutic agent results in a reduction in tumor size or a slowdown in growth greater than the reduction in tumor size or deceleration of tumor growth observed by the administration of either agent alone.

In other embodiments, methods are provided for treating or preventing cancer in an individual, comprising administering to the individual a therapeutically effective amount of at least one CD73 inhibitory compound or composition and at least one CD73 transduction inhibitor. sign (STI). In one particular embodiment, the at least one STI is selected from the group consisting of bcr/abl kinase inhibitors, epidermal growth factor (EGF) receptor inhibitors, her-2/neu receptor inhibitors and farnesyl transferase inhibitors (FTIs).

[0054] In other modalities, methods are provided for au-

ment the rejection of tumor cells in an individual, comprising the administration of a CD73 inhibitory compound or composition together with at least one chemotherapeutic agent and/or radiotherapy, in which the resulting rejection of tumor cells is greater than that obtained by administering the CD73 inhibitor, the chemotherapeutic agent, or radiotherapy alone.

In other embodiments, methods are provided for treating cancer in an individual, comprising administering to the individual a therapeutically effective amount of at least one CD73 inhibitor and at least one immunomodulator other than a CD73 inhibitor. CD73. It is to be understood that, when used herein, a "CD73 inhibitor" refers to compounds provided herein, for example, a compound of any one of Formulas I-IX, a compound of Table 1, or a salt or a pharmaceutically acceptable ester thereof, and to pharmaceutical compositions thereof.

[0056] In some embodiments, methods of treating or preventing a disease, disorder, or condition associated with CD73 in an individual in need thereof are provided, comprising administering a therapeutically effective amount of at least one. CD73 inhibitor or a pharmaceutical composition thereof to the subject, such that the disease, disorder or condition associated with CD73 is treated or prevented in the subject. In some embodiments, the compound is administered in an amount effective to reverse, delay, or halt the progression of CD73-mediated immunosuppression in the individual.

[0057] In some embodiments, the disease, disorder, or condition associated with CD73 is cancer, such as, without limitation, a cancer of the prostate, colon, rectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder , ovary, testicle, head, neck, skin,

mesothelial ment, white blood cell, esophagus, breast, muscle, connective tissue, lung, adrenal gland, thyroid, kidney or bone. In some modalities, the cancer is glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma, choriocarcinoma, cutaneous basal cell carcinoma, or testicular seminoma. In some modalities the cancer is melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, a brain tumor, lymphoma, ovarian cancer, or Kaposi's sarcoma.

[0058] In some embodiments, a disease, disorder, or condition associated with CD73 is an immune disease, disorder, or condition selected from the group consisting of rheumatoid arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, fibromyalgia anemia, Alzheimer's disease, congestive heart failure, stroke, aortic valve stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, Crohn's disease, ulcerative colitis, allergic contact dermatitis, eczema, sclero- if systemic and multiple sclerosis.

In some embodiments, the methods provided herein further comprise administering at least one additional therapeutic agent to the subject. The at least one additional therapeutic agent can be administered concurrently or sequentially with the compound or composition described herein. In some embodiments, the at least one additional therapeutic agent is a chemotherapeutic agent, an immunomodulating and/or inflammation modulating agent, an antihypercholesterolemic agent, or an anti-infective agent. In one embodiment, the at least one additional therapeutic agent is an immunological checkpoint inhibitor, such as, without limitation, ipulimumab, nivolumab, or lambrolizumab.

[0060] In some embodiments, methods are provided for treating or preventing an infectious disorder (eg, a viral infection) in an individual (eg, a human) comprising administering to the individual a therapeutically effective amount of at least a CD73 inhibitor and a therapeutically effective amount of an anti-infective agent(s), such as one or more antimicrobial agents.

In additional embodiments, treatment of an infectious disorder is effected by co-administration of a vaccine in combination with administration of a therapeutically effective amount of a CD73 inhibitor provided herein. In some embodiments, the vaccine is an antiviral vaccine, including, for example, an anti-HIV vaccine. In other modalities, the vaccine is effective against tuberculosis or malaria. In still other embodiments, the vaccine is a tumor vaccine (eg, an effective melanoma vaccine); the tumor vaccine may comprise genetically modified tumor cells or a genetically modified cell line, including genetically modified tumor cells or a genetically modified cell line that has been transfected to express granulocyte-macrophage stimulating factor (GM-CSF ). In particular embodiments, the vaccine includes one or more immunogenic peptides and/or dendritic cells.

[0062] In certain embodiments aimed at treating an infection by administering a CD73 inhibitor and at least one additional therapeutic agent, a symptom of infection observed after administration of the CD73 inhibitor and the additional therapeutic agent is ameliorated with respect thereto. symptom of infection observed after administration alone. In some modalities, the symptom of infection observed can be a reduction in viral load, increase in CD4+ T cell count, decrease in opportunistic infections, increase in survival time, eradication of chronic infection or a combination of these.

[0063] In some embodiments, methods of treating cancer in an individual are provided, comprising administering to the individual an effective amount of a compound or composition described herein and an immunological checkpoint inhibitor , so that the cancer is treated in the individual. The compound or composition described herein and the immunological checkpoint inhibitor can be administered in combination or sequentially. The compound or composition can be administered after the immunological checkpoint inhibitor or prior to administration of the immunological checkpoint inhibitor. In some embodiments, the compound or composition and/or the immunological checkpoint inhibitor are administered prior to, simultaneously with, or subsequent to another anti-cancer treatment, such as, without limitation, radiation treatment. In some embodiments, the immunological checkpoint inhibitor is selected from the group consisting of ipulimumab, nivolumab, and lambrolizumab.

[0064] In a fourth broad aspect, kits comprising the compound or composition described herein are provided. Kits may further comprise a buffer or excipient and/or instructions for use. In some embodiments, the kits further comprise at least one additional therapeutic agent, such as, without limitation, a chemotherapeutic agent, an immunomodulatory and/or inflammation modulating agent, an anti-hypercholesterolemic agent, an anti-infective agent, or a immunological checkpoint inhibitor.

BRIEF DESCRIPTION OF THE DRAWINGS

[0065] For a better understanding of the invention and to show more clearly how it can be carried out, reference will now be made by way of example to the accompanying drawings, which illustrate aspects and characteristics according to embodiments of the present invention, and in which: A FIG. 1 is a graph showing the CD73 inhibition rate (% inhibition vs. Log [Conc.]/nM) for compound 9; and FIG. 2 is a graph showing the CD73 inhibition rate for compound 22.

DETAILED DESCRIPTION

[0066] The number of individuals diagnosed with cancer and the number of deaths attributable to cancer continue to increase. Traditional treatment approaches that comprise chemotherapy and radiotherapy are often difficult for the individual to tolerate and become less effective as cancers (eg, tumors) evolve to circumvent such treatments. Recent experimental evidence indicates that CD73 inhibitors may represent an important new treatment modality for the treatment of cancer (eg, breast cancer).

[0067] Promising data also support the role of inhibitors of CD73 function to inhibit the anti-inflammatory activity of CD73 and/or the immunosuppressive activity of CD73 and, therefore, inhibitors of CD73 may be useful to treat, eg immunosuppressive diseases (eg HIV and AIDS) Inhibition of CD73 may also be an important treatment strategy for individuals with neurological or neuropsychiatric diseases or disorders such as depression.

[0068] Provided herein are, inter alia, small molecule compounds with CD73 inhibitory activity, as well as compositions thereof and methods of using the compounds and compositions for the treatment and prevention of diseases, disorders and conditions in this document described. The compounds provided herein are useful as inhibitors of CD73 and, therefore, useful in the treatment of diseases, disorders and conditions in which CD73 activity plays a role. Furthermore, the compounds provided herein may be useful as inhibitors of adenosine receptors such as, for example, the A2A receptor. Accordingly, the compounds provided herein are useful in the treatment of diseases, disorders and conditions associated with the activity of one or more adenosine receptors.

[0069] In one embodiment, provided herein is a method of treating an individual (e.g., a human) with cancer or a CD73-mediated disorder comprising the step of administering to the individual a therapeutically effective amount of a CD73 inhibitor provided herein, for example, a compound provided herein or a pharmaceutically acceptable composition thereof.

It is to be understood that a pharmaceutical composition comprises a compound described herein (or a pharmaceutically acceptable salt or ester thereof) and a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, the amount of a compound in a composition is such that it is effective as an inhibitor of CD73 in a biological sample (eg, in an in vitro assay, in an in vivo model, etc.) or in an individual. In certain embodiments, the composition is formulated for administration to an individual in need of such a composition. In some modalities, the composition is an injectable formulation. In other embodiments, the composition is formulated for oral administration to an individual.

[0071] Also provided is a method of treating an individual (eg a human) with cancer or a disorder mediated by an adenosine receptor (eg A2AR) which comprises the step of administering to the individual an amount therapeutically effective inhibitor of a CD73 inhibitor herein provided.

of, for example, a compound provided herein or a pharmaceutically acceptable composition thereof. In certain embodiments, the amount of a compound in a composition is such that it is effective as an inhibitor of an adenosine receptor (eg, A2AR) in a biological sample (eg, in an in vitro assay, in a model in vivo, etc.) or in an individual. In certain embodiments, the composition is formulated for administration to an individual in need of such a composition. In some modalities, the composition is an injectable formulation. In other modalities, the composition is formulated for oral administration to an individual. In some embodiments, the composition is in the form of a hard gelatin capsule, a soft gelatin capsule, a wafer, a pill, a tablet, a lozenge, a powder, a granule, a pellet, a lozenge, or a tablet. . In some embodiments, the composition is in the form of a solution, an aqueous liquid suspension, a non-aqueous liquid suspension, an oil-in-water liquid emulsion, a water-in-oil liquid emulsion, an elixir or a syrup. In some embodiments, the composition is enteric coated. In some modalities, the composition is formulated for controlled release.

[0072] In other embodiments, methods are provided for treating or preventing cancer in an individual, comprising administering to the individual a therapeutically effective amount of at least one CD73 inhibitor and at least one signal transduction inhibitor (STI ). In a particular embodiment, the at least one STI is selected from the group consisting of bcr/abl kinase inhibitors, epidermal growth factor (EGF) receptor inhibitors, her-2/neu receptor inhibitors, and farnesyl inhibitors transferase (FTIs). Methods of increasing tumor cell rejection in an individual are also provided, comprising administering an ini-

CD73 inhibitor in conjunction with at least one chemotherapeutic agent and/or radiotherapy, wherein the resulting rejection of tumor cells is greater than that obtained by administering either the CD73 inhibitor, the chemotherapeutic agent, or radiotherapy alone. In other embodiments, methods of treating cancer in a subject are provided, comprising administering to the subject a therapeutically effective amount of at least one CD73 inhibitor and at least one immunomodulator other than a CD73 inhibitor.

[0073] In other embodiments, methods are provided for treating or preventing an infectious disorder (e.g., a viral infection) in an individual (e.g., a human) comprising administering to the individual a therapeutically effective amount of at least a CD73 inhibitor and a therapeutically effective amount of anti-infective agent(s), such as one or more anti-microbial agents.

In further embodiments, treatment of an infectious disorder is effected by co-administration of a vaccine in combination with administration of a therapeutically effective amount of a CD73 inhibitor provided herein. In some embodiments, the vaccine is an antiviral vaccine, including, for example, an anti-HIV vaccine. In other modalities, the vaccine is effective against tuberculosis or malaria. In still other embodiments, the vaccine is a tumor vaccine (eg, an effective melanoma vaccine); the tumor vaccine may comprise genetically modified tumor cells or a genetically modified cell line, including genetically modified tumor cells or a genetically modified cell line that has been transfected to express granulocyte-macrophage stimulating factor (GM-CSF ). In particular embodiments, the vaccine includes one or more immunogenic peptides and/or dendritic cells.

In certain embodiments aimed at treating an infection by administering a CD73 inhibitor and at least one additional therapeutic agent, a symptom of infection observed after administration of the CD73 inhibitor and the additional therapeutic agent is ameliorated relative to it. symptom of infection observed after administration alone. In some modalities, the symptom of infection observed can be a reduction in viral load, increase in CD4+ T cell count, decrease in opportunistic infections, increase in survival time, eradication of chronic infection or a combination of these. Definitions

[0076] In order to provide a clear and consistent understanding of the terms used in this specification, several definitions are provided below. Furthermore, unless defined otherwise, all technical and scientific terms as used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0077] The use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and/or the specification may mean "a", but is also consistent with the meaning of "an or more", "at least one" and "one or more than one". Likewise, the word "other" can mean at least a second or more.

[0078] When used in this specification and in the claim(s), the words "comprising" (and any form of understanding, such as "understand" and "comprises"), "having" (and which - either form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "includes") or "containing" (and any form of containing, such as "contain" and "contains"), are inclusive or open-ended and do not exclude additional unsolicited elements or process steps.

[0079] The term "about" is used to indicate that a value includes an inherent variation of error for the device or method being used to determine the value.

[0080] The term "derivative", when used in this document, is understood to be a substance similar in structure to another compound, but differing in some small structural details.

[0081] The present invention relates to a series of chemical terms and abbreviations used by those skilled in the art. However, definitions of selected terms are provided for clarity and consistency.

As used herein, the term "alkyl" refers to saturated hydrocarbons having from one to thirty carbon atoms, including linear, branched and cyclic alkyl groups. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl , cycloheptyl, cyclooctyl, and the like. The term alkyl includes unsubstituted alkyl groups and substituted alkyl groups. The terms "C1-Cr alkyl" and "C1-n alkyl", where n is an integer from 2 to 30, are used interchangeably to refer to an alkyl group having from 1 to the number "n" indicated in carbon atoms. Alkyl residues can be substituted or unsubstituted. In some embodiments, for example, alkyl may be substituted by hydroxy, amino, carboxy, carboxylic ester, amide, carbamate, or aminoalkyl. In some particular embodiments, "alkyl" is modified by a range of the number of carbon atoms and thus the size of the alkyl group is specifically defined. For example, a C11-C3o alkyl specifies an alkyl group containing at least 11 carbon atoms and no more than 30 carbon atoms.

[0083] When used herein, the term "acyclic" refers to an organic moiety without a ring system. The term "aliphatic group" includes organic moieties specified by straight or branched chains, typically having between 1 and 15 carbon atoms. Aliphatic groups include non-cyclic alkyl groups, alkenyl groups and alkynyl groups.

[0084] As used herein, the term "alkenyl" refers to unsaturated hydrocarbons having from two to thirty carbon atoms, including non-aromatic linear, branched and cyclic alkenyl groups and comprising from one to six carbon double bonds -carbon. Examples of alkenyl groups include, without limitation, vinyl, allyl, 1-propen-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-4-yl, 1-penten-5 -yl, 1,3-pentadien-S-yl, cyclopentenyl, cyclohexenyl, ethylcyclopentenyl, ethylcyclohexenyl, and the like. The term alkenyl includes unsubstituted alkenyl groups and substituted alkenyl groups. The terms "C2-Cr alenyl" and "C2>.n alkenyl", where n is an integer from 3 to 30, are used interchangeably to refer to an alkenyl group having from 2 to the indicated number "n" of carbon atoms. In some particular embodiments, "alkenyl" is modified by a range of the number of carbon atoms and thus the size of the alkenyl group is specifically defined. For example, a C11-C30o alkenyl specifies an alkenyl group containing at least 11 carbon atoms and no more than 30 carbon atoms.

[0085] As used herein, the term "alkynyl" refers to unsaturated hydrocarbons having from two to thirty carbon atoms, including non-aromatic linear, branched and cyclic alkynyl groups and comprising between one to six carbon triple bonds -carbon. Examples of alkynyl groups include, without limitation, ethynyl, 1-propyn-3-yl, 1-butyn-4-yl, 2-butyn-4-yl, 1-pentyn-S-yl,

1,3-pentadiin-5-yl, and the like. The term alkynyl includes unsubstituted alkynyl groups and substituted alkynyl groups. The terms "C2-C, alkynyl" and "Ca." alkynyl", where n is an integer from 3 to 30, are used interchangeably to refer to an alkynyl group having from 2 to the indicated "n" number of carbon atoms. In some particular embodiments, "alkynyl" is modified by a range of the number of carbon atoms and thus the size of the alkynyl group is specifically defined. For example, a specific C11-C30o alkynyl is an alkynyl group containing at least 11 carbon atoms and no more than 30 carbon atoms. carbon.

[0086] Unless the number of carbons is otherwise specified, "lower" as in "lower aliphatic", "lower alkyl", "lower alkenyl" and "lower alkylniyl", when used herein, means that the portion has at least one (two for alkenyl and alkynyl) and equal to or less than 6 carbon atoms.

[0087] The terms "cycloalkyl", "alicyclic", "carbocyclic" and equivalent expressions refer to a group comprising a saturated or partially unsaturated carbocyclic ring in a single spiro (sharing an atom) or fused ( Sharing at least one link) system having three to fifteen ring members. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2 -yl, cyclohexen-3-yl, cycloheptyl, bicyclo[4.3.0]Jnonanyl, norbornyl, and the like. The term cycloalkyl includes unsubstituted cycloalkyl groups and substituted cycloalkyl groups. The terms "C3-Cn cycloalkyl" and "Can cycloalkyl", where n is an integer from 4 to 15, are used interchangeably to refer to a cycloalkyl group having from 3 to the indicated "n" number of atoms of carbon in the ring structure. Unless the number of carbons is specified otherwise, the groups

"lower cycloalkyl", when used herein, have at least 3 and less than or equal to 8 carbon atoms in their ring structure.

[0088] Cycloalkyl residues can be saturated or contain one or more double bonds within the ring system. In particular, they can be saturated or contain a double bond within the ring system. In unsaturated cycloalkyl residues, the double bonds can be present at any suitable positions. Monocycloalkyl residues are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl or cyclotetradecyl, for example. example, it can also be substituted by C1-1 alkyl. Examples of substituted cycloalkyl residues are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl. Examples of parent structures of bicyclic ring systems are norbornane, bicyclo[2.2.1] heptane, bicyclo[2.2.2]octane and bicyclo[3.2.1]octane.

[0089] The term "heterocycloalkyl" and equivalent expressions refer to a group comprising a saturated or partially unsaturated carbocyclic ring in a single spiro (sharing an atom) or fused (sharing at least one bond) carbocyclic ring system having from three to fifteen ring members, including one to six heteroatoms (eg, N, O, S, P) or groups containing such heteroatoms (eg, NH, NRx (Rx is alkyl, acyl, aryl , heteroaryl or cycloalkyl), PO, SO, SO;>, and the like). Heterocycloalkyl groups can be linked to C or linked to a heteroatom (eg, through a nitrogen atom) where this is possible. Examples of heterocycloalkyl groups include, without limitation, pyrrolidino, tetrahydrofuranyl, tetrahydrodithienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, tietanyl, homolapiperidinyl, oxe ,

tiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, imidazolidinyl, imidazolidinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, quinolizinyl and sugars, and the like. The term heterocycloalkyl includes unsubstituted heterocycloalkyl groups and substituted heterocycloalkyl groups. The terms "C3-Cheterocycloalkyl" and "C3-n heterocycloalkyl", where n is an integer from 4 to 15, are used interchangeably to refer to a heterocycloalkyl group having from 3 to the indicated "n" number of atoms in the ring structure, including at least one hetero group or atom as defined above. Unless the number of carbons is specified otherwise, "lower heterocycloalkyl" groups, when used herein, have at least 3 and less than or equal to 8 carbon atoms in their ring structure.

[0090] The terms "aryl" and "aryl ring" refer to aromatic groups having "4n+2" (pi) electrons, where n is an integer from 1 to 7, in a monocyclic or polycyclic system conjugated (fused or not) and having six to fourteen ring atoms. A polycyclic ring system includes at least one aromatic ring. Aryl can be directly joined or connected through a C1-C;s alkyl group (also referred to as arylalkyl or aralkyl). Examples of aryl groups include, without limitation, phenyl, benzyl, phenethyl, 1-phenylethyl, tolyl, naphthyl, biphenyl, terphenyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, azulenyl, acenaphthylenel, fluorenyl, phenanternyl, anthracenyl, and the like. The term aryl includes unsubstituted aryl groups and substituted aryl groups. The terms "Cs-Chn aryl" and "Ceg-n aryl", where n is an integer from 6 to 30, are used interchangeably to refer to an aryl group having from 6 to the indicated "n" number of atoms in the ring structure including at least one hetero group or atom as defined above.

[0091] The terms "heteroaryl" and "heteroaryl ring" refer to an aromatic group having "4n+ 2" (pi) electrons, where n is an integer from 1 to 7, in a conjugated monocyclic or polycyclic system ( fused or unfused) and having five to fourteen ring members, including one to six heteroatoms (eg, N, O, S) or groups containing such heteroatoms (eg, NH, NRx (Rx is alkyl, acyl, aryl, heteroaryl) or cycloalkyl), SO, and the like). A poly-Cyclic ring system includes at least one heteroaromatic ring. Heteroaryls can be directly joined or connected via a C1-C3 alkyl group (also referred to as heteroarylalkyl or heteroaralkyl). Heteroaryl groups can be linked to C or linked to a heteroatom (eg, through a nitrogen atom) where this is possible. Examples of heteroaryl groups include, without limitation, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl; isooxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrollyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, cromenyl, isochromenyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, isoindolyl, pythalazinyl, triindolyl purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinolizinyl, quinolonyl, isoquinolonyl, quinoxalinyl, naphthyridinyl, furopyridinyl, phenanidinyl-acridazolyl, phenanidinyl, phenodinyl, phenodinyl, phenodinyl, phenanidinyl, carbazolyl fenoxazinil, dibenzofurnayl, and the like. The term heteroaryl includes unsubstituted heteroaryl groups and substituted heteroaryl groups. The terms "Cs-Cn heteroaryl" and "Cs.n heteroaryl", where n is an integer from 6 to 29, are used interchangeably to refer to a heteroaryl group having from 5 to the number "n" indicated in atoms in the ring structure, including at least one hetero group or atom as defined above.

The terms "heterocycle" or "heterocyclic" include heterocycloalkyl and heteroaryl groups. Examples of heterocycles include, without limitation, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, chromanylazolyl, carbazolyl, carbazolyl nyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octalinyl, 1-hydroisoquinoyl 2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, fenoxathiinyl, fenoxaz inyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thi-diazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl, and the like. The term heterocycle includes unsubstituted heterocyclic groups and substituted heterocyclic groups.

[0093] The term "amine" or "amino", when used herein, refers to an unsubstituted or substituted portion of the formula --NRaRb, in which Ra and Rb are each independently hydrogen, alkyl, aryl or heterocyclyl, or Ra and Rb, used together with the nitrogen atom to which they are attached, form a heterocyclic ring. The term amino includes compounds or moieties in which a nitrogen atom is covalently bonded to at least one carbon or heteroatom. Thus, the terms "alkylamino" and "dialkylamino", when used herein, mean an amine group having, respectively, one and at least two C1-C6 alkyl groups attached thereto. The terms "arylamino" and "diarylamino" include groups in which nitrogen is attached to at least one or two aryl groups, respectively. The terms "amide" or "aminocarbonyl" include compounds or moieties that contain a nitrogen atom that is attached to the carbon of a carbonyl or thiocarbonyl group. The term "acylamino" refers to an amino group directly linked to an acyl group as defined herein.

The term "bicycle" or "bicyclic" refers to a two-ring ring system that has two ring carbon atoms in common and that can be located at any position along any ring, generally referring to bicyclic hydrocarbon radical, bicyclic aromatic carbon atom ring structure radical, and a saturated or partially unsaturated bicyclic carbon atom ring structure in which one or more ring members contain carbon atoms. have been substituted, where allowed for structural stability, with a heteroatom, such as an O, S, or N atom. The bicyclic system may be a fused ring system, such as cyclo[4.4.0]decane or naphthalene, or a bridged ring system such as bicyclo[2.2.2]octane.

[0095] The term "tricycle" or "tricyclic" refers to a three ring ring system which has three ring carbon atoms in common and which may be located at any position along each ring; generally referring to the tricyclic hydrocarbon radical,

tricyclic aromatic carbon atom ring structure radical and a saturated or partially unsaturated tricyclic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where permitted by structural stability, with a heteroatom, such as an O, S, or N atom. A tricyclic system can have three rings arranged as a fused ring, such as anthracene or tetradecahydroanthracene, or a bridged ring, as in adamantine or tricyclo[3.3.1.1]decane .

[0096] The term "multi-cycle", "multicycle", "multi-cyclic" or "multi-cyclic" means a ring system with more than three rings having more than three carbon ring atoms in common, and which it can be located in any position along any ring. The term generally refers to a multicyclic hydrocarbon radical, a multicyclic aromatic carbon atom ring structure radical, and a saturated or partially unsaturated multicyclic carbon atom ring structure radical in which one or more members of the ring carbon atom have been replaced, where allowed for structural stability, with a heteroatom, such as an O, S or N atom.

[0097] The term "fused ring" or "fused" refers to a polycyclic ring system that contains fused rings. Typically, a fused ring system contains 2 or 3 rings and/or up to 18 ring atoms. As defined above, cycloalkyl radicals, aryl radicals and heterocyclyl radicals can form fused ring systems. Thus, a fused ring system can be aromatic, partially aromatic or non-aromatic and can contain heteroatoms. A spiro ring system is not a fused polycyclic by this definition, however, the fused polycyclic ring systems of the invention may themselves have spiro rings attached to it via a single ring atom of the system. Examples of fused ring systems include, but are not limited to, naphthyl (eg, 2-naphthyl), indenyl, phenanthryl, anthracycline.

la, pyrenyl, benzimidazole, benzothiazole, etc.

[0098] The term "spiral ring" or "spiral" refers to an organic compound, which has a twisted structure of two or more rings (a ring system), in which 2 or 3 rings are linked together by a common atom. Spiro compounds may be fully carbocyclic (all carbon), such as, without limitation, spiro[5.5Jundecane or heterocyclic (having one or more non-carbon atoms), including, but not limited to, spiro carbocyclic compounds, spiro compounds. heterocyclics and polyspiro compounds.

[0099] The term "bridged ring" or "bridged" refers to a carbocyclic or heterocyclic moiety where two or more atoms are shared between two or more ring structures, where any shared atom is C, N, S or another heteroatom arranged in a chemically reasonable substitution pattern. Alternatively, a "bridged" compound also refers to a carbocyclic or heterocyclic ring structure where an atom at any position of a primary ring is attached to a second atom in the primary ring through a chemical bond or atom(s). ) different from a bond which (does not) comprise a part of the primary ring structure. The first and second atoms may or may not be adjacent to each other in the primary ring. Illustrated below are specific non-limiting examples of bridged ring structures contemplated in this document. Other carbocyclic or heterocyclic bridged ring structures are also contemplated, including bridged rings where the bridged atoms are C or heteroatom(s) arranged in chemically reasonable substitution patterns, as are known in technique.

[00100] The term "nitro" means —NO;>; the terms "halo" and "halogen" refer to bromine, chlorine, fluorine or iodine substituents; the terms "tiol", "tio" and "mercapto" mean —SH; and the terms "hydroxy" and "hydroxy" mean -OH. The term "alkylthio" refers to an al- group.

quila, having a sulfhydryl group attached to it. Suitable alkylthio groups include groups having 1 to about 12 carbon atoms, preferably 1 to about 6 carbon atoms. The term "alkylcarboxy", when used herein, means an alkyl group having a carboxyl group attached thereto.

The terms "alkoxy" and "lower alkoxy", when used herein, mean an alkyl group having an oxygen atom attached thereto. Representative alkoxy groups include groups having 1 to about 6 carbon atoms, for example, methoxy, ethoxy, propoxy, tert-butoxy, and the like. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, pentoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, and the like. The term "alkoxy" also includes unsubstituted or substituted alkoxy groups, etc., as well as perhalogenated alkyloxy groups.

[00102] The terms "carbonyl" and "carboxy" include compounds and moieties that contain a carbon connected by a double bond to an oxygen atom. Examples of moieties that contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.

[00103] The term "acyl" refers to a carbonyl group that is attached through its carbon atom to a hydrogen (ie, formyl), an aliphatic group (eg, C1-C> 29 alkyl, C1-C29 alkenyl, C1-Ca29 alkynyl, eg acetyl), a cycloalkyl group (C3-Cg cycloalkyl), a heterocyclic group (C3-Cs8 heterocycloalkyl and Cs-Ce6 heteroaryl), an aromatic group ( Cs aryl, e.g. benzoyl), and the like. Acyl groups can be unsubstituted or substituted acyl groups (eg salicyloyl).

[00104] It is to be understood that "substitution" or "substituted by" includes the implied condition that such substitution is in accordance with the allowable valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound that does not undergo spontaneous transformation, such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all permitted substituents of organic compounds. In a broad aspect, permitted substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Permitted substituents can be one or more. The term "substituted", when used in association with any of the foregoing groups, refers to a group substituted at one or more positions with substituents such as acyl, amino (including simple amino, mono and dialkylamino , mono and diarylamino and alkylarylamino), acylamino (including carbamoyl and ureido), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, alkoxycarbonyl, carboxy, carboxylate, aminocarbonyl, mono and dialkylaminocarbonyl, cyano, azido, halogen, hydroxyl, nitro, trifluoromethyl, thio, alkylthio, arylthio, alkylthiocarbonyl, thiocarboxylate, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, lower alkoxy, aryloxy, aryloxycarbonyloxy, benzylsulfinyl, benzyl alkylsulfinyl, sulfonyl, sulfate, sulfonate, sulfonamide, phosphate, phosphonate, phosphinate, oxo, guanidine, imino, formyl, and the like. Any of the above substituents may be further substituted if permitted, for example if the group contains an alkyl group, an aryl group or the like.

[00105] The term "solvate" refers to a physical association of a compound with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonds. In certain cases, a solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" also encompasses sol-

vates in solution phase and isolatable. Exemplary solvates include, without limitation, hydrates, ethanolates, methanolates, hemiethanolates, and the like.

[00106] A "pharmaceutically acceptable salt" of a compound means a salt of a compound that is pharmaceutically acceptable. Desirable are salts of a compound that maintain or enhance the biological effectiveness and properties of the free acids and bases of the parent compound, as defined herein, or that take advantage of an intrinsically basic, acidic, or charged functionality in the parent compound. molecule and that are not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts are also described, for example, in Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 66, 1-19 (1977). Non-limiting examples of such salts include: (1) acid addition salts, formed in a basic or positively charged functionality, by the addition of inorganic acids, such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, acid sulfamic acid, nitric acid, phosphoric acid, carbonate forming agents and the like; or formed with organic acids such as acetic acid, propionic acid, lactic acid, oxalic acid, glycolic acid, pivalic acid, t-butylacetic acid, B-hydroxybutyric acid, valeric acid, hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid , succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2 acid -ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, cyclohexylaminosulfonic acid, benzenesulfonic acid, sulphanilic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 3-phenylpropionic acid, laurylsulfonic acid, acid lauryl sulfuric acid, oleic acid, palmitic acid, stearic acid, lauric acid, acid

embonic (pamoic) acid, palmoic acid, pantothenic acid, lactobionic acid, alginic acid, galactaric acid, galacturonic acid, gluconic acid, glycoheptonic acid, glutamic acid, naphthoic acid, hydroxynaphthoic acid, salicylic acid, ascorbic acid, acid stearic acid, muconic acid, and the like; (2) base addition salts, formed when an acidic proton present in the parent compound is replaced by a metal ion, including an (alkali metal (eg, lithium, sodium, potassium) ion), an alkaline earth ion (eg. , magnesium, calcium, barium), or other metal ions such as aluminum, zinc, iron, and the like; or coordinated with an organic base such as ammonia, ethylamine, diethylamine, ethylenediamine, N ,N'-dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglycamine, piperazine, chloroprocaine, procaine, choline, lysine, and the like.

[00107] Pharmaceutically acceptable salts can be synthesized from a parent compound that contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base forms of the compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two. Salts can be prepared in situ, during the final isolation or purification of a compound, or by separately reacting a compound in its free acid or base form with the desired corresponding base or acid and isolating the salt so formed. The term "pharmaceutically acceptable salts" also includes zwitterionic compounds containing a cationic group covalently linked to an anionic group, as they are "internal salts". It is to be understood that all acid, salt, base and other ionic and non-ionic forms of compounds described herein are intended to be encompassed. For example, if a compound is shown as an acid herein, the salt forms of the compound are also covered. Likewise, if a compound is shown as a salt, acidic and/or basic forms are also covered.

[00108] The compounds provided herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. The unnatural proportions of an isotope can be defined as ranging from the amount found in nature to a quantity consisting of 100% of the atom in question. For example, the compounds may incorporate radioactive isotopes such as tritium (?H), iodine-125 (21) or carbon-14 (“C), or non-radioactive isotopes such as deuterium (2H) or carbon -13 (°C). Such isotopic variations may provide additional utilities to those described elsewhere in this application. For example, isotopic variants of the compounds of the invention may find additional utility, including, but not limited to, as diagnostic and/or imaging reagents, or as cytotoxic/radiotoxic therapeutic agents. In addition, isotopic variants may have altered pharmacokinetic and pharmacodynamic characteristics that may contribute to enhanced safety, tolerability, or efficacy during treatment. All isotopic variations of compounds given in this document, whether radioactive or not, are to be encompassed in this document.

[00109] Isotopic enrichment is a process by which the relative abundance of isotopes of a given element is altered, thus producing a form of the element that has been enriched (ie, increased) in a specific isotope and reduced or depleted in its other isotopic forms. As used herein, a "isotope enriched" compound or derivative refers to a compound in which one or more specific isotopic forms have been increased, i.e., one or more of the elements have been enriched.

dosed (ie, augmented) into one or more particular isotopes. Generally, in an isotope-enriched compound or derivative, a specific isotopic form of an element at a specific position in the compound is increased. It should be understood, however, that isotopic forms of two or more elements in the compound can be increased. Furthermore, an isotope-enriched compound can be a mixture of isotope-enriched forms that are enriched for more than one particular isotope, more than one element, or both. As used herein, a compound or derivative "enriched with isotopes" has a level of an isotopic form that is greater than the natural abundance of that form. The level of isotope enrichment will vary depending on the natural abundance of a specific isotopic form. In some embodiments, the level of isotope enrichment for a compound, or for an element in a compound, can be from about 2 to about 100 mole percent (%), e.g., about 2%, about 5%, about 17%, about 30%, about 51%, about 83%, about 90%, about 95%, about 96%, about 97%, about 98%, more than about 98%, about 99% or 100%.

[00110] As used herein, an "element of natural abundance" and an "atom of natural abundance" refer to the element or atom, respectively, having the most abundant atomic mass found in nature. For example, the naturally abundant hydrogen is *H (protium); the nitrogen of natural abundance is **N; the oxygen of natural abundance is 160; the natural abundance carbon is *?C; and so on. A "non-isotope enriched" compound is a compound in which all atoms or elements in the compound are isotopes of natural abundance, that is, all atoms or elements have the atomic mass most abundantly found in nature.

[00111] The terms "patient" and "subject" are used interchangeably in this document to refer to a human or a non-human animal (eg, a mammal).

[00112] The terms "administration", "administer", and the like, as they apply to, for example, an individual, cell, tissue, organ or biological fluid, refer to the contact of, for example, a CD73 inhibitor , a pharmaceutical composition comprising the same, or a diagnostic agent to the individual, cell, tissue, organ or biological fluid. In the context of a cell, administration includes contacting (eg, in vitro or ex vivo) a reagent with the cell, as well as contacting a reagent with a fluid, where the fluid is in contact with the cell.

[00113] The terms "treating", "treating", "treatment", and the like refer to a course of action (such as the administration of a CD73 inhibitor or a pharmaceutical composition comprising the same) initiated after a disease , disorder or condition, or a symptom thereof, has been diagnosed, observed, and the like, in order to eliminate, reduce, suppress, mitigate or improve, temporarily or permanently, at least one of the underlying causes of one of the - disease, disorder or condition afflicting an individual, or at least one of the symptoms associated with a disease, disorder, condition afflicting an individual. Thus, treatment includes inhibiting (eg, arresting further development or development of the disease, disorder or condition or associating clinical symptoms with it) an active disease.

[00114] The term "in need of treatment", when used herein, refers to a diagnosis made by a physician or other caregiver that an individual requires or will benefit from treatment. This diagnosis is made based on a variety of factors that depend on the competence of the physician or caregiver.

[00115] The terms "prevent", "preventing", "prevention", and the like refer to a course of action (such as the administration of a CD73 inhibitor or a pharmaceutical composition comprising the same) initiated in a manner (by for example, before the onset of a disease, disorder, condition or symptom thereof) in order to prevent, suppress, inhibit or reduce, temporarily or permanently, an individual's risk of developing a disease, disorder, condition or the like ( as determined, for example, by the absence of symptoms) or delaying their onset: usually in the context of an individual predisposed to a specific disease, disorder or condition. In certain cases, the terms also refer to slowing the progression of the disease, disorder or condition or inhibiting its progression to a harmful or otherwise unwanted state.

[00116] The term "in need of prevention", when used herein, refers to a diagnosis made by a physician or other caregiver that an individual requires or will benefit from preventive care. This diagnosis is made based on a variety of factors that are within the competence of a physician or caregiver.

The terms "therapeutically effective amount" and "effective amount" are used interchangeably herein to refer to the administration of an agent to an individual, alone or as part of a pharmaceutical composition and in a single dose or as part of a series of doses, in an amount capable of having any detectable positive effect on any symptom, aspect or characteristic of a disease, disorder or condition when administered to the individual. The therapeutically effective amount can be determined by measuring the relevant physiological effects and can be adjusted in connection with the dosing regimen and diagnostic analysis of the subject's condition, and the like. By way of example, measuring the serum level of a CD73 inhibitor (or, for example, a metabolite thereof) at a given time post administration may be indicative of whether a therapeutically effective amount has been used. In some embodiments, the terms "therapeutically effective amount" and "effective amount" refer to the amount or dose of a therapeutic agent, such as a compound, upon administration of a single or multiple dose to an individual, which provides the therapeutic effect. co, diagnosis, or desired prognosis in the individual. An effective amount can easily be determined by an attending physician or diagnostician using known techniques and observing the results obtained under analogous circumstances. In determining the effective amount or dose of compound administered, a number of factors are considered, including, but not limited to: the individual's size, age, and general health; the specific disease involved; the degree of involvement or severity of the disease or condition being treated; the response of the particular individual; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the selected dosage regimen; the use of concomitant medication(s); and other relevant considerations.

[00118] The term "substantially pure" is used in this document to indicate that a component constitutes more than about 50% of the total content of the composition and typically more than about 60% of the total content. More typically, "substantially pure" refers to compositions in which at least 75%, at least 85%, at least 90% or more of the total composition is the component of interest. In some cases, the component of interest will constitute more than about 90%) or more than about 95% of the total content of the composition.

[00119] When used in this document, the terms "CD73-associated disease, disorder, or condition" and "CD73-associated disease, disorder, or condition

CD73-mediated disease" are used interchangeably to refer to any disease, disorder, or condition for which treatment with a CD73 inhibitor may be beneficial. In general, CD73-associated or mediated diseases, disorders, and conditions are those in which the CD73 activity plays a biological, mechanistic, or pathological role. These diseases, disorders, and conditions may also be associated with the activity of one or more adenosine receptors. Non-limiting examples of diseases, disorders, and conditions associated with CD73 include disorders related to oncology (cancers, tumors, etc.), disorders related to the immune system, disorders with an inflammatory component, disorders related to microbials, neurological and related disorders related to the CNS, and other diseases (such as, without limitation, cardiovascular, gastrointestinal, metabolic, hepatic, pulmonary, ophthalmic and renal diseases).

[00120] For example, a CD73 inhibitor can be used to prevent or treat a proliferative condition, cancer or tumor; to increase or enhance an immune response; to improve immunization, including increasing vaccine effectiveness; and to increase inflammation. Immune deficiencies associated with immune deficiency diseases, immunosuppressive medical treatment, acute and/or chronic infection, and aging can be treated using CD73 inhibitors described herein. CD73 inhibitors can also be used to stimulate the immune system of patients suffering from iatrogenically induced immune suppression, including those who have undergone bone marrow transplants, chemotherapy, or radiotherapy. In other embodiments, a CD73 inhibitor can be used to treat or prevent any viral, bacterial, fungal, parasitic or other infectious disease, disorder or condition, including, without limitation, HIV and AIDS.

[00121] In some embodiments, a CD73 inhibitor can be used to prevent or treat a disease, disorder, or condition related to the immune system selected from the group consisting of rheumatoid arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, fibromyalgia anemia, Alzheimer's disease, congestive heart failure, stroke, aortic valve stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, Crohn's disease, ulcerative colitis, contact dermatitis allergic, eczema, systemic sclerosis and multiple sclerosis.

[00122] The pharmaceutical compositions provided herein may be formulated to be compatible with the intended method or routine of administration; exemplary administration routines are presented in this document. In addition, the pharmaceutical compositions can be used in combination with other therapeutically active agents or compounds, as described herein, in order to treat or prevent the diseases, disorders and conditions associated with CD73, as contemplated herein.

[00123] Pharmaceutical compositions containing the active ingredient (for example, a CD73 inhibitor) may be in a form suitable for oral use, for example, as tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups, solutions, microspheres or elixirs. Pharmaceutical compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, such as, for example, agents. sweeteners, flavoring agents, coloring agents and preserving agents to provide pharmaceutically acceptable preparations. Tablets, capsules, and the like usually contain the active ingredient in admixture with vehicles or excipients.

non-toxic pharmaceutically acceptable additives which are suitable for the manufacture of tablets. These carriers or excipients can be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.

[00124] “Tablets, capsules, and the like suitable for oral administration may be uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide a prolonged action. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be used. They can also be coated by techniques known in the art to form therapeutic osmotic tablets for controlled release. Additional agents include biodegradable or biocompatible particles or a polymeric substance such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides, polyglycolic acid, ethylenylacetate, methylcellulose, carboxymethylcellulose, protamine sulfate or lactate/glycolide copolymers , polylactide/glycolide copolymers, or ethylene vinylacetate copolymers in order to control the release of an administered composition. For example, the oral agent can be captured in microcapsules prepared by coacervation techniques or by interfacial polymerization, by the use of hydroxymethylcellulose or gelatin microcapsules or poly(methylmetacrolate) microcapsules, respectively, or in a delivery system. colloid drug. Colloidal dispersion systems include macromolecule complexes, nanocapsules, microspheres, microbeads and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles and liposomes. Methods for preparing the aforementioned formulations will be apparent to those skilled in the art.

[00125] “Formulations for oral use can also be presented as hard gelatine capsules, in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose, or as soft gelatine capsules in which the active ingredient is mixed with water or an oily medium, eg peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for their manufacture. Such excipients can be suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, eg a naturally occurring phosphatide (eg lecithin), or condensation products of an alkylene oxide with fatty acids (eg polyoxyethylene stearate) or ethylene oxide condensation products with long-chain aliphatic alcohols (eg to heptadecaethylene-oxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol (eg, polyoxyethylene sorbitol monooleate) or products of condensation of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (eg polyethylene sorbitol monooleate). Aqueous suspensions can also contain one or more preservatives.

[00126] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, eg peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those presented above, and flavoring agents can be added to provide a palatable oral preparation.

[00127] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are known in the art.

[00128] The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these. Suitable emulsifying agents can be naturally occurring gums, for example acacia gum or gum tragacanth; naturally occurring phosphatides, for example soy, lecithin and esters or partial esters derived from fatty acids; hexitol anhydrides, for example sorbitan monooleate; and condensation products of partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.

Pharmaceutical compositions typically comprise a therapeutically effective amount of a CDB84 inhibitory compound provided herein and one or more pharmaceutically and physiologically acceptable formulating agents. Pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients include, but are not limited to, antioxidants (eg, ascorbic acid and sodium bisulfate), preservatives (eg, benzyl alcohol, methyl parabens, ethyl or n-propyl, p-hydroxybenzoate), emulsifying agents, suspending agents, dispersing agents, solvents, fillers, bulking agents, de-

detergents, buffers, vehicles, diluents and/or adjuvants. For example, a suitable vehicle may be physiological saline or citrate-buffered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are other exemplary vehicles. Those skilled in the art will readily recognize a variety of buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases or mixtures thereof. As an example, the buffer components can be water-soluble materials such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid and its salts. Acceptable buffering agents include, for example, a Tris, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-Morpholino) ethanesulfonic acid (MES) buffer , 2-(N-Morpholino)ethanesulfonic acid, sodium salt (MES), 3-(N-Morpholino)propanesulfonic acid (MOPS) and Ntris[Hydroxy-methyl]J-methyl-3-aminopropanesulfonic acid (TAPS). Once a pharmaceutical composition has been formulated, it can be stored in sterile vials as a dehydrated or lyophilized solution, suspension, gel, emulsion, solid, or powder. Such formulations may be stored in a ready-to-use form, a lyophilized form requiring reconstitution prior to use, a liquid form requiring dilution prior to use, or other acceptable form.

[00130] In some embodiments, the pharmaceutical composition is provided in a single-use container (eg, a single-use vial, ampoule, syringe or autoinjector, while a multiple-use container (eg, a multi-purpose vial) it is provided in other modalities.

[00131] The formulations may also include carriers to protect the composition against rapid degradation or elimination from the body, such as a controlled release formulation, including liposomes, hydrogels and microencapsulated delivery systems. For example, a time delay material such as glyceryl monostearate or glyceryl stearate alone, or in combination with a wax, can be used. Any drug delivery device can be used to deliver a CD73 inhibitor, including implants (eg, implantable pumps) and catheter systems, pumps, and slow injection devices, all of which are well known to the art. versed technician.

[00132] The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated according to the known art using the suitable dispersing or wetting agents and suspending agents mentioned herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol. Acceptable diluents, solvents and dispersion media that may be used include water, Ringer's solution, isotonic sodium chloride solution, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Furthermore, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Prolonged absorption of formula

Particular injectables may be achieved by including an agent which delays absorption (eg aluminum monostearate or gelatin).

The CD73 inhibitor compounds and compositions provided herein may be administered to a subject in any appropriate manner known in the art. Suitable administration routines include, without limitation: oral, parenteral (eg, intramuscular, intravenous, subcutaneous (eg, injection or implant), intraperitoneal, intracisternal, intra-articular, intraperitoneal, intracerebral (intraparenchymal) ) and intracerebroventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (eg, transdermal), buccal, and inhalation. Depot injections, which are usually given subcutaneously or intramuscularly, can also be used to release the CD73 inhibitors disclosed herein over a defined period of time. In certain embodiments, the CD73 inhibitor compounds and compositions are administered orally to a subject in need thereof.

The CD73 inhibitor compounds and compositions provided herein may be administered to a subject in an amount depending, for example, on the purpose of administration (eg, the degree of resolution desired); the age, weight, sex and health and physical condition of the individual to whom the formulation is being administered; the administration routine; and the nature of the disease, disorder, condition or symptom thereof. The dosing regimen may also take into account the existence, nature and extent of any adverse effects associated with the agent(s) being administered. Effective dosage amounts and dosage regimens can be readily determined from, for example, safety and dose escalation trials, in vivo studies (for example, animal models) and other methods known to the skilled artisan. In general, dosage parameters dictate that the dosage amount be less than an amount that could be irreversibly toxic to the individual (the maximum tolerated dose (MID)) and not less than an amount necessary to produce an effect. measurable in the individual. These amounts are determined, for example, by the pharmacokinetic and pharmacodynamic parameters associated with ADME, taking into account the administration routine and other factors.

[00135] In some embodiments, a CD73 inhibitor can be administered (eg, orally) at dosage levels from about 0.01 mg/kg to about 50 mg/kg, or about 1 mg µg/kg to about mg/kg of the subject's body weight per day, one or more times a day, to obtain the desired therapeutic effect. For administration of an oral agent, compositions may be provided in the form of tablets, capsules, and the like containing from 1.0 to 1000 milligrams of the active ingredient, particularly 1, 3, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 or 1000 milligrams of active ingredient.

In some embodiments, the dosage of the desired CD73 inhibitor is contained in a "unit dosage form". The phrase "unit dosage form" refers to physically discrete units, each unit containing a predetermined amount of the CD73 inhibitor, alone or in combination with one or more additional agents, sufficient to produce the desired effect. It will be appreciated that the parameters of a unit dosage form will depend on the specific agent(s) and the effect to be achieved.

Also provided herein are kits comprising a CD73 inhibitor compound or composition. Kits are usually in the form of a physical structure that houses several components and can be used, for example, in practicing the methods provided in this document. For example, a Kit can include one or more CD73 inhibitors described herein (provided in, for example, a sterile container), which can be in the form of a pharmaceutical composition suitable for administration to a subject. The CD73 inhibitor may be supplied in a form that is ready to use (eg a tablet or capsule) or in a form that requires, for example, reconstitution or dilution (eg a powder) before administration. When the CD73 inhibitors are in a form that needs to be reconstituted or diluted by a user, the kit may also include diluents (eg, sterile water), buffers, pharmaceutically acceptable excipients, and the like, packaged with or separately from the CD73 inhibitors. CD73. When combination therapy is contemplated, the kit may contain several therapeutic agents separately or they may already be combined in the kit. Each component of the Kkit can be placed inside an individual container and all the various containers can be contained in a single package. A kit of the present invention can be designed for the conditions necessary to properly maintain the components housed in it (eg, refrigeration or freezing).

[00138] A kit may also contain a label or package insert, including identifying information for the components it contains and instructions for their use (eg, dosage parameters, clinical pharmacology of the active ingredient(s) (s), including mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). Labels or package inserts may include manufacturer information such as lot numbers and expiration dates. The label or information leaflet can be, for example, integrated into the physical structure that houses the components, contained separately.

within the physical structure, or affixed to a component of the kit (eg, an ampoule, tube or vial).

EXAMPLES

[00139] The present invention will be more readily understood with reference to the following examples, which are provided to illustrate the invention and should not be construed as limiting its scope in any way.

[00140] Unless defined otherwise or the context clearly dictates otherwise, all technical and scientific terms used in this document have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It is to be understood that any methods and materials similar or equivalent to those described herein can be used in practicing or testing the invention. Compound Synthesis

The compounds provided herein can be prepared using conventional methods and as described in the Examples below. RH Roy | Methylenediphosphonic dichloride = AO mo o No Trimethyl phosphate no-Rs R=o Y No > OH OH >

OH OH OH OH sx

[00142] The amine compound RNH> was obtained from a commercial source or prepared according to methods described in the literature.

[00143] Preparation of Triethylammonium hydrogen carbonate buffer (TEAC). A 1M solution of TEAC was prepared by slowly adding dry ice to a 1M solution of triethylamine in water over several hours until the pH of the solution reached approximately 7.4-7.6 (measured using a pH meter).

[00144] The nucleoside derivative of 2-chloropurine S-x (1 mmol, 1 eq.) was dissolved in trimethyl phosphate (10 mL). The solution was cooled with an ice bath. To the cold solution, a solution of bis(dichlorophosphoryl)methane (4.0 eq.) in trimethyl phosphate (5 ML) was added. The resulting mixture was stirred at 0 °C for 2-4 h, and the reaction was monitored by thin layer chromatography (TLC). The reaction was quenched by TEAC solution, and the pH of the reaction solution was adjusted to 7-8. The mixture was extracted with dichloromethane (DCM) and the aqueous phase was isolated and concentrated. The residual material was purified by reverse phase chromatography with a C18 column, yielding the product as a colorless solid. Example 1. Synthesis of compound 1

[00145] DIEA (diisopropylethylamine; 7.5 mmol, 969 mg, 1.5 eq.) was added dropwise to a solution of 2,6-dichloro-9-(2',3',5'-tri- O-acetyl-BD-ribofuranosyl)purine (5.0 mmol, 2236 mg, 1.0 eq.) and benzylamine (5.0 mmol, 536 mg, 1.0 eq.) in dioxane (25 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, and the residue dissolved in DCM (100 ml), washed with water (2 x 30 ml). The crude product was purified by column chromatography. The intermediate was dissolved in 50 mL of NH3/CH3OH solution and stirred at 35 °C overnight. The solvent was evaporated in vacuo; and the residual material was purified by column chromatography, yielding the nucleoside derivative 2-chloropurine S-1 (1818 mg).

S-1 (1.0 mmol, 392 mg, 1.0 eq.) was dissolved in trimethyl phosphate (10 mL), cooled in an ice bath. To the cold solution, a solution of bis(dichlorophosphoryl)methane (4.0 eq.) in trimethyl phosphate (5 mL) was added. The reaction mixture was stirred at 0 °C for 2-4 h; and the reaction was monitored by TLC. The reaction was quenched by TEAC solution, and the pH of the reaction solution was adjusted to 7-8. The mixture was extracted with DCM, and the aqueous phase was isolated and concentrated. The residual material was purified by reverse phase column chromatography (C18 column), providing compound 1 as a colorless solid (369 mg): *H NMR (500 MHz, CD3OD-ds) 5 ppm 2.46 (t, 2H), 4.23-4.74 (m, 7H), 6.01 (d, 1H), 7.19-7.38 (m, 5H), 8.59 (s, 1H); *C NMR (125 MHz, CD3Cl-d3) 5ppm 40.12, 43.84, 63.92, 69.87, 74.64, 83.71, 88.50, 115.22, 126.92, 127 .47, 128.13, 149.27, 154.08, 154.96, 160.55; !°P NMR (200 MHz, CDsCl-d3) 5ppm 12.94, 18.11; m/z (ESI*) 550.1. Example 2. Synthesis of compound 6

[00147] DIEA(7.5mmol, 969mg, 1.5 eq.) was added dropwise to a solution of 2,6-dichloro-9-(2',3',5'-tri-O-acetyl) -BD-ribofuranosyl) purine (5.0 mmol, 2.2 g, 1.0 eq.) and 1-naphthalenomethanamine (5.0 mmol, 786 mg, 1.0 eq.) in dioxane (25 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, and the residue dissolved in DCM (100ml), washed with water (2x30ml). The solvent was removed (using a rotary evaporator), and the residual material was purified by column chromatography. The intermediate was dissolved in 50 ml NH3/CH3OH solution and stirred at 35 °C overnight. The solvent was evaporated in vacuo, and the residual material was purified by column chromatography, yielding S-6 (1.3 g).

[00148] S-6 (1.0 mmol, 442 mg, 1.0 eq.) was dissolved in trimethyl phosphate (10 mL), cooled in an ice bath. To the cold solution, a solution of bis(dichlorophosphoryl)methane (4.0 eq.) in trimethyl phosphate (5 mL) was added. The resulting mixture was stirred at 0 °C for 2-4 h; and the reaction was monitored by TLC. The reaction was quenched by TEAC solution, and the pH of the reaction mixture was adjusted to 7-8. The mixture was extracted with DCM. The aqueous phase was isolated, concentrated; and the residual material was purified by reverse phase chromatography (column

C18), yielding compound 6 as a colorless solid (110 mg): *H NMR (500 MHz, D2O0) at ppm 0.88-0.91 (m, 3H), 1.34-1.43 (m , 4H), 1.67-1.68 (m, 2H), 2.15-2.26 (m, 2H), 4.16-4.22 (m, 2H), 4.25 -4.31 (m, 2H), 4.38-4.41 (m, 1H), 4.53-4.57 (m, 1H), 4.74-4.76 (m,H ), 6.13-1.15 (m, 1H), 8.70-8.75 (m, 1H); °C NMR (125 MHz, D2O0) 5ppm 13.20, 21.60, 27.24, 27.55, 63.46, 67.12, 70.15, 74.34, 84.08, 84.14, 87.38, 120.98, 142.83, 150.24, 152.49, 153.22; 3*P NMR (200 MHz, D20) 5ppm 16.15, 18.97; m/z (ES) 571.8. Example 3. Synthesis of Compound 7

[00149] DIEA (7.5mmol, 969mg, 1.5 eq.) was added dropwise to a solution of 2,6-dichloro-9-(2',3',5'-tri-O-acetyl) -BD-ribofuranosyl) purine (5.0 mmol, 2.2 g, 1.0 eq.) and 2-naphthalenomethanamine (5.0 mmol, 786 mg, 1.0 eq.) in dioxane (25 mL). The reaction was stirred at room temperature overnight. The solvent was evaporated in vacuo, and the residue dissolved in DCM (100ml), washed with water (2x30ml). The crude product was purified by column chromatography. The intermediate was dissolved in 50 mL of NH3/CH3OH solution and stirred at 35 °C overnight. The solvent was evaporated in vacuo, and the residual material was purified by column chromatography to give the nucleoside derivative 2-chloropurine S-7 (1.159).

[00150] S-7 (1.0 mmol, 442 mg, 1.0 eq.) was dissolved in trimethyl phosphate (10 mL), and the solution was cooled with an ice bath. To the cold solution, a solution of bis(dichlorophosphoryl)|methane (4.0 eq.) in trimethyl phosphate (5 mL) was added. The reaction mixture was stirred at 0 °C for 2-4 h; and the reaction was monitored by TLC. The reaction was quenched by TEAC solution, and the pH of the reaction mixture was adjusted to 7-8. The mixture was extracted with DCM; and the aqueous phase was isolated and concentrated. The residual material was purified by reverse phase chromatography (C18 column), providing compound 7 as a colorless solid (105 mg): *H NMR (500 MHz, D2O0) 5 ppm 2.11 (t, J = 19 .7

Hz, 2H), 4.10 (s, 2H), 4.29 (s, 1H), 4.42 (s, 1H), 4.55 (s, 1H), 4.88 ( s, 2H), 5.79 (s, 1H), 7.36-7.44(m, 4H), 7.71 (d, J = 7.9 Hz, 1H), 7.76 ( d, J = 7.2 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 8.13 (s, 1H); °C NMR (125 MHz, D2O0) 5ppm 27.57, 42.23, 63.39, 70.05, 74.16, 83.59, 86.92, 117.78, 122.74, 125.48, 125.88, 126.05, 126.26, 128.24, 128.43, 130.48, 132.19, 133.08, 139.02, 148.62, 153.86, 154.44. *'P NMR (202 MHz, D20) ô ppm 15.17, 19.58; m/z (ES) 598.2.

Example 4. Synthesis of compound 8

The nucleoside derivative 2-chloropurine S-8 (1.0 mmol, 415 mg, 1.0 eq.) was dissolved in trimethyl phosphate (10 mL); and the solution was cooled with an ice bath. To the cold solution, a solution of bis(dichlorophosphoryl)methane (4.0 eq.) in trimethyl phosphate (5 mL) was added while the ice bath was applied. The resulting mixture was stirred at 0 °C for 2-4 h; and the reaction was monitored by TCL. The reaction was quenched by TEAC solution; and the pH of the reaction mixture was adjusted to 7-8. The mixture was extracted with DCM; and the aqueous phase was isolated and concentrated. The residual material was purified (reverse phase column chromatography, C18 column) to obtain the product as a colorless solid (58 mg). *H NMR (500 MHz, D2O) 5 ppm 2.12 (t, J = 19.7 Hz, 2H), 4.08 (s, 2H), 4.27 (s, 1H), 4, 40 (s, 1H), 4.53 (s, 1H), 4.65 (s, 2H), 5.75 (s, 1H), 7.36 (s, 3H), 7, 65 (s, 2H), 7.69 (d, J = 8.0 Hz, 2H), 8.28 (s, 1H); ?9C NMR (125 MHz, D20) 5ppm 44.04, 63.41, 70.06, 74.19, 83.73, 86.90, 125.50, 125.60, 126.00, 126.34 , 127.38, 128.15, 132.13, 132.71, 135.18, 139.21, 153.96, 154.73; ?*P NMR (202 MHz, D20) 5ppm 15.86, 19.01; m/z (ES) 598.4. Example 5. Synthesis of compound 9

[00152] DIEA (12.5 mmol, 1.6 g, 2.5 eq.) was added dropwise to a solution of 2,6-dichloro-9-(2',3',5'-tri- O-acetyl-BD-ribofuranosyl) purine (5.0 mmol, 2.2 g, 1.0 eq.) and mematine hydrochloride (5.0 mmol, 1.0 g, 1.0 eq.) in 25 mL of dioxane. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, and the residue dissolved in DCM (100 ml), washed with water (2 x 30 ml) and concentrated. The residual material was purified by column chromatography to yield the intermediate. The intermediate was dissolved in 50 mL of NH3/CH3OH solution, and the mixture was stirred at 35 °C overnight. The solvent was evaporated in vacuo, and the residual material was purified by column chromatography to give the nucleoside derivative 2-chloropurine S-9 (1.1 g).

[00153] S-9 (1.0 mmol, 463 mg, 1.0 eq.) was dissolved in trimethyl phosphate (10 mL); and the mixture was cooled with an ice bath. To the cold mixture, a solution of bis(dichlorophosphoryl)methane (4 eq.) in trimethyl phosphate (5 mL) was added. The resulting mixture was stirred at 0 °C for 2-4 h; and the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched by TEAC solution. The pH of the mixture was adjusted to 7-8. The mixture was extracted with DCM, and the aqueous phase was isolated. The aqueous solution was concentrated; and the residue was purified by reverse phase column chromatography (C18 column), providing compound 9 as a colorless solid (200 mg): *H NMR (500 MHz, D20) 5 ppm 0.76 (s, 6 H), 0.98 - 1.12 (m, 2H), 1.22 (s, 2H), 1.31 (d, J = 11.3 Hz, 2H), 1.70 (dd, J = 29.4, 11.9 Hz, 4H), 1.90 (s, 2H), 2.11 (t, J = 19.9 Hz, 3H), 4.07 (s, 2H), 4 .28 (s, 1H), 4.44 (dd, J = 6.5, 2.4 Hz, 1H), 4.67 - 4.63 (m, 1H), 5.91 (d, J = 5.7 Hz, 1H), 8.33 (s, 1H); °C NMR (125 MHz, D2O) 5ppm 25.96, 26.95, 29.97, 32.08, 39.23, 42.32, 50.32, 55.08, 63.73, 70.04, 74.33, 83.78, 87.45, 116.10, 138.34, 148.62, 153.57, 154.16; 3rd*P NMR (200 MHz, D2O) 5ppm 18.12; m/z (ES) 620.2. Example 6. Synthesis of Compound 10

[00154] The nucleoside derivative 2-chloropurine S-10 (1.0 mmol, 451 mg, 1.0 eq.) was dissolved in trimethyl phosphate (10 mL), and the solution was cooled in a bath of ice. To the cold solution, a solution of bis(dichlorophosphoryl)methane (4 eq.) in trimethyl phosphate (5 mL) was added. The resulting mixture was stirred at 0 °C for 2-4 h, and the reaction was monitored by TLC. The reaction was quenched by TEAC solution; and the pH of the reaction solution was adjusted to 7-8. The mixture was extracted with DCM, and the aqueous phase was isolated and concentrated. The residual material was purified by reverse phase column chromatography (C18 column), yielding compound 10 as a colorless solid (60 mg): *H NMR (500 MHz, D2O) 5 ppm 2.27 (t, J = 19 .4Hz, 2H), 4.17 (s, 2H), 4.35 (s, 1H), 4.46 (s, 1H), 6.02 (s, 1H), 7.27 (s, 4H), 7.54 (s, 2H), 7.97 (s, 2H), 8.33 (s, 1H); °C NMR (125 MHz, D2O) ô ppm 16.73, 25.47, 26.48, 27.50, 57.39, 63.69, 70.09, 74.31, 83.84, 87.70, 113.16, 120.00, 122.84, 124.66, 126.42, 138.03, 143.08, 148.86, 152.70, 154.12; ?ºP NMR (200 MHz, D2O0) 5ppm 17.43, 19.35-19.97; m/z (ES) 608.0.

Example 7. Synthesis of Compound 11

[00155] The nucleoside derivative 2-chloropurine S-11 (1.0 mmol, 564 mg, 1.0 eq.) was dissolved in trimethyl phosphate (10 mL). The solution was cooled in an ice bath; and to the cold solution was added a solution of bis(dichlorophosphoryl)methane (4 eq.) in trimethyl phosphate (5 ml). The resulting mixture was stirred at 0 °C for 2-4 h; and the reaction was monitored by TLC. After being quenched by the TEAC solution, the pH of the reaction mixture was adjusted to 7-8. This mixture was extracted with DCM, and the aqueous phase was isolated and concentrated. The residual material was purified by reverse phase column chromatography (C18 column), providing compound 11 as a colorless solid (100 mg): *H NMR (500 MHz, D2O) 5 ppm 0.77 (d, J = 6.5Hz, 3H), 1.22 (s, 14H), 1.55 (s, 2H), 1.92 (s, 4H), 2.12 (t, J = 19, 8Hz, 2H), 2.67 (d, J = 38.2Hz, 4H), 4.03 (s, 2H), 4.19 (s, 1H), 4.40 (s, 1H), 4.60 (s, 1H), 5.20 (d, J = 5.6Hz, 4H), 5.88 (d, J = 4.4Hz, 1H), 8.51 (s, 1H); °C NMR (125 MHz, D2O0) at ppm 13.90, 22.48, 24.71, 25.52, 27.10, 29.26,

29.64, 31.41, 36.86, 37.49, 63.89, 70.44,74.37, 84.15, 86.83, 119.95, 127.82, 129.70, 149, 34, 152.45, 152.86, 164.88, 174.66; **P NMR (200 MHz, D20) ô ppm 16.04.18.65; m/z (ES) 720.4. Example 8. Synthesis of Compound 12

[00156] DIEA (7.5mmol, 969mg, 1.5 eq.) was added dropwise to a solution of 2,6-dichloro-9-(2',3',5'-tri-O-acetyl) -BD-ribofuranosyl) purine (5.0 mmol, 2.23 g, 1.0 eq.) and 2-aminonaphthalene (5.0 mmol, 715 mg, 1.0 eq.) in 25 mL of dioxane. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo; and the residue was dissolved in DCM (100 ml), washed with water (2x 30 ml). The DCM solution was concentrated to dryness; and the residual material was purified by column chromatography, yielding an intermediate. The intermediate was dissolved in 50 mL of NH3/CH3OH solution, and the mixture was stirred at 35 °C overnight. The solvent was evaporated in vacuo, and the residual material was purified by column chromatography to give compound S-12 (670 mg).

[00157] S-12 (1.0 mmol, 427 mg, 1.0 eq.) was dissolved in trimethyl phosphate (10 mL), and the solution was cooled in an ice bath. To the cold solution, a solution of bis(dichlorophosphoryl)methane (4 eq.) in trimethyl phosphate (5 mL) was added. The resulting mixture was stirred at 0 °C for 2-4 h; and the reaction was monitored by TLC. The reaction was quenched by TEAC solution, and the pH of the quenched reaction mixture was adjusted to 7-8. The mixture was extracted with DCM; and the aqueous phase was isolated and concentrated. The residual material was purified by reverse phase column chromatography (C18 column), yielding compound 12 as a colorless solid (100 mg): *H NMR (D2O, 500 MHz) 5 ppm 2.21-2.29 (m , 2H), 4.20-4.22 (m, 2H), 4.40-4.44 (m, 1H), 4.56-4.60 (m, 1H), 4.78 -4.80 (m, 1H), 6.09-6.10 (m, 1H), 7.58-7.64 (m, 3H), 7.71-7.73 (m, 1H) H), 7.97-7.99 (m, 1H) 8.02-8.04 (m, 2H), 8.55 (s, 1H); 19C NMR (D2O, 125 MHz) 5ppm 26.38, 27.37, 28.36, 63.61, 70.33,

84.01, 86.76, 118.06, 121.57, 122.25, 125.52, 126.23, 126.41, 139.82, 149.74, 153.39, 153.47; ?'P NMR (D2O, 200 MHz) 5ppm 16.14, 18.96; m/z (ES) 583.9. Example 9. Synthesis of Compound 15

The nucleoside derivative 2-chloropurine S-15 (1.0 mmol, 513 mg, 1.0 eq.) was dissolved in trimethyl phosphate (10 mL). The mixture was cooled in an ice bath, followed by the addition of a solution of bis(dichlorophosphoryl)methane (4 eq.) in trimethyl phosphate (5 mL). The resulting mixture was stirred at 0 °C for 2-4 h, and the reaction was monitored by TLC. The reaction was quenched by TEAC solution; and the pH of the reaction mixture was adjusted to 7-8. The mixture was extracted with DCM; and the aqueous phase was isolated and concentrated. The residual material was purified by reverse phase column chromatography (C18 column), yielding compound 15 as a colorless solid (30 mg): *H NMR (500 MHz, D2O) 5 ppm 0.70 (t, J = 6 0.3 Hz, 3H) 1.06 (s, 16H), 1.27 (s, 2H), 1.58 (s, 2H), 2.10 (t, J = 19.7 Hz, 2H) , 4.12 (d, J = 32.1 Hz, 4H), 4.27 (s, 1H), 4.46 (s, 1H), 4.66 (s, 1H), 6. 00 (d, J=4.7Hz, 1H), 8.60 (s, 1H); 9C NMR (125 MHz, D20) 5ppm 13.73, 22.40, 25.51, 27.55, 28.40, 29.07, 29.36, 31.66, 63.64, 66.70, 70.27, 74.36, 83.95, 87.18, 120.57, 142.65, 150.05, 152.38, 153.21; °°*P NMR (200 MHz, D20) 5ppm 15.64.18.89; m/z (ES) 670.1. Example 10. Synthesis of Compound 16

[00159] The nucleoside derivative 2-chloropurine S-16 (1.0 mmol, 478 mg, 1.0 eq.) was dissolved in trimethyl phosphate (10 mL); and the mixture was cooled in an ice bath, followed by the addition of a solution of bis(dichlorophosphoryl)methane (4 eq.) in trimethyl phosphate (5 mL). The resulting mixture was stirred at 0 °C for 2-4 h; and the reaction was monitored by TLC. The reaction was quenched by TEAC solution; and the pH of the mixture was adjusted to 7-8. The mixture was extracted with DCM; and the aqueous phase was isolated and concentrated. The residual material was purified.

determined by reverse phase column chromatography (C18 column), providing compound 16 as a colorless solid (250 mg): *H NMR (500 MHz, D2O) 5 ppm 1.64 (s, 11 H), 1 .91 (s, 4H), 2.16 (t, J = 19.8 Hz, 2H), 2.29 (s, 2H), 4.14 (dddd, J = 6.8, 5, 9, 4.1, 1.6 Hz, 3H), 4.30-4.37 (m, 1H), 4.56 - 4.46 (m, 1H), 6.11 (d, J = 5.1 Hz, 1H), 8.72 (s, 1H) °C NMR (125 MHz, D2O0) at ppm 16.75, 27.23, 28.38, 33.41, 36.07, 42.03 , 51.44, 63.47, 70.17, 74.37, 84.19, 87.49, 115.91, 121.90, 143.36, 149.28, 153.15 173.66; ?ºP NMR (200 MHz, D2O0) 5ppm 16.37, 18.85; m/z (ES) 634.1. Example 11. Synthesis of Compound 17

[00160] DIEA (12.5 mmol, 1.6 g, 2.5 eq.) was added dropwise to a solution of 2,6-dichloro-9-(2',3',5'-tri- O-acetyl-BD-ribofuranosyl) purine (5.0 mmol, 2.23 g, 1.0 eq.) and 2-adamantanamine hydrochloride (5.0 mmol, 0.94 g, 1.0 eq.) in 25 ml of dioxane. The mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, and the residue dissolved in DCM (100ml), washed with water (2x30ml). The organic layer was concentrated; and the residual material was purified by column chromatography, yielding an intermediate. This intermediate was dissolved in 50 mL of NH3/CH3OH solution and stirred at 35 °C overnight. After evaporation of the solvent, the residual material was purified by column chromatography, yielding 2-chloropurine S-17 nucleoside derivatives (880 mg).

Compound S-17 (1.0 mmol, 435 mg, 1.0 eq.) was dissolved in trimethyl phosphate (10 mL); and the mixture was cooled in an ice bath. To the cold mixture, a solution of bis(dichlorophosphoryl)methane (4 eq.) in trimethyl phosphate (5 mL) was added. The resulting mixture was stirred at 0 °C for 2-4 h; and the reaction was monitored by TLC. The reaction was quenched by TEAC solution; and the pH of the mixture was adjusted to 7-8. The mixture was extracted with DCM; and the aqueous phase was isolated and concentrated. The residual material was purified by reverse phase column chromatography (C18 column), yielding compound 17 as a colorless solid (30 mg): *H NMR (500 MHz, D2O0) 5 ppm 1.60 (d, J = 12 0.7Hz, 2H), 1.71 (s, 2H), 1.82 (d, J = 20.8Hz, 7H), 1.96 (d, J=19.6Hz, 4H), 2.14 (t, J = 19.8 Hz, 2H), 4.10 (s, 2H), 4.20 (s, 1H), 4.31 (s, 1H), 4.47 ( t, J = 4.2 Hz, 1H), 5.96 (d, J = 5.6 Hz, 1H), 8.41 (s, 1H); °C NMR (125 MHz, D2O0) 5ppm 16.70, 26.77, 30.81, 31.44, 36.48, 36.86, 57.36, 63.51, 70.23, 74.20, 83.97, 86.73, 139.05,154.39; 3°P NMR (200 MHz, D20) ô ppm 15.85.19.04; m/z (ES) 592.0. Example 12. Synthesis of Compound 18

The nucleoside derivative 2-chloropurine S-18 (1.0 mmol, 512 mg, 1.0 eq.) was dissolved in trimethyl phosphate (10 mL). The mixture was cooled in an ice bath, followed by the addition of a solution of bis(dichlorophosphoryl)methane (4 eq.) in trimethyl phosphate (5 mL). The resulting mixture was stirred at 0 °C for 2-4 h; and the reaction was monitored by thin layer chromatography. The reaction was quenched by TEAC solution; and the pH of the mixture was adjusted to 7-8. The mixture was extracted with DCM; and the aqueous phase was isolated and concentrated. The residual material was purified by reverse phase column chromatography (C18 column), yielding compound 18 as a colorless solid (70 mg): *H NMR (500 MHz, CD3OD-ds) ô ppm 0.93 (t , J = 6.8Hz, 3H), 1.52 (s, 18H), 1.60 - 1.74 (m, 2H), 2.33 (t, J = 19.8Hz, 2 H), 3.43 (t, J = 6.6 Hz, 2 H), 4.27 (d, J = 21.4 Hz, 3 H), 4.47 - 4.61 (m, 1 H) , 4.71 (t, J=5.3 Hz, 1H), 6.13 (d, J = 5.4 Hz, 1H), 8.76 (s, 1H); **C NMR (125 MHz, CD3O0D-ds) 5ppm 13.01, 22.30, 26.62, 28.98, 29.28, 31.63, 39.56, 63.95, 70.57, 74.91, 84.44, 87.86, 118.78, 142.32, 150.79, 151.78, 151.97 154.17; 3P NMR (200MHz, CD3O0D-ds) 5ppm 16.03.20.25; m/z(ES), 669.2. Example 13. Synthesis of Compound 19

DIEA (7.5mmol, 969mg, 1.5 eq.) was added dropwise to a solution of 2,6-dichloro-9-(2',3',5'-tri-O-acetyl) -BD-ribofuranosyl)

purine (5.0 mmol, 2.23 g, 1.0 eq.) and di-N-dodecylamine (5.0 mmol, 1.89, 1.0 eq.) in 25 mL of dioxane. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo; and the residue was dissolved in DCM (100 ml), washed with water (2x 30 ml). The organic layer was concentrated to dryness; and the residual material was purified by column chromatography, yielding an intermediate compound. This intermediate was dissolved in 50 mL of NH3/CH3OH solution, and the mixture was stirred at 35 °C overnight. After removal of the solvent in vacuo, the residual material product was purified by column chromatography, yielding 2-chloropurine S-19 nucleoside derivatives (1,39).

[00164] S-19 (1.0 mmol, 637 mg, 1.0 eq.) was dissolved in trimethyl phosphate (10 mL). The mixture was cooled in an ice bath, followed by the addition of a solution of bis(dichlorophosphoryl)methane (4 eq.) in trimethyl phosphate (5 mL). The resulting mixture was stirred at 0 °C for 2-4 h; and the reaction was monitored by TLC. The reaction was quenched by TEAC solution; and the pH of the reaction solution was adjusted to 7-8. The mixture was extracted with DCM; and the aqueous phase was isolated and concentrated. The residual material was purified by reverse phase column chromatography (C18 column), providing compound 19 as a colorless solid (150 mg): *H NMR (500 MHz, CD3OD-ds) 5 ppm 0.93 (t, J = 6.6 Hz, 6H), 1.32 - 1.46 (m, 36H), 1.72 (s, 4H), 2.36 (t, J = 20.0Hz, 2H), 3.70 (s, 2H), 4.11 - 4.382(m, 5H), 4.47 (s, 1H), 4.66 (t, J = 5.2Hz, 1H), 6 .04 (d, J = 5.4 Hz, 1H), 8.37 (s, 1H); *?9C NMR (125 MHz, CD;OD-da) &ppm 13.08, 22.34, 26.44, 29.08, 29.34, 31.68, 64.24, 70.51, 74, 51, 83.84, 87.46 118.27, 137.84, 151.64, 153.46, 154.25; ?ºP NMR (200 MHz, CD3OD-d4s) 5ppm 16.20, 19.99; m/z (ES) 794.6. Example 14. Synthesis of Compound 20

[00165] -DIEA (7.5 mmol, 969 mg, 1.5 eq.) was added dropwise to a solution of 2,6-dichloro-9-(2',3',5'-tri-O -acetyl-BD-ribofuranosyl)

purine (5.0 mmol, 2.23 g, 1.0 eq.) and 2-anthracenamine (5.0 mmol, 1.0 g, 1.0 eq.) in 25 mL of dioxane. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, and the residue dissolved in DCM (100ml), washed with water (2x 30ml). The organic layer was concentrated to dryness; and the residual material was purified by column chromatography, yielding an intermediate compound. This intermediate was dissolved in 50 mL of NH3/CH3OH solution and stirred at 35 °C overnight. The solvent was evaporated in vacuo, and the residual material was purified by column chromatography to give the nucleoside derivative 2-chloropurine S-20 (770 mg).

[00166] S-20 (1.0 mmol, 477 mg, 1.0 eq.) was dissolved in trimethyl phosphate (10 mL). The mixture was cooled in an ice bath, followed by the addition of a solution of bis(dichlorophosphoryl)methane (4 eq.) in trimethyl phosphate (5 mL). The resulting mixture was stirred at 0 °C for 2-4 h; and the reaction was monitored by TLC. The reaction was quenched by TEAC solution; and the pH of the reaction mixture was adjusted to 7-8. The mixture was extracted with DCM; and the aqueous phase was isolated and concentrated. The residual material was purified by reverse phase column chromatography (C18 column), providing compound 20 as a colorless solid (80 mg): *H NMR (500 MHz, D2O) 5 ppm 2.25 (t, Jy = 19 .4Hz, 2H), 4.28 (d, J = 58.1Hz, 3H), 4.46 (s, 2H), 5.56 (s, 1H), 7.19 (s , 3H), 7.57 (d, J = 73.7Hz, 4H), 7.85 (s, 2H), 8.21 (s, 1H); ?ºP NMR (200 MHz, D20) 5ppm 18.42.19.15; m/z (ES) 633.9. Example 15. Synthesis of Compound 22

DIEA (7.5 mmol, 969 mg, 1.5 eq.) was added dropwise to a solution of 2,6-dichloro-9-(2',3',5'-tri-O- acetyl-BD-ribofuranosyl) purine (5.0 mmol, 2.23 g, 1.0 eq.) and 1-adamantanamine (5.0 mmol, 756 mg, 1.0 eq.) in 25 mL of dioxane. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, and the residue dissolved in DCM (100ml), washed with water (2x30ml). After removing the solvent, the residual material was purified by column chromatography, providing an intermediate compound. This intermediate was dissolved in 50 mL of NH3/CH3OH solution, and the mixture was stirred at 35 °C overnight. The solvent was evaporated in vacuo, and the residual material was purified by column chromatography to give the nucleoside derivative 2-chloropurine S-22 (770 mg).

S-22 (1.0 mmol, 435 mg, 1.0 eq.) was dissolved in trimethyl phosphate (10 mL). The mixture was cooled in an ice bath, followed by the addition of a solution of bis(dichlorophosphoryl)methane (4 eq.) in trimethyl phosphate (5 mL). The resulting mixture was stirred at 0 °C for 2-4 h; and the reaction was monitored by TLC. The reaction was quenched by TEAC solution; and the pH of the reaction solution was adjusted to 7-8. The mixture was extracted with DCM; and the aqueous phase was isolated and concentrated. The residual material was purified by reverse phase column chromatography (C18 column), yielding compound 22 as a colorless solid (100 mg): *H NMR (500 MHz, D2O0) 5 ppm 1.64 (s, 6H), 2.06 (d, J = 33.5 Hz, 9H), 2.17 (d, J = 19.9 Hz, 2H), 4.09 (s, 2H), 4.30 (d J = 0.9 Hz, 1H), 4.45 (ddd, J = 5.9, 3.0, 2.0Hz, 1H), 4.68 - 4.65 (m, 1H), 5, 94 (d, J = 5.2 Hz, 1H), 8.38 (s, 1H) °C NMR (125 MHz, D2O0) 5ppm 26.22, 27.22, 29.28, 35.72, 40, 80, 53.50, 63.57, 70.19, 74.20, 83.95, 86.81, 138.60, 148.74, 153.76 154.43; º*P NMR (200 MHz, D2O) 5ppm 16.38, 18.81; m/z (ES-) 592.2. Example 16. Synthesis of Compound 23

[00169] The nucleoside derivative 2-chloropurine S-23 (1.0 mmol, 481 mg, 1.0 eq.) was dissolved in trimethyl phosphate (10 mL), and the mixture was cooled in a bath of ice. To the cold mixture, a solution of bis(dichlorophosphoryl)methane (4 eq.) in trimethyl phosphate (5 mL) was added. The resulting mixture was stirred at 0 °C for 2-4 h; and the re-

action was monitored by TLC. The reaction was quenched by TEAC solution; and the pH of the reaction mixture was adjusted to 7-8. The mixture was extracted with DCM; and the aqueous phase was isolated and concentrated. The residual material was purified by reverse phase column chromatography (C18 column), yielding compound 23 as a colorless solid (141 mg): *H NMR (D2O, 500 MHz) 5 ppm 0.90-0.97 (m, 9H), 1.18-1.20 (m, 1H), 1.36-1.40 (m, 1st H), 1.75-1.80 (m, 1H), 1 .90-1.97 (m, 1H), 2.00-2.30 (m, 2H), 2.40-2.45 (m, 1H), 4.20-4.25 (m) , 2H), 4.40-4.44 (m, 1H), 4.44-4.57 (m, 1H), 4.72-4.73 (m,1H), 4.91 -5.05 (m, 1H), 6.43-6.45 (m, 1H), 9.02 (m, 1H); °C NMR (D2O, 125 MHz) 5 12.74, 18.03, 18.90, 35.91, 44.47, 47.41, 48.45, 63.50, 70.16, 74.34, 83 .22, 84.06, 84.13, 87.37, 120.84, 142.72, 150.23, 152.41, 153.24, 153.45 ppm; 3°P NMR (D2O, 200 MHz) 5ppm 16.49, 18.79; m/z (ES) 638.0. Example 17. Synthesis of Compound 31

[00170] DIEA (7.5 mmol, 969 mg, 1.5 eq.) was added dropwise to a solution of 2,6-dichloro-9-(2',3',5'-tri-O- acetyl-BD-ribofuranosyl) purine (5.0 mmol, 2.23 g, 1.0 eq.) and 3-azaspiro[4.5]decane (5.0 mmol, 696 mg, 1.0 eq.) in 25 ml of dioxane. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, and the residue dissolved in DCM (100ml), washed with water (2x30ml). The organic layer was evaporated to dryness, and the residual material was purified by column chromatography to provide an intermediate compound. This intermediate was dissolved in 50 mL of NH3/CH3OH solution and stirred at 35 °C overnight. The solvent was evaporated in vacuo; and the residual material was purified by column chromatography, yielding the corresponding 2-chloropurine nucleoside derivative, S-31 (1.1 g).

S-31 (1.0 mmol, 423 mg, 1.0 eq.) was dissolved in trimethyl phosphate (10 mL); and the mixture was cooled in an ice bath. To the cold mixture, a solution of bis(dichlorophosphoryl)methane (4 eq.) in trimethyl phosphate (5 mL) was added. The resulting mixture was stirred at 0 °C for 2-4 h; and the reaction was monitored by TLC. The reaction was quenched by TEAC solution; and the pH of the mixture was adjusted to 7-8. The mixture was extracted with DCM; and the aqueous phase was collected and concentrated. The residual material was purified by reverse phase column chromatography (C18 column), yielding compound 31 as a colorless solid (140 mg): *H NMR (500 MHz, D2O0) 5 ppm 1.43 (t, J = 22 0.8 Hz, H), 1.83 (d, J = 52.0 Hz, 2 H), 2.15 (t, J = 19.7 Hz, 2 H), 3.38 (s, 1 H) , 3.58 (s, 1H), 3.79 (s, 1H), 40.1 (s, 1H), 4.12(s, 2H), 4.32 (s, 1H) , 4.49 (t, J = 4.4 Hz, 1H), 4.67 - 4.70 (m, 1H), 5.97-5.98 (d, J = 5.4 Hz, 1H ), 8.36-8.37 (d, J = 6.8 Hz, 1H); °C NMR (125 MHz, D2O) 5ppm 7.67, 8.70, 9.72, 22.92, 27.41.34.49, 45.49, 47.78, 69.61, 73.58, 74.79, 86.08, 87.43, 118.15, 139.22, 150.08, 153.06, 153.84; 3rd*P NMR (200 MHz, D20) 5ppm 15.71,19.11; m/z (ES) 580.0. Example 18. Synthesis of Compound 51

DIEA (7.5 mmol, 969 mg, 1.5 eq.) was added dropwise to a solution of 2,6-dichloro-9-(2',3',5'-tri-O- acetyl-BD-ribofuranosyl) purine (5.0 mmol, 2.23 g, 1.0 eq.) and nortropin (5.0 mmol, 636 mg, 1.0 eq.) in 25 mL of dioxane. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, and the residue dissolved in DCM (100ml), washed with water (2x30ml). The residual material was purified by column chromatography, yielding an intermediate compound. This intermediate was dissolved in 50 mL of NH3/CH3OH solution, and the mixture was stirred at 35 °C overnight. After removal of solvent (in vacuo), the residual material was purified by column chromatography, yielding an S-51 nucleoside derivative of 2-chloropurine (1.2 g).

Compound S-51 (1.0 mmol, 411 mg, 1.0 eq.) was dissolved in trimethyl phosphate (10 mL). The mixture was cooled in an ice bath, followed by the addition of bis(dichlorophosphoryl)methane (4 eq.) in trimethyl phosphate (5 mL). The resulting mixture was stirred at 0 °C for 2-4 h; and the reaction was monitored by TLC. The reaction was quenched by TEAC solution; and the pH of the reaction solution was adjusted to 7-8. The mixture was then extracted with DCM; and the aqueous phase was isolated and concentrated. The residual material was purified by reverse phase column chromatography (C18 column), yielding compound 51 as a colorless solid (160 mg): *H NMR (500 MHz, D20) 5 ppm 1.78 - 2.42 (m) , 11H), 4.06 (s, 1H), 4.12 (s, 2H), 4.28 - 4.37 (m, 1H), 4.45 - 4.55 (m, 1 H), 4.82 - 4.88 (m, 1 H), 5.38 (dd, J = 3.4, 2.4 Hz, 1 H), 5.99 (d, J = 5.6 Hz , 1H), 8.40 (s, 1H); °C NMR (125 MHz, D2O) 5ppm 26.05, 27.10, 27.68, 37.08, 38.20.53.79, 54.40, 64.38, 70.20, 74.09, 83.99, 86.71, 117.78, 138.54, 151.12,154.22; ?ºP NMR (200 MHz, D2O) 5ppm 16.90.18.63; m/z (ES) 568.0. Biological Assays CD73 Inhibitor Screening Assay

To assess the inhibitory effect of the compounds on CD73, the Malachite Green Phosfate Detection Kit (R&D, Cat % DY996) was used. Briefly, compounds were dissolved and diluted to the desired concentration using phosphate-free buffer (Tris-HCI, pH 7.3). ul of the compound solution was added to an equal volume of CD73 protein solution (2x concentration, 0.5 ug/ml, Novoprotein, Cat t C446), followed by a 5 minute incubation at room temperature. 10 ul of Malachite A Green Reagent was added to each well, mixed well and incubated for 10 minutes at room temperature. 10 ul of Malachite B Green Reagent was then added to each well, mixed well and incubated for 20 minutes at room temperature. Finally, the optical density of each well was determined using a microplate reader set at 620 nm. The inhibitory activity of selected compounds is given in Table 2.

Table 2. Inhibitory activity of the compound in the CD73 enzyme assay. | And | And | And | | | and | And | Rj | And | EN | |

FR and | | And | 1"+" denotes IC 50 >100 nM; "++" denotes IC 50 of 10-100 nM; "+++" denotes IC 50 < 10 nM.

2. Cell-based assay of CD73 activity

[00175] Prepare the 5x compound solution by dissolving and diluting the compounds to the desired concentrations using serum free RMPI-1640 containing 1 uM AMP medium. A375 cells are collected and washed twice with PBS, then suspended in serum-free RMPI-1640 medium to a density of 1.125 x 10/ml. Aliquot 80 μl of the cell suspension into a 96-well plate, then

add 20 uL of the 5x compound solution, mix gently and culture for 16 hours at 37°C, 5% CO». After incubation, transfer 50 µl of the supernatant from each well to a new 96-well plate. Then sequentially add 2 μl 2.5 MU ATP and 50 μl Celltiter Glo reagent to each well. Measure luminescence using PheraStar (BMG).

3. Pharmacokinetic evaluation of compounds

Following a single i.v. (1 mg/kg) or i.g. (3 mg/kg) of the compounds to fasting male SD rats, blood samples were collected at 0.08, 0.25, 0.5, 1, 24, 6.8 and 24 h after administration. The plasma was separated by centrifugation (8000 rpm) and frozen (-20°C) until sample analysis. Rat plasma concentrations of compounds were determined by HPLC-MS/MS. Plasma was dispensed into appropriate tubes containing internal standard and methanol or acetonitrile. Tubes were mixed vigorously for 3 minutes to achieve deproteinization and then centrifuged at 8,000 rpm for 5 minutes. The supernatant was transferred to an automatic sample collection vial and injected into the chromatographic system. Pharmacokinetic parameters including AUCo+, Cmax, tmax ti2, MRT, CI and Vd were calculated using WinNonlin 6.3 software. Absolute bioavailability was calculated as follows: F = [AUC (i.g.)*dose(i.v.)] / [AUC (i.v.)*dose (i.v.)]*100%.

[00177] Although this invention is described in detail with reference to its embodiments, these embodiments are offered to illustrate but not to limit the invention. It is possible to make other modalities which use the principles of the invention and which fall within its spirit and scope as defined by the appended claims.

Claims (27)

1. A compound, characterized in that it has the Formula |, or a pharmaceutically acceptable ester or salt thereof: RR O To) NR OH R' (1) in which W is oxygen, sulfur, nitrogen or a methylene group; X is a moiety selected from phosphonyl (—P(=O) (OR)—), sulfonyl (-S(=O)>—) and carbonyl (-C(=O)—), where R is a hydrogen , an ester-forming group, or a protecting group; Y is selected from phosphonate (-PO3R?), sulfonate (-SO3R) and carboxylate (-CO2R), where R is a hydrogen, an ester-forming group or a protecting group; R' is a hydroxyl group or a hydrogen; R? is chlorine or a hydrogen; and R? and R° are independently selected from a hydrogen, an alkyl group, an alkenyl group, and an alkynyl group, wherein at least one of R° and R° has 11 to 30 carbon atoms; or R? and R° are independently selected from a hydrogen and ring system that is a bicycle, tricycle, spiral ring, fused ring, or bridged ring containing a carbocyclic or heterocyclic ring system, whether the carbocyclic ring system is aromatic or not. aromatic, provided that Rº and Rº are not both hydrogen. 2. Compound according to claim 1, characterized in that R° is a hydrogen or a C1.6 alkyl; and Rº is —C(=O)Rº or —C(=0)OR*, where R* is an alkyl group, an al- group. kenyl or an alkynyl group from C11 to C30. 3. Compound according to claim 1, characterized in that R$ is a hydrogen or a C1-6 alkyl; and R° is -C(=O)R° or -C(=0)ORS, where R° is a ring system having a bicycle, tricycle, spiral ring, fused ring, or bridged ring containing a carbocyclic or heterocyclic ring system, the carbocyclic ring system being aromatic or non-aromatic, and the heterocyclic ring system being substituted or unsubstituted. 4. Compound according to claim 1, characterized by the fact that R? it's chlorine. 5. Compound according to any one of claims 1 to 4, characterized in that W is oxygen. 6. Compound according to any one of claims 1 to 3, characterized in that the compound is a compound of Formula IV, or a pharmaceutically acceptable salt or ester thereof: RR The vox o S | NR OH R° (IV). 7. Compound according to any one of claims 1 to 3, characterized in that the compound is a compound of Formula VII or Formula VIII, or a pharmaceutically acceptable salt or ester thereof: RR RR NA NA o O C S C sob to, SA Aee pglnto i SA Ne OR i. 7 OR C > OH Rº (VI), OH Rº (VII) in which R is a hydrogen, an ester-forming group or a protecting group. 8. A compound, characterized in that it has the Formula IX, or a pharmaceutically acceptable salt or ester thereof: RR The pot with the. % Huh OR OR OH R° (IX) in which R is a hydrogen, an ester-forming group or a protecting group; R' is a hydroxyl group or a hydrogen; R° is a hydrogen or a chlorine; and R3 is a hydrogen or a C1-6 alkyl, and R0 is a group containing an adamantyl moiety or a group containing a naphthalyl moiety; or R°, R and the nitrogen atom to which they are attached form a fused tricycle or spiral ring structure. 9. Compound, according to claim 8, characterized in that: Rº is 1-substituted or unsubstituted adamantyl or 2-substituted or unsubstituted adamantyl; or R° is substituted or unsubstituted 1-adamantylmethyl; or R° is substituted or unsubstituted 1-adamantylethyl, 1-substituted or unsubstituted adamantylpropyl, or substituted or unsubstituted 1-adamantylbutyl. 10. Compound, according to claim 8, characterized by the fact that: R° is substituted or unsubstituted a-naphthyl or substituted or unsubstituted B-naphthyl; or R° is substituted or unsubstituted α-naphthylmethyl or substituted or unsubstituted β-naphthylmethyl; or R° is selected from substituted or unsubstituted naphthylpropyl, substituted or unsubstituted naphthylpropyl, and substituted or unsubstituted naphthylpropyl. 11. Compound, characterized by the fact that it is: o LO AT N e EO BR OR-O NON HOT AA o. OH OH OH OH LO AT N eg EO 7 o N 2 po RX R-O o NC! OH OH . OH OH AA AT No o < C AR R-o NO Na HO SH om Co OH OH TO AT No Oo Moftto NNda oH oH Lo OH OH KO EO eo UA " UT N NO cl Ho ho OH OH OH OH N AT N 71 EB e. Ho R O o OH OH OH OH o HN > NS Not the AO | RO R-O NINTH HOT AAA o OH OH OH OH O AT Noo EO "RO OR-O NONOa HOT IA o OH OH OH OH To : AT N 7 o o EO RP R-O NO HOT IA Oo. OH OH OH OH | HN" AT N 98 EIA UM of the N Z HOR Rom NC! OH OH OH OH TO DADA DADAÔS&R HNÍ “O AT No o o BO P-Oo NONE a HO AA Oo. OH OH OH OH H HN AT N 7 F.. SE Ho Ri RO o. OH OH OH OH HNA AT N 2a O UM Of N Z HORROT NC OH OH oh oh o AI AND X N o < |] PO P-O NON o Ho sh o OH OH OH OH ADADAOÔOSDIADÔSÔONW IOÔRADÔAOSÔSAOSÔSASSS N AT N 1 ê 8 SE Ho Rn RO o OH OH OH OH O NDA N go A 1 o N N N Cc! hoi ho OH OH OH OH TS AT N and EMO 1 in N 2 Hot h oa NO OH OH OH OH ú V HN NDA N 7 F.e, Ho ho Oo. OH OH OH OH o 2 To H HN “O AT N 7 2 EO Ho RD R-O NóCI OH OH o OH OH to HN IN THE N 7 2 EO po RX R-O NEI OH OH o OH OH O IN THE N gq TX UM do N Na Cl Ho ho], OH OH OH OH BOO O OS N * Nga TX Ho Ro RO NON DCI OH OH Co OH OH : & NAN eg O po Ro R-o NON OH OH Co OH OH mn z H H DK N 1 É to S Wo HO AA o OH OH oh oh knot SA HnNT TO H AT N eo EO uu DS N Z po RX R7O o NC! OH OH OH OH H, fo] > N—O" H mo N. R N / go Ex no Ro R-O NON CI OH OH Co OH OH N IN THE N 7 "..So Ho Rs RO Oo. OH OH OH OH LS And o o d pod R-o N NOT OH = OH OH AT EO H o C Su B-o NON HOM o oh OH OH KO EO i eo UA & NO NÔ>ECI must o o <ç Z OH OH KO se i 7 o om YOUR PO P-C NO HOM O. OH OH OH OH HN AT N 7 EB E, How ho] OH OH OH OH OF N AT N eg TO 1 in N 2 Ho ho NO OH OH OH OH H CX, IT'S THE AT N / 38 8. E HoBh-om OH OH OH OH O AT N 7 o o EI RO P-O NO HOT O. OH OH oh oh yo HN TO NEAR N eo EO UM — N Z po RX RO o Node CI OH OH oh oh nj IN HN NEAR N eo EO UM — N Z po RX RO o Node CI OH OH OH OH OH “O, HN AT N and EO E NA NE Hof Ro NEI OH OH OH OH J H HN N. * No EO po Rs Ro Y No OH OH = oh oh o YOU AT N 7 WHAT IF HORROR OH OH OH OH H N / HN NR N 1 8 Ex no Re RO o OH OH OH OH IN THE N 1 8 8. SE Ho ho OH OH OH OH | &% N NR N 7 FS e. hoi OH OH OH OH HO O H HN "DO N SN eo A a un N 2 po Ro o Node el OH OH Y 7 OH OH O NH SN o o EO po RR-O o NC! OH OH C OH OH or O EO o o Ho RX $-o o y ão OH O OH OH ; or a pharmaceutically acceptable salt or ester thereof. 12. Compound according to any one of claims 1 to 11, characterized in that the atoms C, H, O and N in the compound are each independently selected from atoms of natural abundance and enriched atoms in isotopes, where isotope-enriched atoms are selected from ºC, 13C, and !C for carbon; selected from *H, 2H and ?H for hydrogen; selected from *ºO, !7O, and *ºO for oxygen; and selected from !*N and *SN for nitrogen. 13. Pharmaceutical composition, characterized in that it comprises the compound or its pharmaceutically acceptable salt or ester, as defined in any one of claims 1 to 12, and a pharmaceutically acceptable carrier. 14. Pharmaceutical composition according to claim 13, characterized by the fact that it is suitable for oral or injectable administration. 15. Use of a compound or a pharmaceutical salt or ester. acceptable term thereof, as defined in any one of claims 1 to 12, characterized in that it is for the manufacture of a pharmaceutical composition to treat or prevent a disease, disorder or condition associated with CD73 in an individual in need thereof. , wherein the CD73-associated disease, disorder, or condition is CD73-mediated immunosuppression; an immunological related disease, disorder or condition; or cancer. 16. Use according to claim 15, characterized in that said compound is administered in an amount effective to reverse, delay or stop the progression of immunosuppression mediated by CD73 in the individual. 17. Use according to claim 15 or 16, characterized in that the disease, disorder or condition associated with CD73 is cancer. 18. Use according to claim 17, characterized in that said cancer is a cancer of the prostate, colon, rectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head , neck, skin, mesothelial lining, white blood cells, esophagus, breast, muscle, connective tissue, lung, adrenal gland, thyroid, kidney or bone; or where said cancer is glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma, choriocarcinoma, cutaneous basal cell carcinoma or testicular seminoma; or where said cancer is selected from the group consisting of melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, a brain tumor, lymphoma, ovarian cancer and sarcoma of Kaposi. 19. Use according to claim 15, characterized in that the disease, disorder or condition associated with CD73 is a disease, disorder or condition related to the immune system. co selected from the group consisting of rheumatoid arthritis, kidney failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, anemia, fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, valve stenosis aortic disease, arteriosclerosis, osteoporosis, Parkinson's disease, infections, Crohn's disease, ulcerative colitis, allergic contact dermatitis, eczema, systemic sclerosis and multiple sclerosis. 20. Use according to any one of claims 19, characterized in that it further comprises the administration of at least one additional therapeutic agent to the individual, wherein at least one additional therapeutic agent is a checkpoint inhibitor immune. 21. Use according to claim 20, characterized in that the immune checkpoint inhibitor is selected from the group consisting of ipulimumab, nivolumab and lambrolizumab. 22. Kit, characterized in that it comprises the compound or pharmaceutically acceptable salt or ester thereof, as defined in any one of claims 1 to 12, and at least one additional therapeutic agent. 23. Kit according to claim 22, characterized in that the at least one additional therapeutic agent is a chemotherapeutic agent, an immunomodulatory agent and/or modulator of inflammation, an anti-hypercholesterolemia agent, an anti- infectious or an inhibitory immune checkpoint. 24. Kit, according to claim 22 or 23, characterized in that it further comprises a buffer or excipient and/or instructions for its use. A compound, or a pharmaceutically acceptable salt or ester thereof, as claimed in any one of claims 1 to 12, characterized by the fact that it is for the treatment or prevention of a disease, disorder or condition associated with CD73 in a subject in need thereof, specified by the fact that the CD73-associated disease, disorder or condition is CD73-mediated immunosuppression; an immunological related disease, disorder or condition; or cancer. 26. Pharmaceutical composition according to claim 13 or 14, characterized in that it is for the treatment or prevention of a disease, disorder or condition associated with CD73 in a subject in need thereof, in which the disease, CD73-associated disorder or condition is CD73-mediated immunosuppression; an immunological related disease, disorder or condition; or cancer. 27. Invention, characterized by any of its claim modalities or categories encompassed by the matter initially described in the patent application or in its examples in the present document presented.