BR112020016509A2 - COMPOUND, COMPOUND FOR USE IN THE TREATMENT OR PROPHYLAXIS OF LIVER CANCER, PHARMACEUTICAL COMPOSITION OR MEDICINE, USE AND METHOD FOR THE TREATMENT OR PROPHYLAXIS OF LIVER CANCER - Google Patents

Abstract

the present invention relates to the compounds of formula (i), wherein r1, r2 and r3 are as described in the present application, and their prodrugs or enantiomers or diastereomers or pharmaceutically acceptable salts, for the (use in) treatment and / or prophylaxis of liver cancer.

Description

“COMPOUND, COMPOUND FOR USE IN THE TREATMENT OR PROPHYLAXIS OF LIVER CANCER, PHARMACEUTICAL COMPOSITION OR MEDICINE, USE AND METHOD FOR THE TREATMENT OR PROPHYLAXIS OF LIVER CANCER”

[001] The present invention relates to new sulfonimidoilpurinone derivatives that have in vivo Toll-like receptor agonism activity (Toll-like receptor), for the (use in) treatment and / or prophylaxis of liver cancer.

BACKGROUND OF THE I NVENTION

[002] Liver cancer is the fifth most common form of cancer. Approximately 750,000 new cases are diagnosed each year and about 700,000 people die from the disease each year, making this cancer the third most common cause of cancer death worldwide (Ferlay et al., Int. J. Cancer 127: 2893 -2917 (2010)). In the United States, the incidence of primary liver cancer has increased and, although there has been some progress in the detection and treatment of localized diseases, the five-year survival rate for advanced liver cancer is still well below 10% (American- Cancer- Society. 2012. Cancer Facts & Figures 2012. Atlanta: American Cancer Society).

[003] Treatments established for liver cancer include surgical removal of part of the liver that contains the tumor (partial hepatectomy), liver transplantation, transcatheter arterial chemoembolization (TACE), in situ destruction of the tumor by different methods, such as ablation radiofrequency (RFA) or cryosurgery and administration of sorafenib. Treatment options for patients with advanced liver cancer are limited. Thus, effective treatments for liver cancer remain a significant unmet medical need.

[004] The present invention relates to compounds of formula (I): (I), wherein from R 1 to R 3 are described below, or are diastereomer or enantiomer or pharmaceutically acceptable salt thereof.

[005] Toll-like receptors (TLRs, from English Toll-like receptors) detect a wide range of molecular patterns associated with conserved pathogens (PAMPs). They play an important role in the detection of invading pathogens and the subsequent initiation of innate immune responses. There are 10 known members of the TLR family in humans, which are type I transmembrane proteins that have a domain rich in extracellular leucine and a cytoplasmic tail that contains a conserved Toll / interleukin (IL) -1 (TIR) receptor domain. Within this family, TLR3, TLR7, TLR8 and TLR9 are located within endosomes.

[006] TLR7 can be activated by binding to a specific small molecule-type ligand (ie TLR7 agonist) or its native ligand (ie, single-stranded RNA, ssRNA). After binding of ssRNA to TLR7, it is believed that the receptor in its dimerized form undergoes a structural change that leads to the subsequent recruitment of adapter proteins into its cytoplasmic domain, including the myeloid differentiation primary response gene (MyD88). After the receptor signaling cascade begins via the MyD88 pathway, cytoplasmic transcription factors, such as interferon regulating factor 7 (IRF-7) and nuclear factor kappa B (NF-kB) are activated. These transcription factors then translocate to the nucleus and initiate the transcription of several genes, for example, IFN-α and other antiviral cytokine genes.

[007] WO201772662 refers to 'TLR7 agonist - anti-HER2' conjugates for the treatment of HER2-positive cancers. Hotz et al., Oncoimmunology 2012, 227-228 refer to the treatment of cancer with TLR7 agonists. However, until now, no TLR7 agonist is used systemically for the treatment of cancer. Only the topical TLR7 agonist, imiquimod, is known to induce immune-mediated rejection of skin metastases in patients with breast cancer (Adams S., Kozhaya L., Martiniuk F., Meng TC, Chiriboga L., Liebes L. , Hochman T., Shuman N., Axelrod D., Speyer J., et al. Clin. Cancer Res. 2012; 18: 6748–6757).

BRIEF DESCRIPTION OF THE I NVENTION

[008] The present invention relates to a series of new compounds of 6-amino-2-sulfonimidoyl-9-substituted-7-substituted-purin-8-one that are endowed with agonistic activity of the Toll-type receptor and its pro-proteins. drugs for use in the treatment or prophylaxis (prevention) of liver cancer.

[009] It has been discovered that the potent and safe TLR7 agonist prodrugs described in the present invention are effective in the treatment of liver cancer, either alone or in combination with other agents.

[010] The present invention provides a series of new 6-amino-2-sulfonimidoyl-9-substituted-7-substituted-purin-8-one compounds which are endowed with agonistic activity of the Toll-type receptor and prodrugs thereof. The invention also provides the bioactivity of such compounds to induce the release of cytokine / chemokine, increased level of SEAP by activation of Toll-type receptors, such as the TLR7 receptor, the metabolic conversion of prodrugs into parent compounds in the presence of hepatocytes humans and the therapeutic or prophylactic use of such compounds and their pharmaceutical compositions comprising such compounds and their prodrugs to treat or prevent liver cancer. The present invention also provides compounds with superior activity. In addition, the compounds of formula (I) also show good solubility and PK profiles.

[011] The present invention relates to new compounds of formula (I): (I), in which: - R1 is C1-6 alkyl; - R2 is benzyl, said benzyl not substituted or substituted by one, two or three substituents, independently selected from halogen and C1-6 alkyl; - R3 is -NR4R5, where - R4 is C1-6 alkyl or C1-6 alkoxy-C1-6 alkyl; - R5 is (C1-6alkyl) 2NCOO-C1-6alkyl, C1-6alkoxy-C1-6alkyl, C1-6 alkoxycarbonyl (C1-6alkyl) amino C1-6alkyl, C1-6 alkoxycarbonyl (phenyl) C1alkyl -6, C1-6 alkoxycarbonyl C1-6alkyl, C1-6 alkoxycarbonyl C1-6alkyl, C1-6alkyl, C1-6alkyl (C1-6alkyl) amino C1-6alkyl or pyrrolidinylcarbamoyloxy C1-6alkyl; or

- R4 and R5 together with the nitrogen to which they are attached form a heterocyclyl; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof; - for use in the treatment or prophylaxis of liver cancer; - on the condition that they are excluded; -6-amino-9-benzyl-2- (propylsulfonimidoyl) -7- (pyrrolidine-1-carbonyl) purin-8-one; -6-amino-9-benzyl-7- (piperidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (morpholine-4-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (3,3-dimethylpyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; Ethyl -1- [6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] pyrrolidine-2-carboxylate; -6-amino-7- (2-azospiro [3.3] heptane-2-carbonyl) -9-benzyl-2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (2-oxa-6-azospiro [3.3] heptane-6-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (3,3-difluoropyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (3-fluoro-3-methyl-pyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; - and their enantiomers or diastereomers.

[012] These prodrug compounds are especially useful for the treatment of liver cancer as they are activated (converted into their active forms) in the liver. They show valuable antitumor efficacy in in vivo studies in liver cancer cell models (alone or in combination with anti-PD1 / PD1 antibodies or with anti-angiogenic agents) and in in vitro studies against liver cancer cells (by cell activation peripheral blood and / or factors).

[013] The invention also relates to the use of these in the manufacture of a medicament for the treatment or prophylaxis of liver cancer, medicaments based on a compound according to the invention for the treatment or prophylaxis of liver cancer.

Consequently, the compounds of formula (I) are useful for the treatment or prophylaxis of liver cancer, especially for the treatment or prophylaxis of hepatocellular carcinoma, hepatoma, cholangiocarcinoma, hepatoblastoma, liver carcinoma, liver angiosarcoma or metastatic liver cancer.

DETAILED DESCRIPTION OF THE INVENTION

[014] Unless otherwise defined, all technical and scientific terms used in the present have the same meaning as is commonly understood by a technician versed in the subject to which this invention belongs. In addition, the following definitions are presented to illustrate and define the meaning and scope of the various terms used to describe the present invention.

[015] The term "C1-6alkyl" means a saturated straight or branched chain alkyl group that contains from 1 to 6, particularly from 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. Specific "C 1-6 alkyl" groups are methyl, ethyl and n-propyl.

[016] The term "C1-6 alkoxy" means a group of the formula C1-6-alkyl- O-. Examples of C 1-6 alkoxy group include, but are not limited to,

methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Specific "C1-6 alkoxy" groups are methoxy, ethoxy and isopropoxy. A more specific C 1-6 alkoxy group is ethoxy.

[017] The term "halogen" and "halo" are used interchangeably in the present invention and denote fluoro, chloro, bromo, or iodo.

[018] The term "heterocyclyl" indicates a monovalent, saturated or partially unsaturated, monovalent, mono- or bicyclic ring system, having 3 to 10 ring atoms, comprising 1 to 5 ring hetero atoms selected from N, O and S , carbon being the atoms remaining in the ring. In specific embodiments, heterocyclyl is a saturated, monovalent monocyclic ring system with 4 to 7 ring atoms, comprising 1, 2, or 3 ring hetero atoms selected from N, O and S, the remaining atoms being carbon in the ring. Examples of monocyclic saturated heterocyclyl are aziridinila, oxiranila, azetidinyl, oxetanila, pyrrolidinyl, dimetilpirrolidinila, etoxicarbonilpirrolidinila, tetrahydrofuranyl, tetrahydro-thienyl, pirazolidinila, imidazolidinila, oxazolidinila, isoxazolidinila, tiazolidinila, piperidinyl, tetrahydropyranyl, tetrahidrotiopiranila, piperazinyl, morpholinyl, tiomorfolinila, dioxotiomorfolinila, azepanila, diazepanila, homopiperazinila, or oxazepanila.

The saturated monocyclic heterocyclyl can also be substituted by one to three substituents, independently selected from halogen, C1-6 alkyl and C1-6 alkoxycarbonyl. Examples for substituted monocyclic saturated heterocyclyl are 4-methylpiperazinyl, dimethylpyrrolidinyl, ethoxycarbonylpyrrolidinyl, difluoropyrrolidinyl, fluoro (methyl) pyrrolidinyl.

Examples for saturated bicyclic heterocyclyl are azabicycles [3.2.1] octyl, quinuclidinyl, oxa-azabicycles [3.2.1] octyl, azabicycles [3.3.1] nonila, oxazazabicycles [3.3.1] nonila, thiaazabicycles [3.3.1] nonila, azaespiro [3.3] heptanila and oxa-azaespiro [3.3] heptanila. Examples for partially unsaturated heterocyclyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydropyridinyl and dihydropyranyl.

[019] The term "carbonyl", alone or in combination, means the group -C (O) -.

[020] The term "C 1-6 alkylcarbonyl" refers to a C1-6-C (O) - alkyl group, where "C 1-6 alkyl" is as defined above. A particular "C 1-6 alkylcarbonyl" group is acetyl.

[021] The term "enantiomers" denotes two stereoisomers of a compound that are mirror images not superimposable to each other.

[022] The term “diastereomer” refers to a stereoisomer with two or more chirality centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, for example, melting point, boiling point, spectral properties and reactivities.

[023] The term "pharmaceutically acceptable salts" means salts that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include acid and basic addition salts.

[024] The term "pharmaceutically acceptable acid addition salt" means pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and organic acids selected from aryl aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid maloneic, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid mesylate, ethanesulfonic acid , p-toluenesulfonic acid, and salicylic acid.

[025] The term "pharmaceutically acceptable base addition salt" means pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylamine and piperidine.

[026] The compounds of the general formula (I) and their prodrugs that contain one or more chiral centers may be present in the form of racemates, diastereomeric mixtures, or simple optically active isomers. Racemates can be separated into enantiomers according to known methods. In particular, diastereomeric salts that can be separated by crystallization are formed from racemic mixtures by reaction with an optically active acid such as, for example, D- or L-tartaric acid, mandelic acid, malic acid, lactic or camphor sulfonic acid.

[027] The term "prodrug" means a form or derivative of a compound that is metabolized in vivo, for example, by biological fluids or enzymes by a patient after administration, in a pharmacologically active form of the compound in order to produce the desired pharmacological effect. Prodrugs are described, for example, in “The Organic Chemistry of Drug Design and Drug Action”, by Richard B. Silverman, Academic Press, San Diego, 2004, Chapter 8 of Prodrugs and Drug Delivery Systems, p. 497-558.

[028] A "pharmaceutically active metabolite" is intended to designate a pharmacologically active product produced through the metabolism in the body of a specified compound or salt thereof.

After entering the body, most drugs are substrates for chemical reactions that can alter their physical properties and biological effects. These metabolic conversions, which usually affect the polarity of the compound of the invention, change the way drugs are distributed and excreted from the body. However, in some cases, the metabolism of a drug is necessary for the therapeutic effect.

[029] The term "therapeutically effective amount" denotes an amount of the compound or molecule of the present invention that, when administered to a subject, is capable of (i) treating or preventing a certain disease, condition or disorder, (ii) alleviating, improving or eliminate one or more symptoms of the particular disease, condition, disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, the condition of the disease to be treated, the severity of the disease treated, the age and relative health of the patient, the route and form of administration, the discretion of the attending or veterinarian and others factors.

[030] The term "pharmaceutical compositions" means a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients to be administered to a mammal, for example, a human, in need of such treatment .

TLR7 AGONIST AND PRO-DRUG

[031] The present invention relates to a compound of formula (I): (I), in which: - R1 is C1-6 alkyl; - R2 is benzyl, said benzyl not substituted or substituted by one, two or three substituents, independently selected from halogen and C1-6 alkyl; - R3 is -NR4R5, where - R4 is C1-6 alkyl or C1-6 alkoxy-C1-6 alkyl; - R5 is (C1-6alkyl) 2NCOO-C1-6alkyl, C1-6alkoxy-C1-6alkyl, C1-6 alkoxycarbonyl (C1-6alkyl) amino C1-6alkyl, C1-6 alkoxycarbonyl (phenyl) C1alkyl -6, C1-6 alkoxycarbonyl C1-6alkyl, C1-6 alkoxycarbonyl C1-6alkyl, C1-6alkyl, C1-6alkyl (C1-6alkyl) amino C1-6alkyl or pyrrolidinylcarbamoyloxy C1-6alkyl; or - R4 and R5 together with the nitrogen to which they are attached form a heterocyclyl; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof; - for use in the treatment or prophylaxis of liver cancer; - on the condition that they are excluded;

-6-amino-9-benzyl-2- (propylsulfonimidoyl) -7- (pyrrolidine-1-carbonyl) purin-8-one; -6-amino-9-benzyl-7- (piperidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (morpholine-4-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (3,3-dimethylpyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; Ethyl -1- [6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] pyrrolidine-2-carboxylate; -6-amino-7- (2-azospiro [3.3] heptane-2-carbonyl) -9-benzyl-2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (2-oxa-6-azospiro [3.3] heptane-6-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (3,3-difluoropyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (3-fluoro-3-methyl-pyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; - and their enantiomers or diastereomers.

[032] An additional embodiment of the present invention is (ii) a compound of formula (I), in which: - R1 is C1-6 alkyl; - R2 is benzyl, said benzyl not substituted or substituted by halogen or C1-6 alkyl; - R3 is azetidinyl; - piperazinyl substituted by C1-6 alkyl; - piperidinyl replaced by piperidinyl; - pyrrolidinyl; or

- NR4R5, where: - R4 is C1-6 alkyl or C1-6 alkoxy-C1-6 alkyl; - R5 is (C1-6alkyl) 2NCOO-C1-6alkyl, C1-6alkoxy-C1-6alkyl, C1-6 alkoxycarbonyl (C1-6alkyl) amino C1-6alkyl, C1-6 alkoxycarbonyl (phenyl) C1alkyl -6, C1-6 alkoxycarbonyl C1-6alkyl, C1-6 alkoxycarbonyl C1-6alkyl, C1-6alkyl, C1-6alkyl (C1-6alkyl) amino C1-6alkyl or pyrrolidinylcarbamoyloxy C1-6alkyl; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of liver cancer.

[033] An additional embodiment of the present invention is (iii) a compound of formula (I), in which: - R1 is ethyl or propyl; - R2 is benzyl, bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl; - R3 is azetidinyl; - 4-methylpiperazinyl; - piperidinylpiperidinyl; - pyrrolidinyl; or -NR4R5, where: - R4 is methyl, ethyl, propyl or methoxyethyl; - R5 is acetyl (methyl) aminoethyl, butyl, butyl (methyl) carbamoyloxyethyl, diethylcarbamoyloxyethyl, ethoxycarbonyl (methyl) aminoethyl, ethoxycarbonylethyl, ethoxycarbonylisobutyl, ethoxycarbonylisopentyl, ethoxycarbonylmethyl, ethoxycarbonylyloxy, ethoxycarbonyloxy (ethyl) ) ethyl, isopropyl, methoxycarbonyl (methyl) aminoethyl, methoxyethyl, methoxypropyl, propyl, propyl (methyl) carbamoyloxyethyl, pyrrolidinylcarbamoyloxyethyl, terti-

butoxycarbonyl (methyl) aminoethyl, tert-butoxycarbonylethyl, tert-butoxycarbonylisopentyl or tert-butoxycarbonyl (phenyl) ethyl; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of liver cancer.

[034] An additional embodiment of the present invention is (iii-1) a compound of formula (I), in which: - R1 is ethyl or propyl; - R2 is benzyl, chlorobenzyl, fluorobenzyl or methylbenzyl; - R3 is azetidinyl; - 4-methylpiperazinyl; - piperidinylpiperidinyl; - pyrrolidinyl; or -NR4R5, where: - R4 is methyl, ethyl, propyl or methoxyethyl; - R5 is acetyl (methyl) aminoethyl, butyl, butyl (methyl) carbamoyloxyethyl, diethylcarbamoyloxyethyl, ethoxycarbonyl (methyl) aminoethyl, ethoxycarbonylethyl, ethoxycarbonylisobutyl, ethoxycarbonylisopentyl, ethoxycarbonylmethyl, ethoxycarbonylyloxy, ethoxycarbonyloxy (ethyl) ) ethyl, isopropyl, methoxycarbonyl (methyl) aminoethyl, methoxyethyl, methoxypropyl, propyl, propyl (methyl) carbamoyloxyethyl, pyrrolidinylcarbamoyloxyethyl, tert-butoxycarbonyl (methyl) aminoethyl, tert-butoxycarbonylethyl, tert-butoxycarbonyl and tert-butoxycarbonyl; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of liver cancer.

[035] An additional embodiment of the present invention is (iv) a compound of formula (I), wherein R3 is azetidinyl, 4-methylpiperazinyl, piperidinylpiperidinyl, pyrrolidinyl, acetyl (methyl) aminoethyl (methyl) amino, bis (methoxyethyl) ) amino, butyl (ethyl) amino, butyl (methyl) amino, butyl (methyl) carbamoyloxyethyl (methyl) amino, diethylcarbamoyloxyethyl (methyl) amino, ethoxycarbonyl (methyl) aminoethyl (methyl) amino, ethoxycarbonylethyl (methyl) amino, ethoxycarbonylisobutyl (methyl ) amino, ethoxycarbonylisopentyl (methyl) amino, ethoxycarbonylmethyl (methyl) amino, ethoxycarbonyloxyethyl (methyl) amino, ethoxycarbonyl (phenyl) ethyl (methyl) amino, ethyl (methyl) amino, isobutyl (methyl) amino, isopropoxycarbonylisopentyl (methyl) amino, isopropoxycarbonylisopentyl (methyl) amino, isopropylcarbonylisopentyl (methyl) amino, (phenyl) ethyl (methyl) amino, isopropyl (methyl) amino, methoxycarbonyl (methyl) aminoethyl (methyl) amino, methoxyethyl (ethyl) amino, methoxyethyl (methyl) amino, methoxyethyl (propyl) amino, methoxypropyl (methyl) amino, propyl (ethyl) amino, propyl (methyl) amino, propyl (methyl) carbamoyloxyethyl (methyl) amino, pyrrolidinylcarbamoyloxy ethyl (methyl) amino, tert-butoxycarbonyl (methyl) aminoethyl (methyl) amino, tert-butoxycarbonylethyl (methyl) amino, tert-butoxycarbonylisopentyl (methyl) amino or tert-butoxycarbonyl (phenyl) ethyl (methyl) amino; or pharmaceutically acceptable salt, enantiomer or diastereomer thereof, for use in the treatment or prophylaxis of liver cancer.

[036] An additional embodiment of the present invention is (v) a compound of formula (I), in which R1 is ethyl, for use in the treatment or prophylaxis of liver cancer.

[037] An additional embodiment of the present invention is (vi) a compound of formula (I), wherein R2 is benzyl substituted by halogen or C1-6 alkyl, for use in the treatment or prophylaxis of liver cancer.

[038] An additional embodiment of the present invention is (vii) a compound of formula (I), wherein R2 is bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl, for use in the treatment or prophylaxis of liver cancer.

[039] An additional embodiment of the present invention is (vii-1) a compound of formula (I), wherein R2 is chlorobenzyl, fluorobenzyl or methylbenzyl, for use in the treatment or prophylaxis of liver cancer.

[040] An additional embodiment of the present invention is (viii) a compound of formula (I), wherein R2 is bromobenzyl, chlorobenzyl or fluorobenzyl, for use in the treatment or prophylaxis of liver cancer.

[041] An additional embodiment of the present invention is (viii-1) a compound of formula (I), wherein R2 is chlorobenzyl or fluorobenzyl, for use in the treatment or prophylaxis of liver cancer.

[042] An additional embodiment of the present invention is (ix) a compound of formula (I), where R3 is -NR4R5, where R4 is C1-6 alkyl, R5 is C1-6 alkyl, for use in treatment or prophylaxis of liver cancer.

[043] An additional embodiment of the present invention is (x) a compound of formula (I), wherein R3 is propyl (methyl) amino or ethyl (methyl) amino, for use in the treatment or prophylaxis of liver cancer.

[044] An additional embodiment of the present invention is (xi) a compound of formula (I), in which: - R1 is C1-6 alkyl; - R2 is benzyl, said benzyl being replaced by halogen or C1-6 alkyl; - R3 is -NR4R5, where R4 is C1-6 alkyl, R5 is C1-6 alkyl; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of liver cancer.

[045] An additional embodiment of the present invention is (xii) a compound of formula (I), in which: - R1 is ethyl;

- R2 is methylbenzyl, bromobenzyl, chlorobenzyl or fluorobenzyl; - R3 is propyl (methyl) amino or ethyl (methyl) amino; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of liver cancer.

[046] An additional embodiment of the present invention is (xii-1) a compound of formula (I), in which: - R1 is ethyl; - R2 is methylbenzyl, chlorobenzyl or fluorobenzyl; - R3 is propyl (methyl) amino or ethyl (methyl) amino; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of liver cancer.

[047] Another example of carrying out the present invention is that (xiii) certain compounds of formula (I) are as follows: -6-Amino-9-benzyl-N-methyl-8-oxo-N-propyl-2- ( propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N- (2-methoxyethyl) -N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N-ethyl-8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-7- [4- (1-piperidyl) piperidine-1-carbonyl] -2- (propylsulfonimidoyl) purin-8-one; -6-Amino-9-benzyl-N-ethyl-N- (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N-butyl-N-ethyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-7- (azetidine-1-carbonyl) -9-benzyl-2-

(propylsulfonimidoyl) purin-8-one;

-6-Amino-9-benzyl-N-isopropyl-N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-9-benzyl-7- (4-methylpiperazine-1-carbonyl) -2-

(propylsulfonimidoyl) purin-8-one;

-6-Amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-9-benzyl-N-isobutyl-N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

carbonyl] -methyl-amino] ethyl acetate;

-3 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] propanoate;

-3 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

tert-butyl carbonyl] -methyl-amino] propanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] propanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

tert-butyl carbonyl] -methyl-amino] -4-methyl pentanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

carbonyl] -methyl-amino] -4-methyl-isopropyl pentanoate;

- ethyl (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] -3-methyl-butanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

carbonyl] -methyl-amino] -4-methyl-pentanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] -3-phenyl-propanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

isopropyl carbonyl] -methyl-amino] -3-phenyl-propanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

tert-butyl carbonyl] -methyl-amino] -3-phenyl-propanoate;

-N- [2- [Acetyl (methyl) amino] ethyl] -6-amino-9-benzyl-N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

methyl carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;

-N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

tert-butyl carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;

-N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;

-N [Butyl-N-methyl-carbamate of 2 - [[6-Amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-Pyrrolidine-1-carboxylate of 2 - [[6-Amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-N [Methyl-N-propyl-carbamate of 2 - [[6-Amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-N, N - Diethylcarbamate of 2 - [[6-Amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-El 2 - [[6-Amino-9-benzyl-8-oxo-2- ethyl carbonate

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-6-Amino-N-butyl-9 - [(4-chlorophenyl) methyl] -N-methyl-8-oxo-2- [S (S) -propylsulfonimidoyl] purine-7-carboxamide;

-6-amino-N-butyl-9 - [(4-chlorophenyl) methyl] -N-methyl-8-oxo-2- [S (S) -

propylsulfonimidoyl] purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-N-methyl-8-oxo-N-propyl-2 [S (S) -propylsulfonimidoyl] -9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-N-methyl-8-oxo-N-propyl-2 [S (R) -propylsulfonimidoyl] -9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-2- [S (S) -propylsulfonimidoyl] -9- (p-tolylmethyl) -7- (pyrrolidine-

1-carbonyl) purin-8-one;

-6-Amino-2- [S (R) -propylsulfonimidoyl] -9- (p-tolylmethyl) -7- (pyrrolidine-

1-carbonyl) purin-8-one;

-6-Amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [S (S) -

propylsulfonimidoyl] -9- (p-tolylmethyl) purine-7-carboxamide;

-6-Amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [S (R) -

propylsulfonimidoyl] -9- (p-tolylmethyl) purine-7-carboxamide;

-6-Amino-N-ethyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) -9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-N-butyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) -9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-

oxo-N-propyl-purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -2- [S (S) -ethylsulfonimidoyl] -N-methyl-8-

oxo-N-propyl-purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-

methyl-8-oxo-purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide;

-6-Amino-2- [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-2- [S (S) ethylsulfonimidoyl] -9 - [(4-fluorophenyl) methyl] -N-methyl-8-

oxo-N-propyl-purine-7-carboxamide;

-6-Amino-2- [S (R) ethylsulfonimidoyl] -9 - [(4-fluorophenyl) methyl] -N-methyl-8-

oxo-N-propyl-purine-7-carboxamide;

-6-Amino-N-ethyl-2- (ethylsulfonimidoyl) -9 - [(4-fluorophenyl) methyl] -N-methyl-

8-oxo-purine-7-carboxamide;

-6-Amino-N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - 9 - [(4-fluorophenyl) methyl] -N-

methyl-8-oxo-purine-7-carboxamide;

-6-Amino-N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - 9 - [(4-fluorophenyl) methyl] -N-

methyl-8-oxo-purine-7-carboxamide;

-6-Amino-9 - [(4-bromophenyl) methyl] -2- (ethylsulfonimidoyl) -N-methyl-8-oxo-

N-propyl-purine-7-carboxamide;

-6-Amino-2- [S (R) -ethylsulfonimidoyl] -9 - [(4-bromophenyl) methyl] -N-methyl-

8-oxo-N-propyl-purine-7-carboxamide;

-6-Amino-2- [S (S) -ethylsulfonimidoyl] -9 - [(4-bromophenyl) methyl] -N-methyl-

8-oxo-N-propyl-purine-7-carboxamide;

-6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimidoyl) -N-methyl-

8-oxo-purine-7-carboxamide;

-6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; and

-6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] -

N-methyl-8-oxo-purine-7-carboxamide; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of liver cancer.

[048] Another example of carrying out the present invention is that (xiv) more particular compounds of formula (I) are the following: -6-Amino-9-benzyl-N-methyl-8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9 - [(4-chlorophenyl) methyl] -2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide; -6-Amino-9 - [(4-chlorophenyl) methyl] -2- [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide; -6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-2- [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide; -6-Amino-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide; -6-Amino-N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide; -6-Amino-N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide; -6-amino-2- (ethylsulfonimidoyl) -9 - [(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide; -6-Amino-2- [S (S) ethylsulfonimidoyl] -9 - [(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

-6-Amino-2- [S (R) ethylsulfonimidoyl] -9 - [(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide; -6-Amino-N-ethyl-2- (ethylsulfonimidoyl) -9 - [(4-fluorophenyl) methyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - 9 - [(4-fluorophenyl) methyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - 9 - [(4-fluorophenyl) methyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -2- (ethylsulfonimidoyl) -N-methyl-8-oxo-N-propyl-purine-7-carboxamide; -6-Amino-2- [S (R) -ethylsulfonimidoyl] -9 - [(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide; -6-Amino-2- [S (S) -ethylsulfonimidoyl] -9 - [(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimidoyl) -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; and -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of liver cancer.

[049] Another example of the present invention is that (xv) more particular compounds of formula (I) are as follows: -6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] - N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimidoyl] -

N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimidoyl) -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; and -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of liver cancer.

[050] In some embodiments, the compounds of the present invention have been tested and compared to the following reference compounds. As the most successful biopharmaceutical companies focused on the discovery and development of TLR7 agonists for the treatment of liver disease, Gilead has the most advanced pipeline of TLR7 agonists with leading compounds such as GS-96 20, which has entered into studies of Phase II. Gilead compound GS-9620 disclosed in US20100143301 as an example 49, compound S-2 and S-3 disclosed in JP1999193282 were all selected as the reference compound in the present application: (GS-9620), (S -two),

(S-3).

SYNTHESIS

[051] The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes set out below and in the examples. All substituents, in particular from R1 to R14, are as previously defined unless otherwise indicated. In addition, and unless otherwise explicitly stated, all reactions, reaction conditions, abbreviations and symbols have the meanings widely known to a person normally versed in organic chemistry.

SCHEME 1

VII VI V IV III II I

[052] A compound of formula VI is prepared by cyclization of isocyanate VII with aminomalononitrile p-toluenesulfonate.

Then bicycle V is synthesized by reacting the compound of formula VI with benzoyl isothiocyanate in the presence of inorganic base, such as NaOH or KOH. Alkylation of bicycle V with alkyl halide in the presence of base, such as K2CO3, NaH or Cs2CO3, provides the compound of formula IV. The compound of formula III is prepared by oxidizing the compound of formula IV with an oxidizing agent, such as meta-chloroperoxybenzoic acid, hydrogen urea peroxide adduct and HIO4. The compound of formula II is obtained by imitating the compound of formula III with an imitating reagent, such as sodium azide in acid, and said acid is, for example, Eaton's reagent or PPA. The compound of formula I is obtained by reacting the compound of formula II with carbamoyl chloride in the presence of a mixed base, such as pyridine and triethylamine, pyridine and DIPEA, DMAP and triethylamine, or DMAP and DIPEA.

SCHEME 2

XII IX X

XI CF3COOH PMBNH 2

IV VIII IVa

II III

[053] The compound of formula II can also be prepared as set out in Scheme 2.

[054] A compound of formula X is prepared by reacting the compound of formula XI with R2NH2. Reduction of compound X with a reducing reagent, such as zinc or iron powder in AcOH, provides the compound of formula IX. Cyclization of the compound of formula IX with cyclization reagents, such as phosgene, carbonyl diimidazole, diethyl carbonate and triphosgene, provides the compound of formula VIII. A compound of formula IVa is prepared by treating the compound of formula VIII with PMBNH2. A compound of formula III is prepared by deprotecting the compound of formula IVa with acid, such as CF3COOH, followed by oxidation with an oxidant, such as meta-chloroperoxybenzoic acid, urea adduct - hydrogen peroxide and HIO4. The compound of formula II is obtained by imitating the compound of formula III with an imitating reagent, such as sodium azide in acid, the said being, for example, Eaton reagent or PPA.

[055] The present invention also relates to a process for the preparation of a compound of formula (I) which comprises the reaction of: - a compound of formula (II): (II), - with carbamoyl chloride in the presence a mixed base; and - where R1 and R2 are as previously defined.

[056] In the above step, the mixed base can be, for example, pyridine and triethylamine, pyridine and DIPEA, DMAP and triethylamine, or DMAP and DIPEA.

[057] A compound of formula (I) when manufactured according to the aforementioned process, for use in the treatment or prophylaxis of liver cancer is also an object of the present invention.

PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION

[058] Another exemplary embodiment provides pharmaceutical compositions or medicaments for use in the treatment or prophylaxis of liver cancer containing the compounds of the invention and a therapeutically inert carrier, vehicle, diluent or excipient, as well as methods of using the compounds of the invention for prepare these compositions and medicines.

In one example, the compounds of formula (I) can be formulated by mixing at room temperature, at an appropriate pH, and with the desired degree of purity, with physiologically acceptable vehicles, that is, vehicles that are non-toxic to recipients at dosages and concentrations used in a galenic form of administration. The pH of the formulation depends mainly on the specific use and concentration of the compounds, but can vary between about 3 to 8. In one example, a compound of formula (I) is formulated in an acetate buffer, at pH 5. In another example embodiments, the compounds of formula (I) are sterile. The compound can be stored, for example, as a solid or amorphous composition, such as a lyophilized formulation or aqueous solution.

[059] The compositions are formulated, dosed and administered in a manner consistent with good medical practice. Factors to be considered in this context include the specific disorder to be treated, the specific mammal to be treated, the patient's clinical condition, the cause of the disorder, the place of delivery of the agent, the method of administration, the administration schedule and other factors known to doctors. The “effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount needed to activate the TLR7 receptor and lead to the production of INF-α and other cytokines, which can be used, but not limited, to the treatment or prevention of hepatitis B and / or viral C in infected patients.

[060] In one example, the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.1 to 50 mg / kg, alternatively about 0.1 to 30 mg / kg patient's body weight per day, with the typical initial range of the compound used from 0.3 to 15 mg / kg / day. In another embodiment, oral unit dosage forms, such as tablets and capsules, preferably contain about 20 to about 1,000 mg of the compound of the invention.

[061] The compounds of the invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal, and if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[062] The compounds of the present invention can be administered in any convenient form of administration, for example, in tablets, powders, capsules, solutions, dispersions, suspensions, syrups, aerosols, suppositories, gels, emulsions, adhesives, etc. Such compositions may contain conventional components in pharmaceutical preparations, for example, diluents, vehicles, pH modifiers, sweeteners, bulking agents, and additional active agents.

[063] A typical formulation is prepared by mixing the compounds of the present invention and a vehicle or excipient. Suitable vehicles and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients.

Chicago, Pharmaceutical Press, 2005. The formulations can also include one or more buffers, stabilizing agents, surfactants, humectants, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, fluidizers, processing additives, dyes, sweeteners , perfume agents, flavoring diluents and other known additive agents to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or to assist in the manufacture of the pharmaceutical product (i.e., the drug).

[064] An example of a suitable oral dosage form is a tablet containing about 20 to 1,000 mg of the compound of the invention composed of about 30 to 90 mg of anhydrous lactose, about 5 to 40 mg croscarmellose sodium, about 5 to 30 mg of polyvinylpyrrolidone (PVP) K30, and about 1 to 10 mg of magnesium stearate. The powdered ingredients are first mixed and then mixed with a PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate and compressed to form tablets using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example, 20 to 1,000 mg, of the invention in a suitable buffer solution, for example, phosphate buffer, adding a toner, for example, a salt such as chloride sodium, if desired. The solution can be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

[065] An exemplary embodiment, therefore, includes a pharmaceutical composition comprising a compound of formula (I), or its enantiomers or diastereomers or pharmaceutically acceptable salts.

[066] An additional embodiment example further includes a pharmaceutical composition comprising a compound of formula (I), or its pharmaceutically acceptable enantiomers or diastereomers or salts, together with a pharmaceutically acceptable carrier or excipient.

[067] Another exemplary embodiment includes a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salts or enantiomers or diastereomers for use in the treatment of hepatitis B virus infection.

INDICATIONS AND TREATMENT METHODS

[068] The present invention provides methods for the treatment or prevention of liver cancer in a patient with such a need. In some embodiments, liver cancer is hepatocellular carcinoma, hepatoma, cholangiocarcinoma, hepatoblastoma, liver carcinoma, liver angiosarcoma or metastatic liver cancer. In some instances, liver cancer is refractory cancer.

[069] The terms "cancer" and "cancerous" refer to, or describe, the physiological condition in mammals that is normally characterized by the growth / proliferation of cells in an unregulated manner. Examples of liver cancer include, but are not limited to, hepatocellular carcinoma, hepatoma, hepatoblastoma, cholangiocarcinoma, hepatoblastoma, liver carcinoma, sarcoma, lymphoma and liver angiosarcoma. In several embodiments, liver cancer (e.g., HCC) can be intermediate, advanced, or terminal. Liver cancer (for example, HCC) can be metastatic or non-metastatic. Liver cancer (for example, HCC) can be resectable or unresectable.

Liver cancer (eg, HCC) can comprise a single tumor, multiple tumors, or an ill-defined tumor with an infiltrative growth pattern (in portal veins or hepatic veins). Liver cancer (eg, HCC) can comprise a fibrolamellar, pseudoglandular (adenoid), pleomorphic (giant cell) or clear pattern. Liver cancer (for example, HCC) can comprise a very differentiated form, and tumor cells resemble hepatocytes, form trabeculae, cords and nests and / or contain bile pigments in the cytoplasm. Liver cancer (for example, HCC) can comprise a slightly differentiated form, and malignant epithelial cells are discoesive, pleomorphic, anaplastic and / or giant. In some embodiments, liver cancer (eg, HCC) is associated with hepatitis B, hepatitis C, cirrhosis or type 2 diabetes. The term “cellular hyperproliferative disorder” and “proliferative disorder” refer to disorders that are to some degree associated with abnormal cell proliferation. In one example of an embodiment, the disorder of cell proliferation is cancer.

[070] In an example of an embodiment of the present invention, the compounds (and pharmaceutical compositions and medicaments thereof) described in the present invention are used in the prophylaxis / prevention of liver cancer in patients at high risk of developing liver cancer.

[071] In a preferred embodiment of the invention, the compounds described in the present invention are especially useful as prodrugs that are converted into the active drug predominantly in the liver. An exemplary embodiment of the invention are the prodrug compounds described in the present invention for use in the treatment of liver cancer, wherein the compounds are prodrugs of the formula (I): (I), where: - R1 is alkyl C1-6; - R2 is benzyl, said benzyl not substituted or substituted by one, two or three substituents, independently selected from halogen and C1-6 alkyl; - R3 is -NR4R5, where - R4 is C1-6 alkyl or C1-6 alkoxy-C1-6 alkyl;

- R5 is (C1-6alkyl) 2NCOO-C1-6alkyl, C1-6 alkoxy-C1-6alkyl,

C1-6 alkoxycarbonyl (C1-6alkyl) C1-6alkylalkyl, C1-6 alkoxycarbonyl (phenyl) alkyl

C1-6, C1-6 alkoxycarbonyl C1-6 alkyl, C1-6 alkoxycarbonyl C1-6 oxyalkyl, C1- alkyl

6, C1-6 alkyl-carbonyl (C1-6 alkyl) C1-6 alkylalkyl or pyrrolidinylcarbamoyloxy C1-6 alkyl; or

- R4 and R5 together with the nitrogen to which they are attached form a heterocyclyl;

- or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof;

- for use in the treatment or prophylaxis of liver cancer;

- on the condition that they are excluded;

-6-amino-9-benzyl-2- (propylsulfonimidoyl) -7- (pyrrolidine-1-

carbonyl) purin-8-one;

-6-amino-9-benzyl-7- (piperidine-1-carbonyl) -2-

(propylsulfonimidoyl) purin-8-one;

-6-amino-9-benzyl-7- (morpholine-4-carbonyl) -2-

(propylsulfonimidoyl) purin-8-one;

-6-amino-9-benzyl-7- (3,3-dimethylpyrrolidine-1-carbonyl) -2-

(propylsulfonimidoyl) purin-8-one;

-1- [6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

carbonyl] ethyl pyrrolidine-2-carboxylate;

-6-amino-7- (2-azospiro [3.3] heptane-2-carbonyl) -9-benzyl-2-

(propylsulfonimidoyl) purin-8-one;

-6-amino-9-benzyl-7- (2-oxa-6-azospiro [3.3] heptane-6-carbonyl) -2-

(propylsulfonimidoyl) purin-8-one;

-6-amino-9-benzyl-7- (3,3-difluoropyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one;

-6-amino-9-benzyl-7- (3-fluoro-3-methyl-pyrrolidine-1-carbonyl) -2-

(propylsulfonimidoyl) purin-8-one; - and its enantiomers or diastereomers; - and wherein the prodrug compounds of general formula I are converted in the human liver to the active drug of formula II: (II), - where R1 and R2 are as defined above.

[072] Exemplary conversion ratios using human liver microsomes are shown in Example 50. In Example 61 it also demonstrates the liver as the primary site of conversion of the prodrug into its active form.

[073] An example of a preferred embodiment of the invention are the compounds (prodrugs) described in the present invention in which the compounds are susceptible to conversion into their active form by the liver enzymes, CYP2C9 and CYP2C19. An example of a preferred embodiment of the invention are the compounds (prodrugs) described in the present invention, where the compounds show a conversion rate in the active compound of ≥10 nmol / min / mg of protein in human hepatocytes and ≤ 2 nmol / min / mg protein in human enterocytes (as measured in an appropriate assay using human hepatocytes and enterocytes).

COMBINED TREATMENT

[074] One aspect of the invention is the combined treatment of a liver cancer patient with the compound of formula I with.

[075] It was surprisingly found that a combination therapy of compounds of formula I and a treatment with anti-axial agent

PD-L1 / PD1 is highly effective in liver tumors.

[076] Therefore, an aspect of the invention is a compound of formula (I) (or a medicament or a pharmaceutical composition comprising that compound): (I), in which: - R1 is C1-6 alkyl; - R2 is benzyl, said benzyl not substituted or substituted by one, two or three substituents, independently selected from halogen and C1-6 alkyl; - R3 is -NR4R5, where - R4 is C1-6 alkyl or C1-6 alkoxy-C1-6 alkyl; - R5 is (C1-6alkyl) 2NCOO-C1-6alkyl, C1-6alkoxy-C1-6alkyl, C1-6 alkoxycarbonyl (C1-6alkyl) amino C1-6alkyl, C1-6 alkoxycarbonyl (phenyl) C1alkyl -6, C1-6 alkoxycarbonyl C1-6alkyl, C1-6 alkoxycarbonyl C1-6alkyl, C1-6alkyl, C1-6alkyl (C1-6alkyl) amino C1-6alkyl or pyrrolidinylcarbamoyloxy C1-6alkyl; or - R4 and R5 together with the nitrogen to which they are attached form a heterocyclyl; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof; - on the condition that they are excluded; -6-amino-9-benzyl-2- (propylsulfonimidoyl) -7- (pyrrolidine-1-carbonyl) purin-8-one;

-6-amino-9-benzyl-7- (piperidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (morpholine-4-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (3,3-dimethylpyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; Ethyl -1- [6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] pyrrolidine-2-carboxylate; -6-amino-7- (2-azospiro [3.3] heptane-2-carbonyl) -9-benzyl-2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (2-oxa-6-azospiro [3.3] heptane-6-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (3,3-difluoropyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (3-fluoro-3-methyl-pyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; - and their enantiomers or diastereomers, - for use: a) in the treatment of liver cancer in combination with a PD1 antagonist or PD-L1 antagonist antibody, or b) in the treatment of a patient suffering from liver cancer in combination with a PD1 antagonist or PD-L1 antagonist antibody.

[077] An example of an embodiment of the invention is a compound of formula (I) (or a medicament or a pharmaceutical composition comprising that compound):

(I), where:

- R1 is C1-6 alkyl;

- R2 is benzyl, said benzyl not substituted or substituted by one, two or three substituents, independently selected from halogen and C1-6 alkyl;

- R3 is -NR4R5, where

- R4 is C1-6 alkyl or C1-6 alkoxy-C1-6 alkyl;

- R5 is (C1-6alkyl) 2NCOO-C1-6alkyl, C1-6 alkoxy-C1-6alkyl,

C1-6 alkoxycarbonyl (C1-6alkyl) C1-6alkylalkyl, C1-6 alkoxycarbonyl (phenyl) alkyl

C1-6, C1-6 alkoxycarbonyl C1-6 alkyl, C1-6 alkoxycarbonyl C1-6 oxyalkyl, C1- alkyl

6, C1-6 alkyl-carbonyl (C1-6 alkyl) C1-6 alkylalkyl or pyrrolidinylcarbamoyloxy C1-6 alkyl; or

- R4 and R5 together with the nitrogen to which they are attached form a heterocyclyl;

- or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof;

- on the condition that they are excluded;

-6-amino-9-benzyl-2- (propylsulfonimidoyl) -7- (pyrrolidine-1-

carbonyl) purin-8-one;

-6-amino-9-benzyl-7- (piperidine-1-carbonyl) -2-

(propylsulfonimidoyl) purin-8-one;

-6-amino-9-benzyl-7- (morpholine-4-carbonyl) -2-

(propylsulfonimidoyl) purin-8-one;

-6-amino-9-benzyl-7- (3,3-dimethylpyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; Ethyl -1- [6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] pyrrolidine-2-carboxylate; -6-amino-7- (2-azospiro [3.3] heptane-2-carbonyl) -9-benzyl-2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (2-oxa-6-azospiro [3.3] heptane-6-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (3,3-difluoropyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (3-fluoro-3-methyl-pyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; - and its enantiomers or diastereomers, - for use in the treatment or prophylaxis of liver cancer; and - in which a PD1 antagonist or PD-L1 antagonist antibody is co-administered (wherein the treatment is combined with a PD1 antagonist or PD-L1 antagonist antibody).

[078] An example of an embodiment of the invention is the use of a compound of formula (I): (I), in which: - R1 is C1-6 alkyl; - R2 is benzyl, said benzyl not substituted or substituted by one, two or three substituents, independently selected from halogen and C1-6 alkyl;

- R3 is -NR4R5, where

- R4 is C1-6 alkyl or C1-6 alkoxy-C1-6 alkyl;

- R5 is (C1-6alkyl) 2NCOO-C1-6alkyl, C1-6 alkoxy-C1-6alkyl,

C1-6 alkoxycarbonyl (C1-6alkyl) C1-6alkylalkyl, C1-6 alkoxycarbonyl (phenyl) alkyl

C1-6, C1-6 alkoxycarbonyl C1-6 alkyl, C1-6 alkoxycarbonyl C1-6 oxyalkyl, C1- alkyl

6, C1-6 alkyl-carbonyl (C1-6 alkyl) C1-6 alkylalkyl or pyrrolidinylcarbamoyloxy C1-6 alkyl; or

- R4 and R5 together with the nitrogen to which they are attached form a heterocyclyl;

- or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof;

- on the condition that they are excluded;

-6-amino-9-benzyl-2- (propylsulfonimidoyl) -7- (pyrrolidine-1-

carbonyl) purin-8-one;

-6-amino-9-benzyl-7- (piperidine-1-carbonyl) -2-

(propylsulfonimidoyl) purin-8-one;

-6-amino-9-benzyl-7- (morpholine-4-carbonyl) -2-

(propylsulfonimidoyl) purin-8-one;

-6-amino-9-benzyl-7- (3,3-dimethylpyrrolidine-1-carbonyl) -2-

(propylsulfonimidoyl) purin-8-one;

-1- [6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

carbonyl] ethyl pyrrolidine-2-carboxylate;

-6-amino-7- (2-azospiro [3.3] heptane-2-carbonyl) -9-benzyl-2-

(propylsulfonimidoyl) purin-8-one;

-6-amino-9-benzyl-7- (2-oxa-6-azospiro [3.3] heptane-6-carbonyl) -2- (propylsulfonimidoyl) purin-8-one;

-6-amino-9-benzyl-7- (3,3-difluoropyrrolidine-1-carbonyl) -2-

(propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (3-fluoro-3-methyl-pyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; - and its enantiomers or diastereomers, - for the preparation of a medicine for the treatment or prophylaxis of liver cancer; and - in which a PD1 antagonist or PD-L1 antagonist antibody is co-administered (wherein the treatment is combined with a PD1 antagonist or PD-L1 antagonist antibody).

[079] In another embodiment of the present invention, the specific compounds of formula (I) that are used in combination therapy with the PD1 antagonist or PD-L1 antagonist antibody are selected from the following compounds: -6-Amino -9-benzyl-N-methyl-8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N- (2-methoxyethyl) -N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N-ethyl-8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-7- [4- (1-piperidyl) piperidine-1-carbonyl] -2- (propylsulfonimidoyl) purin-8-one; -6-Amino-9-benzyl-N-ethyl-N- (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N-butyl-N-ethyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-7- (azetidine-1-carbonyl) -9-benzyl-2-

(propylsulfonimidoyl) purin-8-one;

-6-Amino-9-benzyl-N-isopropyl-N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-9-benzyl-7- (4-methylpiperazine-1-carbonyl) -2-

(propylsulfonimidoyl) purin-8-one;

-6-Amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-9-benzyl-N-isobutyl-N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

carbonyl] -methyl-amino] ethyl acetate;

-3 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] propanoate;

-3 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

tert-butyl carbonyl] -methyl-amino] propanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] propanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

tert-butyl carbonyl] -methyl-amino] -4-methyl pentanoate;

- (2S) -2 - [[6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

carbonyl] -methyl-amino] -4-methyl-isopropyl pentanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] -3-methyl-butanoate;

- ethyl (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] -3-phenyl-propanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

isopropyl carbonyl] -methyl-amino] -3-phenyl-propanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

tert-butyl carbonyl] -methyl-amino] -3-phenyl-propanoate;

-N- [2- [Acetyl (methyl) amino] ethyl] -6-amino-9-benzyl-N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

methyl carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;

-N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

tert-butyl carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;

-N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;

-N-Butyl-N-methyl-carbamate of 2 - [[6-amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-Pyrrolidine-1-carboxylate of 2 - [[6-amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-N-Methyl-N-propyl-carbamate of 2 - [[6-amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-N, 2 - [[6-amino-9-benzyl-8-oxo-2- N-diethylcarbamate

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-Ethyl carbonate of 2 - [[6-amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-6-Amino-N-butyl-9 - [(4-chlorophenyl) methyl] -N-methyl-8-oxo-2- [S (S) -

propylsulfonimidoyl] purine-7-carboxamide;

-6-amino-N-butyl-9 - [(4-chlorophenyl) methyl] -N-methyl-8-oxo-2- [S (S) -propylsulfonimidoyl] purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-N-methyl-8-oxo-N-propyl-2 [S (S) -propylsulfonimidoyl] -9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-N-methyl-8-oxo-N-propyl-2 [S (R) -propylsulfonimidoyl] -9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-2- [S (S) -propylsulfonimidoyl] -9- (p-tolylmethyl) -7- (pyrrolidine-

1-carbonyl) purin-8-one;

-6-Amino-2- [S (R) -propylsulfonimidoyl] -9- (p-tolylmethyl) -7- (pyrrolidine-

1-carbonyl) purin-8-one;

-6-Amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [S (S) -

propylsulfonimidoyl] -9- (p-tolylmethyl) purine-7-carboxamide;

-6-Amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [S (R) -

propylsulfonimidoyl] -9- (p-tolylmethyl) purine-7-carboxamide;

-6-Amino-N-ethyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) -9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-N-butyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) -9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-

oxo-N-propyl-purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -2- [S (S) -ethylsulfonimidoyl] -N-methyl-8-

oxo-N-propyl-purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-

methyl-8-oxo-purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-

methyl-8-oxo-purine-7-carboxamide;

-6-Amino-2- [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;

-6-Amino-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-2- [S (S) ethylsulfonimidoyl] -9 - [(4-fluorophenyl) methyl] -N-methyl-8-

oxo-N-propyl-purine-7-carboxamide;

-6-Amino-2- [S (R) ethylsulfonimidoyl] -9 - [(4-fluorophenyl) methyl] -N-methyl-8-

oxo-N-propyl-purine-7-carboxamide;

-6-Amino-N-ethyl-2- (ethylsulfonimidoyl) -9 - [(4-fluorophenyl) methyl] -N-methyl-

8-oxo-purine-7-carboxamide;

-6-Amino-N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - 9 - [(4-fluorophenyl) methyl] -N-

methyl-8-oxo-purine-7-carboxamide;

-6-Amino-N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - 9 - [(4-fluorophenyl) methyl] -N-

methyl-8-oxo-purine-7-carboxamide;

-6-Amino-9 - [(4-bromophenyl) methyl] -2- (ethylsulfonimidoyl) -N-methyl-8-oxo-

N-propyl-purine-7-carboxamide;

-6-Amino-2- [S (R) -ethylsulfonimidoyl] -9 - [(4-bromophenyl) methyl] -N-methyl-

8-oxo-N-propyl-purine-7-carboxamide;

-6-Amino-2- [S (S) -ethylsulfonimidoyl] -9 - [(4-bromophenyl) methyl] -N-methyl-

8-oxo-N-propyl-purine-7-carboxamide;

-6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimidoyl) -N-methyl-

8-oxo-purine-7-carboxamide;

-6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] -

N-methyl-8-oxo-purine-7-carboxamide; and

-6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide;

- or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof.

[080] In another embodiment of the present invention, the specific compounds of formula (I) that are used in combination therapy with the PD1 antagonist or PD-L1 antagonist antibody are selected from the following compounds: -6-Amino -9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimidoyl) -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; and -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof.

[081] In another embodiment of the present invention, the specific compound of formula (I) that is used in combination therapy with the PD1 antagonist or PD-L1 antagonist antibody is: 6-Amino-9 - [(4- chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide.

[082] In one embodiment, the co-administration (or combination therapy or combination treatment or combination treatment) of the compound of formula I and the PD1 antagonist or PD-L1 antagonist antibody is done simultaneously (simultaneously). In one embodiment, co-administration (or combination therapy or combination treatment or combination treatment) of the compound of formula I and the PD1 antagonist or PD-L1 antagonist antibody is done sequentially (sequentially).

[083] The terms "administered in combination with" or "co-administered", "co-administered", "combined therapy", "combined treatment", "in combination with" or "treatment combination" refer to the administration of the formula compound I described in the present invention, and the PD1 antagonist or PD-L1 antagonist antibody, as described in the present invention, for example, as separate formulations / applications (or as a single formulation / application). Co-administration can be simultaneous or sequential in any order, where there is a period of time, while both active agents (or all) simultaneously exercise their biological activities. Co-administration is simultaneous or sequential (for example, intravenous (iv) through a continuous infusion. In one embodiment, co-administration is simultaneous. In one example, co-administration is sequential. Co-administration is both simultaneous and sequential (for example, intravenous (iv) via continuous infusion).

[084] It is evident that antibodies are administered to the patient in a “therapeutically effective amount” (or simply “effective amount”), which is the amount of the respective compound or combination that will trigger the biological or medical response of a tissue, system , animal or human, which is being sought by the researcher, veterinarian, doctor or other clinician.

[085] The amount of co-administration and the co-administration time will depend on the type (species, sex, age, weight, etc.) and the condition of the patient being treated and the severity of the disease or condition being treated. Said compounds of formula I and said antibodies are suitably co-administered to the patient at the same time or in a series of treatments, for example, on the same day or the following day.

VIA PD-1 / PD-L1 / PD-L2

[086] An important negative co-stimulation signal that regulates T cell activation is provided by programmed death receptor 1 (PD-1) (CD279) and its PD-L1 binding partners (B7-H1, CD274; SEQ ID NO : 13) and PD-L2 (B7-DC, CD273). The negative regulatory role of PD-1 was revealed by knockout models for PD-1 (Pdcd1 - / -), which are prone to autoimmunity. Nishimura et al., Immunity 11: 141-51 (1999); Nishimura et al., Science 291: 319-22 (2001). PD-1 is related to CD28 and CTLA-4, but lacks the proximal membrane cysteine that allows homodimerization. The cytoplasmic domain of PD-1 contains a tyrosine-based immunoreceptor inhibition motif (ITIM, V / IxYxxL / V). PD-1 binds only to PD-L1 and PD-L2. Freeman et al., J. Exp. Med. 192: 1-9 (2000); Dong et al., Nature Med. 5: 1365-1369 (1999); Latchman et al., Nature Immunol. 2: 261-268 (2001); Tseng et al., J. Exp. Med. 193: 839-846 (2001).

[087] PD-1 can be expressed in T cells, B cells, natural killer T cells (NK), activated monocytes and dendritic cells (DCs). PD-1 is expressed by activated, but not by unstimulated human CD4 + and CD8 + T cells, B cells and myeloid cells. This contrasts with the more restricted expression of CD28 and CTLA-4. Nishimura et al., Int. Immunol. 8: 773-80 (1996); Boettler et al., J. Virol. 80: 3532-40 (2006). There are at least 4 variant forms of PD-1 that have been cloned from activated human T cells, including transcripts that lack (i) exon 2, (ii) exon 3, (iii) exons 2 and 3 or ( iv) exons 2 to 4. Nielsen et al., Cell. Immunol. 235: 109-16 (2005). With the exception of PD-1 deltaex3, all variants are expressed at levels similar to full-length PD-1 in resting peripheral blood mononuclear cells (PBMCs). The expression of all variants is significantly induced after activation of human T cells with anti-CD3 and anti-CD28. The PD-1deltaex3 variants do not have a transmembrane domain and resemble soluble CTLA-4, which plays an important role in autoimmunity. Ueda et al., Nature 423: 506-11 (2003). This variant is enriched in the synovial fluid and serum of patients with rheumatoid arthritis. Wan et al., J. Immunol. 177: 8844-50 (2006).

[088] The two PD-1 ligands differ in their expression patterns. PD-L1 is constitutively expressed in mouse T and B cells, CDs, macrophages, mesenchymal stem cells and mast cells derived from bone marrow. Yamazaki et al., J. Immunol. 169: 5538-45 (2002). PD-L1 is expressed in a wide range of non-hematopoietic cells (eg, cornea, lung, vascular epithelium, liver non-parenchymal cells, mesenchymal stem cells, pancreatic islets, placental syncytiotrofoblasts, keratinocytes, etc.) [Keir et al. , Annu. Rev. Immunol. 26: 677-704 (2008)], and is regulated positively in several cell types after activation. Both type I and type II interferons (IFNs) increase PD-L1. Eppihimer et al., Microcirculation 9: 133-45 (2002); Schreiner et al., J. Neuroimmunol. 155: 172-82 (2004). The expression of PD-L1 in cell lines decreases when MyD88, TRAF6 and MEK are inhibited.

Liu et al., Blood 110: 296-304 (2007). JAK2 has also been implicated in PD-L1 induction. Lee et al., FEBS Lett. 580: 755-62 (2006); Liu et al., Blood 110: 296-304 (2007). Loss or inhibition of phosphatase and tensin homologue (PTEN), a cellular phosphatase that modifies phosphatidylinositol 3-kinase (PI3K) and Akt signaling, increased post-transcriptional PD-L1 expression in cancers. Parsa et al., Nat. Med. 13: 84-88 (2007).

[089] The expression of PD-L2 is more restricted than PD-L1. PD-L2 is inducibly expressed in DC, macrophages and mast cells derived from bone marrow. PD-L2 is also expressed in about half to two thirds of resting peritoneal B1 cells, but not in conventional B B2 cells. Zhong et al., Eur. J. Immunol. 37: 2405-10 (2007). B1 PD-L2 + cells bind to phosphatidylcholine and may be important for innate immune responses against bacterial antigens. The induction of PD-L2 by IFN-gamma is partially dependent on NF-kappaB. Liang et al., Eur. J.

Immunol. 33: 2706-16 (2003). PD-L2 can also be induced in monocytes and macrophages by GM-CF, IL-4 and IFN-gamma. Yamazaki et al., J.

Immunol. 169: 5538-45 (2002); Loke et al., PNAS 100: 5336-41 (2003).

[090] Typical PD-1 signaling has a greater effect on cytokine production than on cell proliferation, with significant effects on the production of IFN-gamma, TNF-alpha and IL-2. PD-1-mediated inhibitory signaling also depends on the strength of TCR signaling, with greater inhibition administered at low levels of TCR stimulation. This reduction can be overcome by co-stimulation through CD28 [Freeman et al., J. Exp. Med. 192: 1027-34 (2000)] or the presence of IL-2 [Carter et al., Eur. J. Immunol. 32: 634-43 (2002)].

[091] There is more evidence that signaling via PD-L1 and PD-L2 can be bidirectional. That is, in addition to modifying TCR or BCR signaling, signaling can also be delivered back to cells that express PD-L1 and PD-L2. Although treatment of dendritic cells with a naturally human anti-PD-L2 antibody isolated from a patient with Waldenstrom macroglobulinemia did not regulate the MHC II or B7 co-stimulatory molecules, such cells produced a greater amount of pro-inflammatory cytokines, particularly TNF-alpha and IL-6, and stimulate the proliferation of T cells. Nguyen et al., J. Exp. Med. 196: 1393-98 (2002). The treatment of mice with this antibody also (1) increased resistance to transplanted melanoma b16 and quickly induced tumor-specific CTLs. Radhakrishnan et al., J. Immunol. 170: 1830-38 (2003);

Radhakrishnan et al., Cancer Res. 64: 4965-72 (2004); Heckman et al., Eur. J.

Immunol. 37: 1827-35 (2007); (2) blocked the development of inflammatory airway disease in a mouse model of allergic asthma. Radhakrishnan et al., J. Immunol. 173: 1360-65 (2004); Radhakrishnan et al., J. Allergy Clin. Immunol. 116: 668-74 (2005).

[092] Further evidence of reverse signaling in dendritic cells (“DC's”) results from studies with bone marrow-derived DCs cultured with soluble PD-1 (EC domain of PD-1 fused in the Ig constant region - “s-PD- 1"). Kuipers et al., Eur. J. Immunol. 36: 2472-82 (2006). This sPD-1 inhibited the activation of DCs and increased the production of IL-10, reversibly through the administration of anti-PD-1.

[093] In addition, several studies show a receptor for PD-L1 or PD-L2 that is independent of PD-1. B7.1 has already been identified as a liaison partner for PD-L1. Butte et al., Immunity 27: 111-22 (2007).

Chemical cross-linking studies suggest that PD-L1 and B7.1 may interact through their IgV-like domains. The interactions of B7.1: PD-L1 can induce an inhibitory signal in T cells. The binding of PD-L1 in CD4 + T cells by B7.1 or the binding of B7.1 in CD4 + T cells by PD-L1 provides a inhibitory signal. T cells that lack CD28 and CTLA-4 show decreased proliferation and cytokine production when stimulated by anti-CD3 plus B7.1 coated beads. In T cells that lack all B7.1 receptors (ie, CD28, CTLA-4 and PD-L1), proliferation and cytokine production were no longer inhibited by anti-CD3 plus B7.1 coated beads. . This indicates that B7.1 acts specifically through PD-L1 in the T cell in the absence of CD28 and CTLA-

4. Similarly, T cells that do not have PD-1 showed decreased proliferation and cytokine production when stimulated in the presence of spheres coated with anti-CD3 plus PD-L1, demonstrating the inhibitory effect of PD-L1 binding in B7.1 on T cells. When T cells that lack all known receptors for PD-L1 (ie, without PD-1 and B7.1), the proliferation of T cells is no longer damaged by anti-coated beads. -CD3 plus PD-L1. Thus, PD-L1 can have an inhibitory effect on T cells, either through B7.1 or PD-1.

[094] The direct interaction between B7.1 and PD-L1 suggests that the current understanding of co-stimulation is incomplete and highlights the significance of the expression of these molecules in T cells. Studies with T cells PD-L1 - / - indicate that PD- L1 in T cells can reduce cytokine production in T cells. Latchman et al., Proc. Natl. Acad. Sci. USA 101: 10691-96 (2004).

Since PD-L1 and B7.1 are expressed in T cells, B cells, DCs and macrophages, there is the potential for directional interactions between B7.1 and PD-L1 in these cell types. In addition, PD-L1 in non-hematopoietic cells can interact with B7.1, as well as PD-1 in T cells, increasing the question of whether PD-L1 is involved in its regulation. A possible explanation for the inhibitory effect of the B7.1: PD-L1 interaction is that the PD-L1 T cell can disrupt or separate APC B7.1 from the interaction with CD28.

[095] As a result, antagonism of signaling via PD-L1, including blocking PD-L1 from interaction with PD-1, B7.1 or both, thus prevents PD-L1 from sending a signal negative co-stimulator for T cells and other antigen presenting cells, probably to increase immunity in response to infection (for example, acute and chronic) and tumor immunity.

[096] An exemplary PD-L1 antagonist is the anti-PD-L1 antibody atezolizumab. Other PD-L1 antagonistic antibodies are durvalumab and avelumab.

[097] In another embodiment, the anti-PD-L1 / PD1 interaction can be blocked by anti-PD1 antagonist antibodies, such as PD1 antagonist antibodies pembrolizumab or nivolumab or an anti-PD1 antibody comprising the heavy chain and chain domains light variable from PD1-0103-0312.

[098] The term "human PD-L1" refers to the human protein PD-L1 (SEQ ID NO: 13, typically from PD-1 signaling). As used in the present invention, "binding to human PD-L1" or "specific binding to human PD-L1" or "binding to human PD-L1" or "anti-PD-L1 antibody" or "PD-antagonist" L1 ”refer to an antibody that specifically binds to the CSF-1R antigen with a binding affinity with a KD value of 1.0 x 10-8 mol / L or less, in an example embodiment with a KD value of 1 , 0 x 10-9 mol / L or less. The binding affinity is determined with a standard binding assay, such as by the surface plasmon resonance technique (Biacore ®, GE-Healthcare Uppsala, Sweden). Thus, a "human PD-L1 binding antibody", as used in the present invention, refers to an antibody that specifically binds to the human PD-L1 antigen with a 1.0 x KD binding affinity 10-8 mol / L or less (in a 1.0 x 10 -10 mol / L - 1.0 x 10-13 mol / L embodiment), in an embodiment, with a 1.0 x KD 10-9 mol / L or less (in an embodiment 1.0 x 10 -9 mol / L - 1.0 x 10-13 mol / L).

[099] The term "human PD1" refers to the human PD1 protein (SEQ ID NO: 14, typically from PD-1 signaling). As used in the present invention, "binding to human PD1" or "binding specific to human PD1" or "binding to human PD1" or "anti-PD1 antibody" or "PD1 antagonist" refers to an antibody that is specifically binds to the human PD1 antigen with a binding affinity with a KD value of 1.0 x 10-8 mol / L or less, in an embodiment with a KD value of 1.0 x 10-9 mol / L or less . The binding affinity is determined with a standard binding assay, such as by the surface plasmon resonance technique (Biacore ®, GE-Healthcare Uppsala, Sweden). Thus, a "human PD1 binding antibody", as used in the present invention, refers to an antibody that specifically binds to the human PD1 antigen with a binding affinity with a KD of 1.0 x 10-8 mol / L or less (in an embodiment 1.0 x 10 -8 mol / L - 1.0 x 10-13 mol / L), in an embodiment, with a KD 1.0 x 10-9 mol / L or less (in an embodiment 1.0 x 10 -9 mol / L - 1.0 x 10-13 mol / L).

[100] The term “variable domain” (variable domain of a light chain (VL), variable domain of a heavy chain (VH)) as used herein denotes each of the pairs of light and heavy chains that are directly involved in binding of the antibody with the antigen.

The variable domains of human light and heavy chains have the same general structure and each domain is composed of four regions (FR) with sequences that are largely conserved, linked by three “hypervariable regions” (or complementarity determining regions, CDRs). The framework regions (framework or FR) adopt a β-sheet conformation and the CDRs can form loops linking the β-sheet structure. The CDRs in each chain are maintained in their three-dimensional structure by the framework regions and together with the CDRs in the other chain form the antigen binding site. The antibody light and heavy chain CDR3 regions play a particularly important role in the specificity / binding affinity of the antibodies according to the invention and therefore provide an additional object of the invention.

[101] The term "constant region" as used in this application denotes the sum of domains of an antibody that do not belong to the variable region. The constant region is not directly involved in the binding of an antigen, but exhibits several effector functions. Depending on the amino acid sequence of the constant region of their heavy chains, the antibodies can be divided into classes: IgA, IgD, IgE, IgG and IgM, and several of them can be further divided into subclasses, such as IgG 1, IgG2, IgG3, and IgG4, IgA1 and IgA2. The heavy chain constant regions that correspond to the different classes of antibodies are called α, δ, ε, γ, and μ, respectively. The light chain constant regions that can be found in all five classes of antibodies are called κ (kappa) and λ (lambda).

[102] The terms “human derived constant region” or “human constant region” used in this application denote a heavy chain constant region of a human antibody of the subclass IgG1, IgG2, IgG3, IgG4 or and / or a constant region light chain kappa or lambda. Such constant regions are well known in the art and described, for example, in Kabat, EA, et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991 ) (see also, for example, Johnson, G., and Wu, TT, Nucleic Acids Res. 28 (2000) 214-218; Kabat, EA, et al., Proc.

Natl. Acad. Sci. USA 72 (1975) 2785-2788). This application uses the EU numbering system (EU Index) according to Kabat for numbering positions and mutations (Kabat, EA, et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991)) and referred to as “numbering according to the EU Kabat index”.

[103] In one embodiment, the antagonist anti-PD1 antibody that binds to human DP1 used in the combination therapy described in the present invention is nivolumab or pembrolizumab and is characterized by comprising the following VH and VL sequences, as described in gift.

TABLE

Anti-PD-L1 antibody Amino acid sequence of amino acid sequence of heavy chain variable domain VH, SEQ ID NO: light VL, SEQ ID NO: nivolumab 1 2 pembrolizumabe 3 4

[104] In a preferred embodiment of the invention, the compound of formula I used in the combined therapy described in the present invention is selected from the following compounds: -6-Amino-9 - [(4-chlorophenyl) methyl] -N -ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimidoyl) -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; or -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof; (in a preferred embodiment example 6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide) ; - and the PD1 antagonist antibody used in the combination therapy is nivolumab or pembrolizumab.

[105] In one embodiment, the anti-PD1 antagonist antibody that binds to the human PD1 used in the combination therapy described herein, is a mono- or multispecific anti-PD1 antagonist antibody and has the following variable domain domain composition. VH heavy chain and VL light chain variable domain, as described herein.

TABLE

Anti-PD1 antibody amino acid sequence of the variable chain amino acid sequence of the heavy chain variable domain VH, SEQ ID NO: light VL, SEQ ID NO: PD1-0103-0312 5 6

[106] Preferably, this anti-PD1 antibody based on the sequences of the VH heavy chain variable domain and the VL light chain variable domain of PD1-0103-0312, comprises a heavy chain constant region of the IgG 1 subtype (for example, SEQ ID NO: 16 or SEQ ID NO: 17, and eventually also comprises additional mutations, see bispecific realization example below) and a human kappa light chain constant region (for example, SEQ ID NO: 15).

[107] In one embodiment, such an anti-PD1 antibody based on the sequences of the heavy chain variable domain VH and light chain variable domain VL of PD1-0103-0312 is, for example, bispecific and (i) the bispecific antibody comprises a heavy chain constant region of the human IgG 1 subclass comprising mutations L234A, L235A and P329G (numbers according to the EU Kabat Index); and where (ii) in the heavy chain constant region, mutations S354C and T366W are comprised in one CH3 domain and mutations Y349C, T366S, L368A and Y407V are included in the other CH3 domain (numbers according to the EU Kabat Index ).

[108] In another preferred embodiment of the invention, the compound of formula I used in the combined therapy described in the present invention is selected from the following compounds: -6-Amino-9 - [(4-chlorophenyl) methyl] -N -ethyl-2 [S (S) -ethylsulfonimidoyl] - N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimidoyl] - N-methyl-8-oxo-purine-7-carboxamide;

-6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimidoyl) -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; or -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof; (in a preferred embodiment example 6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide) ; - and the PD1 antagonist antibody used in the combination therapy comprises a VH heavy chain variable domain with an amino acid sequence of SEQ ID NO: 5 and a VL light chain variable domain with an amino acid sequence of SEQ ID NO: 6 .

[109] In one embodiment, the antibody that binds to human PD-L1 used in the combination therapy described in the present invention is atezolizumab or durvalumab or avelumab and is characterized by comprising the following VH and VL sequences, as described in gift.

TABLE Anti-PD-L1 antibody Amino acid sequence of the amino acid sequence of the heavy chain variable domain VH, SEQ ID NO: light VL, SEQ ID NO: atezolizumab 7 8 durvalumabe 9 10 avelumab 11 12

[110] In another preferred embodiment of the invention, the compounds of formula I used in the combined therapy described in the present invention are selected from the following compounds: -6-Amino-9 - [(4-chlorophenyl) methyl] -N -ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-

8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimidoyl) -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; or -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof; (in a preferred embodiment example 6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide) ; - and the PD-L1 antagonist antibody used in the combination therapy is atezolizumab or durvalumab or avelumab (in a preferred embodiment, atezolizumab).

[111] Another aspect of the invention is the combined treatment (combination of treatments) of a patient suffering from liver cancer with the compound of formula I, as described above, in combination with an antiangiogenic agent. The antiangiogenic agent can be co-administered with compounds of formula I, alone or in addition to the combined therapy of compounds of formula I with a treatment of the anti-axis PD-L1 / PD1. The antiangiogenic agents used here include (but are not limited to) small molecule tyrosine kinase inhibitors (TKIs) that competitively bind to intracellular receptor domains of VEGF, PDGF and other angiogenic growth factors, such as sorafenib (4 (4 - {3- [4-Chloro-3- (trifluoromethyl) phenyl] ureido} phenoxy) -2-methylpyridine-2-carboxamide; Nexavar®), regorafenib 4- (4 - [{(4-Chloro-3- [trifluoromethyl ] phenyl) carbamoyl} amino] -3-fluorophenoxy) -

N-methylpyridin-2-carboxamide - hydrate; Stivarga®), and sunitinib (N- [2- (Diethylamino) ethyl] -5 - [(Z) - (5-fluor-1,2-dihydro-2-oxo-3H-indol-3-iliden) -methyl] -2,4-dimethyl-1H-pyrrole-3-carboxamide; Sutent®), but also include anti-VEGF or anti-VEGF antibodies such as bevacizumab (Avastin®).

[112] In an example of a preferred embodiment of the invention, the compound of formula I used in combination therapy with an antiangiogenic agent described in the present invention is selected from the following compounds: -6-Amino-9-benzyl-N-methyl- 8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N- (2-methoxyethyl) -N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N-ethyl-8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-7- [4- (1-piperidyl) piperidine-1-carbonyl] -2- (propylsulfonimidoyl) purin-8-one; -6-Amino-9-benzyl-N-ethyl-N- (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N-butyl-N-ethyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-7- (azetidine-1-carbonyl) -9-benzyl-2- (propylsulfonimidoyl) purin-8-one; -6-Amino-9-benzyl-N-isopropyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-9-benzyl-7- (4-methylpiperazine-1-carbonyl) -2-

(propylsulfonimidoyl) purin-8-one;

-6-Amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-9-benzyl-N-isobutyl-N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -

methyl-amino] ethyl acetate;

-3 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -

methyl methyl amino] propanoate;

-3 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -

tert-butyl methyl amino] propanoate;

- (2S) -2 - [[6Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] propanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

tert-butyl carbonyl] -methyl-amino] -4-methyl pentanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

carbonyl] -methyl-amino] -4-methyl-isopropyl pentanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] -3-methyl-butanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

carbonyl] -methyl-amino] -4-methyl-pentanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] -3-phenyl-propanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

isopropyl carbonyl] -methyl-amino] -3-phenyl-propanoate; - (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

tert-butyl carbonyl] -methyl-amino] -3-phenyl-propanoate;

-N- [2- [Acetyl (methyl) amino] ethyl] -6-amino-9-benzyl-N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

methyl carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;

-N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

tert-butyl carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;

-N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;

-N-Butyl-N-methyl-carbamate of 2 - [[6-amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-Pyrrolidine-1-carboxylate of 2 - [[6-amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-N-Methyl-N-propyl-carbamate of 2 - [[6-amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-N, 2 - [[6-amino-9-benzyl-8-oxo-2- N-diethylcarbamate

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-Ethyl carbonate of 2 - [[6-amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-6-Amino-N-butyl-9 - [(4-chlorophenyl) methyl] -N-methyl-8-oxo-2- [S (S) -

propylsulfonimidoyl] purine-7-carboxamide;

-6-amino-N-butyl-9 - [(4-chlorophenyl) methyl] -N-methyl-8-oxo-2- [S (S) -

propylsulfonimidoyl] purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-N-methyl-8-oxo-N-propyl-2 [S (S) -propylsulfonimidoyl] -9- (p-

tolylmethyl) purine-7-carboxamide; -6-Amino-N-methyl-8-oxo-N-propyl-2 [S (R) -propylsulfonimidoyl] -9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-2- [S (S) -propylsulfonimidoyl] -9- (p-tolylmethyl) -7- (pyrrolidine-1-

carbonyl) purin-8-one;

-6-Amino-2- [S [S (R) -propylsulfonimidoyl] -9- (p-tolylmethyl) -7- (pyrrolidine-1-

carbonyl) purin-8-one;

-6-Amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [S (S) -propylsulfonimidoyl] -

9- (p-tolylmethyl) purine-7-carboxamide;

-6-Amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [S (R) -propylsulfonimidoyl] -

9- (p-tolylmethyl) purine-7-carboxamide;

-6-Amino-N-ethyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) -9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-N-butyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) -9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-

oxo-N-propyl-purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -2- [S (S) -ethylsulfonimidoyl] -N-methyl-8-

oxo-N-propyl-purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-

8-oxo-purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-

methyl-8-oxo-purine-7-carboxamide;

-6-Amino-2- [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-9- (p-

tolylmethyl) purine-7-carboxamide; -6-Amino-N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-2- [S (S) ethylsulfonimidoyl] -9 - [(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide; -6-Amino-2- [S (R) ethylsulfonimidoyl] -9 - [(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide; -6-Amino-N-ethyl-2- (ethylsulfonimidoyl) -9 - [(4-fluorophenyl) methyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - 9 - [(4-fluorophenyl) methyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - 9 - [(4-fluorophenyl) methyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -2- (ethylsulfonimidoyl) -N-methyl-8-oxo-N-propyl-purine-7-carboxamide; -6-Amino-2- [S (R) -ethylsulfonimidoyl] -9 - [(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide; -6-Amino-2- [S (S) -ethylsulfonimidoyl] -9 - [(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimidoyl) -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; and -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof; - and the antiangiogenic agent used in the combination therapy is sorafenib, regorafenib, sunitinib or bevacizumab (preferably sorafenib or bevacizumab).

[113] In a preferred embodiment of the invention, the compound of formula I used in combination therapy with an antiangiogenic agent described in the present invention is selected from the following compounds: -6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimidoyl) -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; or -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof; (in a preferred embodiment example 6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide) ; - and the antiangiogenic agent used in the combination therapy is sorafenib, regorafenib, sunitinib or bevacizumab (preferably sorafenib or bevacizumab).

[114] In a preferred embodiment of the invention, the compound of formula I used in combination therapy with a PD1 antagonist or PD-L1 antagonist antibody and an antiangiogenic agent described in the present invention is selected from the following compounds: - 6-Amino-9-benzyl-N-methyl-8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N- (2-methoxyethyl) -N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-9-benzyl-N-ethyl-8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-

7-carboxamide;

-6-Amino-9-benzyl-7- [4- (1-piperidyl) piperidine-1-carbonyl] -2-

(propylsulfonimidoyl) purin-8-one;

-6-Amino-9-benzyl-N-ethyl-N- (2-methoxyethyl) -8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-9-benzyl-N-butyl-N-ethyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

carboxamide;

-6-Amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-7- (azetidine-1-carbonyl) -9-benzyl-2-

(propylsulfonimidoyl) purin-8-one;

-6-Amino-9-benzyl-N-isopropyl-N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-9-benzyl-7- (4-methylpiperazine-1-carbonyl) -2-

(propylsulfonimidoyl) purin-8-one;

-6-Amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-9-benzyl-N-isobutyl-N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -

methyl-amino] ethyl acetate;

-3 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -

methyl methyl amino] propanoate; -3 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -

tert-butyl methyl amino] propanoate;

- (2S) -2 - [[6Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] propanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

tert-butyl carbonyl] -methyl-amino] -4-methyl pentanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

carbonyl] -methyl-amino] -4-methyl-isopropyl pentanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] -3-methyl-butanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

carbonyl] -methyl-amino] -4-methyl-pentanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] -3-phenyl-propanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

isopropyl carbonyl] -methyl-amino] -3-phenyl-propanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

tert-butyl carbonyl] -methyl-amino] -3-phenyl-propanoate;

-N- [2- [Acetyl (methyl) amino] ethyl] -6-amino-9-benzyl-N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

methyl carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;

-N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

tert-butyl carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;

-N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;

-N-Butyl-N-methyl-carbamate of 2 - [[6-amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl; -Pyrrolidine-1-carboxylate of 2 - [[6-amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-N-Methyl-N-propyl-carbamate of 2 - [[6-amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-N, 2 - [[6-amino-9-benzyl-8-oxo-2- N-diethylcarbamate

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-Ethyl carbonate of 2 - [[6-amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-6-Amino-N-butyl-9 - [(4-chlorophenyl) methyl] -N-methyl-8-oxo-2- [S (S) -

propylsulfonimidoyl] purine-7-carboxamide;

-6-amino-N-butyl-9 - [(4-chlorophenyl) methyl] -N-methyl-8-oxo-2- [S (S) -

propylsulfonimidoyl] purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-N-methyl-8-oxo-N-propyl-2 [S (S) -propylsulfonimidoyl] -9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-N-methyl-8-oxo-N-propyl-2 [S (R) -propylsulfonimidoyl] -9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-2- [S (S) -propylsulfonimidoyl] -9- (p-tolylmethyl) -7- (pyrrolidine-1-

carbonyl) purin-8-one;

-6-Amino-2- [S (R) -propylsulfonimidoyl] -9- (p-tolylmethyl) -7- (pyrrolidine-1-

carbonyl) purin-8-one;

-6-Amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [S (S) -propylsulfonimidoyl] -

9- (p-tolylmethyl) purine-7-carboxamide;

-6-Amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [S (R) -propylsulfonimidoyl] -

9- (p-tolylmethyl) purine-7-carboxamide;

-6-Amino-N-ethyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) -9- (p-

tolylmethyl) purine-7-carboxamide; -6-Amino-N-butyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) -9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-

oxo-N-propyl-purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -2- [S (S) -ethylsulfonimidoyl] -N-methyl-8-

oxo-N-propyl-purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-

8-oxo-purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-

methyl-8-oxo-purine-7-carboxamide;

-6-Amino-2- [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-2- [S (S) ethylsulfonimidoyl] -9 - [(4-fluorophenyl) methyl] -N-methyl-8-

oxo-N-propyl-purine-7-carboxamide;

-6-Amino-2- [S (R) ethylsulfonimidoyl] -9 - [(4-fluorophenyl) methyl] -N-methyl-8-

oxo-N-propyl-purine-7-carboxamide;

-6-Amino-N-ethyl-2- (ethylsulfonimidoyl) -9 - [(4-fluorophenyl) methyl] -N-methyl-8-

oxo-purine-7-carboxamide;

-6-Amino-N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - 9 - [(4-fluorophenyl) methyl] -N-

methyl-8-oxo-purine-7-carboxamide;

-6-Amino-N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - 9 - [(4-fluorophenyl) methyl] -N-

methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -2- (ethylsulfonimidoyl) -N-methyl-8-oxo-N-

propyl-purine-7-carboxamide;

-6-Amino-2- [S (R) -ethylsulfonimidoyl] -9 - [(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide; -6-Amino-2- [S (S) -ethylsulfonimidoyl] -9 - [(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimidoyl) -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; and -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof; and i) the antagonist antibody PD1 is nivolumab or pembrolizumab or comprises a VH heavy chain variable domain of SEQ ID NO: 5 and a VL light chain variable domain of SEQ ID NO: 6; ii) the PD-L1 antagonist antibody used in the combination therapy is atezolizumab or durvalumab or avelumab (in an example of a preferred embodiment is atezolizumab); - and the antiangiogenic agent used in the combination therapy is sorafenib, regorafenib, sunitinib or bevacizumab (preferably sorafenib or bevacizumab).

[115] In a preferred embodiment of the invention, the compound of formula I used in combination therapy with a PD1 antagonist or PD-L1 antagonist antibody and an antiangiogenic agent described in the present invention is selected from the following compounds: - 6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-

methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimidoyl) -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; or -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof; (in a preferred embodiment example 6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide) ; and i) the antagonist antibody PD1 is nivolumab or pembrolizumab or comprises a VH heavy chain variable domain of SEQ ID NO: 5 and a VL light chain variable domain of SEQ ID NO: 6; ii) the PD-L1 antagonist antibody used in the combination therapy is atezolizumab or durvalumab or avelumab (in an example of a preferred embodiment is atezolizumab); - and the antiangiogenic agent used in the combination therapy is sorafenib, regorafenib, sunitinib or bevacizumab (preferably sorafenib or bevacizumab).

THE FOLLOWING EXAMPLES SPECIFIC TO THE INVENTION ARE INCLUDED:

[116] 1. A compound of formula (I): (I), in which:

- R1 is C1-6 alkyl;

- R2 is benzyl, said benzyl not substituted or substituted by one, two or three substituents, independently selected from halogen and C1-6 alkyl;

- R3 is -NR4R5, where

- R4 is C1-6 alkyl or C1-6 alkoxy-C1-6 alkyl;

- R5 is (C1-6alkyl) 2NCOO-C1-6alkyl, C1-6 alkoxy-C1-6alkyl,

C1-6 alkoxycarbonyl (C1-6alkyl) C1-6alkylalkyl, C1-6 alkoxycarbonyl (phenyl) C1-6alkyl,

C1-6 alkoxycarbonyl C1-6 alkyl, C1-6 alkoxycarbonyl C1-6 oxyalkyl, C1-6 alkyl, alkyl

C1-6-carbonyl (C1-6alkyl) C1-6alkylalkyl or pyrrolidinylcarbamoyloxy C1-6alkyl; or

- R4 and R5 together with the nitrogen to which they are attached form a heterocyclyl;

- or enantiomer or diastereomer or pharmaceutically acceptable salt thereof; (or a pharmaceutical composition or medication thereof);

- for use in the treatment or prophylaxis of liver cancer;

- on the condition that they are excluded;

-6-amino-9-benzyl-2- (propylsulfonimidoyl) -7- (pyrrolidine-1-

carbonyl) purin-8-one;

-6-amino-9-benzyl-7- (piperidine-1-carbonyl) -2-

(propylsulfonimidoyl) purin-8-one;

-6-amino-9-benzyl-7- (morpholine-4-carbonyl) -2-

(propylsulfonimidoyl) purin-8-one;

-6-amino-9-benzyl-7- (3,3-dimethylpyrrolidine-1-carbonyl) -2-

(propylsulfonimidoyl) purin-8-one;

Ethyl -1- [6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] pyrrolidine-2-carboxylate;

-6-amino-7- (2-azospiro [3.3] heptane-2-carbonyl) -9-benzyl-2-

(propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (2-oxa-6-azospiro [3.3] heptane-6-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (3,3-difluoropyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (3-fluoro-3-methyl-pyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; - and their enantiomers or diastereomers.

[117] 2. The compound for use according to embodiment example 1, in which: - R1 is C1-6 alkyl; - R2 is benzyl, said benzyl not substituted or substituted by halogen or C1-6 alkyl; - R3 is azetidinyl; - piperazinyl substituted by C1-6 alkyl; - piperidinyl replaced by piperidinyl; - pyrrolidinyl; or -NR4R5, where - R4 is C1-6 alkyl or C1-6 alkoxy-C1-6 alkyl; and - R5 is (C1-6 alkyl) 2NCOO-C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxycarbonyl (C1-6 alkyl) amino C1-6alkyl, C1-6 alkoxycarbonyl (phenyl) alkyl C1-6, C1-6 alkoxycarbonyl, C1-6 alkyl, C1-6 alkoxycarbonyl, C1-6 alkyl, C1-6 alkyl, C1-6 alkyl, (C1-6 alkyl) amino, C1-6 alkyl or C1-6 pyrrolidinylcarbamoyloxy C1-6 alkyl.

[118] 3. The compound for use according to Example 1 or 2, where: - R1 is ethyl or propyl; - R2 is benzyl, bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl;

- R3 is azetidinyl; - 4-methylpiperazinyl; - piperidinylpiperidinyl; - pyrrolidinyl; or -NR4R5, where: - R4 is methyl, ethyl, propyl or methoxyethyl; and - R5 is acetyl (methyl) aminoethyl, butyl, butyl (methyl) carbamoyloxyethyl, diethylcarbamoyloxyethyl, ethoxycarbonyl (methyl) aminoethyl, ethoxycarbonylethyl, ethoxycarbonylisobutyl, ethoxycarbonylisopentyl, ethoxycarbonylmethyl, ethoxycarbonyloxy (ethyl), ethoxycarbonyloxy (ethyl) phenyl) ethyl, isopropyl, methoxycarbonyl (methyl) aminoethyl, methoxyethyl, methoxypropyl, propyl, propyl (methyl) carbamoyloxyethyl, pyrrolidinylcarbamoyloxyethyl, tert-butoxycarbonyl (methyl) aminoethyl, tert-butoxycarbonylethyl, tert-butoxycarbonyl, tert-butoxycarbonyl, tertiary-butylcarbonyl).

[119] 4. The compound for use according to Example 3, wherein R3 is azetidinyl, 4-methylpiperazinyl, piperidinylpiperidinyl, pyrrolidinyl, acetyl (methyl) aminoethyl (methyl) amino, bis (methoxyethyl) amino, butyl ( ethyl) amino, butyl (methyl) amino, butyl (methyl) carbamoyloxyethyl (methyl) amino, diethylcarbamoyloxyethyl (methyl) amino, ethoxycarbonyl (methyl) aminoethyl (methyl) amino, ethoxycarbonylethyl (methyl) amino, ethoxycarbonylisobutyl (methyl) amino, ethoxycarbonylisyl methyl) amino, ethoxycarbonylmethyl (methyl) amino, ethoxycarbonyloxyethyl (methyl) amino, ethoxycarbonyl (phenyl) ethyl (methyl) amino, ethyl (methyl) amino, isobutyl (methyl) amino, isopropoxycarbonylisopentyl (methyl) amino, isopropoxycarbonyl (phenyl) ethyl methyl) amino, isopropyl (methyl) amino, methoxycarbonyl (methyl) aminoethyl (methyl) amino, methoxyethyl (ethyl) amino, methoxyethyl (methyl) amino, methoxyethyl (propyl) amino, methoxypropyl (methyl) amino, propyl (ethyl) amino, propyl (methyl) amino, propyl (methyl) carbamoyloxyethyl (methyl) amino,

pyrrolidinylcarbamoyloxyethyl (methyl) amino, tert-butoxycarbonyl (methyl) aminoethyl (methyl) amino, tert-butoxycarbonylethyl (methyl) amino, tert-butoxycarbonylisopentyl (methyl) amino or tert-butoxycarbonyl (phenyl) ethyl (methyl) amino.

[120] 5. The compound for use according to any of embodiment examples 1 to 4, where R1 is ethyl.

[121] 6. The compound for use according to Example 1 or 2, wherein R2 represents a benzyl group substituted by halogen or C1-6-alkyl.

[122] 7. The compound for use according to any of embodiment examples 2 to 6, wherein R2 is bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl.

[123] 8. The compound for use according to embodiment example 7, wherein R2 is bromobenzyl, chlorobenzyl or fluorobenzyl.

[124] 9. The compound for use according to Example 1 or 2, where R3 is -NR4R5, where R4 is C1-6 alkyl, R5 is C1-6 alkyl.

[125] 10. The compound for use according to embodiment example 9, wherein R3 is propyl (methyl) amino or ethyl (methyl) amino.

[126] 11. The compound for use according to any of embodiment examples 1, 2, 6 and 9, wherein: - R1 is C1-6 alkyl; - R2 is benzyl, said benzyl being replaced by halogen or C1-6 alkyl; and - R3 is -NR4R5, where R4 is C1-6 alkyl, R5 is C1-6 alkyl.

[127] 12. The compound for use according to embodiment example 11, in which: - R1 is ethyl; - R2 is methylbenzyl, bromobenzyl, chlorobenzyl or fluorobenzyl; and - R3 is propyl (methyl) amino or ethyl (methyl) amino.

[128] 13. A compound for use in the treatment or prophylaxis of liver cancer selected from:

-6-Amino-9-benzyl-N-methyl-8-oxo-N-propyl-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-9-benzyl-N- (2-methoxyethyl) -N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-9-benzyl-N-ethyl-8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-

7-carboxamide;

-6-Amino-9-benzyl-7- [4- (1-piperidyl) piperidine-1-carbonyl] -2-

(propylsulfonimidoyl) purin-8-one;

-6-Amino-9-benzyl-N-ethyl-N- (2-methoxyethyl) -8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-9-benzyl-N-butyl-N-ethyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

carboxamide;

-6-Amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-7- (azetidine-1-carbonyl) -9-benzyl-2-

(propylsulfonimidoyl) purin-8-one;

-6-Amino-9-benzyl-N-isopropyl-N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-9-benzyl-7- (4-methylpiperazine-1-carbonyl) -2-

(propylsulfonimidoyl) purin-8-one;

-6-Amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N-isobutyl-N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -

methyl-amino] ethyl acetate;

-3 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -

methyl methyl amino] propanoate;

-3 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -

tert-butyl methyl amino] propanoate;

- (2S) -2 - [[6Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] propanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

tert-butyl carbonyl] -methyl-amino] -4-methyl pentanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

carbonyl] -methyl-amino] -4-methyl-isopropyl pentanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] -3-methyl-butanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

carbonyl] -methyl-amino] -4-methyl-pentanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] -3-phenyl-propanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

isopropyl carbonyl] -methyl-amino] -3-phenyl-propanoate;

- (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

tert-butyl carbonyl] -methyl-amino] -3-phenyl-propanoate;

-N- [2- [Acetyl (methyl) amino] ethyl] -6-amino-9-benzyl-N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

methyl carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate; -N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

tert-butyl carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;

-N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-

ethyl carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;

-N-Butyl-N-methyl-carbamate of 2 - [[6-amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-Pyrrolidine-1-carboxylate of 2 - [[6-amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-N-Methyl-N-propyl-carbamate of 2 - [[6-amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-N, 2 - [[6-amino-9-benzyl-8-oxo-2- N-diethylcarbamate

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-Ethyl carbonate of 2 - [[6-amino-9-benzyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl;

-6-Amino-N-butyl-9 - [(4-chlorophenyl) methyl] -N-methyl-8-oxo-2- [S (S) -

propylsulfonimidoyl] purine-7-carboxamide;

-6-amino-N-butyl-9 - [(4-chlorophenyl) methyl] -N-methyl-8-oxo-2- [S (S) -

propylsulfonimidoyl] purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-N-methyl-8-oxo-2-

(propylsulfonimidoyl) purine-7-carboxamide;

-6-Amino-N-methyl-8-oxo-N-propyl-2 [S (S) -propylsulfonimidoyl] -9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-N-methyl-8-oxo-N-propyl-2 [S (R) -propylsulfonimidoyl] -9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-2- [S (S) -propylsulfonimidoyl] -9- (p-tolylmethyl) -7- (pyrrolidine-1-

carbonyl) purin-8-one;

-6-Amino-2- [S (R) -propylsulfonimidoyl] -9- (p-tolylmethyl) -7- (pyrrolidine-1-

carbonyl) purin-8-one; -6-Amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [S (S) -propylsulfonimidoyl] -

9- (p-tolylmethyl) purine-7-carboxamide;

-6-Amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [S (R) -propylsulfonimidoyl] -

9- (p-tolylmethyl) purine-7-carboxamide;

-6-Amino-N-ethyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) -9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-N-butyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) -9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-

oxo-N-propyl-purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -2- [S (S) -ethylsulfonimidoyl] -N-methyl-8-

oxo-N-propyl-purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-

8-oxo-purine-7-carboxamide;

-6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-

methyl-8-oxo-purine-7-carboxamide;

-6-Amino-2- [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-9- (p-

tolylmethyl) purine-7-carboxamide;

-6-Amino-2- [S (S) ethylsulfonimidoyl] -9 - [(4-fluorophenyl) methyl] -N-methyl-8-

oxo-N-propyl-purine-7-carboxamide;

-6-Amino-2- [S (R) ethylsulfonimidoyl] -9 - [(4-fluorophenyl) methyl] -N-methyl-8-

oxo-N-propyl-purine-7-carboxamide; -6-Amino-N-ethyl-2- (ethylsulfonimidoyl) -9 - [(4-fluorophenyl) methyl] -N-methyl-8-

oxo-purine-7-carboxamide;

-6-Amino-N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - 9 - [(4-fluorophenyl) methyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - 9 - [(4-fluorophenyl) methyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -2- (ethylsulfonimidoyl) -N-methyl-8-oxo-N-propyl-purine-7-carboxamide; -6-Amino-2- [S (R) -ethylsulfonimidoyl] -9 - [(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide; -6-Amino-2- [S (S) -ethylsulfonimidoyl] -9 - [(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimidoyl) -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; and -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof.

[129] 14. The compound according to Example 13, selected from: -6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimidoyl) -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; and

-6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof.

[130] 14. The compound for use according to embodiment example 13: - wherein the compound is 6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) - ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide.

[131] 16. The pharmaceutically acceptable compound or salt, enantiomer or diastereomer for use according to any of the realization examples 1 to 15, in which the liver cancer is hepatocellular carcinoma, hepatoma, cholangiocarcinoma, hepatoblastoma, liver carcinoma, liver angiosarcoma, or metastatic liver cancer.

[132] 17. The pharmaceutically acceptable compound or salt, enantiomer or diastereomer for use according to any of the embodiment examples 1 to 15, in which liver cancer is hepatocellular carcinoma.

[133] 18. A pharmaceutical composition or medicament comprising a compound according to any of embodiment 1 to 15 and a therapeutically inert carrier, for use in the treatment or prophylaxis of liver cancer.

[134] 19. The use of a compound according to any of Examples 1 through 14 for the preparation of a medicament for the treatment or prophylaxis of liver cancer.

[135] 20. A method for the treatment or prophylaxis of liver cancer, the method of which comprises administering a therapeutically effective amount of a compound as defined in any of the embodiment examples 1 to 15.

[136] 21. A compound as defined in any of Examples 1 through 15, or a pharmaceutical composition or a drug comprising such a compound for use: a) in the treatment or prophylaxis of liver cancer in combination with an antagonist antibody PD1 or PD-L1 antagonist, or b) in the treatment of a patient suffering from liver cancer in combination with a PD1 antagonist or PD-L1 antagonist antibody.

[137] 22. A compound as defined in any of Examples 1 to 15, or a pharmaceutical composition or a drug comprising such a compound: - for use in the treatment or prophylaxis of liver cancer; and - wherein the treatment is combined with a PD1 antagonist antibody or PD-L1 antagonist antibody.

[138] 23. Use of a compound as defined in any of Examples 1 through 15: - for the preparation of a drug for the treatment or prophylaxis of liver cancer; and - wherein the treatment is combined with a PD1 antagonist antibody or PD-L1 antagonist antibody.

[139] 24. The compound, composition, drug or use, according to any of the embodiment examples 21 to 23: - wherein the treatment is combined with a PD1 antagonist antibody.

[140] 25. The compound, composition, drug or use, according to embodiment example 24: - wherein the PD1 antagonist antibody is nivolumab or pemprolizumab.

[141] 26. The compound, composition, medication or use, according to embodiment example 24, where the compound is 6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide.

[142] 27. The compound, composition, medicament or use according to embodiment example 23, wherein the PD1 antagonist antibody comprises a VH heavy chain variable domain with an amino acid sequence of SEQ ID NO: 5 and a VL light chain variable domain with an amino acid sequence of SEQ ID NO: 6.

[143] 28. The compound, composition, medication or use, according to embodiment example 27, wherein the compound is 6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide.

[144] 29. The compound, composition, drug or use, according to any of the embodiment examples 21 to 23: - wherein the treatment is combined with a PD-L1 antagonist antibody.

[145] 30. The compound, composition, drug or use, according to embodiment example 29: - wherein the PD-L1 antagonist antibody used in the combination therapy is atezolizumab or durvalumab or avelumab (in an example of preferred embodiment) is atezolizumab).

[146] 31. The compound, composition, medication or use, according to embodiment example 30, wherein the compound is 6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide.

[147] 32. The compound, composition, medication or use according to any of the embodiment examples 21 to 31 wherein additionally an antiangiogenic agent is used in the combination therapy.

[148] 33. The compound, composition, medication or use according to any of the embodiment examples 21 to 31 wherein additionally an antiangiogenic agent selected from sorafenib,

regorafenib, sunitinib or bevacizumab (in one preferred embodiment the antiangiogenic agent is sorafenib; in a preferred embodiment the antiangiogenic agent is bevacizumab) is used in combination therapy.

[149] 34. A compound as defined in any of Examples 1 through 15, or a pharmaceutical composition or a drug comprising such a compound for use: a) in the treatment or prophylaxis of liver cancer in combination with an antiangiogenic agent , or b) in the treatment of a patient suffering from liver cancer in combination with an antiangiogenic agent.

[150] 35. A compound as defined in any of Examples 1 to 15, or a pharmaceutical composition or a drug comprising such a compound: - for use in the treatment or prophylaxis of liver cancer; and - where the treatment is combined with an antiangiogenic agent.

[151] 36. Use of a compound as defined in any of Examples 1 through 15: - for the preparation of a medicine for the treatment or prophylaxis of liver cancer; and - where the treatment is combined with an antiangiogenic agent.

[152] 37. The compound, composition, medicament or use according to any of embodiment examples 34 to 36 in which the antiangiogenic agent is selected from sorafenib, regorafenib, sunitinib or bevacizumab (in an example of preferred embodiment o antiangiogenic agent is sorafenib; in one preferred embodiment the antiangiogenic agent is bevacizumab).

[153] 38. The compound, composition, medication or use, according to embodiment example 37, where the compound is 6-Amino-9 - [(4-

chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide.

[154] 39. The invention as described above.

DESCRIPTION OF AMINO ACID SEQUENCES

[155] SEQ ID NO: 1 heavy chain variable domain of the anti-PD1 antibody nivolumab.

[156] SEQ ID NO: 2 light chain variable domain of the anti-PD1 nivolumab antibody.

[157] SEQ ID NO: 3 heavy chain variable domain of the anti-PD1 antibody pembrolizumab.

[158] SEQ ID NO: 4 light chain variable domain of the anti-PD1 antibody pembrolizumab.

[159] SEQ ID NO: 5 heavy chain variable domain of the anti-PD1 antibody PD1-0103-0312.

[160] SEQ ID NO: 6 anti-PD1 antibody PD1-0103-0312 light chain variable domain.

[161] SEQ ID NO: 7 heavy chain variable domain of the anti-PD-L1 antibody atezolizumab.

[162] SEQ ID NO: 8 anti-PD-L1 antibody light chain variable domain atezolizumab.

[163] SEQ ID NO: 9 heavy-chain variable domain of the anti-PD-L1 antibody durvalumab.

[164] SEQ ID NO: 10 light chain variable domain of the anti-PD-L1 antibody durvalumab.

[165] SEQ ID NO: 11 heavy chain variable domain of anti-PD-L1 avelumab antibody.

[166] SEQ ID NO: 12 light chain variable domain of anti-PD-L1 avelumab antibody.

[167] SEQ ID NO: 13: exemplary human PD-L1.

[168] SEQ ID NO: 14: exemplary human PD1.

[169] SEQ ID NO: 15 Human kappa light chain constant region.

[170] SEQ ID NO: 16 IgG1 derived human heavy chain constant region.

[171] SEQ ID NO: 17 IgG1-derived human heavy chain constant region with L234A, L235A, P329G mutations.

BRIEF DESCRIPTION OF THE FIGURES

[172] Figure 1: The combination of a prodrug form of the compounds of the present invention (compound 41-A) and sorafenib results in 2 tumor-free mice in the mouse model of iAST hepatocellular carcinoma; Figure 1A: Synergistic effect of compound 41-A and sorafenib on tumor burden (tumor-free mice); Figure 1B: Combined weight of the liver and tumor after treatment.

[173] Figure 2: Treatment with a prodrug form of the compounds of the present invention (compound 41-A) induces the expression of PD-L1 in tumor cells in the hepatocellular carcinoma model in iAST mice. Figure 2A: infiltrate of total CD45 + immune cells, Figure 2B: PD-L1 on CD45-, Figure 2C: CD11b- lymphoid cells, Figure 2D: CD11b + myeloid cells.

[174] Figure 3: The triple combination with a prodrug form of the compounds of the present invention (compounds 41-A), Sorafenib and anti-DP-1 results in increased median survival.

[175] Figure 4: Treatment with a prodrug form of the compounds of the present invention (compound 41-A) results in tumor stasis in the hepatocellular carcinoma model in mice transplanted with Hep55.1c.

[176] Figure 5A: Treatment with a prodrug form of the compounds of the present invention (compound 41-A) and anti-PD-1 antibodies results in the survival benefit in the hepatocellular carcinoma model of mice transplanted with Hep55. 1c.

[177] Figure 5B: In vivo efficacy of compound 42-A (6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8- oxo-purine-7-carboxamide), alone and in combination with anti-PD-1 in hepatocellular carcinoma.

[178] Figure 6: Treatment with an active form of the compounds of the present invention does not induce an increase in tumor cell proliferation in cell lines originating from hepatocellular carcinoma and cholangiocarcinoma.

Figure 6A: compound 41c-B, Figure 6B: compound 41c-A.

[179] Figure 7: 7A and 7B: The factors released into peripheral blood after treatment with an active form of the compounds of the present invention (compound 41c-B) result in inhibition of the proliferation of tumor cell lines. Figure 7A: Hep3B, SNU449, HLF, JHH2, Huh7, OZ, JHH1, HepG2 cell lines, Figure 7B: JHH4, HLE, JHH6, JHH5, SkHep1, EGI1 cell lines.

[180] 7C: Factors released into peripheral blood after treatment with an active form of the compounds of the present invention (compound 41c-A) result in inhibition of the proliferation of tumor cell lines.

[181] Figure 8: Single crystal X-ray diffraction from Example 41-B.

[182] Figure 9: Single crystal X-ray diffraction of Example 42-A.

[183] Figure 10: Single crystal X-ray diffraction from Example 43-B.

EXAMPLES

[184] The present invention will be more fully understood by reference to the examples set out below. However, such

Examples should not be construed as limiting the scope of the invention.

[185] Abbreviations: - aq. Aqueous; - BSA: N, O-bis (trimethylsilyl) acetamide; - CDI N, N'-carbonyl diimidazole; - DIEPA: N, N-diethylpropylamine; - DBU: 1,8-Diazabicicloundec-7-eno; - DPPA: diphenylphosphoryl azide; - EC50: the molar concentration of an agonist, which produces 50% of the maximum possible response for that agonist; - EDC: N1 - ((ethylimino) methylene) -N3, N3-dimethylpropane-1,3-diamine; - EtOAc or EA: Ethyl acetate; - HATU: (1- [Bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-hexafluorophosphate oxide); - hr (s): hour (s); - HPLC: high performance liquid chromatography; - HOBt: N-hydroxybenzotriazole; - MS (ESI): Mass spectrometry (electrospray ionization (Electron Spray); - m-CPBA: 3-chloroperbenzoic acid; - MTEB: tert-butylmethyl ether; - NMP: N-Methylpyrrolidone; - Observed; - PE : petroleum ether - PMB: p-methoxybenzyl - PPA: polyphosphoric acid - QOD: every other day - QW: once a week (weekly);

- TA or TA: room temperature; - sat. Saturated; - TFA: trifluoroacetic acid; - TEA: triethylamine; and - V / V: ratio by volume.

GENERAL EXPERIMENTAL CONDITIONS

[186] The intermediate and final compounds were purified by means of flash chromatography using one of the following instruments: i) Biotage SP1 system and Quad 12/25 Cartridge module. ii) ISCO combi-flash chromatography instrument. Marks of silica gel and pore dimensions: i) KP-SIL 60 Å, particle size: 40-60 μm; ii) CAS registration No.: Silica Gel: 63231-6 7-4, particle size: silica gel 47-60 micrometers; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 200-300 or 300-400.

[187] The intermediate and final compounds were purified by means of preparative HPLC on a reversed phase column using the X Bridge® Prep C18 column (5 μm, OBD® 30 x 100 mm) or SunFire® Prep C18 column (5 μm , OBD® 30 x 100 mm).

[188] LC / MS spectra were obtained using a Waters UPLC-SQD Mass instrument. The standard LC / MS conditions were as follows (operating time 3 minutes).

[189] Acid condition: A: 0.1% formic acid and 1% acetonitrile in H2O; B: 0.1% formic acid in acetonitrile.

[190] Basic condition: A: 0.05% NH3-H2O in H2O; B: acetonitrile.

[191] Mass spectrum (MS): only ions that indicate apparent mass are generally reported and, unless otherwise stated, the mass ion cited is the positive mass ion (M + H) +.

[192] NMR spectra were obtained using the instrument

Bruker Advance 400MHz.

[193] All reactions involving air-sensitive reagents were carried out under an argon atmosphere. The reagents were used as received from commercial suppliers without further purification, unless otherwise specified.

PREPARATIVE EXAMPLES PREPARATION OF INTERMEDIARIES INTERMEDIATE AA N-METHYL-N-PROPYL-CARBAMOYL CHLORIDE AA

[194] In a mixture of N-methylpropan-1-amine (5 g, 68.4 mmol) and sodium hydrogen carbonate (11.5 g, 137 mmol) in DCM (70 mL) at 0 ° C, bis carbonate was added (trichloromethyl) (8.11 g, 27.3 mmol) in DCM (30 mL) by dripping. The mixture was stirred at room temperature for two hours and filtered. The filtrate was concentrated in vacuo. The obtained N-methyl-N-propylcarbamoyl chloride (7.2 g, intermediate AA) was used in the next step without any further purification.

INTERMEDIATE AB N- (2-METOXYETHYL) -N-METHYL-CARBAMOYL CHLORIDE

AB

[195] Intermediate AB was prepared analogously to intermediate AA by using 2-methoxy-N-methyl-ethanamine in place of N-methylpropan-1-amine. N- (2-Methoxyethyl) -N-methyl-carbamoyl chloride (8 g, Intermediate AB) was obtained and used in the next step without any further purification.

INTERMEDIATE AC N-ETHYL-N-PROPYL-CARBAMOYL CHLORIDE B.C

[196] Intermediate AC was prepared analogously to intermediate AA by using N-ethylpropan-1-amine in place of N-methylpropan-1-amine. N-ethyl-N-propyl-carbamoyl chloride (12.6 g, Intermediate AC) was obtained as a yellow oil and used in the next step without any further purification.

INTERMEDIATE AD N-ETHYL-N- (2-METOXYETHYL) CARBAMOILE

AD

[197] Intermediate AD was prepared analogously to intermediate AA by using N-ethyl-2-methoxyethanamine in place of N-methylpropan-1-amine. Crude N-ethyl-N- (2-methoxyethyl) carbamoyl chloride (2.5 g, Intermediate AD) was obtained as a light yellow oil and used in the next step without any further purification.

INTERMEDIATE A AND N-BUTYL-N-ETHYL-CARBAMOYL CHLORIDE AE

[198] Intermediate AE was prepared in a manner analogous to Intermediate AA by using N-ethylbutan-1-amine (5 g) in place of N-methylpropan-1-amine. Crude N-butyl-N-ethyl-carbamoyl chloride (6.3 g, Intermediate AE) was obtained as a light yellow oil and used in the next step without further purification.

INTERMEDIATE AF N- (2-METOXYETHYL) -N-PROPYL-CARBAMOYL CHLORIDE

AF

[199] Intermediate AF was prepared in a manner analogous to Intermediate AA by using N- (2-methoxyethyl) propan-1-amine (2 g, 17.1 mmol) in place of N-methylpropan-1-amine. Crude N- (2-methoxyethyl) -N-propyl-carbamoyl chloride (2.5 g, Intermediate AF) was obtained as a light yellow oil and used in the next step without further purification.

INTERMEDIATE AG N, N-BIS (2-METOXYETHY) CARBAMOILE CHLORIDE

AG

[200] Intermediate AG was prepared in a manner analogous to Intermediate AA by using bis (2-methoxyethyl) amine (2 g, 15 mmol) in place of N-methylpropan-1-amine. The crude product N, N-bis (2-methoxyethyl) carbamoyl chloride (2.6 g, Intermediate AG) was obtained as a light yellow oil and used in the next step without further purification.

INTERMEDIATE AH AZETIDINE-1-CARBONYL CHLORIDE

AH

[201] Intermediate AH was prepared in a manner analogous to Intermediate AA by using azetidine hydrochloride (10.7 g, 107 mmol) and sodium bicarbonate (3 equiv.) In place of N-methylpropan-1-amine and bicarbonate sodium (2 equiv.). Crude azetidine-1-carbonyl chloride (1.5 g, Intermediate AH) was obtained as a light yellow oil and used in the next step without further purification.

INTERMEDIATE AI N-ISOPROPYL-N-METHYL-CARBAMOYL CHLORIDE THERE

[202] Intermediate AI was prepared in a manner analogous to Intermediate AA by using N-methylpropan-2-amine (5 g, 19.4 mmol) in place of N-methylpropan-1-amine. Crude N-isopropyl-N-methyl-carbamoyl chloride (8.6 g, Intermediate AI) was obtained as a yellow oil and used in the next step without further purification.

INTERMEDIATE AL N-ISOBUTYL-N-METHYL-CARBAMOILE CHLORIDE AL

[203] Intermediate AL was prepared in a manner analogous to Intermediate AA by using N-2-dimethylpropan-1-amine (4.8 g) in place of N-methylpropan-1-amine. Crude N-isobutyl-N-methyl-carbamoyl chloride (8.1 g, Intermediate AL) was obtained as a light yellow oil and used in the next step without further purification.

INTERMEDIATE AP 2- [CHLOROCARBONIL (METHYL) AMINO] ETHYL ACETATE

AP

[204] To a solution of triphosgene (728 mg, 2.45 mmol) in DCM (5 mL) a solution of hydrochloride of 2- (methylamino) ethyl acetate (1.3 g, 8.46 mmol) was added and pyridine (1 ml) in DCM (5 ml) dropwise at 0oC. The reaction mixture turned orange and a yellow precipitate appeared, then it was allowed to warm to room temperature. After being stirred for 1 hr, aqueous HCl (0.1N, 25 mL) was added to the reaction mixture, the organic layer was separated, washed with 0.1 N HCl (10 mL) twice, saline (10 ml), dried over Na2SO4 and concentrated in vacuo to provide crude ethyl 2- [chlorocarbonyl (methyl) amino] (2.0 g, Intermediate AP) as a light yellow oil and used in the next step without further purification.

INTERMEDIATE AR 3- [CHLOROCARBONIL (METHYL) AMINO] TERC-BUTYL PROPANOATE

AIR STEP 1: PREPARATION OF 3- (METHYLAMINE) TERC-BUTYL PROPANOATE (COMPOUND AR-1) AR-1

[205] To a solution of tert-butyl acrylate (3 g) in DMF (40 ml) methylamine hydrochloride (4.74 g, 70 mmol) and DBU were added

(21.4 g, 140 mmol) at -45 ° C. Then, the reaction temperature was allowed to warm up to -10 ºC. The reaction mixture was stirred at the same temperature for 2.5 hours. Et 2O (200 ml) was added and the resulting mixture was washed with saline (50 ml) four times. The separated organic layer was dried over Na 2SO4 and concentrated in vacuo to provide tert-butyl 3- (methylamino) propanoate (3.5 g, Compound AR-1) as a light yellow oil.

STEP 2: P REPAIR OF 3- [CHLOROCARBONIL (METHYL) AMINO] TERC-BUTYL PROPANOATE (I NTERMEDIARY AR)

AIR

[206] Intermediate AR was prepared in a manner analogous to Intermediate AP by using tert-butyl 3- (methylamino) propanoate (3.4 g, Compound AR-1) in place of 2- (methylamino) acetate hydrochloride ethyl.

Crude tert-butyl 3- [chlorocarbonyl (methyl) amino] propanoate (3.5 g, Intermediate AR) was obtained and used in the next step without further purification.

I NTERMEDIARY AS (2S) -2- [CHLOROCARBONIL (METHYL) AMINO] ETHYL PROPANOATE

AS STEP 1: P REPARATION OF (2S) -2- (METHYLAMINE) ETHYL PROPANOATE (AS-1 COMPOUND)

AS-1

[207] In a solution of (2S) -2- (methylamino) propanoic acid (1 g, 9.70 mmol) in EtOH (10 mL) SOCl 2 (1.50 g, 12.61 mmol) was added dropwise drop at 0 ºC for 0.5 h. The reaction mixture was stirred at 25 ° C for 15.5 hours, and then diluted with EA (20 ml), washed with H 2 O (5 ml) and saline (5 ml). The organic layer was dried over Na 2SO 4 and concentrated in vacuo. ethyl (2S) -2- (methylamino) propanoate hydrochloride (1.8 g, Compound AS-1) was obtained as a yellow oil and used in the next step without further purification.

STEP 2: P REPARATION OF (2S) -2- (METHYLAMINE) ETHYL PROPANOATE (AS-2 COMPOUND) AS-2

[208] A solution of ethyl (2S) -2- (methylamino) propanoate hydrochloride (1.8 g, Compound AS-1) in EA (10 mL) was adjusted to pH = 8 with 10% by weight of NaHCO Aqueous. The reaction mixture was stirred at room temperature for 0.5 h. The organic layer was washed with saline (5 ml), dried over Na 2SO4 and concentrated in vacuo. Ethyl (2S) -2- (methylamino) propanoate (620 mg, Compound AS-2) was obtained as a yellow oil and used in the next step without further purification. STEP 3: P REPAIR OF (2S) -2- [CHLOROCARBONIL (METHYL) AMINO] PROPANOATE

OF ETHYL (I NTERMEDIARY AS) AT

[209] Intermediate AS was prepared in a manner analogous to Intermediate AP by using ethyl (2S) -2- (methylamino) propanoate (260 mg, Compound AS-2) in place of 2- (methylamino) acetate hydrochloride ethyl. Crude ethyl (2S) -2- [chlorocarbonyl (methyl) amino] propanoate (200 mg, Intermediate AS) was obtained as a yellow oil and used in the next step without further purification.

I NTERMEDIARY AT (2S) -2- [CHLOROCARBONIL (METHIL) AMINO] -4-METHYL-TERC -BUTYL PENTANOATE

AT STEP 1: P REPAIR OF (2S) -4-METHYL 2- (METHYLAMINE) TERC-BUTYL PENTANOATE (AT-1 COMPOUND) AT-1

[210] 2-Methylpropene (25 g, 446 mmol) was bubbled in DCM (50 mL) at -78 ° C. Then, the 2-methylpropene solution was added in a solution of (S) -4-methyl-2- (methylamino) pentanoic acid hydrochloride (500 mg, 2.75 mmol) and H 2SO4 (3.68 g, 2 mL, 37.5 mmol) in dioxane (20 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 18 hours in a sealed tube. The reaction solution was poured into an aqueous KOH solution in an ice bath (8.4 g in water (30mL)) and the resulting mixture was extracted with DCM (50 mL) twice. The combined organic layer was washed with saline (30 mL) twice, dried over Na 2SO4 and concentrated in vacuo to provide the tert-butyl crude product (2S) -4-methyl-2- (methylamino) pentanoate (Compound AT -1) as a light yellow oil.

STEP 2: P REPAIR OF (2S) -2- [CHLOROCARBONIL (METHYL) AMINO] -4-METHY - TERC-BUTYL PENTANOATE (I NTERMEDIARY AT)

AT

[211] Intermediate AT was prepared in a manner analogous to Intermediate AP by using tert-butyl (2S) -4-methyl-2- (methylamino) pentanoate (300 mg, Compound AT-1) in place of hydrochloride of 2 - (methylamino) ethyl acetate. Crude tert-butyl (2S) -2- [chlorocarbonyl (methyl) amino] -4-methyl pentanoate (350 mg, Intermediate AT) was obtained as a light yellow oil and used in the next step without further purification.

I NTERMEDIARY AU (2S) -2- [CHLOROCARBONIL (METHYL) AMINO] -4-ISOPROPYL-METHYL-PENTANOATE

AU STEP 1: PREPARATION OF (2S) -4-METHYL-2- (METHYLAMINE) ISOPROPYL PENTANOATE (AU-1 COMPOUND) AU-1

[212] To a solution of (S) -4-methyl-2- (methylamino) pentanoic acid hydrochloride (0.5 g) in i-PrOH (7.8 g, 10 mL) was added thionyl chloride (655 mg, 402 µL) dropwise at room temperature. The resulting mixture was subjected to stirring and reflux for 16 hours and then concentrated in vacuo. The residue was basified with saturated aqueous NaHCO3 solution (30 ml) and extracted with DCM (50 ml). The organic layer was washed with saline, dried over Na2SO4 and concentrated in vacuo. The residue was salified with HCl / EtOAc (10 mL, 1 mmol / mL) and concentrated to provide isopropyl (2S) -4-methyl-2- (methylamino) pentanoate hydrochloride (510 mg, Compound AU-1) as a white solid.

STEP 2: PREPARATION OF (2S) -2- [CHLOROCARBONIL (METHYL) AMINO] -4-METHYL- ISOPROPYL PENTANOATE (INTERMEDIATE AU)

AU

[213] Intermediate AU was prepared in a manner analogous to Intermediate AP by using isopropyl (2S) -4-methyl-2- (methylamino) pentanoate hydrochloride (500 mg, Compound AU-1) in place of 2 - (methylamino) ethyl acetate. Crude isopropyl (2S) -2- [chlorocarbonyl (methyl) amino] -4-methyl pentanoate (650 mg, Intermediate AU) was obtained as a light yellow oil and used in the next step without further purification.

INTERMEDIATE AV (2S) -2- [CHLOROCARBONIL (METHIL) AMINO] -3-METHYL-BUTANOATE OF ETHYL

AV STEP 1: PREPARATION OF (2S) -3-METHYL-2- (METHYLAMINE) ETHYL BUTANOATE (AV-1 COMPOUND) AV-1

[214] In a solution of (2S) -3-methyl-2- (methylamino) butanoic acid (1.0 g, 7.6 mmol) in EtOH (10 mL), thionyl chloride (2.45 g, 21 mmol) dropwise at room temperature. The resulting mixture was subjected to stirring and reflux for 16 hours and then concentrated in vacuo. The residue was basified with saturated aqueous NaHCO3 solution (30 ml) and extracted with DCM (50 ml) twice. The combined organic layer was washed with saline, dried over Na 2SO4 and concentrated in vacuo. The residue was dissolved in HCl / EtOAc (10 mL, 1 M) and concentrated to provide ethyl (2S) -3-methyl-2- (methylamino) butanoate hydrochloride (1.9 g, Compound AV-1) as a white solid.

STEP 2: PREPARATION OF (2S) -2- [CHLOROCARBONIL (METHYL) AMINO] -3-METHYL-ETHYL BUTANOATE (AV INTERMEDIATE)

AV

[215] Intermediate AV was prepared in a manner analogous to Intermediate AP by using ethyl (2S) -3-methyl-2- (methylamino) butanoate hydrochloride (500 mg, Compound AV-1) in place of 2 hydrochloride - (methylamino) ethyl acetate. The crude ethyl (2S) -2- [chlorocarbonyl (methyl) amino] -3-methyl-butanoate (600 mg, Intermediate AV) was obtained as a light yellow oil and used in the next step without further purification.

INTERMEDIATE AW (2S) -2- [CHLOROCARBONIL (METHYL) AMINO] -4-ETHYL-METHYL-PENTANOATE

AW STEP 1: P REPAIR OF (2S) -4-METHYL CHLORIDRATE -2-

(METHYLAMINE) ETHYL PENTANOATE (COMPOUND AW-1) AW-1

[216] In a solution of (2S) -4-methyl-2- (methylamino) pentanoic acid (1 g, 6.9 mmol) in EtOH (10 mL), thionyl chloride (1.07 g, 8, 3 mmol) dropwise at room temperature. The resulting mixture was subjected to stirring at reflux for 16 hours and then concentrated in vacuo. The residue was basified with saturated aqueous NaHCO3 solution (30 ml) and extracted with DCM (50 ml). The organic layer was washed with saline, dried over Na2SO4 and concentrated in vacuo. The residue was salified with HCl / EtOAc (10 mL, 1 mmol / mL) and concentrated to provide ethyl (2S) -4-methyl-2- (methylamino) pentanoate hydrochloride (1.8 g, Compound AW-1) as a white solid.

STEP 2: PREPARATION OF (2S) -2- [CHLOROCARBONIL (METHYL) AMINO] -4-METHYL-ETHYL PENTANOATE (INTERMEDIATE AW)

A W

[217] Intermediate AW was prepared in a manner analogous to Intermediate AP by using ethyl (2S) -4-methyl-2- (methylamino) pentanoate hydrochloride (610 mg, AW-1) in place of 2- (methylamino) ethyl acetate. The crude ethyl (2S) - 2- [chlorocarbonyl (methyl) amino] -4-methyl pentanoate (280 mg, Intermediate AW) was obtained as a light yellow oil and used in the next step without further purification.

INTERMEDIATE AX

(2S) -2- [CHLOROCARBONIL (METHYL) AMINO] -3-PHENYL-ETHYL PROPANOATE

AX

[218] Intermediate AX was prepared in a similar way to Intermediate AP by using (S) -ethyl-2- (methylamino) -3-phenylpropanoate in place of ethyl 2- (methylamino) acetate hydrochloride. Crude ethyl (2S) -2- [chlorocarbonyl (methyl) amino] -3-phenylpropanoate (200 mg, Intermediate AX) was obtained as a light yellow oil and used in the next step without further purification.

I NTERMEDIARY AY (2S) -2- [CHLOROCARBONIL (METHYL) AMINO] -3-PHENYL-ISOPROPYLPROPANOATE

AY

[219] Intermediate AY was prepared in a manner similar to Intermediate AP by using isopropyl (2S) -2- (methylamino) -3-phenylpropanoate (190 mg) in place of 2- (methylamino) acetate hydrochloride ethyl.

Crude isopropyl (2S) -2- [chlorocarbonyl (methyl) amino] -3-phenylpropanoate (220 mg, Intermediate AY) was obtained as a light brown oil and used in the next step without further purification.

I NTERMEDIARY AZ 2 - ((C LOROCARBONIL) (METHIL) AMINO) -3-PHENYLPROPANOATE OF (S) -TERC-BUTYL

AZ STEP 1: P REPAIR OF (2S) -2- (METHYLAMINE) -3-PHENYL-PROPANOATE OF TERC-BUTYL (COMPOUND AZ-1) AZ-1

[220] 2-Methylpropene (25 g, 446 mmol) was bubbled in DCM (50 ml) at -78 ° C. Then, the 2-methylpropene solution was added in a solution of (S) -2- (methylamino) -3-phenylpropanoic acid (500 mg) and H2SO4 (3.68 g, 2 ml) in dioxane (20 ml) at 0 ºC. The reaction mixture was stirred at room temperature for 18 hours in a sealed tube. The reaction mixture was poured into an aqueous KOH solution in an ice bath (8.4 g in water (30 ml)) and the resulting mixture was extracted with DCM (50 ml) twice. The organic layer was washed twice with saline (30 ml), dried over Na 2SO 4 and concentrated in vacuo to provide tert-butyl (2S) -2- (methylamino) -3-phenyl-propanoate (710 mg, Compound AZ -1) as a light yellow oil.

STEP 2: P REPARATION OF 2 - ((CHLOROCARBONIL) (METHYL) AMINO) -3- (S) -TERC -BUTYL PHENYLPROPANOATE (INTERMEDIATE AZ)

AZ

[221] Intermediate AZ was prepared analogously to Intermediate AP by using tert-butyl (2S) -2- (methylamino) -3-phenyl-propanoate (Compound AZ-1) in place of 2- ( methylamino) ethyl acetate. Crude tert-butyl (2S) -2- [chlorocarbonyl (methyl) amino] -3-phenyl-propanoate (360 mg, Intermediate AZ) was obtained as a light yellow oil and used in the next step without further purification

I NTERMEDIARY BA N- [2- [ACETYL (METHYL) AMINO] ETHYL] -N-METHYL-CARBAMOYL CHLORIDE

BA STEP 1: P REPAIR OF N- [2- [ACETYL (METHYL) AMINO] ETHYL] -N-METHYL - TERC CARBAMATE -BUTYL (BA-1 COMPOUND)

BA-1

[222] In a solution of tert-butyl methyl (2- (methylamino) ethyl) carbamate (1.13 g, 6 mmol) in pyridine (10 mL) was added acetic anhydrous (3.06 g, 30 mmol) drop the drop at 0ºC. Then, the solution was stirred at room temperature for 0.5 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc (50 ml) and saturated aqueous NaHCO 3 solution (25 ml). The organic layer was separated, washed with saline (20 ml), dried over Na 2SO 4 and concentrated in vacuo to provide tert-butyl N- [2- [acetyl (methyl) amino] ethyl] -N-methyl-carbamate ( 1.28 g, Compound BA-1) as a yellow oil.

STEP 2: P REPAIR OF N-METHYL CHLORIDATE -N- (2- (METHYLAMINE) ETHYL) ACETAMIDE (BA-2 COMPOUND) BA-2

[223] A mixture of tert-butyl N- [2- [acetyl (methyl) amino] ethyl] -N-methyl-carbamate (1.1 g, Compound BA-1) in HCl / EtOAc (10 mL, 1N HCl in EtOAc) was stirred at room temperature for 2 hours, then the mixture was filtered. The collected solid was washed three times with EtOAc (5 ml) and dried in vacuo to provide the crude N-methyl-N- (2- (methylamino) ethyl) acetamide hydrochloride (460 mg, Compound BA-2) as a solid White.

STEP 3: P REPAIR OF N- [2- [ACETYL (METHYL) AMINO] ETHYL] -N- METHYL-CARBAMOYL CHLORIDE (I NTERMEDIARY BA)

BA

[224] Intermediate BA was prepared in a similar way to Intermediate AP by using N-methyl-N- (2- (methylamino) ethyl) acetamide hydrochloride (200 mg, Compound BA-2) in place of 2- hydrochloride (methylamino) crude ethyl acetate. N- [2- [acetyl (methyl) amino] ethyl] -N-methyl-carbamoyl chloride (300 mg, Intermediate BA) was obtained and used in the next step without further purification.

I NTERMEDIARY BB N- [2- [CHLOROCARBONIL (METHYL) AMINO] ETHYL] -N-METHYL -METHIL CARBAMATE

BB STEP 1: P REPAIR OF N-METHYL-N- [2- (METHYLAMINE) ETHYL] METHYL CARBAMATE (BB-1 COMPOUND) BB-1

[225] In a solution of N, N'-dimethylethane-1,2-diamine (10 g)

in THF (40 mL) methyl chloroformate (1.92 g) was added dropwise at -70 ° C in 1 h. The mixture was stirred at 25 ° C for 15 hours and then filtered and washed with water and saline. The organic layer was dried and concentrated to provide a yellow residue, which was purified by column chromatography to provide methyl N-methyl-N- [2- (methylamino) ethyl] carbamate (2 g, Compound BB-1) as a colorless oil.

STEP 2: PREPARATION OF N- [2- [CHLOROCARBONYL (METHYL) AMINO] ETHYL] -N-METHYL- METHYL CARBAMATE (INTERMEDIATE BB)

BB

[226] Intermediate BB was prepared in a manner analogous to Intermediate AP by the use of methyl N-methyl- [2- (methylamino) ethyl] carbamate (2.0 g, Compound BB-1) in place of 2- (methylamino) ethyl acetate. The crude methyl N- [2- [chlorocarbonyl (methyl) amino] ethyl] -N-methyl-carbamate (2.2 g, Intermediate BB) was obtained and used in the next step without further purification.

INTERMEDIATE BC N- [2- [CHLOROCARBONIL (METHYL) AMINO] ETHYL] -N-METHYL-CARBAMATE TERC-BUTYL

BC

STEP 1: PREPARATION OF N-METHYL-N- [2- (METHYLAMINE) ETHYL] TERC-BUTYL CARBAMATE (COMPOUND BC-1) BC-1

[227] In a solution of N, N'-dimethylethane-1,2-diamine (40.4 g) in DCM (300 mL) a solution of Boc 2O (10 g, 10.6 mL, 45.8) was added mmol) in DCM (100 mL) dropwise at 0 ° C over 1 h. The reaction mixture was stirred at room temperature for 18 hours. The organic layer was washed with saturated aqueous NaHCO 3 solution (50 ml), saline (50 ml), dried over Na 2SO4 and concentrated in vacuo. The residue was purified by column chromatography to provide tert-butyl N-methyl-N- [2- (methylamino) ethyl] carbamate (6.8 g, Compound BC-1) as a yellow oil. 1H NMR (400MHz, CDCl 3) δ ppm: 3.34 (br. S., 2H), 2.89 (s, 3H), 2.74 (t, J = 6.7 Hz, 2H), 2, 46 (s, 3H), 1.47 (s, 9H).

STEP 2: PREPARATION OF N- [2- [CHLOROCARBONYL (METHYL) AMINO] ETHYL] -N-METHYL-TERC-BUTYL CARBAMATE (INTERMEDIATE BC)

BC

[228] Intermediate BC was prepared in a manner analogous to Intermediate AP by using tert-butyl N-methyl-N- [2- (methylamino) ethyl] carbamate (1.15 g, Compound BC-1) in place of 2- (methylamino) ethyl acetate hydrochloride. The crude tert-butyl N- [2- [chlorocarbonyl (methyl) amino] ethyl] -N-methyl-carbamate (1.3 g, Intermediate BC) was obtained and used in the next step without further purification.

INTERMEDIATE BD N- [2- [CHLOROCARBONIL (METHYL) AMINO] ETHYL] -N-METHYL-ETHYL CARBAMATE

BD STEP 1: PREPARATION OF N-METHYL-N- [2- (METHYLAMINE) ETHYL] ETHYL CARBAMATE (BD-1 COMPOUND) BD-1

[229] In a solution of N, N'-dimethylethane-1,2-diamine (10 g) in DCM (40 mL), ethyl chloroformate (2.58 g) was added dropwise at - 70ºC in 1 h. The reaction mixture was stirred at 25 ° C for 15 hours and then filtered and washed with water and saline. The organic layer was dried and concentrated in vacuo. The yellow residue was purified by column chromatography to provide ethyl N-methyl-N- [2- (methylamino) ethyl] carbamate (2 g, Compound BD-1) as a colorless oil.

STEP 2: PREPARATION OF N- [2- [CHLOROCARBONIL (METHYL) AMINO] ETHYL] -N-METHYL ETHYL CARBAMATE (INTERMEDIATE BD)

BD

[230] Intermediate BD was prepared in a manner analogous to Intermediate AA by using ethyl N-methyl-N- [2- (methylamino) ethyl] carbamate (Compound BD-1) in place of 2- (methylamino) hydrochloride ethyl acetate. The crude ethyl N- [2- [chlorocarbonyl (methyl) amino] ethyl] -N-methyl-carbamate (2.2 g, Intermediate BD) was obtained and used in the next step without further purification.

I N INTERMEDIATE BE N-BUTYL-N-METHYL-CARBAMATE OF 2- [CHLOROCARBONYL (METHYL) AMINO] ETHYL

BE STEP 1: P REPARATION OF N- (2-HYDROXYETHIL) -N-METHYL-CARBAMATE FROM TERC - BUTYL (BE-1 COMPOUND) BE-1

[231] In a solution of 2- (methylamino) ethanol (10 g, 133.14 mmol) in DCM (10 mL) Boc 2O (34.87 g, 159.77 mmol) was added at 25 ° C. The mixture was stirred at 25 ° C for 16 hours and then concentrated. The residue was purified by column chromatography to provide tert-butyl N- (2-hydroxyethyl) -N-methyl-carbamate (20 g, Compound BE-1) as a colorless oil.

STEP 2: P REPAIR OF 2- [TERC- BUTOXICARBONIL (METHYL) AMINO] N-BUTYL -N-METHYL-CARBAMATE ETHYL (BE-2 COMPOUND) BE-2

[232] In a solution of tert-butyl N- (2-hydroxyethyl) -N-methyl-carbamate (880 mg, Compound BE-1) and Et3N (1 g, 10.08 mmol) in DCM (10 mL) N-butyl-N-methyl-carbamoyl chloride (903 mg, 7.04 mmol) was added dropwise at -10 ° C in 1 h. The reaction mixture was stirred at 25 ° C for 15 hours and then filtered and washed with water and saline. The organic layer was dried and concentrated to provide 2- [tert-butoxycarbonyl (methyl) amino] ethyl N-butyl-N-methyl-carbamate (2 g, Compound BE-2) as a colorless oil.

STEP 3: PREPARATION OF N-BUTYL-N-METHYL-CARBAMATE OF 2- (METHYLAMINE) ETHYL (BE-3 COMPOUND) BE-3

[233] In a solution of 2- [tert-butoxycarbonyl (methyl) amino] ethyl N-butyl-N-methyl-carbamate (1 g, Compound BE-2) was added HCl / EA (40 mL, 1M). The reaction mixture was stirred at 0 ° C for 0.5 h and heated to 25 ° C and stirred for another 15.5 hours. The reaction mixture was concentrated to provide 2- (methylamino) ethyl-N-butyl-N-methyl-carbamate hydrochloride (400 mg,

Compound BE-3) as a colorless oil.

STEP 4: PREPARATION OF N-BUTYL-N-METHYL-CARBAMATE OF 2- [CHLOROCARBONYL (METHYL) AMINO] ETHYL (BE INTERMEDIATE)

BE

[234] Intermediate BE was prepared in a manner analogous to Intermediate AP by using 2- (methylamino) ethyl N-butyl-N-methyl-carbamate hydrochloride (374 mg, Compound BE-3) in place of 2-hydrochloride - (methylamino) ethyl acetate. Crude 2- [chlorocarbonyl (methyl) amino] ethyl N-butyl-N-methyl-carbamate (330 mg, Intermediate BE) was obtained and used in the next step without further purification.

INTERMEDIATE BF PYRROLIDINE-1-CARBOXYLATE OF 2- [CHLOROCARBONIL (METHYL) AMINO] ETHYL

BF STEP 1: PREPARATION OF N- (2-HYDROXYETHIL) -N-METHYL-CARBAMATE FROM TERC-BUTYL (COMPOUND BF-1) BF-1

[235] In a solution of 2- (methylamino) ethanol (10 g, 133.14 mmol) in DCM (10 mL) Boc2O (34.87 g, 159.77 mmol) was added at 25 ° C.

The mixture was stirred at 25 ° C for 16 hours. The reaction mixture was concentrated to provide the residue, which was purified by column chromatography to provide tert-butyl N- (2-hydroxyethyl) -N-methyl-carbamate (20 g, Compound BF-1) as an oil colorless.

STEP 2: PREPARATION OF PIRROLIDIN-1-CARBOXYLATE OF 2- [TERC- BUTOXICARBONYL (METHOD) AMINO] ETHYL (COMPOUND BF-2) BF-2

[236] In a solution of tert-butyl N- (2-hydroxyethyl) -N-methyl-carbamate (300 mg, 1.71 mmol, Compound BF-1) and Et3N (578 mg, 5.71 mmol) in DCM (5 ml) was added pyrrolidine-1-carbonyl chloride (458 mg, 3.4 mmol) dropwise at 0 ° C for 0.5 h and then stirred at 25 ° C for 15.5 hours. After filtration, the filtrate was washed with water and saline. The organic layer was dried and concentrated to provide 2- [tert-butoxycarbonyl (methyl) amino] ethyl pyrrolidine-1-carboxylate (335 mg, Compound BF-2) as a colorless oil.

STEP 3: PREPARATION OF PYRROLIDIN-1-CARBOXYLATE HYDROCHL 2-(METHYLAMINE) ETHYL (COMPOUND BF-3) BF-3

[237] 2- [tert-butoxycarbonyl (methyl) amino] ethyl pyrrolidine-1-carboxylate (335 mg, Compound BF-2) was added to HCl in EA (12.3 mL, 1M) and the mixture was stirred at 0ºC for 0.5 h and then at 25ºC for another 15.5 hours. The reaction mixture was concentrated to provide 2- (methylamino) ethyl pyrrolidine-1-carboxylate hydrochloride (300 mg, Compound BF-3) as a colorless oil.

STEP 4: PREPARATION OF PYRROLIDIN-1-CARBOXYLATE OF 2- [CHLOROCARBONIL (METHYL) AMINO] ETHYL (BF INTERMEDIATE)

BF

[238] Intermediate BF was prepared in a manner analogous to Intermediate AP by using 2- (methylamino) ethyl pyrrolidine-1-carboxylate hydrochloride (299 mg, Compound BF-3) in place of 2- (methylamino) hydrochloride ethyl acetate. Crude 2- [chlorocarbonyl (methyl) amino] ethyl pyrrolidine-1-carboxylate (230 mg, Intermediate BF) was obtained and used in the next step without further purification.

INTERMEDIATE BG N-METHYL-N-PROPYL-CARBAMATE OF 2- [CHLOROCARBONIL (METHYL) AMINO] ETHYL

BG STEP 1: PREPARATION OF N- (2-HYDROXYETHIL) -N-METHYL-CARBAMATE FROM TERC-BUTYL (COMPOUND BG-1) BG-1

[239] In a solution of 2- (methylamino) ethanol (10 g, 133.14 mmol) in DCM (10 mL) Boc 2O (34.87 g, 159.77 mmol) was added at 25 ° C. The reaction mixture was stirred at 25 ° C for 16 hours, and then concentrated to provide the residue, which was purified by column chromatography to provide tert-butyl N- (2-hydroxyethyl) -N-methyl-carbamate (20 g, Compound BG-1) as a colorless oil.

STEP 2: P REPAIR OF TERC-BUTYL CARBAMATE -N-METHIL -N- [2- [METHYL (PROPIL) CARBAMOIL] OXYETHIL] (COMPOUND BG-2) BG-2

[240] In a solution of tert-butyl N- (2-hydroxyethyl) -N-methyl-carbamate (265 mg, Compound BG-1) and Et3N (1 mL, 5.71 mmol) in DCM (5 mL) N-methyl-N-propyl-carbamoyl chloride (410 mg, 1.83 mmol) was added dropwise at 0 ° C over 0.5 h. The reaction mixture was stirred at 25 ° C for 15.5 hours and then filtered and the filtrate was washed with water and saline. The organic layer was dried and concentrated to provide tert-butyl N-methyl-N- [2- [methyl (propyl) carbamoyl] oxyethyl] carbamate (380 mg, Compound BG-2) as a colorless oil.

STEP 3: P REPAIR OF N-METHYL CHLORIDATE -N-PROPYL-2- (METHYLAMINE) ETHYL (COMPOUND BG-3) BG-3

[241] N-Methyl-N- [2- [methyl (propyl) carbamoyl] oxyethyl] tert-butyl carbamate (380 mg, Compound BG-2) was added to HCl in EA (13.7 ml, 1M). The mixture was stirred at 0 ° C for 0.5 h. Then the mixture was stirred at 25 ° C for an additional 15.5 hours and concentrated to provide 2- (methylamino) ethyl N-methyl-N-propyl-carbamate hydrochloride (300 mg,

Compound BG-3) as a colorless oil.

STEP 4: PREPARATION OF N-METHYL-N-PROPYL-CARBAMATE FROM 2- [CHLOROCARBONYL (METHYL) AMINO] ETHYL (BG INTERMEDIATE)

BG

[242] Intermediate BG was prepared in a manner analogous to Intermediate AP by using 2- (methylamino) ethyl N-methyl-N-propyl-carbamate hydrochloride (330 mg, Compound BG-3) in place of 2 hydrochloride - (methylamino) ethyl acetate. 2- [chlorocarbonyl (methyl) amino] ethyl-N-methyl-N-propyl-carbamate (300 mg, Intermediate BG) was obtained and used in the next step without further purification.

INTERMEDIATE BH N, N-DIETHYLCARBAMATE OF 2- [CHLOROCARBONIL (METHYL) AMINO] ETHYL

BH STEP 1: PREPARATION OF N- (2-HYDROXYETHYL) -N-METHYL-CARBAMATE FROM TERC-BUTYL (BH-1 COMPOUND) BH-1

[243] In a solution of 2- (methylamino) ethanol (10 g, 133.14 mmol) in DCM (10 mL) Boc2O (34.87 g, 159.77 mmol) was added at 25 ° C. The mixture was stirred at 25 ° C for 16 hours and then concentrated, the residue was purified by column chromatography to provide N- (2-

tert-butyl hydroxyethyl) -N-methyl-carbamate (20 g, Compound BH-1) as a colorless oil.

STEP 2: PREPARATION OF 2- [TERC-BUTOXICARBONIL (METHYL) AMINO] ETHYL-N, N-DIETHYLCARBAMATE (BH-2 COMPOUND) BH-2

[244] In a solution of tert-butyl N- (2-hydroxyethyl) -N-methyl-carbamate (200 mg, 1.14 mmol, Compound BH-1) and Et3N (578 mg, 5.71 mmol) in DCM (5 ml) was added N, N-diethylcarbamoyl chloride (248 mg, 1.83 mmol) dropwise at 0 ° C for 0.5 h and the solution was stirred at 25 ° C for 15.5 hours. After filtration, the filtrate was washed with water and saline. The organic layer was dried and concentrated to provide 2- [tert-butoxycarbonyl (methyl) amino] ethyl N, N-diethylcarbamate (313 mg, Compound BH-2) as a colorless oil.

STEP 3: PREPARATION OF 2- (METHYLAMINE) ETHYL N, N-DIETYL CARBAMATE (BH-3 COMPOUND) BH-3

[245] 2- [tert-butoxycarbonyl (methyl) amino] ethyl N, N-Diethylcarbamate (436 mg, 1.77 mmol, Compound BH-2) was added to HCl in EA (17 mL, 1M). The mixture was stirred at 0 ° C for 0.5 h. Then the mixture was stirred at 25 ° C for an additional 15.5 hours and concentrated to provide 2- (methylamino) ethyl N, N-diethylcarbamate hydrochloride (230 mg, Compound BH-3) as a colorless oil.

STEP 4: PREPARATION OF N, N-DIETHYL CARBAMATE OF 2- [CHLOROCARBONIL (METHYL) AMINO] ETHYL (INTERMEDIATE BH)

BH

[246] Intermediate BH was prepared in a manner analogous to Intermediate AP by using 2- (methylamino) ethyl N, N-diethylcarbamate hydrochloride (274 mg, Compound BH-3) in place of 2- (methylamino) hydrochloride ethyl acetate. The crude N, N-diethylcarbamate of 2- [chlorocarbonyl (methyl) amino] ethyl (250 mg, Intermediate BH) was obtained and used in the next step without further purification.

INTERMEDIATE BI 2- [CHLOROCARBONIL (METHYL) AMINO] ETHYL ETHYL CARBONATE

BI STEP 1: PREPARATION OF N- (2-HYDROXYETHIL) -N-METHYL-CARBAMATE FROM TERC-BUTYL (BI-1 COMPOUND) BI-1

[247] In a solution of 2- (methylamino) ethanol (1 g, 13.31 mmol) in DCM (10 mL) Boc2O (3.49 g, 15.98 mmol) was added at 25 ° C. The reaction mixture was stirred at 25 ° C for 16 hours, and then concentrated to provide the crude product, which was purified by column chromatography to provide tert-butyl N- (2-hydroxyethyl) -N-methyl-carbamate (1, 6 g, Compound BI-1) as a colorless oil.

STEP 2: PREPARATION OF METHYL CARBONATE OF 2- [TERC- BUTOXICARBONIL (METHYL) AMINO] ETHYL (BI-2 COMPOUND) BI-2

[248] In a solution of tert-butyl N- (2-hydroxyethyl) -N-methyl-carbamate (1 g, Compound BI-1), DMAP (0.1 g) and pyridine (1.15 g, 11 , 41 mmol) in EA (20 mL) methyl chloroformate (1.21 g, 11.15 mmol) was added dropwise at -10 ° C. The mixture was stirred at -10 ° C for 1 h. The reaction mixture was filtered and the filtrate was washed with 5% citric acid and saline. The organic layer was dried and concentrated to provide 2- [tert-butoxycarbonyl (methyl) amino] ethyl methyl carbonate (1.22 g, Compound BI-2) as a colorless oil.

STEP 3: PREPARATION OF 2- (METHYLAMINE) ETHYL CARBONATE ETHYL CARBONATE (BI-3 COMPOUND) BI-3

[249] Methyl carbonate 2- [tert-butoxycarbonyl (methyl) amino] ethyl (1.22 g, 4.94 mmol, Compound BI-2) was added to HCl in EA (10 mL, 40 mmol) and the mixture was stirred at 0 ºC for 0.5 h to 25 ºC for another 15.5 hours. The reaction mixture was concentrated to provide ethyl 2- (methylamino) ethyl carbonate hydrochloride (1.06 g, Compound BI-3).

STEP 4: P REPAIR OF ETHYL CARBONATE OF 2- [CHLOROCARBONYL (METHYL) AMINO] ETHYL (INTERMEDIATE BI)

BI

[250] Intermediate BI was prepared in a manner analogous to Intermediate AP by using ethyl 2- (methylamino) ethyl carbonate hydrochloride (150 mg, Intermediate BI-3) in place of ethyl 2- (methylamino) acetate hydrochloride . Crude ethyl 2- [chlorocarbonyl (methyl) amino] ethyl carbonate (145 mg, Intermediate BI) was obtained and used in the next step without further purification.

AND PREPARATIVE XAMPLES AND XEMPLO 1 6-AMINO-9-BENZIL -N-METHYL-8-OXO-N-PROPIL-2- (PROPILSULFONIMIDOIL) PURINE - 7-CARBOXAMIDE 1

METHOD A STEP 1: PREPARATION OF 4-AMINO-3-BENZYL-2-OXO-1H-IMIDAZOL-5-CARBONITRILE (COMPOUND 1A) 1a

[251] To a solution of aminomalononitrile p-toluenesulfonate (25 g, 98.5 mmol, TCI, catalog number: A1119 - 25G) in dry THF (100 mL) was added benzyl isocyanate (13.2 g, 98 , 5 mmol) and TEA (10.2 g, 79.0 mmol) at RT. After being subjected to stirring at RT for 24 hours, the reaction was concentrated in vacuo and the residue was partitioned between EtOAc (500 mL) and water (250 mL). The separated organic layer was washed with saline (50 ml) twice, and extracted with sodium hydroxide solution (50 ml, 1N) twice. The combined sodium hydroxide solution layer was neutralized with 10% by weight sodium hydrogen sulfate solution and extracted with EtOAc.

The separated organic layer was washed with saline, dried over Na 2SO4, filtered and concentrated in vacuo. The residue was triturated in 2 - isopropoxypropane, and then the suspension was filtered to provide 4-amino-3-benzyl-2-oxo-1H-imidazole-5-carbonitrile (15 g, Compound 1a) as a yellow solid. The product was used in the next step without further purification. Observed MS (ESI +) [(M + H) +]: 215.

STEP 2: P REPAIR OF 6-AMINO -9-BENZIL -2-SULFANIL -7H-PURIN -8-ONA (COMPOUND 1 B) 1b

[252] To a solution of 4-amino-3-benzyl-2-oxo-1H-imidazole-5-carbonitrile (15.0 g, 70.0 mmol, Compound 1a) in THF (700 mL) was added benzoyl isothiocyanate ( 28.6 g, 175.1 mmol, TCI, catalog number: A11596-100G) drop by drop. After being subjected to stirring at RT for 12 hours, the reaction mixture was concentrated in vacuo. The residue was triturated in diethyl ether (100 ml) and the resulting precipitate was collected by filtration.

[253] In a solution of the precipitate obtained in THF (700 ml), sodium hydroxide (70 ml, 2 N) was added. The mixture was refluxed for 50 hours, and then acidified to pH = 3 with 10% by weight of aqueous sodium hydrogen sulfate solution. The resulting precipitate was collected by filtration to provide crude 6-amino-9-benzyl-2-sulfanyl-7H-purin-8-one (8.1 g, Compound 1b) as a yellow solid. The product was used in the next step without further purification. Observed MS (ESI +) [(M + H) +]: 274.

STEP 3: P REPAIR OF 6-AMINO -9-BENZIL -2- (2-PROPILSULFANIL) -7H-PURIN - 8-ONA (COMPOUND 1 C)

1c

[254] In a solution of 6-amino-9-benzyl-2-sulfanyl-7H-purin-8-one (5.46 g, 20.0 mmol, Compound 1b) in DMF, potassium carbonate (2, 76 g, 20.0 mmol). And then, 1-bromopropane (2.44 g, 20.0 mmol, TCI, catalog number: B0638-500G) in DMF (5.0 mL) was slowly added to the previous solution. After being subjected to stirring at RT for 12 hours, the reaction mixture was poured into water (200 ml), and then acidified with 10% by weight aqueous sodium hydrogen sulfate solution and extracted with EtOAc (100 ml) twice. The organic layer was washed with saline, dried over Na 2SO 4 and concentrated in vacuo to provide the crude product, which was purified by flash chromatography on silica gel to provide 6-amino-9-benzyl-2- (2-propylsulfanyl) - 7H-purin-8-one (4.8 g, Compound 1c) as a white solid. Observed MS (ESI +) [(M + H) +]: 316.

STEP 4: PREPARATION OF 6-AMINO-9-BENZYL-2-PROPYLSULFINYL-7H-PURIN-8-ONA (COMPOUND 1D) 1d

[255] In a suspension of compound 6-amino-9-benzyl-2-

(2-propylsulfanyl) -7H-purin-8-one (2.7 g, 8.7 mmol, Compound 1c) in DCM / MeOH (500 mL, V / V = 1: 1) 3-chloroperbenzoic acid ( 2.15 g, 8.7 mmol, 70% purity, Aldrich, catalog number: 273031-100G). After the reaction mixture was subjected to stirring for 2 hours, the volume of the reaction mixture was reduced in vacuo to about 50 ml. The resulting precipitate was collected by filtration, washed with methanol and dried to provide 6-amino-9-benzyl-2-propylsulfinyl-7H-purin-8-one (1.0 g, Compound 1d) as a white solid. The product was used in the next step without further purification. Observed MS (ESI +) [(M + H) +]: 332.

STEP 5: PREPARATION OF 6-AMINO-9-BENZIL-2- (PROPILSULFONIMIDOIL) -7H-PURIN- 8-ONA (COMPOUND 1E) 1e

[256] In a solution of 6-amino-9-benzyl-2-propylsulfinyl-7H-purin-8-one (1.52 g, 4.6 mmol, Compound 1d) in Eaton's reagent (40 mL, phosphorus, 7.5% by weight in methanesulfonic acid, Aldrich, catalog number: 380814-100ML), sodium azide (360 mg, 5.5 mmol) was added at 50 ºC. After being stirred at that temperature for 30 minutes, the reaction mixture was cooled to RT and poured into aqueous sat. of baking soda. The reaction mixture was extracted with n-BuOH (100 ml) twice, and the organic phase was concentrated in vacuo. The residue was subjected to preparative HPLC purification to provide 6-amino-9-benzyl-2-

(propylsulfonimidoyl) -7H-purin-8-one (1.2 g, Compound 1e) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.65 (br. S., 1H), 7.26-7.37 (m, 5H), 6.98 (br. S., 2H), 4.97 (s, 2H), 4.02 (s, 1H), 3.33 (t, J = 7.53 Hz, 2H), 1.55-1.74 (m, 2H), 0.92 (t, J = 7.53 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 347.

[257] Separation of compound 1e by chiral HPLC provided Compound 1e-A (slowest elution, 500 mg) and Compound 1e-B (fastest elution, 490 mg) as a white solid.

(Separation condition: 5% -40% methanol (0.05% DEA) / CO 2 in a ChiralPak AS-3 column.)

[258] Compound 1e-A: 1H NMR (DMSO-d6, 400 MHz)  ppm: 10.56 (s, 1H), 7.21 - 7.46 (m, 5H), 7.03 (s, 2H ), 4.96 (s, 2H), 4.04 (s, 1H), 3.25 - 3.33 (m, 2H), 1.59 - 1.67 (m, 2H), 0.92 ( t, J = 7.4 Hz, 3H).

[259] Compound 1e-B: 1H NMR (DMSO-d6, 400 MHz)  ppm: 10.57 (s, 1H), 7.23 - 7.39 (m, 5H), 6.97 (s, 2H ), 4.96 (s, 2H), 4.05 (s, 1H), 3.31 - 3.30 (m, 2H), 1.49 - 1.74 (m, 2H), 0.91 ( t, J = 7.4 Hz, 3H).

STEP 6: PREPARATION OF 6-AMINO-9-BENZIL-N-METHYL-8-OXO-N-PROPIL-2- (PROPILSULFONIMIDOIL) PURINE-7-CARBOXAMIDE (EXAMPLE 1) 1

[260] In a solution of 6-amino-9-benzyl-2- (propylsulfonimidoyl) -7H-purin-8-one (300 mg, Compound 1e), pyridine (329 mg, 4.2 mmol) and DIPEA (538 mg, 4.2 mmol) in NMP (5 mL) N-methyl-N-propyl carbamoyl chloride (564 mg, 4.2 mmol, Intermediate AA) was added in TA. The mixture was stirred at RT for 10 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC to provide 6-amino-9-benzyl-N-methyl-8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide (108 mg, Example 1) as a white solid. 1H NMR (400 MHz, DMSO-d 6) δ ppm: 7.45 - 7.24 (m, 5H), 6.89 (s, 2H), 5.01 (s, 2H), 4.17 (s , 1H), 3.44 - 3.34 (m, 2H), 3.36 - 3.34 (m, 2H), 3.10 - 3.00 (m, 3H), 1.74 - 1.52 (m, 4H), 1.01 - 0.72 (m, 6H). Observed MS (ESI +) [(M + H) +]: 446.

[261] Separation of the compound of Example 1 by chiral HPLC gave Example 1-A (slower elution, 50 mg) and Example 1-B (faster elution, 40 mg) as a white solid with 5% isopropanol -40% (0.05% DEA) / CO 2 on ChiralPak AD-3 column.

[262] Example 1-A: 1H NMR (400 MHz, DMSO-d 6) δ ppm: 7.44-7.24 (m, 5H), 6.89 (s, 2H), 5.01 (s, 2H), 4.17 (s, 1H), 3.44-3.37 (m, 2H), 3.37-3.35 (m, 2H), 3.10-3.00 (m, 3H) , 1.74-1.52 (m, 4H), 1.00-0.72 (m, 6H). Observed MS (ESI +) [(M + H) +]: 446.

[263] Example 1-B: 1H NMR (400 MHz, DMSO-d 6) δ ppm: 7.45-7.26 (m, 5H), 6.88 (s, 2H), 5.01 (s, 2H), 4.15 (s, 1H), 3.44-3.36 (m, 2H), 3.34 (s, 2H), 3.10-3.01 (m, 3H), 1.77 -1.52 (m, 4H), 1.02-0.67 (m, 6H).

Observed MS (ESI +) [(M + H) +]: 446.

METHOD B: ALTERNATIVE METHOD FOR PREPARING 6-AMINO-9-BENZIL -2- (PROPILSULFONIMIDOIL) -7H-PURIN -8-ONA (C OPTIMUM 1E)

1e STEP 1: PREPARATION OF N-BENZYL-6-CHLORINE-5-NITRO-2-PROPYLSULPHANYL-PYRIMIDIN-4-AMINE (COMPOUND 1F) 1f

[264] In a solution of 4,6-dichloro-5-nitro-2-propylsulfanylpyrimidine (150.0 g, 559.5 mmol) and DIPEA (108.5 g, 839.2 mmol) in THF (1.5 L) phenylmethanamine (60.0 g, 559.5 mmol) in THF (200 mL) was added slowly at a temperature of -78 ° C. After the addition, the mixture was heated to 25 ° C, and stirred at that temperature for 16 hours. The resulting mixture was diluted with EA (1 L), washed with water (400 ml) three times and saline (500 ml). The separated organic phase was dried over Na2SO4, filtered and concentrated in vacuo to provide N-benzyl-6-chloro-5-nitro-2-propylsulfanyl-pyrimidin-4-amine (180.0 g, Compound 1f) as a yellow solid and used in the next step without further purification. Observed MS (ESI +) [(M + H) +]: 339.1.

STEP 2: PREPARATION OF N4-BENZYL-6-CHLORINE-2-PROPYLSULPHANYL-PYRIMIDINE-4,5-DIAMINE (COMPOUND 1G)

1g

[265] In a solution of N-benzyl-6-chloro-5-nitro-2-propylsulfanyl-pyrimidin-4-amine (180 g, Compound 1f) and HOAc (319 g, 5.31 mol) in THF (3.0 L) Zn (174 g, 2.66 mol) was added slowly at a temperature of 25ºC. After the addition, the mixture was stirred at 25 ºC for 16 hours. The reaction was filtered and the filtrate was basified with aq. saturated NaHCO3 (800 mL), extracted three times with EA (400 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel to provide N4-benzyl-6-chloro-2-propylsulfanyl-pyrimidine-4,5-diamine (125 g, Compound 1g) with a brownish solid. Observed MS (ESI +) [(M + H) +]: 309.1.

STEP 3: PREPARATION OF 9-BENZYL-6-CHLORINE-2-PROPYLSULPHANYL-7H-PURIN-8-ONA (1H COMPOUND) 1h

[266] A solution of N-benzyl-6-chloro-2- (propylsulfanyl) pyrimidine-4,5-diamine (72.0 g, 233.1 mmol, Compound 1g) and CDI (75.2 g, 233, 1 mmol) in THF (800mL) was stirred at 80ºC for 16 hours. The resulting mixture was diluted with EA (400 ml), washed with water (200 ml) twice and saline (200 ml). The separated organic layer was dried over Na2SO4, concentrated in vacuo. The residue was washed with MTBE (200 ml) to provide 9-benzyl-6-chloro-2-propylsulfanyl-7H-purin-8-one (58.0 g, Compound

1h) as a white solid and used in the next step without further purification. Observed MS (ESI +) [(M + H) +]: 335.1.

STEP 4: PREPARATION OF 9-BENZIL-6 - [(4-METOXYphenyl) METHYLAMINE] -2- PROPILSULFANIL-7H-PURIN-8-ONA (COMPOUND 1I) 1i

[267] A solution of 9-benzyl-6-chloro-2-propylsulfanyl-7H-purin-8-one (58.0 g, Compound 1h) and PMBNH2 (54.7 g, 398.42 mmol) in n- BuOH (600 mL) was stirred at 120 ºC for 20 hours. The reaction was concentrated and the residue was washed with MTBE (400 ml) to provide 9-benzyl-6 - [(4-methoxyphenyl) methylamino] -2-propylsulfanyl-7H-purin-8-one (75 g, Compound 1i) as a white solid and used in the next step without further purification. Observed MS (ESI +) [(M + H) +]: 436.2.

STEP 5: PREPARATION OF 6-AMINO-9-BENZYL-2-PROPYLSULPHANYL-7H-PURIN-8-ONA (COMPOUND 1C) 1c

[268] 9-Benzyl-6 - [(4-methoxyphenyl) methylamino] -2-propylsulfanyl-7H-purin-8-one (87.0 g, Compound 1i) in TFA (200 ml) was stirred at 80 ° C for 16 hours. The resulting reaction mixture was concentrated, basified with aq. saturated NaHCO3 (600 mL). The resulting precipitate was collected by filtration and washed with (PE / DCM = 2: 1, 400mL) to provide 6-amino-9-

benzyl-2-propylsulfanyl-7H-purin-8-one (38.0 g, Compound 1c) as a white solid. Observed MS (ESI +) [(M + H) +]: 316.1.

STEP 6: PREPARATION OF 6-AMINO-9-BENZYL-2-PROPYLSULFINYL-7H-PURIN-8-ONA (COMPOUND 1D) 1d

[269] A solution of m-CPBA (22.98 g, 113.2 mmol) in THF (50 mL) was added dropwise in a suspension of 6-amino-9-benzyl-2-propylsulfanyl-7H-purin -8-one (35.0 g, compound 1c) in THF (200 mL) at 0 ° C.

After the addition, the reaction mixture was stirred at 25 ºC for 0.5 h. The mixture was filtered and washed with MeCN (400 ml), MTBE (500 ml) to provide 6-amino-9-benzyl-2-propylsulfinyl-7H-purin-8-one (35.1 g, Compound 1d) as a white solid, which was used in the next step without further purification. Observed MS (ESI +) [(M + H) +]: 332.1.

STEP 7: PREPARATION OF 6-AMINO-9-BENZIL-2- (PROPILSULFONIMIDOIL) -7H-PURIN- 8-ONA (COMPOUND 1E) 1e

[270] In a solution of 6-amino-9-benzyl-2-propylsulfinyl-7H-purin-8-one (34.0 g, Compound 1d) in Eaton's reagent (170.0 mL, 7.5% in weight in methanesulfonic acid) NaN3 (15.34 g, 253.97 mmol) was slowly added at 60 ºC. Then the mixture was stirred at 60 ° C for 30 mins. The resulting reaction mixture was cooled to 25 ºC, poured into ice-cold NH 3.H2O in an ice bath (500 mL, 1 mol / L), extracted with n-BuOH (100 mL) four times and concentrated in vacuo. The residue was purified by preparative HPLC to provide 6-amino-9-benzyl-2- (propylsulfonimidoyl) -7H-purin-8-one (10 g, Compound 1e). 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.65 (br. S., 1H), 7.26-7.37 (m, 5H), 6.98 (br. S., 2H), 4.97 (s, 2H), 4.02 (s, 1H), 3.33 (t, J = 7.53 Hz, 2H), 1.55-1.74 (m, 2H), 0.92 (t, J = 7.53 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 347.

EXAMPLE 2 6-AMINO-9-BENZYL-N- (2-METOXYETHIL) -N-METHYL-8-OXO-2- (PROPILSULFONIMIDOIL) PURINE-7-CARBOXAMIDE 2

[271] The title compound was prepared analogously to Example 1, Method A, Step 6 by using N- (2-methoxyethyl) -N-methyl-carbamoyl chloride (Intermediate AB) in place of N-methyl chloride -N-propyl-carbamoyl (Intermediate AA). 6-Amino-9-benzyl-N- (2-methoxyethyl) -N-methyl-8-oxo- 2- (propylsulfonimidoyl) purine-7-carboxamide (120 mg, Example 2) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.27-7.39 (m, 5H), 6.89 (br. S., 1H), 6.78 (br. S., 1H), 5.00 (s, 2H), 4.16 (br. D, J = 4 Hz, 1H), 3.62 (br. Dd, J = 4, 12 Hz, 2H), 3.28-3.42 (m, 6H), 3.12 (d, J = 12 Hz, 3H), 3.05 (s, 1H), 1.58-1.72 (m, 2H), 0.93 (t, J = 8 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 462.

[272] Separation of the compound of Example 2 by chiral HPLC gave Example 2-A (fastest elution, 33 mg) and Example 2-B (slowest elution, 46 mg) as a white solid with 5% methanol - 40% (0.05% DEA) / CO2 in ChiralPak OJ-3 column.

[273] Example 2-A: 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.27- 7.39 (m, 5H), 6.89 (br. S., 1H), 6.78 ( br., 1H), 5.00 (s, 2H), 4.16 (br. d, J = 4 Hz, 1H), 3.62 (br. dd, J = 4, 12 Hz, 2H) , 3.28-3.42 (m, 6H), 3.12 (d, J = 12 Hz, 3H), 3.05 (s, 1H), 1.58-1.72 (m, 2H), 0.93 (t, J = 8 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 462.

[274] Example 2-B: 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.27- 7.39 (m, 5H), 6.89 (br. S., 1H), 6.78 ( br., 1H), 5.00 (s, 2H), 4.16 (br. d, J = 4 Hz, 1H), 3.62 (br. dd, J = 4, 12 Hz, 2H) , 3.28-3.42 (m, 6H), 3.12 (d, J = 12 Hz, 3H), 3.05 (s, 1H), 1.58-1.72 (m, 2H), 0.93 (t, J = 8 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 462.

EXAMPLE 3 6-AMINO-9-BENZIL-N-ETYL-8-OXO-N-PROPIL-2- (PROPILSULFONIMIDOIL) PURINA-7-

CARBOXAMIDE 3

[275] The title compound was prepared in a similar way to

Example 1, Method A, Step 6 by using N-ethyl-N-propyl-carbamoyl chloride (Intermediate AC) in place of N-methyl-N-propyl-carbamoyl chloride (Intermediate AA). 6-Amino-9-benzyl-N-ethyl-8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide (51 mg, Example 3) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.27-7.39 (m, 5H), 6.85 (br. S., 2H), 4.99 (s, 2H), 4.20 (br. d, J = 8.0 Hz, 1H), 3.13-3.54 (m, 4H), 1.46-1.72 (m, 4H), 1.30-1.39 (m , 1H), 1.00-1.26 (m, 6H), 0.81-0.95 (m, 5H), 0.73 (t, J = 8 Hz, 1H). Observed MS (ESI +) [(M + H) +]: 474.

EXAMPLE 4 6-AMINO-9-BENZIL-7- [4- (1-PIPERIDIL) PIPERIDIN-1-CARBONIL] -2- (PROPILSULFONIMIDOIL) PURIN-8-ONA 4

[276] The title compound was prepared analogously to Example 1, Method A, Step 6 by using (1,4'-bipiperidine) -1'-carbonyl chloride in place of N-methyl-N-propyl chloride -carbamoyl (Intermediate AA). 6-Amino-9-benzyl-7- [4- (1-piperidyl) piperidine-1-carbonyl] -2- (propylsulfonimidoyl) purin-8-one (55 mg, Example 4) was obtained as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.39 - 7.27 (m, 5H), 6.97 (br. S., 2H), 4.99 (s, 2H), 4.20 (br. s., 2H), 3.85 (d, J = 12.5 Hz, 1H), 3.43 - 3.15 (m, 3H), 2.96 (t, J = 12.3 Hz , 2H), 2.56 (m, 4H), 1.83 (m, 1H), 1.79 - 1.54 (m, 4H),

1.50 (br. S., 4H), 1.45 - 1.33 (m, 3H), 0.93 (t, J = 7.4 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 541.2.

EXAMPLE 5 6-AMINO-9-BENZYL-N-ETYL-N- (2-METOXYETHIL) -8-OXO-2- (PROPYLSULFONIMIDOIL) PURINE-7-CARBOXAMIDE 5

[277] The title compound was prepared analogously to Example 1, Method A, Step 6 by using N-ethyl-N- (2-methoxyethyl) carbamoyl chloride (Intermediate AD) in place of N-methyl- N-propyl carbamoyl (Intermediate AA). 6-Amino-9-benzyl-N-ethyl-N- (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide (34 mg, Example 5) was obtained as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.39 - 7.28 (m, 5H), 6.89 (br. S., 1H), 6.74 (br. S., 1H), 4.99 (s, 2H), 4.17 (d, J = 8.1 Hz, 1H), 3.67 (br.

s., 2H), 3.63 - 3.51 (m, 2H), 3.50 - 3.34 (m, 4H), 3.29 (s, 1H), 3.11 (s, 2H), 1.73 - 1.59 (m, 2H), 1.23 - 1.07 (m, 3H), 0.93 (t, J = 7.5 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 476.3.

EXAMPLE 6 6-AMINO-9-BENZIL-N-BUTYL-N-ETYL-8-OXO-2- (PROPILSULFONIMIDOIL) PURINA-7-

CARBOXAMIDE

[278] The title compound was prepared analogously to Example 1, Method A, Step 6 by using N-butyl-N-ethyl-carbamoyl chloride (Intermediate AE) in place of N-methyl-N-propyl chloride -carbamoyl (Intermediate AA). 6-Amino-9-benzyl-N-butyl-N-ethyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide (51 mg, Example 6) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.27-7.39 (m, 5H), 6.85 (br. S., 2H), 4.99 (s, 2H), 4.20 (br. d, J = 8.0 Hz, 1H), 3.13-3.54 (m, 4H), 1.46-1.72 (m, 4H), 1.30-1.39 (m , 1H), 1.00-1.26 (m, 6H), 0.81-0.95 (m, 5H), 0.73 (t, J = 8 Hz, 1H). Observed MS (ESI +) [(M + H) +]: 474.

EXAMPLE 7 6-AMINO-9-BENZIL-N- (2-METOXYETHIL) -8-OXO-N-PROPIL-2- (PROPILSULFONIMIDOIL) PURINE-7-CARBOXAMIDE 7

[279] The title compound was prepared in a manner similar to

Example 1, Method A, Step 6 by using N-ethyl-N- (2-methoxyethyl) carbamoyl chloride (Intermediate AF) in place of N-methyl-N-propyl-carbamoyl chloride (Intermediate AA). 6-amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide (35 mg, Example 7) was obtained as a white powder. 1H NMR (400 MHz, DMSO-d 6) δ ppm: 7.40 - 7.28 (m, 5H), 6.89 (br., 1H), 6.75 (br., 1H) , 5.00 (d, J = 5.5 Hz, 2H), 4.24 - 4.16 (m, 1H), 3.77 (br., 1H), 3.67 (br. S. , 1H), 3.62 - 3.53 (m, 1H), 3.42 - 3.27 (m, 5H), 3.23 - 3.02 (m, 3H), 1.66-1.38 (m, 4H), 0.96 - 0.70 (m, 6H). Observed MS (ESI +) [(M + H) +]: 490.5.

E XEMPLO 8 6-AMINO-9-BENZIL -N, N-BIS (2-METOXYETHIL) -8-OXO-2- (PROPILSULFONIMIDOIL) PURINE-7-CARBOXAMIDE 8

[280] The title compound was prepared analogously to Example 1, Method A, Step 6 by using carbamic bis (2-methoxyethyl) chloride (Intermediate AG) in place of N-methyl-N-propyl-carbamoyl chloride (Intermediate AA). 6-Amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide (35 mg, Example 8) was obtained as a white powder. 1H NMR (400 MHz, DMSO-d 6) δ ppm: 7.40 - 7.28 (m, 5H), 6.83 (br., 2H), 4.99 (s, 2H), 3, 71 (br., 3H),

3.52 - 3.27 (m, 11H), 3.09 (s, 3H), 1.73 - 1.59 (m, 2H), 0.93 (t, J = 7.5 Hz, 3H) . Observed MS (ESI +) [(M + H) +]: 506.

E XAMPLE 9 6-AMINO-7- (AZETIDINE-1-CARBONYL) -9-BENZIL-2- (PROPILSULFONIMIDOIL) PURIN-8-

ONA 9

[281] The title compound was prepared in a manner analogous to Example 1, Method A, Step 6 by the use of azetidine-1-carbonyl chloride (Intermediate AH) in place of N-methyl-N-propyl-carbamoyl chloride (Intermediate AA). 6-Amino-7- (azetidine-1-carbonyl) -9-benzyl-2- (propylsulfonimidoyl) purin-8-one (120 mg, Example 9) was obtained as a white powder. 1HNMR (400 MHz, DMSO-d6) δ ppm: 7.02 - 7.43 (m, 7H), 4.99 (s, 2H), 4.31 (t, J = 7.65 Hz, 2H), 4.08 - 4.23 (m, 3H), 3.34 - 3.41 (m, 2H), 2.28 (m, 2H), 1.56 - 1.73 (m, 2H), 0, 93 (t, J = 7.40 Hz, 3H). Observed MS (ESI +) [(M + H) +]:

430.

EXAMPLE 10 6-AMINO-9-BENZYL-N-ISOPROPIL-N-METHYL-8-OXO-2- (PROPILSULFONIMIDOIL) PURINE- 7-CARBOXAMIDE 10

[282] The title compound was prepared analogously to Example 1, Method A, Step 6 by using N-isopropyl-N-methyl-carbamoyl chloride (Intermediate AI) in place of N-methyl-N-propyl chloride -carbamoyl (Intermediate AA). 6-Amino-9-benzyl-N-isopropyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide (97 mg, Example 10) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.27-7.39 (m, 5H), 6.87 (br. S., 2H), 4.99 (s, 2H), 4.38 -4.45 (m, 1H), 4.09-4.21 (m, 1H), 3.29-3.43 (m, 2H), 2.89-2.95 (m, 3H), 1 , 58-1.73 (m, 2H), 1.21 (br d, J = 8 Hz, 6H), 0.93 (t, J = 8 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 446.

EXAMPLE 11 6-AMINO-9-BENZIL-7- (4-METHYLPIPERAZINE-1-CARBONYL) -2- (PROPILSULFONIMIDOIL) PURIN-8-ONA 11

[283] The title compound was prepared analogously to Example 1, Method A, Step 6 by using 4-methylpiperazine-1-carbonyl chloride in place of N-methyl-N-propyl-carbamoyl chloride (Intermediate AA) .

6-Amino-9-benzyl-7- (4-methylpiperazine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one (59.5 mg, Example 11) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6)  ppm: 7.39 - 7.31 (m, 5H), 6.99 (s, 2H), 4.98 (s, 2H), 4.18 (s, 1H), 3.58 - 3.49 (m, 6H), 2.42 (m, 4H), 2.22 (s, 3H), 1.66 - 1.61 (m, 2H), 0.95 - 0.91 (t, J = 7.2 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 473.

EXAMPLE 12 6-AMINO-9-BENZIL-N- (3-METOXYPROPYL) -N-METHYL-8-OXO-2- (PROPILSULFONIMIDOIL) PURINE-7-CARBOXAMIDE 12

[284] The title compound was prepared analogously to Example 1, Method A, Step 6 by using N- (3-methoxypropyl) -N-methyl-carbamoyl chloride in place of N-methyl-N-propyl chloride -carbamoyl (Intermediate AA). 6-Amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide (92.2 mg, Example 12) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6)  ppm: 7.23 - 7.45 (m, 5H), 6.94 (s., 2H), 4.93-5.08 (m, 2H), 4 , 19 (s, 1H), 3.30 - 3.62 (m, 6H), 3.25 (s, 3H), 3.02 - 3.10 (m, 3H), 1.74 - 1.90 (m, 2H), 1.55 - 1.77 (m, 2H), 0.98 - 0.82 (m, 3H). Observed MS (ESI +) [(M + H) +]: 476.3.

EXAMPLE 13 6-AMINO-9-BENZYL-N-ISOBUTYL-N-METHYL-8-OXO-2- (PROPILSULFONIMIDOIL) PURINA-7-

CARBOXAMIDE 13

[285] The title compound was prepared analogously to Example 1, Method A, Step 6 by using N-isobutyl-N-methyl-carbamoyl chloride (Intermediate AL) in place of N-methyl-N-propyl chloride - carbamoyl (Intermediate AA). 6-Amino-9-benzyl-N-isobutyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide (64 mg, Example 13) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d 6) δ ppm: 7.27-7.40 (m, 5H), 6.89 (br. S., 2H), 5.00 (s, 2H), 4, 16 (br. S, 1H), 3.25-3.44 (m, 4H), 3.07 (s, 2H), 3.03 (s, 1H), 1.87-2.09 (m , 1H), 1.57-1.74 (m, 2H), 0.75-0.99 (m, 9H). Observed MS (ESI +) [(M + H) +]: 460.

E XAMPLE 14 2 - [[6-AMINO-9-BENZIL-8-OXO-2- (PROPILSULFONIMIDOIL) PURINA-7-CARBONIL] - METHYL-AMINO] ETHYL ACETATE 14

[286] The title compound was prepared analogously to Example 1, Method A, Step 6 by using ethyl 2- ((chlorocarbonyl) (methyl) amino) acetate (Intermediate AP) in place of N-methyl chloride. N-propyl-carbamoyl (Intermediate AA). 2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl acetate (38 mg, Example 14) was obtained as a yellow powder clear.

1H NMR (400MHz, DMSO-d 6) δ ppm: 7.41 - 7.27 (m, 5H), 6.82 (br. S., 1H), 5.04 - 4.95 (m, 2H) , 4.35 (br. S, 1H), 4.28 (br. S, 1H), 4.23 - 4.16 (m, 2H), 4.08 (q, J = 7.2 Hz , 1H), 3.43 - 3.28 (m, 3H), 3.15 (s, 2H), 3.08 (s, 1H), 1.71 - 1.58 (m, 2H), 1, 24 (t, J = 7.0 Hz, 2H), 1.12 (t, J = 7.0 Hz, 1H), 0.93 (t, J = 7.4 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 490.

E XAMPLE 15 3 - [[6-AMINO-9-BENZIL-8-OXO-2- (PROPILSULFONIMIDOIL) PURINE-7-CARBONY] - METHYL-AMINO] ETHYL PROPANOATE 15

[287] The title compound was prepared in a manner analogous to Example 1, Method A, Step 6 by using ethyl 3- ((chlorocarbonyl) (methyl) amino) propanoate in place of N-methyl-N-propyl- carbamoyl (Intermediate AA). 3 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] propanoate (35 mg, Example 15) was obtained as a white powder. 1H NMR (400MHz, DMSO-d 6) δ ppm: 7.43 - 7.26 (m, 5H), 6.93 (br. S., 2H), 4.99 (s, 2H), 4.16 (s, 1H), 4.08 (q, J = 7.1 Hz, 1H), 3.99 (d, J = 7.0 Hz, 1H), 3.67 (br. s., 2H), 3.40 - 3.29 (m, 2H), 3.08 (s, 2H), 2.99 (s, 1H), 2.71 (t, J = 6.4 Hz, 2H), 1.74 - 1.56 (m, 2H), 1.27 - 1.05 (m, 3H), 0.93 (t, J = 7.5 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 504.

EXAMPLE 16 3 - [[6-AMINO-9-BENZIL-8-OXO-2- (PROPILSULFONIMIDOIL) PURINE-7-CARBONY] -METHYL-AMINO] TERC-BUTYL PROPANOATE 16

[288] The title compound was prepared analogously to Example 1, Method A, Step 6 by using tert-butyl 3- [chlorocarbonyl (methyl) amino] propanoate (Intermediate AR) in place of N-methyl chloride N-propyl-carbamoyl (Intermediate AA). 3 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] propanoate (60 mg, Example 16) was obtained as a white powder . 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.41 - 7.27 (m, 5H), 6.93 (br. S., 2H), 4.99 (s, 2H), 4.15 (s, 1H), 3.64 (br., 2H), 3.51 - 3.33 (m, 2H), 3.08 (s, 2H), 2.98 (s, 1H), 2 , 62 (t, J = 6.9 Hz, 2H), 1.71 - 1.57 (m, 2H), 1.41 (s, 6H), 1.34 (s, 3H), 0.93 ( t, J = 7.4 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 532.

EXAMPLE 17 (2S) -2 - [[6 AMINO-9-BENZIL-8-OXO-2- (PROPILSULFONIMIDOIL) PURINA-7-CARBONIL] - METHYL-AMINO] ETHYL PROPANOATE

[289] The title compound was prepared in a manner analogous to Example 1, Method A, Step 6 by the use of ethyl (2S) -2- [chlorocarbonyl (methyl) amino] propanoate (Intermediate AS) in place of N- methyl-N-propyl-carbamoyl (Intermediate AA). (2S) -2 - [[6Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] propanoate (34.1 mg, Example 17) was obtained as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.22 - 7.49 (m, 5 H), 6.78 (br. S., 2H), 4.93 - 5.08 (m, 2H ), 4.75 (br. S., 1H), 3.96 - 4.29 (m, 3H), 3.30 - 3.46 (m, 2H), 3.09 (s, 2H), 2 , 93 (br. S., 1H), 1.55 - 1.77 (m, 2H), 1.48 (d, J = 7.16 Hz, 3H), 1.09 - 1.29 (m, 3H), 0.94 (t, J = 7.44 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 504.2.

EXAMPLE 18 (2S) -2 - [[6-AMINO-9-BENZYL-8-OXO-2- (PROPYLSULFONIMIDOIL) PURINE-7-CARBONY] - METHYL-AMINO] -4-METHYL-PENTANOATE TERC-BUTYLE 18

[290] The title compound was prepared in a similar way to

Example 1, Method A, Step 6 by using tert-butyl (2S) -2- [chlorocarbonyl (methyl) amino] -4-methyl pentanoate (Intermediate AT) in place of N-methyl-N-propyl chloride -carbamoyl (Intermediate AA).

(2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] -4-methyl-tert-butyl pentanoate (22 mg, Example 18) was obtained as a white solid. 1H NMR (400MHz, DMSO-d 6) δ ppm: 7.42 - 7.27 (m, 5H), 6.78 (br. S., 2H), 5.05 - 4.96 (m, 2H) , 4.78 (br. S, 1H), 4.33 (br. S, 1H), 3.51 - 3.37 (m, 2H), 3.01 (s, 3H), 1.75 - 1.54 (m, 4H), 1.44 (s, 8H), 1.33 - 1.11 (m, 2H), 0.99 - 0.82 (m, 9H). Observed MS (ESI +) [(M + H) +]: 574.3.

E XAMPLE 19 (2S) -2 - [[6-AMINO-9-BENZIL -8-OXO-2- (PROPILSULFONIMIDOIL) PURINE -7- CARBONY] - METHYL - AMINO] -4-METHYL- ISOPROPYL PENTANOATE 19

[291] The title compound was prepared analogously to Example 1, Method A, Step 6 by using isopropyl (2S) -2- [chlorocarbonyl (methyl) amino] -4-methyl pentanoate (Intermediate AU) in place of N-methyl-N-propyl-carbamoyl chloride (Intermediate AA).

(2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] - methyl-amino] -4-methyl-pentanoate (43 mg, Example 19 ) was obtained as a white powder. 1H NMR (400MHz, DMSO-d6) δ ppm: 7.43 - 7.27 (m, 5H), 6.75 (br. S., 2H), 5.05 - 4.94 (m, 3H), 4.88 (br. S, 1H), 4.19 (br. S, 1H), 3.43 - 3.34 (m, 2H), 3.01 (s, 3H), 1.91 ( br., 1H), 1.77 - 1.56 (m, 4H), 1.25 - 1.16 (m, 6H), 0.99 - 0.83 (m, 9H). Observed MS (ESI +) [(M + H) +]: 560.3.

E XAMPLE 20 (2S) -2 - [[6-AMINO-9-BENZIL -8-OXO-2- (PROPILSULFONIMIDOIL) PURINE -7- CARBONY] - METHYL - AMINO] -3-METHYL-BUTANOATE 20

[292] The title compound was prepared in a manner analogous to Example 1, Method A, Step 6 by the use of ethyl (2S) -2- [chlorocarbonyl (methyl) amino] -3-methyl-butanoate (Intermediate AV) in place of N-methyl-N-propyl-carbamoyl chloride (Intermediate AA). (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] -3-methyl-butanoate (51.5 mg, Example 20) was obtained as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.23 - 7.51 (m, 5H), 6.76 (br., 2H), 5.01 (br., 2H), 4.42 (br. S., 1H), 3.97 - 4.26 (m, 3H), 3.34 - 3.45 (m, 2H), 3.12 (br. S, 3H), 2.24 (br., 1H), 1.65 (br., 2H), 1.13 - 1.29 (m, 3H), 0.88 - 1.10 (m, 9H). Observed MS (ESI +) [M + H +]: 532.2.

EXAMPLE 21 (2S) -2 - [[6-AMINO-9-BENZYL-8-OXO-2- (PROPYLSULFONIMIDOIL) PURINE-7-CARBONY] -METHYL-

AMINO] -4-ETHYL-METHYL-PENTANOATE 21

[293] The title compound was prepared in a manner analogous to Example 1, Method A, Step 6 by using ethyl (2S) -2- [chlorocarbonyl (methyl) amino] -4-methyl pentanoate (Intermediate AW) in place of N-methyl-N-propyl-carbamoyl chloride (Intermediate AA). (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate (17.3 mg, Example 21) was obtained as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.26 - 7.45 (m, 5H), 6.73 (br. S., 2H), 4.91 - 5.09 (m, 3H) , 4.06 - 4.25 (m, 3H), 3.34 - 3.45 (m, 2H), 3.04 (br., 3H), 1.93 (br., 1H) , 1.54 - 1.78 (m, 4H), 1.22 (t, J = 7.09 Hz, 3H), 0.77 - 1.01 (m, 9H). Observed MS (ESI +) [(M + H) +]: 546.3.

EXAMPLE 22 (2S) -2 - [[6-AMINO-9-BENZYL-8-OXO-2- (PROPYLSULFONIMIDOIL) PURINE-7-CARBONY] -METHYL-AMINO] -3-PHENYL-PROPANOATE 22

[294] The title compound was prepared in a manner analogous to Example 1, Method A, Step 6 by the use of ethyl (2S) -2- [chlorocarbonyl (methyl) amino] -3-phenyl-propanoate (Intermediate AX) in place of N-methyl-N-propyl-carbamoyl chloride (Intermediate AA). (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate (30 mg, Example 22 ) was obtained as a white powder. 1H NMR (400MHz, DMSO-d6) δ ppm: 7.42 - 7.16 (m, 10H), 4.97 (s, 3H), 4.19 (q, J = 7.1 Hz, 2H), 3.35 - 3.15 (m, 6H), 3.10 - 2.90 (m, 3H), 1.71 - 1.46 (m, 2H), 1.28 - 1.18 (m, 4H ), 0.97 - 0.85 (m, 3H). Observed MS (ESI +) [(M + H) +]: 580.

EXAMPLE 23 (2S) -2 - [[6-AMINO-9-BENZYL-8-OXO-2- (PROPYLSULFONIMIDOIL) PURINE-7-CARBONY] -METHYL-AMINO] -3-PHENYL-PROPANOATE OF ISOPROPYLA 23

[295] The title compound was prepared in a manner analogous to Example 1, Method A, Step 6 by the use of isopropyl (2S) -2- [chlorocarbonyl (methyl) amino] -3-phenylpropanoate (Intermediate AY) in place of N-methyl-N-propyl-carbamoyl chloride (Intermediate AA). (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate (22 mg, Example 23 ) was obtained as a white powder. 1H NMR (400MHz, DMSO-d6) δ ppm: 7.35 - 7.01 (m, 10H), 5.02-4.89 (m, 3H), 3.37-3.17 (m, 3H) , 3.02 - 3.09 (m, 3H), 3.10 - 2.90 (m, 3H), 1.66 - 1.62 (m, 2H), 1.22 - 1.11 (m, 8H), 0.92 (t, J = 7.4 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 594.

EXAMPLE 24 (2S) -2 - [[6-AMINO-9-BENZYL-8-OXO-2- (PROPYLSULFONIMIDOIL) PURIN-7-CARBONY] - METHYL-AMINO] -3-PHENYL-PROPANOATE OF TERC-BUTYLE 24

[296] The title compound was prepared in a manner analogous to Example 1, Method A, Step 6 by the use of tert-butyl (2S) -2- [chlorocarbonyl (methyl) amino] -3-phenyl-propanoate (Intermediate AZ) in place of N-methyl-N-propyl-carbamoyl chloride (Intermediate AA). (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate tert-butyl (34 mg, Example 24) was obtained as a white powder. 1H NMR (400MHz, DMSO-d6) δ ppm: 7.42 - 7.16 (m, 10H), 5.03 - 4.90 (m, 3H), 3.68 - 3.24 (m, 5H) , 3.24 - 3.09 (m, 2H), 3.01 (s, 3H), 1.68 - 1.57 (m, 2H), 1.43 (s, 9H), 0.99 - 0 , 85 (m, 3H). Observed MS (ESI +) [(M + H) +]: 608.3.

EXAMPLE 25 N- [2- [ACETYL (METHYL) AMINO] ETHYL] -6-AMINO-9-BENZYL-N-METHYL-8-OXO-2- (PROPYLSULFONIMIDOIL) PURINE-7-CARBOXAMIDE 25

[297] The title compound was prepared analogously to Example 1, Method A, Step 6 by using N- [2- [acetyl (methyl) amino] ethyl] -N-methyl-carbamoyl chloride (Intermediate BA) in place of N-methyl-N-propyl-carbamoyl chloride (Intermediate AA). N- [2- [Acetyl (methyl) amino] ethyl] -6-amino-9-benzyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide (26.1 mg, Example 25) was obtained as a white powder.RNN 1H (400MHz, DMSO-d6) δ ppm: 7.43 - 7.27 (m, 5H), 7.02 (br, 2H), 5.04 - 4.97 (m , 2H), 4.19 - 4.13 (m, 1H), 3.57 (d, J = 5.5 Hz, 2H), 3.49 - 3.34 (m, 2H), 3.14 ( s, 1H), 3.12 - 3.02 (m, 4H), 2.86 (d, J = 7.5 Hz, 2H), 2.69 - 2.64 (m, 1H), 2.05 (s, 1H), 1.99 (s, 1H), 1.91 - 1.83 (m, 1H), 1.70 - 1.59 (m, 2H), 0.97 - 0.90 (m , 3H). Observed MS (ESI +) [(M + H) +]: 503.2.

EXAMPLE 26 N- [2 - [[6-AMINO-9-BENZYL-8-OXO-2- (PROPYLSULFONIMIDOIL) PURINE-7-CARBONY] - METHYL-AMINO] ETHYL] -N-METHYL-CARBAMATE 26

[298] The title compound was prepared in a manner analogous to Example 1, Method A, Step 6 by the use of methyl N- [2- [chlorocarbonyl (methyl) amino] ethyl] -N-methyl-carbamate (Intermediate BB) in place of N-methyl-N-propyl-carbamoyl chloride (Intermediate AA).

N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] - methyl-amino] ethyl] -N-methyl-carbamate (65 mg, Example 26) was obtained as a yellow solid. 1H NMR (400 MHz, CDCl 3) δ ppm: 7.29 -

7.49 (m, 5H), 5.63 - 5.92 (m, 2H), 5.03 - 5.17 (m, 2H), 3.43 - 3.69 (m, 8H), 3, 13 - 3.27 (m, 3H), 2.96 - 3.05 (m, 2H), 2.72 (br. S., 1H), 1.05 (t, J = 7.40 Hz, 3H ), 1.87 (dd, J = 14.12, 6.96 Hz, 2H). Observed MS (ESI +) [(M + H) +]: 519.2.

E XAMPLE 27 N- [2 - [[6-AMINO-9-BENZIL -8-OXO-2- (PROPILSULFONIMIDOIL) PURINE -7- CARBONY] - METHYL - AMINO] ETHYL] -N-METHY- TERC - BUTYL CARBAMATE 27

[299] The title compound was prepared in a manner analogous to Example 1, Method A, Step 6 by the use of tert-butyl N- [2- [chlorocarbonyl (methyl) amino] ethyl] -N-methyl-carbamate (Intermediate BC ) in place of N-methyl-N-propyl-carbamoyl chloride (Intermediate AA). Tert-butyl N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate (32 mg , Example 27) was obtained as a white powder. 1H NMR (400MHz, DMSO-d6) δ ppm: 7.43 - 7.26 (m, 5H), 6.89 (br. S., 2H), 4.99 (d, J = 5.0 Hz, 2H), 4.16 (s, 1H), 3.55 (br., 2H), 3.48 - 3.34 (m, 2H), 3.10 (s, 2H), 3.07 ( s, 1H), 2.86 (d, J = 12.8 Hz, 2H), 2.74 (d, J = 9.5 Hz, 1H), 2.70 - 2.60 (m, 1H), 1.72 - 1.54 (m, 2H), 1.39 (s, 6H), 1.23 (s, 2H), 1.13 (s, 2H), 0.93 (t, J = 7, 4 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 562.

E XAMPLE 28 N- [2 - [[6-AMINO-9-BENZYL-8-OXO-2- (PROPYLSULFONIMIDOIL) PURINE -7-CARBONY] - METHYL-AMINO] ETHYL] -N-METHYL-CARBAMATE ETHYL 28

[300] The title compound was prepared in a manner analogous to Example 1, Method A, Step 6 by the use of ethyl N- [2- [chlorocarbonyl (methyl) amino] ethyl] -N-methyl-carbamate (Intermediate BD) in place of N-methyl-N-propyl-carbamoyl chloride (Intermediate AA).

N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate (87 mg, Example 28) was obtained as a yellow solid.RNN 1H (400 MHz, CDCl 3) δ ppm: 7.29 - 7.53 (m, 5H), 5.65 - 5.90 (m, 2H), 5.02 - 5.14 (m, 2H), 3.38 - 4.21 (m, 9H), 3.14 - 3.26 (m, 3H), 3.00 (br., 2H), 2, 73 (s, 1H), 1.76 - 1.99 (m, 2H), 1.22 - 1.31 (m, 3H), 1.05 (s, 3H). Observed MS (ESI +) [(M + H) +]: 533.2.

E EXAMPLE 29 N - BUTYL -N-METHYL-CARBAMATE OF 2 - [[6-AMINO-9-BENZYL-8-OXO-2- (PROPILSULFONIMIDOIL) PURINE -7-CARBONY] -METHYL-AMINO] ETHYL

[301] The title compound was prepared analogously to Example 1, Method A, Step 6 by using 2- [chlorocarbonyl (methyl) amino] ethyl N-butyl-N-methyl-carbamate (Intermediate BE) instead of N-methyl-N-propyl-carbamoyl chloride (Intermediate AA). 2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl N-butyl-N-methyl-carbamate (19 mg, Compound 29) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d 6) δ ppm: 7.25 - 7.48 (m, 5H), 6.96 (br., 2H), 4.99 (s, 2H), 4, 06 - 4.36 (m, 3H), 3.59 - 3.83 (m, 1H), 3.33 - 3.49 (m, 3H), 3.07 - 3.21 (m, 4H), 2.79 (s, 2H), 1.65 (br., 2H), 1.05 - 1.47 (m, 6H), 0.93 (t, J = 7.40 Hz, 3H), 0.70 - 0.87 (m, 3H). Observed MS (ESI +) [(M + H) +]: 561.2.

E XEMPLO 30 P IRROLIDIN -1-CARBOXYLATE 2 - [[6-AMINO-9-BENZYL-8-OXO-2- (PROPYLSULFONIMIDOIL) PURINE -7-CARBONY] -METHYL-AMINO] ETHYL

[302] The title compound was prepared analogously to Example 1, Method A, Step 6 by using 2- [chlorocarbonyl (methyl) amino] ethyl pyrrolidine-1-carboxylate (Intermediate BF) in place of N- methyl-N-propyl-carbamoyl (Intermediate AA). 2- [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl pyrrolidine-1-carboxylate (10.0 mg, Example 30) was obtained like a yellow solid. 1H NMR (400 MHz, DMSO-d 6) δ ppm: 7.26 - 7.41 (m, 5H), 6.96 (br.s., 2H), 4.99 (s, 2H), 4, 01 - 4.35 (m, 4H), 3.29 - 3.47 (m, 3H), 3.23 (br. S., 3H), 3.03 - 3.17 (m, 4H), 1 , 52 - 1.84 (m, 6H), 0.90 - 0.96 (m, 3H). Observed MS (ESI +) [(M + H) +]: 545.2.

E EXAMPLE 31 N - METHYL -N-PROPYL-CARBAMATE OF 2 - [[6-AMINO-9-BENZYL-8-OXO-2- (PROPYLSULFONIMIDOIL) PURINE -7-CARBONY] -METHYL-AMINO] ETHYL 31

[303] The title compound was prepared analogously to Example 1, Method A, Step 6 by using 2- [chlorocarbonyl (methyl) amino] ethyl N-methyl-N-propyl-carbamate (Intermediate BG) in place of N-methyl-N-propyl-carbamoyl chloride (Intermediate AA). 2- [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl N-methyl-N-propyl-carbamate (3.7 mg, Example 31) was obtained as a yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm: 7.22 - 7.48 (m, 5H), 5.09 - 5.22 (m, 4H), 4.55 (s, 2H), 3.38 - 3.57 (m, 4H), 3.13 (s, 3H), 1.61 - 1.85 (m, 4H), 1.22 - 1.41 (m, 3H), 0.88 - 1, 13 (m, 6H). Observed MS (ESI +) [(M + H) +]: 547.2.

EXAMPLE 32 N, 2-[[6-AMINO-9-BENZYL-8-OXO-2- (PROPYLSULFONIMIDOIL) PURINE-7-CARBONYL] -METHYL-AMINO] ETHYL 32

[304] The title compound was prepared in a manner analogous to Example 1, Method A, Step 6 by using 2- [chlorocarbonyl (methyl) amino] ethyl N, N-diethylcarbamate (Intermediate BH) in place of N- methyl-N-propyl-carbamoyl (Intermediate AA). 2 - [[6- Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl (21.7 mg, Example 32) N, N-diethylcarbamate (21.7 mg, Example 32) was obtained like a yellow solid. 1H NMR (400 MHz,

DMSO-d6) δ ppm: 7.25 - 7.41 (m, 5H), 6.96 (br. S., 2H), 4.99 (s, 2H), 4.08 - 4.36 (m , 3H), 3.70 (br, 1H), 3.33 - 3.46 (m, 3H), 3.01 - 3.24 (m, 7H), 1.55 - 1.74 (m, 2H ), 0.86 - 1.05 (m, 9H). Observed MS (ESI +) [(M + H) +]: 547.2.

EXAMPLE 33 2 - [[6-AMINO-9-BENZYL-8-OXO-2- (PROPILSULFONIMIDOIL) PURINE- 7-CARBONY] -METHYL-AMINO] ETHYL CARBONATE] ETHYL 33

[305] The title compound was prepared analogously to Example 1, Method A, Step 6 by using 2- [chlorocarbonyl (methyl) amino] ethyl ethyl carbonate (Intermediate BI) in place of N-methyl- N chloride -propyl carbamoyl (Intermediate AA). 2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl ethyl carbonate (46 mg, Example 33) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 0.82 - 0.99 (m, 3H), 1.02 - 1.28 (m, 3H), 1.56 - 1.76 (m, 2H ), 3.05 - 3.18 (m, 3H), 3.35 - 3.48 (m, 3H), 3.73 (t, J = 5.08 Hz, 2H), 4.08 - 4, 27 (m, 3H), 4.37 (br., 1H), 5.00 (s, 2H), 6.76 - 7.11 (m, 2H), 7.22 - 7.45 (m , 5H). Observed MS (ESI +) [(M + H) +]: 520.

EXAMPLE 34-AE EXAMPLE 34-B 6-AMINO-N-BUTYL-9 - [(4-CHLOROPHENYL) METHIL] -N-METHYL-8-OXO-2- [S (S) - PROPYLSULFONIMIDOIL] PURINE-7-CARBOXAMIDE E 6-AMINO-N-BUTYL-9 - [(4-CHLOROPHENYL) METHIL] -N-METHYL-8-OXO-2- [S (S) -PROPYLSULFONIMIDOIL]

CARBOXAMIDE STEP 1: PREPARATION OF 4-AMINO-3 - [(4-CHLOROPHENYL) METHIL] -2-OXO-1H-IMIDAZOL-5-CARBONITRILLA (COMPOUND 34A) 34a

[306] Compound 34a was prepared in a manner analogous to Example 1, Method A, Step 1 by the use of benzyl 4-chloroisocyanate in place of benzyl isocyanate. 4-Amino-3 - [(4-chlorophenyl) methyl] -2-oxo-1H-imidazole-5-carbonitrile (8.0 g, Compound 34a) was obtained as a yellow solid. Observed MS (ESI +) [(M + H) +]: 249.

STEP 2: PREPARATION OF 6-AMINO-9 - [(4-CHLOROPHENYL) METHIL] -2-SULPHANYL-7H- PURIN-8-ONA (COMPOUND 34B) 34b

[307] Compound 34b was prepared analogously to Example 1, Method A, Step 2 by using 4-Amino-3 - [(4-chlorophenyl) methyl] -2-oxo-1H-imidazole-5-carbonitrile ( Compound 34a) in place of 4-amino-3-phenylmethyl-2-oxo-1H-imidazole-5-carbonitrile (Compound 1a). 6-Amino-9 - [(4-chlorophenyl) methyl] -2-sulfanyl-7H-purin-8-one (6.4 g, Compound 34b) was obtained as a yellow solid and was used in the next step without further purification .

Observed MS (ESI +) [(M + H) +]: 308.

STEP 3: PREPARATION OF 6-AMINO-9 - [(4-CHLOROPHENYL) METHIL] -2-PROPYLSULFANYL-7H-PURIN-8-ONA (COMPOUND 34C) 34c

[308] Compound 34c was prepared analogously to Example 1, Method A, Step 3 by using 6-amino-9 - [(4-chlorophenyl) methyl] -2-sulfanyl-7H-purin-8-one ( Compound 34b) in place of 6-amino-9-phenylmethyl-2-sulfanyl-7H-purin-8-one (Compound 1b). 6-Amino-9 - [(4-chlorophenyl) methyl] -2-propylsulfanyl-7H-purin-8-one (800 mg, Compound 34c) was obtained as a white solid. Observed MS (ESI +) [(M + H) +]: 350.

STEP 4: PREPARATION OF 6-AMINO-9 - [(4-CHLOROPHENYL) METHIL] -2-PROPYLSULFINYL-7H-PURIN-8-ONA (COMPOUND 34D) 34d

[309] Compound 34d was prepared analogously to Example 1, Method A, Step 4 by using 6-amino-9 - [(4-chlorophenyl) methyl] -2-propylsulfanyl-7H-purin-8-one ( Compound 34c) in place of 6-amino-9-benzyl-2-propylsulfanyl-7H-purin-8-one (Compound 1c). 6-Amino-9 - [(4-chlorophenyl) methyl] -2-propylsulfinyl-7H-purin-8-one (150 mg, Compound 34d) was obtained as a white solid. Observed MS (ESI +) [(M + H) +]: 366.

STEP 5: PREPARATION OF 6-AMINO-9 - [(4-CHLOROPHENYL) METHIL] -2- (PROPILSULFONIMIDOIL) -7H-PURIN-8-ONA (COMPOUND 34E), 6-AMINO-9 - [(4-CHLOROPHENYL) Methyl] -2- [S (S) -PROPILSULFONIMIDOIL) -7H-PURIN-8-ONA AND 6-AMINO-9- [((4-CHLOROPHENYL) METHIL] -2- [S (S) -PROPILSULFONIMIDOIL) -7H- PURIN-8-ONA (COMPOUND 34E-AE COMPOUND 34E-B) 34e

34E-A AND 34E-B

[310] Compound 34e was prepared analogously to Example 1, Method A, Step 5 by using 6-amino-9 - [(4-chlorophenyl) methyl] -2-propylsulfinyl-7H-purin-8-one ( Compound 34d) in place of 6-amino-9-benzyl-2- (2-propylsulfinyl) -7H-purin-8-one (Compound 1d). 6-Amino-9 - [(4-chlorophenyl) methyl] -2- (propylsulfonimidoyl) -7H-purin-8-one (250 mg, compound 34e) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.60 (br. S, 1H), 7.32- 7.42 (m, 4H), 6.98 (br. S, 2H), 4, 96 (s, 2H), 4.03 (s, 1H), 3.25-3.41 (m, 2H), 1.56-1.68 (m, 2H), 0.91 (t, J = 8 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 381.

[311] The compound separation of Compound 34e by chiral HPLC provided Compound 34e-A (fastest elution, 110 mg) and Compound 34e-B (slowest elution, 100 mg) as a white solid with 5% methanol -40% (0.05% DEA) / CO2 in ChiralPak OJ-3 column.

[312] Compound 34e-A: 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.63 (br. S, 1H), 7.33-7.42 (m, 4H), 6.99 (br . s, 2H), 4.96 (s, 2H), 4.05 (br. s, 1H), 3.26-3.39 (m, 2H), 1.53-1.69 (m, 2H ), 0.91 (t, J = 7.4 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 381.

[313] Compound 34e-B: 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.63 (br. S, 1H), 7.33-7.42 (m, 4H), 6.99 (br . s, 2H), 4.96 (s, 2H), 4.05 (br. s, 1H), 3.26-3.40 (m, 2H), 1.54-1.69 (m, 2H ), 0.91 (t, J = 7.5 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 381.

STEP 6: 6-AMINO-N-BUTYL-9 - [(4-CHLOROPHENYL) METHIL] -N-METHYL-8-OXO-2- [S (S) - PROPILSULFONIMIDOIL] PURINE-7-CARBOXAMIDE AND 6-AMINO- N-BUTYL-9 - [(4-CHLOROPHENYL) METHIL] -N-METHYL-8-OXO-2- [S (S) -PROPYLSULFONIMIDOIL] PURINE-7-CARBOXAMIDE (EXAMPLE 34-AE EXAMPLE 34-B)

[314] Example 34-A was prepared analogously to Example 1, Method A, Step 6 by using Compound 34e-A and N-butyl-N-methyl-carbamoyl chloride in place of 6-amino-9- benzyl-2- (propylsulfonimidoyl) -7H-purin-8-one (Compound 1e) and N-methyl-N-propyl-carbamoyl chloride (Intermediate AA).

[315] Example 34-A (160 mg): 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.37-7.45 (m, 4H), 6.91 (br. S., 2H), 4.99 (s, 2H), 4.17 (s, 1H), 3.28-3.40 (m, 4H), 3.05 (s, 2H), 3.02 (s, 1H), 1 , 49-1.70 (m, 4H), 1.15-1.37 (m, 2H), 0.89-0.94 (m, 5H), 0.76 (t, J = 8 Hz, 1H ). Observed MS (ESI +) [(M + H) +]: 494.

[316] Example 34-B (167 mg) was prepared in a manner analogous to Example 34-A by the use of Compound 34e-B in place of Compound 34e-A.

[317] Example 34-B: 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.36- 7.45 (m, 4H), 6.91 (br., 2H), 4.99 ( s, 2H), 4.17 (s, 1H), 3.28-3.41 (m, 4H), 3.05 (s, 2H), 3.02 (s, 1H), 1.50-1 , 71 (m, 4H), 1.15-1.37 (m, 2H), 0.89-0.94 (m, 5H), 0.76 (t, J = 7.4 Hz, 1H). Observed MS (ESI +) [(M + H) +]: 494.

EXAMPLE 35 6-AMINO-9 - [(4-CHLOROPHENYL) METHIL] -N-ETHYL-N-METHYL-8-OXO-2- (PROPILSULFONIMIDOIL) PURINE-7-CARBOXAMIDE 35

[318] The title compound was prepared analogously to Example 1, Method A, Step 6 by using 6-amino-9 - [(4-chlorophenyl) methyl] -2- (propylsulfonimidoyl) -7H-purin-8- one (Compound 34e) and N-ethyl-N-methyl-carbamoyl chloride in place of 6-amino-9-benzyl-2- (propylsulfonimidoyl) -7H-purin-8-one (Compound 1e) and N- methyl-N-propyl-carbamoyl (Intermediate AA). 6- Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide (60 mg, Example 35) was obtained as a white solid . 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.40 (s, 4H), 6.91 (br s, 2H), 4.99 (s, 2H), 4.16 (s, 1H), 3.34 - 3.44 (m, 4H), 3.05 (s, 2H), 3.01 (s, 1H), 1.58-1.67 (m, 2H), 1.18 (t, J = 8.0 Hz, 3H), 0.92 (t, J = 8.0 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 466.

EXAMPLE 36-AE EXAMPLE 36-B 6-AMINO-N-METHYL-8-OXO-N-PROPIL-2 [S (S) -PROPILSULFONIMIDOIL] -9- (P-TOLYLMETHIL) PURINE -7-CARBOXAMIDE AND 6-AMINO -N-METHYL-8-OXO-N-PROPIL - 2 [S (R) -PROPILSULFONIMIDOIL] -9- (P -TOLYLMETHIL) PURINE-7-CARBOXAMIDE

STEP 1: P REPAIR OF 6-CHLORINE -5-NITRO-2-PROPYLSULPHANYL -N- (P - TOLYLMETHIL) PYRIMIDIN -4- AMINE (COMPOUND 36A) 36a

[319] Compound 36a was prepared in a manner analogous to Example 1, Method B, Step 1 by the use of p-tolylmethylamine in place of phenylmethanamine. 6-Chloro-5-nitro-2-propylsulfanyl-N- (p-tolylmethyl) pyrimidin-4-amine (3.9 g, Compound 36a) was obtained as a white solid. Observed MS (ESI +) [(M + H) +]: 353.

STEP 2: PREPARATION OF 6-CHLORINE-2-PROPYLSULPHANYL-N4- (P-TOLYLMETHIL) PYRIMIDIN-4,5-DIAMINE (COMPOUND 36B) 36b

[320] Compound 36b was prepared in a manner analogous to Example 1, Method B, Step 2 by the use of 6-chloro-5-nitro-2-propylsulfanyl-N-

(p-tolylmethyl) pyrimidin-4-amine (Compound 36a) in place of N-benzyl-6-chloro-5-nitro-2-propylsulfanyl-pyrimidin-4-amine (Compound 1f). 6-Chloro-2-propylsulfanyl-N4- (p-tolylmethyl) pyrimidine-4,5-diamine (2.2 g, Compound 36b) was obtained as a white solid. Observed MS (ESI +) [(M + H) +]: 323.

STEP 3: PREPARATION OF 6-CHLORINE-2-PROPYLSULPHANYL-9- (P-TOLYLMETHYL) -7H- PURIN-8-ONA (COMPOUND 36C) 36c

[321] Compound 36c was prepared analogously to Example 1, Method B, Step 3 by using 6-chloro-2-propylsulfanyl-N4- (p-tolylmethyl) pyrimidine-4,5-diamine (Compound 36b) in instead of N-benzyl-6-chloro-2- (propylsulfanyl) pyrimidine-4,5-diamine (Compound 1g). 6-Chloro-2-propylsulfanyl-9- (p-tolylmethyl) -7H-purin-8-one (2.2 g, Compound 36c) was obtained as a white solid. Observed MS (ESI +) [(M + H) +]: 349.

STEP 4: PREPARATION OF 6 - [(4-METOXYphenyl) METHYLAMINE] -2-PROPYLSULPHANYL-9- (P-TOLYLMETHIL) -7H-PURIN-8-ONA (36D COMPOUND) 36d

[322] Compound 36d was prepared analogously to Example 1, Method B, Step 4, using 6-chloro-2-propylsulfanyl-9- (p-tolylmethyl) -7H-purin-8-one (Compound 36c ) in place of 9-benzyl-6-chloro-2-propylsulfanyl-7H-purin-8-one (Compound 1h). 6 - [(4-methoxyphenyl) methylamino] -2-

propylsulfanyl-9- (p-tolylmethyl) -7H-purin-8-one (2.0 g, Compound 36d) was obtained as a white solid. Observed MS (ESI +) [(M + H) +]: 450.

STEP 5: PREPARATION OF 6-AMINO-2-PROPYLSULPHANYL-9- (P-TOLYLMETHIL) -7H-PURIN- 8-ONA (COMPOUND 36E) 36e

[323] Compound 36e was prepared analogously to Example 1, Method B, Step 5 by using 6 - [(4-methoxyphenyl) methylamino] -2-propylsulfanyl-9- (p-tolylmethyl) -7H-purin- 8-one (Compound 36d) in place of 6-amino-9-benzyl-2-propylsulfanyl-7H-purin-8-one (Compound 1i). 6-amino-2-propylsulfanyl-9- (p-tolylmethyl) -7H-purin-8-one (1.0 g, Compound 36e) was obtained as a white solid. Observed MS (ESI +) [(M + H) +]: 330.

STEP 6: PREPARATION OF 6-AMINO-2-PROPYLSULFINYL-9- (P-TOLYLMETHYL) -7H-PURIN- 8-ONA (36F COMPOUND) 36f

[324] Compound 36f was prepared analogously to Example 1, Method B, Step 6 by using 6-amino-2-propylsulfanyl-9- (p-tolylmethyl) -7H-purin-8-one (Compound 36e) in place of 6-amino-9-benzyl-2- (2-propylsulfanyl) -7H-purin-8-one (Compound 1c). 6-amino-2-propylsulfinyl-9- (p-tolylmethyl) -7H-purin-8-one (220 mg, Compound 36f) was obtained as an observed white solid MS (ESI +) [(M + H) +]: 345.

STEP 7: PREPARATION OF 6-AMINO-2- (PROPILSULFONIMIDOIL) -9- (P-TOLYLMETHY) -7H- PURIN-8-ONA (COMPOUND 36G) 36g

[325] Compound 36g was prepared analogously to Example 1, Method B, Step 7 by using 6-amino-2-propylsulfinyl-9- (p-tolylmethyl) -7H-purin-8-one (Compound 36f) in place of 6-amino-9-benzyl-2-propylsulfinyl-7H-purin-8-one (Compound 1d). 6-Amino-2- (propylsulfonimidoyl) -9- (p-tolylmethyl) -7H-purin-8-one (127 mg, Compound 36g) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.67 (br. S., 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8 , 0 Hz, 2H), 6.98 (br., 2H), 4.91 (s, 2H), 4.05 (s, 1H), 3.34-3.27 (m, 2H), 2.26 (s, 3H), 1.67-1.62 (m, 2H), 0.92 (t, J = 8.0 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 361.

[326] Separation of compound 36g by chiral HPLC gave compound 36g-A (fastest elution, 50 mg) and compound 36g-B (slowest elution, 49 mg) as a white solid with 30% isopropanol ( 0.05% DEA) / CO2 in ChiralPak AD-3 column.

[327] Compound 36g-A: 1H NMR: (400 MHz, DMSO-d6) δ ppm: 10.51 (s, 1 H), 7.22 (d, J = 8.0 Hz, 2H), 7, 12 (d, J = 8.0 Hz, 2H), 7.00 (s, 2 H), 4.91 (s, 2H), 4.03 (s, 1H), 3.35 - 3.31 ( m, 2H), 2.26 (s, 3H), 1.70 - 1.58 (m, 2H), 0.93 (t, J = 7.40 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 361.

[328] Compound 36g-B: 1H NMR: (400 MHz, DMSO-d6) δ ppm: 10.54 (s, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.97 (s, 2H), 4.91 (s, 2H), 4.04 (s, 1H), 3.34 - 3.30 (m, 2H), 2.26 (s, 3H), 1.72 - 1.57 (m, 2H),

0.93 (t, J = 7.40 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 361.

STEP 8: PREPARATION OF 6-AMINO-N-METHYL-8-OXO-N-PROPIL-2 [S (S) - PROPILSULFONIMIDOIL] -9- (P-TOLYLMETHYL) PURINE-7-CARBOXAMIDE AND 6-AMINO-N- METHYL-8-OXO-N-PROPIL-2 [S (R) -PROPYLSULFONIMIDOIL] -9- (P-TOLYLMETHY) PURINE-7-CARBOXAMIDE (EXAMPLE 36-AE EXAMPLE 36-B)

[329] Example 36-A was prepared analogously to Example 1, Method A, Step 6 by using Compound 36g-A in place of 6-amino-9-benzyl-2- (propylsulfonimidoyl) -7H-purin- 8-one (Compound 1e). Example 36-A (108 mg) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.27 (d, J = 8 Hz, 2H), 7.14 (d, J = 8 Hz, 2H), 6.87 (br. S., 2H), 4.95 (s, 2H), 4.15 (s, 1H), 3.33-3.57 (m, 4H), 3.05 (s, 2H), 3.02 (s, 1H ), 2.26 (s, 3H), 1.52-1.73 (m, 4H), 0.75-0.97 (m, 6H). Observed MS (ESI +) [(M + H) +]: 460.

[330] Example 36-B was prepared analogously to Example 1, Method A, Step 6 by using Compound 36g-B in place of 6-amino-9-benzyl-2- (propylsulfonimidoyl) -7H-purin- 8-one (compound 1e). Example 36-B (125 mg): 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.27 (d, J = 8 Hz, 2H), 7.14 (d, J = 8 Hz, 2H), 6.87 (br. S, 2H), 4.95 (s, 2H), 4.15 (s, 1H), 3.33-3.57 (m, 4H), 3.05 (s, 2H ), 3.02 (s, 1H), 2.26 (s, 3H), 1.52-1.73 (m, 4H), 0.75-0.97 (m, 5H). Observed MS (ESI +) [(M + H) +]: 460.

EXAMPLE 37-AE EXAMPLE 37-B 6-AMINO-2- [S (S) -PROPILSULFONIMIDOIL] -9- (P-TOLYLMETHYL) -7- (PIRROLIDINE-1-CARBONY) PURIN-8-ONA AND 6-AMINO- 2- [S (R) -PROPILSULFONIMIDOIL] -9- (P- TOLYLMETHIL) -7- (PIRROLIDINE-1-CARBONY) PURIN-8-ONA

[331] Example 37-A was prepared analogously to Example 1, Method A, Step 6 by using Compound 36g-A and pyrrolidine-1-carbonyl chloride in place of 6-amino-9-benzyl-2- (propylsulfonimidoyl) -7H-purin-8-one (Compound 1e) and N-methyl-N-propyl-carbamoyl chloride (Intermediate AA).

[332] Example 37-A (390 mg) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6)  ppm: 7.31 - 7.11 (m, 4H), 7.04 (s, 2H), 4.95 (s, 2H), 4.15 (s, 1H), 3.65 - 3.47 (m, 4H), 3.37 (m, 2H), 2.27 (s, 3H), 1.97 - 1.81 (m, 4H), 1.71 - 1.59 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 458.2.

[333] Example 37-B (125 mg) was prepared analogously to Example 37-A by using Compound 36g-B in place of Compound 36g-A. 1H NMR (400 MHz, DMSO-d6)  ppm: 7.28 - 7.14 (m, 4H), 7.04 (s, 2H), 4.95 (s, 2H), 4.15 (s, 1H), 3.65 - 3.47 (m, 4H), 3.37 (m, 2H), 2.27 (s, 3H), 1.93 - 1.84 (m, 4H), 1.65 - 1.60 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 458.3.

EXAMPLE 38-AE EXAMPLE 38-B 6-AMINO-N- (2-METOXYETHIL) -N-METHYL-8-OXO-2- [S (S) -PROPILSULFONIMIDOIL] -9- (P-TOLYLMETHYL) PURINE-7- CARBOXAMIDE AND 6-AMINO-N- (2-METOXYETHIL) -N-METHYL-8-OXO-2- [S (R) -PROPILSULFONIMIDOIL] -9- (P-TOLYLMETHIL) PURINE-7-CARBOXAMIDE

[334] Example 38-A was prepared analogously to Example 1, Method A, Step 6 by using Compound 36g-A and N- (2-methoxyethyl) -N-methyl-carbamoyl chloride (Intermediate AB) in place of 6-amino-9-benzyl- 2- (propylsulfonimidoyl) -7H-purin-8-one (Compound 1e) and N-methyl-N-propyl-carbamoyl chloride (Intermediate AA).

[335] Example 38-A (57.8 mg) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6)  ppm: 7.26 (d, J = 7.6 Hz, 2H), 7.14 (d, J = 7.6 Hz, 2H), 6.89 - 6 , 78 (m, 2H), 4.95 (s, 2H), 4.18 (s, 1H), 3.62 -3.58 (m, 2H), 3.43 - 3.37 (m, 2H ), 3.30 - 3.10 (m, 3H), 3.09 - 3.08 (m, 3H), 3.08 - 3.05 (m, 2H), 2.27 (s, 3H), 1.77 - 1.54 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 476.3.

[336] Example 38-B (46.6 mg) was prepared in a similar manner to Example 38-A by using Compound 36g-B in place of Compound 36g-A. 1H NMR (400 MHz, DMSO-d6)  ppm: 7.26 (d, J = 7.6 Hz, 2H), 7.14 (d, J = 7.6 Hz, 2H), 6.89 - 6 , 78 (m, 2H), 4.95 (s, 2H), 4.18 (s, 1H), 3.62 -3.58 (m, 2H), 3.43 - 3.37 (m, 2H ), 3.30 - 3.10 (m, 3H), 3.09 - 3.08 (m, 3H), 3.08 - 3.05 (m,

2H), 2.27 (s, 3H), 1.77 - 1.54 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 476.3.

EXAMPLE 39 6-AMINO-N-ETHYL-N-METHYL-8-OXO-2- (PROPILSULFONIMIDOIL) -9- (P-TOLYLMETHY) PURINE-7-CARBOXAMIDE 39

[337] The title compound was prepared analogously to Example 1, Method A, Step 6 using N-ethyl-N-methyl-carbamoyl chloride and 6- amino-2- (propylsulfonimidoyl) -9- (p- tolylmethyl) -7H-purin-8-one (Compound 36g) in place of N-methyl-N-propyl-carbamoyl chloride (Intermediate AA) and 6-amino-9-benzyl-2- (propylsulfonimidoyl) -7H-purin -8-one (Compound 1e). 6-Amino-N-ethyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) -9- (p-tolylmethyl) purine-7-carboxamide (141.8 mg, Example 39) was obtained as a light yellow solid . 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.26 (d, J = 7.9 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 6.89 (s , 2H), 4.95 (s, 2H), 4.24 - 4.07 (m, 1H), 3.52 - 3.35 (m, 4H), 3.10 - 2.95 (m, 3H ), 2.26 (s, 3H), 1.77 - 1.55 (m, 2H), 1.24 - 1.10 (m, 3H), 0.95 (t, J = 7.4 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 446.1.

EXAMPLE 40 6-AMINO-N-BUTYL-N-METHYL-8-OXO-2- (PROPYLSULFONIMIDOIL) -9- (P-TOLYLMETHY) PURINE-7-CARBOXAMIDE

[338] The title compound was prepared analogously to Example 1, Method A, Step 6 by using 6-amino-2- (propylsulfonimidoyl) -9- (p-tolylmethyl) -7H-purin-8-one (Compound 36g) and N-butyl-N-methyl-carbamoyl chloride in place of 6-amino-9-benzyl-2- (propylsulfonimidoyl) -7H-purin-8-one (Compound 1e) and N-methyl-N chloride -propyl carbamoyl (Intermediate AA). 6- Amino-N-butyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) -9- (p-tolylmethyl) purine-7-carboxamide (32 mg, Example 40) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6)  ppm: 7.28 - 7.14 (m, 4H), 6.88 (s, 2H), 4.95 (s, 2H), 4.16 (s, 1H), 3.41 - 3.36 (m, 2H), 3.10 - 2.99 (m, 3H), 2.53 - 2.51 (m, 2H), 2.27 (s, 3H) , 1.71 - 1.63 (m, 2H), 1.62 - 1.51 (m, 2H), 1.42 - 1.26 (m, 2H), 0.97 - 0.74 (m, 6H). Observed MS (ESI +) [(M + H) +]: 474.3.

EXAMPLE 41-AE EXAMPLE 41-B 6-AMINO-9 - [(4-CHLOROPHENYL) METHIL] -2- [S (R) -ETHYLSULFONIMIDOIL] -N-METHYL-8-OXO-N-PROPYL-PURINE-7- CARBOXAMIDE (EXAMPLE 41-A) AND 6-AMINO-9 - [(4-CHLOROPHENYL) METHIL] -2- [S (S) -ETHYLSULFONIMIDOIL] -N-METHYL-8-OXO-N-PROPIL-PURINE- 7- CARBOXAMIDE (EXAMPLE 41-B) 41-A 41-B

STEP 1: PREPARATION OF 6-AMINO-9 - [(4-CHLOROPHENYL) METHIL] -2-ETHYLSULPHANYL-7H- PURIN-8-ONA (COMPOUND 41A) 41a

[339] Compound 41a was prepared analogously to Example 1, Method A, Step 3 using iodoethane and 6-amino-9 - [(4-chlorophenyl) methyl] -2-sulfanyl-7H-purin-8- one (Compound 34b) in place of bromopropane and 6-amino-9-phenylmethyl-2-sulfanyl-7H-purin-8-one (Compound 1b).

6-Amino-9 - [(4-chlorophenyl) methyl] -2-ethylsulfanyl-7H-purin-8-one (2.5 g, Compound 41a) was obtained as a white solid. Observed MS (ESI +) [(M + H) +]: 336.

STEP 2: PREPARATION OF 6-AMINO-9- (4-CHLOROBENZYL) -2-ETHYLSULFINYL-7H-PURIN- 8-ONA (COMPOUND 41B) 41b

[340] Compound 41b was prepared analogously to Example 1, Method A, Step 4 by using 6-amino-9 - [(4-chlorophenyl) methyl] -2-ethylsulfanyl-7H-purin-8-one ( Compound 41a) in place of 6-amino-9-benzyl-2-propylsulfanyl-7H-purin-8-one (Compound 1c). 6-Amino-9- (4-chlorobenzyl) -2-ethylsulfinyl-7H-purin-8-one (1.94 g, Compound 41b) was obtained as a white solid. Observed MS (ESI +) [(M + H) +]: 352.

STEP 3: PREPARATION OF 6-AMINO-9 - [(4-CHLOROPHENYL) METHIL] -2- (ETHYLSULFONIMIDOIL) -7H-PURIN-8-ONA (COMPOUND 41C) 41c

[341] Compound 41c was prepared analogously to Example 1, Method A, Step 5 by using 6-amino-9- (4-chlorobenzyl) -2-ethylsulfinyl-7H-purin-8-one (Compound 41b) in place of 6-amino-9-benzyl-2- (2-methylsulfinyl) -7H-purin-8-one (Compound 1d). 6-Amino-9 - [(4-chlorophenyl) methyl] -2- (ethylsulfonimidoyl) -7H-purin-8-one (217 mg, Example 41c) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d 6)  ppm: 10.61 (s, 1H), 7.42 - 7.35 (m, 4H), 6.98 (s, 2H), 4.96 (s , 2H), 4.05 (s, 1H), 3.42 - 3.37 (m, 2H), 1.16 (t, J = 7.4 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 367.0.

[342] Compound separation of Compound 41c by chiral HPLC provided Compound 41c-A (fastest elution, 31.8 mg) and Compound 41c-B (slowest elution, 10 mg) as a white solid with methanol 5% -40% (0.05% DEA) / CO 2 in a ChiralPak IC-3 column.

41c-A

[343] Compound 41c-A: 1H NMR (400 MHz, DMSO-d 6)  ppm: 10.76 (s, 1H), 7.45 - 7.33 (m, 4H), 7.01 (s, 2H), 4.96 (s, 2H), 4.03 (s, 1H), 3.40 - 3.34 (m, 2H), 1.17 (t, J = 7.4 Hz, 3H). Observed MS (ESI +) [(M + H) +]:

367.0.

41c-B

[344] Compound 41c-B: 1H NMR (400 MHz, DMSO-d6)  ppm: 10.70 (s, 1H), 7.46 -7.28 (m, 4H), 7.01 (s, 2H ), 4.96 (s, 2H), 4.03 (s, 1H), 3.44 - 3.36 (m, 2H), 1.17 (t, J = 7.4 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 367.0.

STEP 4: 6-AMINO-9 - [(4-CHLOROPHENYL) METHIL] -2- [S (R) -ETHYLSULFONIMIDOIL] -N-METHYL-8-OXO-N-PROPYL-PURINE-7-CARBOXAMIDE (EXAMPLE 41- A) E 6-AMINO-9 - [(4-CHLOROPHENYL) METHIL] -2- [S (S) -ETHYLSULFONIMIDOIL] -N-METHYL-8-OXO-N-PROPYL-PURINY-7-CARBOXAMIDE (EXAMPLE 41- B) 41-A 41-B

[345] Example 41-A was prepared analogously to Example 1, Method A, Step 6 by using Compound 41c-B in place of 6-amino-9-benzyl-2- (propylsulfonimidoyl) -7H-purin-8 -one (Compound 1e). 6-Amino- 9 - [(4-chlorophenyl) methyl] -2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide (Example 41-A, 78 mg) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6)  ppm: 7.43 - 7.41 (m, 4H), 6.90 (s, 2H), 5.00 (s, 2H), 4.19 (s, 1H), 3.46-3.39 (m, 2H), 3.39 - 3.38 (m, 2H), 3.09-2.99 (m, 3H), 1.69 - 1.52 ( m, 2H), 1.19 (t, J = 7.28 Hz, 3H), 0.95 - 0.66 (m, 3H). Observed MS (ESI +) [(M + H) +]: 466.1.

[346] Example 41-B (125 mg) was prepared in a manner analogous to Example 1, Method A, Step 6 by using Compound 41c-A in place of 6-amino-9-benzyl-2- (propylsulfonimidoyl) - 7H-purin-8-one (Compound 1e).

6-Amino-9 - [(4-chlorophenyl) methyl] -2- [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide (Example 41-B, 38 mg) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6)  ppm: 7.43 - 7.41 (m, 4H), 6.90 (s, 2H), 5.00 (s, 2H), 4.20 (s, 1H), 3.46 - 3.41 (m, 2H), 3.40 - 3.39 (m, 2H), 3.10 - 3.00 (m, 3H), 1.69 - 1.50 ( m, 2H), 1.24 - 1.12 (m, 3H), 0.93 - 0.73 (m, 3H). (Observed MS (ESI +) [(M + H) +]: 466.2.

[347] The stereochemistry of Example 41-B was determined by single crystal X-ray diffraction shown in Figure 1.

EXAMPLE 42-AE EXAMPLE 42-B 6-AMINO-9 - [(4-CHLOROPHENYL) METHIL] -N-ETHYL-2 [S (S) -ETHYLSULFONIMIDOIL] -N-METHYL-8-OXO-PURINE-7-CARBOXAMIDE (EXAMPLE 42-A) E 6-AMINO-9 - [(4-CHLOROPHENYL) METHIL] -N-ETHYL-2- [S (R) -ETHYLSULFONIMIDOIL] -N-METHYL-8-OXO-PURINE-7-CARBOXAMIDE (EXAMPLE 42-B) 42-A 42-B

[348] Example 42-A was prepared analogously to Example 1, Method A, step 6 by using Compound 41c-A and N-ethyl-N-methyl-carbamoyl chloride in place of 6-amino-9- benzyl-2- (propylsulfonimidoyl) -7H-purin-8-one (Compound 1e) and N-methyl-N-propyl-carbamoyl chloride (Intermediate AA). 6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] - N-methyl-8-oxo-purine-7-carboxamide (Example 42-A, 40 mg ) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6)  ppm: 7.43 - 7.41 (m, 4H), 6.90 (s, 2H), 4.99 (s, 2H), 4.18 (s, 1H), 3.48 - 3.40 (m, 2H), 3.39 (s, 2H), 3.05 - 3.01 (m, 3H), 1.20 - 1.14 (m, 6H) . Observed MS (ESI +) [(M + H) +]: 452.2.

[349] Example 42-B was prepared analogously to Example 1, Method A, Step 6 by using Compound 41c-B and N-ethyl-N-methyl-carbamoyl chloride in place of 6-amino-9- benzyl-2- (propylsulfonimidoyl) -7H-purin-8-one (Compound 1e) and N-methyl-N-propyl-carbamoyl chloride (Intermediate AA). 6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide (Example 42-B, 38 mg) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6)  ppm: 7.43 - 7.41 (m, 4H), 6.91 (s, 2H), 4.98 (s, 2H), 4.19 (s, 1H), 3.48 - 3.40 (m, 2H), 3.39 (s, 2H), 3.09 - 2.97 (m, 3H), 1.23 - 1.11 (m, 6H) . Observed MS (ESI +) [(M + H) +]: 452.2.

[350] The stereochemistry of Example 42-A was determined by single crystal X-ray diffraction shown in Figure 2.

EXAMPLE 43-AE EXAMPLE 43-B 6-AMINO-2- [S (R) -ETHYLSULFONIMIDOIL] -N-METHYL-8-OXO-N-PROPIL-9- (P-TOLYLMETHIL) PURINE-7-CARBOXAMIDE (EXAMPLE 43 -A) AND 6-AMINO-2- [S (S) - ETHYLSULFONIMIDOIL] -N-METHYL-8-OXO-N-PROPIL-9- (P-TOLYLMETHIL) PURINE-7- CARBOXAMIDE (EXAMPLE 43-B) 43 -A 43-B

STEP 1: PREPARATION OF 4-AMINO-2-OXO-3- (P-TOLYLMETHIL) -1H-IMIDAZOLE-5-CARBONITRILLA (COMPOUND 43A)

[351] Compound 43a was prepared analogously to Example 1, Method A, Step 1 by using benzyl 4-methylisocyanate in place of benzyl isocyanate. 4-Amino-2-oxo-3- (p-tolylmethyl) -1H-imidazole-5-carbonitrile (26.6 g, Compound 43a) was obtained as a gray solid and used directly in the next step without further purification. Observed MS (ESI +) [(M + H) +]: 229.2.

STEP 2: PREPARATION OF 6-AMINO-9- (P-TOLYLMETHIL) -2-SULFANIL-7H-PURIN-8-ONA (COMPOUND 43B) 43b

[352] Compound 43b was prepared in a manner analogous to Example 1, Method A, Step 2 by using 4-amino-2-oxo-3- (p-tolylmethyl) -1H-imidazole-5-carbonitrile (compound 43a) in place of 4-amino-3-benzyl-2-oxo-1H-imidazole-5-carbonitrile (Compound 1a). 6-Amino-9- (p-tolylmethyl) -2-sulfanyl-7H-purin-8-one (20.0 g, Compound 43b) was obtained as a yellow solid. Observed MS (ESI +) [(M + H) +]: 288.

STEP 3: PREPARATION OF 6-AMINO-2-ETHYLSULPHANYL-9- (P-TOLYLMETHIL) -7H-PURIN-8- ONA (COMPOUND 43C) 43c

[353] Compound 43c was prepared in a manner analogous to Example 1, Method A, Step 3 by using 6-amino-9- (p-tolylmethyl) -2-sulfanyl-7H-purin-8-one (Compound 43b) and iodoethane in place of 6-amino-9-benzyl-2-sulfanyl-7H-purin-8-one (Compound 1b) and bromopropane. 6-Amino-2-ethylsulfanyl-9- (p-tolylmethyl) -7H-purin-8-one (13 g, Compound 43c) was obtained as a yellow solid. Observed MS (ESI +) [(M + H) +]: 316.

STEP 4: PREPARATION OF 6-AMINO-2-ETHYLSULPHINYL-9- (P-TOLYLMETHYL) -7H-PURIN-8- ONA (COMPOUND 43D) 43d

[354] Compound 43d was prepared analogously to Example 1, Method A, Step 4 by using 6-amino-2-ethylsulfanyl-9- (p-tolylmethyl) - 7H-purin-8-one (Compound 43c) in place of 6-amino-9-benzyl-2-methylsulfanyl-7H-purin-8-one (Compound 1c). 6-Amino-2-ethylsulfinyl-9- (p-tolylmethyl) -7H-purin-8-one6 (3.5 g, Compound 43d) was obtained as a yellow solid. Observed MS (ESI +) [(M + H) +]: 332.

STEP 5: PREPARATION OF 6-AMINO-2- (ETHYLSULFONIMIDOIL) -9- (P-TOLYLMETHY) -7H- PURIN-8-ONA (COMPOUND 43E) 43e

[355] Compound 43e was prepared analogously to Example 1, Method A, Step 5 by using 6-amino-2-ethylsulfinyl-9- (p-tolylmethyl) - 7H-purin-8-one (Compound 43d) in place of 6-amino-9-benzyl-2-methylsulfinyl-7H-purin-8-one (Compound 1d). 6-Amino-2- (ethylsulfonimidoyl) -9- (p-tolylmethyl) -7H-purin-8-one (530 mg, Compound 43e) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6)  ppm: 10.53 (s, 1H), 7.24 (d, J = 8.03 Hz, 2H), 7.13 (d, J = 8.03 Hz , 2H), 6.94 (br., 2H), 4.91 (s, 2H), 4.03 (s, 1H), 3.36 - 3.41 (m, 2H), 2.26 (s, 3H), 1.18 (t, J = 7.28 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 347.

[356] Compound separation of Compound 43e by chiral HPLC provided Compound 43e-A (fastest elution, 56.8 mg) and Compound 43e-B (slowest elution, 56.7 mg) as a white solid with 5% -40% methanol (0.05% DEA) / CO2 on a ChiralPak AD-3 column.

43e-A

[357] Compound 43e-A: 1H NMR (400 MHz, DMSO-d6)  ppm: 10.52 (br. S., 1H), 7.23 (d, J = 8.0 Hz, 2H), 7 , 13 (d, J = 7.9 Hz, 2H), 6.94 (br. S, 2H), 4.90 (s, 2H), 4.03 (s, 1H), 3.42 - 3 , 33 (m, 2H), 2.25 (s, 3H), 1.17 (t, J = 7.3 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 347.

43e-B

[358] Compound 43e-B: 1H NMR (400 MHz, DMSO-d6)  ppm: 10.56 (br. S., 1H), 7.23 (d, J = 8.0 Hz, 2H), 7 , 13 (d, J = 8.0 Hz, 2H), 6.95 (br. S, 2H), 4.90 (s, 2H) 4.03 (s, 1H), 3.44 - 3, 29 (m, 2H), 2.25 (s, 3H), 1.17 (t, J = 7.3 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 347.

STEP 6: PREPARATION OF 6-AMINO-2- [S (R) -ETHYLSULFONIMIDOIL] -N-METHYL-8-OXO-N-PROPIL-9- (P-TOLYLMETHY) PURINE-7-CARBOXAMIDE (EXAMPLE 43-A) E 6-AMINO-2- [S (S) -ETHYLSULFONIMIDOIL] -N-METHYL-8-OXO-N-PROPIL-9- (P-TOLYLMETHIL) PURINE-7-CARBOXAMIDE (EXAMPLE 43-B) 43-A 43 -B

[359] Example 43-A was prepared analogously to Example 1, Method A, Step 6 by using Compound 43e-A in place of 6-amino-9-benzyl-2- (propylsulfonimidoyl) -7H-purin- 8-one (Compound 1e). 6- Amino-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide (Example 43-A, 58.1 mg, faster elution, isopropanol from 5% to 40% (0.05% DEA) / CO 2 on ChiralPak AD-3 column) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.28 (d, J = 7.8 Hz, 2H), 7.15 (d, J = 7.8 Hz, 2H), 6.88 (br . s., 2H), 5.03 - 4.87 (m, 2H), 4.19 (s, 1H), 3.61 - 3.36 (m, 4H), 3.11 - 2.96 ( m, 3H), 2.26 (s, 3H), 1.72 -

1.45 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H), 0.97 - 0.65 (m, 3H). Observed MS (ESI +) [(M + H) +]: 446.

[360] Example 43-B was prepared analogously to Example 1, Method A, Step 6 by using Compound 43e-B in place of 6-amino-9-benzyl-2- (propylsulfonimidoyl) -7H-purin- 8-one (Compound 1e). 6- Amino-2- [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide (Example 43-B, 40.1 mg, slower elution, isopropanol from 5% to 40% (0.05% DEA) / CO 2 on a ChiralPak AD-3 column was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.28 (d, J = 7.5 Hz, 2H), 7.15 (d, J = 7.5 Hz, 2H), 6.89 (br., 2H), 5.03 - 4, 86 (m, 2H), 4.19 (s, 1H), 3.49 - 3.37 (m, 4H), 3.08 - 3.00 (m, 3H), 2.27 (s, 3H) , 1.70 - 1.48 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H), 0.95 - 0.71 (m, 3H). Observed MS (ESI +) [(M + H) +]: 446.3.

[361] The stereochemistry of Example 43-B was determined by single crystal X-ray diffraction shown in Figure 3.

EXAMPLE 44-AE EXAMPLE 44-B 6-AMINO-N-ETHYL-2 [S (S) -ETHYLSULFONIMIDOIL] -N-METHYL-8-OXO-9- (P-TOLYLMETHIL) PURINE-7-CARBOXAMIDE (EXAMPLE 44- A) E 6-AMINO-N-ETYL-2- [S (R) -ETHYLSULFONIMIDOIL] -N-METHYL-8-OXO-9- (P-TOLYLMETHY) PURINE-7- CARBOXAMIDE (EXAMPLE 44-B) 44- A 44-B

[362] Example 44-A was prepared analogously to Example 1, Method A, Step 6 by using Compound 43e-B and N-

ethyl-N-methyl-carbamoyl in place of 6-amino-9-benzyl-2- (propylsulfonimidoyl) - 7H-purin-8-one (Compound 1e) and N-methyl-N-propyl-carbamoyl chloride (Intermediate AA ). 6-Amino-N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide (Example 44-A, 73.1 mg) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.28 (d, J = 7.8 Hz, 2H), 7.15 (d, J = 7.8 Hz, 2H), 6.90 (br . s., 2H), 4.95 (s, 2H), 4.19 (br., 1H), 3.48 - 3.39 (m, 4H), 3.06 - 3.00 (m , 3H), 2.27 (s, 3H), 1.29 - 1.04 (m, 6H).

Observed MS (ESI +) [(M + H) +]: 432.

[363] Example 44-B was prepared analogously to Example 1, Method A, Step 6 by using Compound 43e-A and N-ethyl-N-methyl-carbamoyl chloride in place of 6-amino-9- benzyl-2- (propylsulfonimidoyl) - 7H-purin-8-one (Compound 1e) and N-methyl-N-propyl-carbamoyl chloride (Intermediate AA). 6-Amino-N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide (Example 44-B, 46.7 mg) was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.28 (d, J = 7.9 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H ), 6.90 (br., 2H), 4.95 (s, 2H), 4.19 (br., 1H), 3.50 - 3.39 (m, 4H), 3, 10 - 2.96 (m, 3H), 2.27 (s, 3H), 1.27 - 1.10 (m, 6H).

Observed MS (ESI +) [(M + H) +]: 432.

EXAMPLE 45-AE EXAMPLE 45-B 6-AMINO-2- [S (R) ETHYLSULFONIMIDOIL] -9 - [(4-FLUOROFENYL) METHIL] -N-METHYL-8-OXO- N-PROPYL-PURINE-7-CARBOXAMIDE E 6-AMINO-2- [S (S) ETHYLSULFONIMIDOIL] -9 - [(4-FLUOROFENYL) METHIL] -N-METHYL-8-OXO-N-PROPIL-PURINE-7-CARBOXAMIDE

STEP 1: PREPARATION OF 4-AMINO-3 - [(4-FLUOROFENYL) METHIL] -2-OXO-1H- IMIDAZOL-5-CARBONITRILLA (COMPOUND 45A) 45a

[364] Compound 45a was prepared in a manner analogous to Example 1, Method A, Step 1 by using benzyl 4-fluoroisocyanate in place of benzyl isocyanate. 4-Amino-3 - [(4-fluorophenyl) methyl] -2-oxo-1H-imidazole-5-carbonitrile (48 g, Compound 45a) was obtained as a light yellow solid and was used directly in the next step without further purification . Observed MS (ESI +) [(M + H) +]: 233.

STEP 2: PREPARATION OF 6-AMINO-9 - [(4-FLUOROFENYL) METHIL] -2-SULFANIL-7H- PURIN-8-ONA (COMPOUND 45B) 45b

[365] Compound 45b was prepared analogously to Example 1, Method A, Step 2 by using 4-amino-3 - [(4-fluorophenyl) methyl] -2-oxo-1H-imidazole-5-carbonitrile ( Compound 45a) in place of 4-amino-3-phenylmethyl-2-oxo-1H-imidazole-5-carbonitrile (Compound 1a). 6-Amino-9 - [(4-fluorophenyl) methyl] -2-sulfanyl-7H-purin-8-one (32.0 g, Compound 45b) was obtained as a yellow solid. Observed MS (ESI +) [(M + H) +]: 292.

STEP 3: PREPARATION OF 6-AMINO-2-ETHYLSULPHANYL-9 - [(4-FLUOROFENYL) METHIL] - 7H-PURIN-8-ONA (COMPOUND 45C) 45c

[366] Compound 45c was prepared in a manner analogous to Example 1, Method A, Step 3 using 6-amino-9 - [(4-fluorophenyl) methyl] -2-sulfanyl-7H-purin-8-one ( Compound 45b) and iodoethane in place of 6-amino-9-benzyl-2-sulfanyl-7H-purin-8-one (Compound 1b) and bromopropane. 6-Amino-2-ethylsulfanyl-9 - [(4-fluorophenyl) methyl] -7H-purin-8-one (5.6 g, Compound 45c) was obtained as a yellow solid. Observed MS (ESI +) [(M + H) +]: 320.

STEP 5: PREPARATION OF 6-AMINO-2-ETHYLSULFINYL-9 - [(4-FLUOROFENYL) METHIL] - 7H-PURIN-8-ONA (COMPOUND 45D) 45d

[367] Compound 45d was prepared in a manner analogous to Example 1, Method A, Step 4 using 6-amino-2-ethylsulfanyl-9 - [(4-fluorophenyl) methyl] -7H-purin-8-one ( Compound 45c) in place of 6-amino-9-benzyl-2-propylsulfanyl-7H-purin-8-one (Compound 1c). 6-Amino-2-ethylsulfinyl-9- [(4-fluorophenyl) methyl] -7H-purin-8-one (4.8 g, Compound 45d) was obtained as a yellow solid. Observed MS (ESI +) [(M + H) +]: 332.

STEP 6: PREPARATION OF 6-AMINO-2- (ETHYLSULFONIMIDOIL) -9 - [(4-FLUOROFENYL) METHIL] -7H-PURIN-8-ONA (45E COMPOUND) 45e

[368] Compound 45e was prepared analogously to Example 1, Method A, Step 5 by using 6-amino-2-ethylsulfinyl-9 - [(4-fluorophenyl) methyl] -7H-purin-8-one ( Compound 45d) in place of 6-amino-9-benzyl-2-propylsulfinyl-7H-purin-8-one (Compound 1d). 6-Amino-2- (ethylsulfonimidoyl) -9 - [(4-fluorophenyl) methyl] -7H-purin-8-one (2.9 g, Compound 45e) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.57 (br. S., 1H), 7.40 (dd, J = 8.5, 5.5 Hz, 2H), 7.16 (t , J = 8.9 Hz, 2H), 6.97 (br. S, 2H), 4.94 (s, 2H), 4.07 (s, 1H), 3.43 - 3.36 (m , 2H), 1.17 (t, J = 7.4 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 351.

[369] Compound separation of Compound 45e by chiral HPLC provided Compound 45e-A (fastest elution, 85.4 mg) and Compound 45e-B (slowest elution, 36.4 mg) as a white solid with 5% -40% methanol (0.05% DEA) / CO2 on a ChiralPak AD-3 column.

[370] Compound 45e-A: 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.53 (br. S., 1H), 7.41 (dd, J = 8.5, 5.5 Hz, 2H), 7.17 (t, J = 8.9 Hz, 2H), 6.98 (br. S., 2H), 4.95 (s, 2H), 4.07 (s, 1H), 3 , 45 - 3.36 (m, 2H), 1.17 (t, J = 7.3 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 351.

[371] Compound 45e-B: 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.53 (br. S., 1H), 7.41 (dd, J = 8.5, 5.5 Hz, 2H), 7.17 (t, J = 8.9 Hz, 2H), 6.98 (br. S., 2H), 4.95 (s, 2H), 4.07 (s, 1H), 3 , 44 - 3.37 (m, 2H) 1.17 (t, J = 7.3 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 351.

STEP 7: PREPARATION OF 6-AMINO-2- (ETHYLSULFONIMIDOIL) -9 - [(4-FLUOROFENYL) METHIL] -N-METHYL-8-OXO-N-PROPYL-PURINE-7-CARBOXAMIDE (EXAMPLE 45), 6- AMINO-2- [S (R) ETILSULFONIMIDOIL] -9 - [(4-FLUOROFENIL) METIL] - N-METHYL-8-OXO-N-PROPIL-PURINE-7-CARBOXAMIDE AND 6-AMINO-2- [S ( S) ETHYLSULFONIMIDOIL] -9 - [(4-FLUOROFENYL) METHIL] -N-METHYL-8-OXO-N-PROPIL-PURINE-7-CARBOXAMIDE (EXAMPLE 45-AE EXAMPLE 45-B).

(Example 45) (EXAMPLE 45-A AND EXAMPLE 45-B)

[372] Example 45 was prepared analogously to Example 1, Method A, Step 6 by using 6-amino-2- (ethylsulfonimidoyl) -9- [(4-fluorophenyl) methyl] -7H-purin-8- one (Compound 45e) in place of 6-amino-9-benzyl-2- (propylsulfonimidoyl) -7H-purin-8-one (Compound 1e). 6-Amino-2- (ethylsulfonimidoyl) -9 - [(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide (162.4 mg, Example 45) was obtained as a white solid.

[373] Separation of the compound of Example 45 by chiral HPLC provided Example 45-A (fastest elution, 85.3 mg) and Example 45-B (slowest elution, 52 mg) as a white solid with methanol 5% -40% (0.05% DEA) / CO2 in ChiralPak AD-3 column.

[374] Example 45-A: 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.53 - 7.38 (m, 2H), 7.18 (t, J = 8.9 Hz, 2H), 6.90 (br., 2H), 4.99 (s, 2H), 4.21 (s, 1H), 3.48 - 3.37 (m, 4H), 3.10 - 3.01 (m, 3H), 1.69 - 1.49 (m, 2H), 1.25 - 1.14 (m, 3H), 0.94 - 0.72 (m, 3H). Observed MS (ESI +) [(M + H) +]: 450.

[375] Example 45-B: 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.54 - 7.38 (m, 2H), 7.18 (t, J = 8.9 Hz, 2H), 7.01 - 6.72 (m, 2H), 4.99 (s, 2H), 4.21 (s, 1H), 3.46 - 3.38 (m, 4H), 3.10 - 3, 01 (m, 3H), 1.76 - 1.50 (m, 2H), 1.25 - 1.16 (m, 3H), 0.99 - 0.69 (m, 3H). Observed MS (ESI +) [(M + H) +]: 450.

EXAMPLE 46-AE EXAMPLE 46-B 6-AMINO-N-ETHYL 2- (ETHYLSULFONIMIDOIL) -9 - [(4-FLUOROFENYL) METHIL] -N-METHYL-8- OXO-PURINE -7-CARBOXAMIDE (EXAMPLE 46) , 6-AMINO-N-ETHYL 2- [S (S) - (ETHYLSULFONIMIDOIL)] - 9 - [(4-FLUOROFENYL) METHIL] -N-METHYL-8-OXO-PURINE-7-CARBOXAMIDE AND 6-AMINO -N-ETHYL-2- [S (R) - (ETHYLSULFONIMIDOIL)] - 9 - [(4-FLUOROFENYL) METHIL] -N-METHYL-8-OXO-PURINE-7-CARBOXAMIDE (EXAMPLE 46-AE EXAMPLE 46- B).

(Example 46)

(EXAMPLE 46-A AND EXAMPLE 46-B)

[376] Example 46 was prepared analogously to Example 1, Method A, Step 6 by using 6-amino-2- (ethylsulfonimidoyl) -9 - [(4-fluorophenyl) methyl] - 7H-purin-8- one (Compound 45e) and N-ethyl-N-methyl carbamoyl chloride in place of 6-amino-9-benzyl-2- (propylsulfonimidoyl) -7H-purin-8-one (Compound 1e) and N-methyl chloride -N-propyl-carbamoyl (Intermediate AA). 6-Amino-N-ethyl-2- (ethylsulfonimidoyl) -9- [(4-fluorophenyl) methyl] -N-methyl-8-oxo-purine-7-carboxamide (51 mg, Example 46) was obtained as a solid White. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.46 - 7.43 (m, 2H), 7.20-7.15 (m, 2H), 6.90 (br. S., 2H) , 4.98 (s, 2H), 4.18 (s, 1H), 3.47 - 3.32 (m, 4H), 3.05 - 3.01 (m, 3H), 1.21 - 1 , 14 (m, 6H). Observed MS (ESI +) [(M + H) +]: 436.

[377] Separation of the compound of Example 46 by chiral HPLC provided Example 46-A (fastest elution, 72 mg) and Example 46-B (slowest elution, 45 mg) as a white solid with 5% methanol -40% (0.05% DEA) / CO2 in ChiralPak AD-3 column.

[378] Example 46-A: 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.46 - 7.43 (m, 2H), 7.20-7.16 (m, 2H), 6.90 (br. s, 2H), 4.98 (s, 2H), 4.18 (s, 1H), 3.47 - 3.32 (m, 4H), 3.05 - 3.01 (m, 3H), 1.21 - 1.14 (m, 6H). Observed MS (ESI +) [(M + H) +]:

436.

[379] Example 46-B: 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.46 - 7.43 (m, 2H), 7.20-7.14 (m, 2H), 6.92 (br., 2H), 4.98 (s, 2H), 4.20 (br. s., 1H), 3.47 - 3.32 (m, 4H), 3.05 - 3.01 (m, 3H), 1.23 - 1.19 (m, 6H). Observed MS (ESI +) [(M + H) +]: 436.

EXAMPLE 47-AE EXAMPLE 47-B 6-AMINO-9 - [(4-BROMOPHENYL) METHIL] -2- (ETHYLSULFONIMIDOIL) -N-METHYL-8-OXO-N-PROPYL-PURINE-7-CARBOXAMIDE (EXAMPLE 47) , 6-AMINO-2- [S (R) - ETHYLSULFONIMIDOIL] -9 - [(4-BROMOPHENYL) METHIL] -N-METHYL-8-OXO-N-PROPYL-PURINE - 7-CARBOXAMIDE AND 6-AMINO-2 - [S (S) -ETHYLSULFONIMIDOIL] -9 - [(4-BROMOPHYL) METHIL] -N-METHYL-8-OXO-N-PROPYL-PURINE -7-CARBOXAMIDE

(Example 47) (Example 47-A and Example 47-B) STEP 1: PREPARATION OF 4-AMINO-3 - [(4-BROMOPHENYL) METHIL] -2-OXO-1H-IMIDAZOL-5-CARBONITRIL (COMPOUND 47A) 47a

[380] Compound 47a was prepared in a manner analogous to Example 1, Method A, Step 1 by the use of benzyl 4-bromoisocyanate in place of benzyl isocyanate. 4-Amino-3 - [(4-bromophenyl) methyl] -2-oxo-1H-imidazole-5-carbonitrile (500 mg, Compound 47a) was obtained as a light yellow solid and was used directly in the next step without further purification . 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.94 (S, 1H), 7.55-7.53 (d, J

= 8.0 Hz, 2H), 7.20-7.18 (d, J = 8.0 Hz, 2H), 6.52 (br. S., 2H), 4.74 (s, 2H).

Observed MS (ESI +) [(M + H) +]: 293.

STEP 2: PREPARATION OF 6-AMINO-9 - [(4-BROMOFENYL) METHIL] -2-SULFANIL-7H- PURIN-8-ONA (COMPOUND 47B) 47b

[381] Compound 47b was prepared in a manner analogous to Example 1, Method A, Step 2 using 4-amino-3 - [(4-bromophenyl) methyl] - 2-oxo-1H-imidazole-5-carbonitrile ( Compound 47a) in place of 4-amino-3-phenylmethyl-2-oxo-1H-imidazole-5-carbonitrile (Compound 1a). 6-Amino-9 - [(4-bromophenyl) methyl] -2-sulfanyl-7H-purin-8-one (300 mg, Compound 47b) was obtained as a yellow solid. Observed MS (ESI +) [(M + H) +]: 352.

STEP 3: PREPARATION OF 6-AMINO-2-ETHYLSULPHANYL-9 - [(4-BROMOPHENYL) METHIL] - 7H-PURIN-8-ONA (COMPOUND 47C) 47c

[382] Compound 47c was prepared analogously to Example 1, Method A, Step 3 by using 6-amino-9 - [(4-bromophenyl) methyl] - 2-sulfanyl-7H-purin-8-one ( Compound 45b) and iodoethane in place of 6-amino-9-benzyl-2-sulfanyl-7H-purin-8-one (Compound 1b) and bromopropane. 6-Amino-2-ethylsulfanyl-9 - [(4-bromophenyl) methyl] -7H-purin-8-one (5.6 g, Compound 47c) was obtained as a yellow solid. Observed MS (ESI +) [(M + H) +]: 380.

STEP 4: PREPARATION OF 6-AMINO-9 - [(4-BROMOFENYL) METHIL] -2-ETHYLSULFINYL-7H- PURIN-8-ONA (COMPOUND 47D) 47d

[383] Compound 47d was prepared analogously to Example 1, Method B, Step 6 by using 6-amino-9 - [(4-bromophenyl) methyl] - 2-ethylsulfanyl-7H-purin-8-one ( Compound 47c) in place of 6-amino-9-benzyl- 2- (2-propylsulfanyl) -7H-purin-8-one (Compound 1c). 6-Amino-9 - [(4-bromophenyl) methyl] -2-ethylsulfinyl-7H-purin-8-one (3.2 g, Compound 47d) was obtained as a white solid. Observed MS (ESI +) [(M + H) +]: 396.

STEP 5: PREPARATION OF 6-AMINO-9 - [(4-BROMOFENYL) METHIL] -2- (ETHYLSULFONIMIDOIL) -7H-PURIN-8-ONA (COMPOUND 47E) 47e

[384] Compound 47e was prepared analogously to Example 1, Method B, Step 7 by using 6-amino-9 - [(4-bromophenyl) methyl] -2-ethylsulfinyl-7H-purin-8-one ( Compound 47d) in place of 6-amino-9-benzyl-2-propylsulfinyl-7H-purin-8-one (Compound 1d). 6-Amino-9 - [(4-bromophenyl) methyl] -2- (ethylsulfonimidoyl) -7H-purin-8-one (4.0 g, Compound 47e)

was obtained as a white solid. Observed MS (ESI +) [(M + H) +]: 411.

COMPOUND 47E-A AND COMPOUND 47E-B

[385] Compound separation of Compound 47e by chiral HPLC provided Compound 47e-A (fastest elution, 112 mg) and Compound 47e-B (slowest elution, 99 mg) as a white solid with 5% methanol -40% (0.05% DEA) / CO2 in ChiralPak AD-3 column.

[386] Compound 47e-A: 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.58 (br. S., 1H), 7.52-7.54 (d, J = 8.0, 2H ), 7.31-7.29 (t, J = 8.0 Hz, 2H), 6.54 (br. S., 2H), 4.93 (s, 2H), 4.05 (s, 1H ), 3.42 - 3.31 (m, 2H), 1.15 (t, J = 7.3 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 411.

[387] Compound 47e-B: 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.58 (br. S., 1H), 7.54-7.52 (d, J = 8.0, 2H ), 7.31-7.29 (t, J = 8.0 Hz, 2H), 6.98 (br. S., 2H), 4.93 (s, 2H), 4.06 (s, 1H ), 3.40 - 3.37 (m, 2H), 1.15 (t, J = 7.3 Hz, 3H). Observed MS (ESI +) [(M + H) +]: 411.

STEP 6: PREPARATION OF 6-AMINO-9 - [(4-BROMOFENYL) METHIL] -2- (ETHYLSULFONIMIDOIL) -N-METHYL-8-OXO-N-PROPYL-PURINE-7-CARBOXAMIDE (EXAMPLE 47), 6- AMINO-9 - [(4-BROMOFENYL) METHIL] -2- [S (R) -ETHYLSULFONIMIDOIL] - N-METHYL-8-OXO-N-PROPIL-PURINE-7-CARBOXAMIDE AND 6-AMINO-9 - [( 4- BROMOFENIL) METHIL] -2- [S (S) -ETHYLSULFONIMIDOIL] -N-METHYL-8-OXO-N-PROPIL-PURINE-7-CARBOXAMIDE (EXAMPLE 47-AE EXAMPLE 47-B).

(Example 47) (Example 47-A and Example 47-B)

[388] Example 47 was prepared analogously to Example 1, Method A, Step 6 by using 6-amino-9 - [(4-bromophenyl) methyl] -2- (ethylsulfonimidoyl) -7H-purin-8- one (Compound 47e) in place of 6-amino-9-benzyl-2- (propylsulfonimidoyl) -7H-purin-8-one (Compound 1e). 6-Amino-9 - [(4-bromophenyl) methyl] -2- (ethylsulfonimidoyl) -N-methyl-8-oxo-N-propyl-purine-7-carboxamide (570 mg, Example 47) was obtained as a solid White. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.56 - 7.53 (m, 2H), 7.36-7.34 (m, 2H), 6.92 (br.

s., 2H), 4.97 (s, 2H), 4.18 (s, 1H), 3.45 - 3.38 (m, 4H), 3.05 - 3.02 (m, 3H), 1.65-1.56 (m, 2H), 1.19 (t, J = 8.0 Hz, 3H), 0.93-0.75 (m, 3H). Observed MS (ESI +) [(M + H) +]: 510.

[389] Separation of the compound of Example 47 by chiral HPLC provided Example 47-A (fastest elution, 260 mg) and Example 47-B (slowest elution, 266 mg) as a white solid with 5% methanol - 40% (0.05% DEA) / CO2 in a ChiralPak AD-3 column.

[390] Example 47-A: 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.56 - 7.54 (d, J = 8.0 Hz, 2H), 7.36-7.33 (d , J = 8.0 Hz, 2H), 6.90 (br. S., 2H), 4.97 (s,

2H), 4.21 (s, 1H), 3.46 - 3.41 (m, 4H), 3.05 - 3.02 (m, 3H), 1.65-1.54 (m, 2H) , 1.24-1.16 (m, 3H), 0.93-0.75 (m, 3H). Observed MS (ESI +) [(M + H) +]: 510.

[391] Example 47-B: 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.54 - 7.53 (d, J = 8.0 Hz, 2H), 7.36-7.33 (d , J = 8.0 Hz, 2H), 6.90 (br. S, 2H), 4.97 (s, 2H), 4.21 (s, 1H), 3.46 - 3.41 (m , 4H), 3.06 - 3.02 (m, 3H), 1.65-1.54 (m, 2H), 1.20-1.16 (m, 3H), 0.93-0.75 (m, 3H). Observed MS (ESI +) [(M + H) +]: 510.

EXAMPLE 48-AE EXAMPLE 48-B 6-AMINO-9 - [(4-BROMOPHENYL) METHIL] -N-ETHYL 2- (ETHYLSULFONIMIDOIL) -N-METHYL-8-OXO- PURINE-7-CARBOXAMIDE (EXAMPLE 48) , 6-AMINO-9 - [(4-BROMOFENYL) METHIL] -N-ETYL 2- [S (S) - (ETHYLSULFONIMIDOIL)] - N-METYL-8-OXO-PURINE-7-CARBOXAMIDE AND 6-AMINO - 9 - [(4-BROMOFENYL) METHIL] -N-ETHYL-2- [S (R) - (ETHYLSULFONIMIDOIL)] - N-METHYL-8-OXO- PURINE-7-CARBOXAMIDE (EXAMPLE 48-AE EXAMPLE 48- B).

(Example 48) (Example 48-A and Example 48-B)

42-A 42-B

[392] Example 48 was prepared analogously to Example 1, Method A, Step 6 by using 6-amino-9 - [(4-bromophenyl) methyl] -2- (ethylsulfonimidoyl) -7H-purin-8- one (Compound 47e) and N-ethyl-N-methyl-carbamoyl chloride in place of 6-amino-9-benzyl-2- (propylsulfonimidoyl) -7H-purin-8-one (Compound 1e) and N- methyl-N-propyl-carbamoyl (Intermediate AA). 6- Amino-9 - [(4-bromophenyl) methyl] -2- (ethylsulfonimidoyl) -N-methyl-8-oxo-N-propyl-purine-7-carboxamide (469 mg, Example 48) was obtained as a solid White. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.56 - 7.54 (d, J = 8.0 Hz, 2H), 7.36-7.34 (d, J = 8.0 Hz, 2H), 6.98 (br., 2H), 4.97 (s, 2H), 3.53 - 3.46 (m, 4H), 3.05 - 3.01 (m, 3H), 1.22-1.16 (m, 6H). Observed MS (ESI +) [(M + H) +]: 496.

[393] Separation of the compound of Example 48 by chiral HPLC provided Example 48-A (fastest elution, 198 mg) and Example 48-B (slowest elution, 202 mg) as a white solid with 5% methanol - 40% (0.05% DEA) / CO2 in a ChiralPak AD-3 column.

[394] Example 48-A: 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.56 - 7.54 (d, J = 8.0 Hz, 2H), 7.36-7.34 (d , J = 8.0 Hz, 2H), 6.92 (br., 2H), 4.97 (s, 2H), 4.19 - 4.18 (m, 1H), 3.46 - 3 , 41 (m, 4H), 3.05 - 3.01 (m, 3H), 1.20-1.14 (m, 6H). Observed MS (ESI +) [(M + H) +]: 496.

[395] Example 48-B: 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.56 - 7.54 (d, J = 8.0 Hz, 2H), 7.36-7.34 (d , J = 8.0 Hz, 2H), 6.92 (br., 2H), 4.97 (s, 2H), 4.24 (br., 1H), 3.58 - 3, 41 (m, 4H), 3.05 - 3.01 (m, 3H), 1.26-1.01 (m, 6H). Observed MS (ESI +) [(M + H) +]: 496.

EXAMPLE 49 COMPOUNDS AND EXAMPLES ACTIVITY IN HEK293-HTLR-7 TEST HEK293-BLUE-HTLR-7 CELL TEST

[396] A stable HEK293-Blue-hTLR-7 cell line was purchased from InvivoGen (Cat #: hkbhtlr7, San Diego, California, USA). These cells were developed to study the stimulation of human TLR7 by monitoring the activation of NF-κB. A SEAP reporter gene (secreted embryonic alkaline phosphatase) was placed under the control of the minimal IFN-β promoter fused to five NF-κB and AP-1- binding sites.

SEAP was induced by the activation of NF-κB and AP-1 by stimulating HEK-Blue hTLR7 cells with TLR7 ligands. For this reason, reporter expression was regulated by means of the NF-κB promoter by stimulating human TLR7 for 20 hours. The SEAP reporter activity of the cell culture supernatant was determined using the QUANTI-Blue® kit (Cat. No.: rep-qb1, Invivogen, San Diego, Ca, USA) at a wavelength of 640 nm, a medium detection that turns purple or blue in the presence of alkaline phosphatase.

[397] HEK293-Blue-hTLR7 cells were incubated at a density of 250,000 ~ 450,000 cells / mL in a volume of 180 μL in a 96-well plate in Dulbecco's Modified Eagle's (DMEM) medium containing 4.5 g / L glucose, 50 U / ml penicillin, 50 mg / ml streptomycin, 100 mg / ml Normocin, 2 mM L-glutamine, 10% heat inactivated fetal bovine serum (V / V) for 24 hours. Then, HEK293-Blue-hTLR-7 cells were incubated with the addition of 20 μL of test compound in a serial dilution in the presence of 1% final DMSO and incubation at 37ºC in a CO2 oven for 20 hours. Then, 20 μL of the supernatant from each well were incubated with 180 μL of Quanti-blue substrate solution at 37ºC for 2 hours and the absorbance was read at 620 ~ 655 nm using a spectrophotometer. The signaling pathway in which TLR7 activation leads to downstream NF-κB activation has been widely accepted, and therefore the similar reporter assay has also been widely used to assess the TLR7 agonist (Tsuneyasu Kaisho and Takashi Tanaka, Trends in Immunology, Volume 29 (7), July 2008, Page 329, sci; Hiroaki Hemmi et al, Nature Immunology 3, 196 - 200 (2002)).

[398] The Compounds and Examples of the present invention were tested in the HEK293-hTLR-7 assay for their TLR7 agonism activity, as described in the present application and the results are listed in Table 1. Examples of prodrugs showed EC50 values from about 2.1 μM to about 1000 μM, the Compounds in the active forms exhibited EC50 values less than 0.2 μM. The calculated ratio of EC 50 (prodrug) / EC50 (active form) was within the range of 32 to about 7600.

TABLE 1

ACTIVITY OF THE EXAMPLES AND COMPOUNDS OF THE PRESENT INVENTION IN THE HEK293-HTLR-7 TEST. HEK293-hTLR-7 HEK293-hTLR-7 EC50 ratio Active form EC50 Pro-drug (EC50 (pro-drug) / (Pro-drug, corresponding (Active form, EC50 (active form)) µM) µM) Example 1 50, 4 Compound 1e 0.065 775.4 Example 1-A 42.5 Compound 1e-A 0.067 634.3 Example 1-B 27 Compound 1e-B 0.086 314.0 Example 2 32 Compound 1e 0.065 372.1 Example 2-A 3, 7 Compound 1e-B 0.086 43.0 Example 2-B 4.4 Compound 1e-A 0.067 65.7 Example 3 15.1 Compound 1e 0.065 232.3 Example 4 23 Compound 1e 0.065 353.8

HEK293-hTLR-7 HEK293-hTLR-7 EC50 ratio Active form EC50 Pro-drug (EC50 (pro-drug) / (Pro-drug, corresponding (Active form, EC50 (active form)) µM) µM) µM)

Example 5 41 Compound 1e 0.065 630.8

Example 6 82.3 Compound 1e 0.065 1266.2

Example 7 19.9 Compound 1e 0.065 306.2

Example 8 2.1 Compound 1e 0.065 32.3

Example 9 19.2 Compound 1e 0.065 295.4

Example 10 68.5 Compound 1e 0.065 1053.8

Example 11 5.6 Compound 1e 0.065 86.2

Example 12 43.9 Compound 1e 0.065 675.4

Example 13 67 Compound 1e 0.065 1030.8

Example 14 2.4 Compound 1e 0.065 36.9

Example 15 494 Compound 1e 0.065 7600

Example 16 32.1 Compound 1e 0.065 493.8

Example 25 24.2 Compound 1e 0.065 372.3

Example 26 13.4 Compound 1e 0.065 206.2

Example 27 31.7 Compound 1e 0.065 487.7

Example 28 6.9 Compound 1e 0.065 106.2

Example 29 48.8 Compound 1e 0.065 750.8

Example 32 22.5 Compound 1e 0.065 346.2

Example 34-A 6.0 Compound 34e-A 0.014 428.6

Example 34-B 6.36 Compound 34e-B 0.011 578.2

Example 36-A 31.8 Compound 36g-A 0.019 1673.7

HEK293-hTLR-7 HEK293-hTLR-7 EC50 ratio Active form EC50 Pro-drug (EC50 (pro-drug) / (Pro-drug, corresponding (Active form, EC50 (active form)) µM) µM) µM)

Example 37-A 26.6 Compound 36g-A 0.019 1400

Example 37-B 47.4 Compound 36g-B 0.022 2154.5

Example 38-A 26.2 Compound 36g-A 0.019 1378.9

Example 38-B 19.5 Compound 36g-B 0.022 886.4

Example 39 4.3 Compound 36g 0.027 159.3

Example 40 52.8 Compound 36g 0.027 1955.6

Example 41 36 Compound 41c 0.053 679.2

Example 41-A 44.1 Compound 41c-B 0.085 518.8

Example 41-B 32.1 Compound 41c-A 0.071 452.1

Example 42-A 40.5 Compound 41c-A 0.071 570.4

Example 42-B 49.2 Compound 41c-B 0.085 578.8

Example 43-A 110 Compound 43e-A 0.11 1000

Example 43-B 78.4 Compound 43e-B 0.035 2240

Example 44-A 65.4 Compound 43e-B 0.035 1868.6

Example 44-B 96.7 Compound 43e-A 0.11 879.1

Compound 45e-B Example 45-A 153 or 0.26 or 0.39 588 or 392 Compound 45e-A Compound 45e-B Example 45-B> 1000 or 0.26 or 0.39> 3846 or> 2564 Compound 45e- A Compound 45e-A Example 46-A 45.5 or 0.26 or 0.39 175 or 116.7 Compound 45e-B Compound 45e-B Example 46-B 45.7 or 0.26 or 0.39 175, 7 or 117.2 Compound 45e-A Compound 47e-A Example 47-A 10.9 0.021 or 0.025 519.0 or 436 or

HEK293-hTLR-7 HEK293-hTLR-7 EC50 ratio Active form EC50 Pro-drug (EC50 (pro-drug) / (Pro-drug, corresponding (Active form, EC50 (active form)) µM) µM) Compound 47e-B Compound 47e-A or Example 47-B 13.1 0.021 or 0.025 623.8 or 524 Compound 47e-B Compound 47e-A or Example 48-A 18.3 0.021 or 0.025 871.4 or 732 Compound 47e-B Compound 47e -A Example 48-B 20.8 or 0.021 or 0.025 990.5 or 832 Compound 47e-B EXAMPLE 50 METABOLISM OF COMPOUND PRO-DRUGS OF FORMULA (I)

[399] A study was carried out to assess the metabolic conversion of prodrugs, composed of formula (I), to their corresponding active form.

The compounds of formula (I), if provided as prodrugs, can be metabolized to the active compound or other compounds of the invention in the body. Microsomes of the human liver are often used to assess the degree of metabolic conversion of prodrugs in the body of the animal or human.

MATERIALS

[400] The NADPH cofactor system including β-Nicotinamide adenine dinucleotide phosphate (NADP), isocitric acid and isocitric dehydrogenase were purchased from Sigma-Aldrich Co. (St. Louis, MO, USA). Human liver microsomes (Cat. No. 452117, Lot No. 38290) were obtained from Corning (Woburn, MA, USA). The mouse liver microsomes (Cat. No. M1000, Lot No. 1310028) were obtained from Xenotech.

COMPOUND WORKING SOLUTION AND ANOTHER SOLUTION

[401] The compounds were dissolved in DMSO to produce 10 mM stock solutions. 10 μL of the stock solution was diluted with acetonitrile (990 μL) providing 100 μM of working solution.

INCUBATION

[402] Microsomes were pre-incubated with test compound for 10 minutes at 37ºC in 100 mM potassium phosphate buffer, pH 7.4. The reactions were initiated by the addition of the NADPH regeneration system to provide a final incubation volume of 200 μL and subjected to agitation in a water bath at 37ºC. The incubation mixtures consisted of liver microsomes (0.5 mg microsomal protein / mL), substrates (1.0 μM), and NADP (1 mM), isocitric dehydrogenase (1 unit / mL), isocitric acid (6 mM) .

SAMPLE PREPARATION FOR ANALYSIS

[403] At 30 min., The reaction was stopped by adding 600 μL of cold acetonitrile (including 100 ng / mL tolbutamide and 100 ng / mL labetalol as an internal standard). The samples were centrifuged at 4000 rpm for 20 minutes and the resulting supernatants were subjected to analysis by LC-MS / MS.

[404] The samples for the calibration curve were prepared as follows. 100 μL / well of liver microsomes and 98 μL / well of NADPH regeneration solution were dispensed in 96-well plates. First, 600 μL of the reaction blocking solution was added and then 2 μL of the standard curve and QC working solution.

BIOANALYSIS

[405] The compounds were quantified on an API4000 LC-MC / MC instrument in the MRM ESI - Positive mode.

[406] A study was carried out to evaluate the metabolic conversion of prodrugs (1μM), Example 1, Example 1-A, Example 1-B, Example 2, Example 2-A, Example 2-B, Example 3, Example 4, Example 5, Example 6, Example 7, Example 8, Example 9, Example 10, Example 11, Example 12, Example 13, Example 14, Example 15, Example 16,

Example 17, Example 21, Example 22, Example 23, Example 25, Example 26, Example 27, Example 28, Example 29, Example 30, Example 31, Example 32, Example 33, Example 34-A, Example 34-B, Example 36-A, Example 36-B, Example 37-A, Example 37-B, Example 38-A, Example 38-B, Example 39, Example 40, Example 41, Example 41-A, Example 41-B, Example 42 , Example 42-A, Example 42-B, Example 43, Example 43-A, Example 43-B, Example 44, Example 44-A, Example 44-B and Example 45-A, Example 46-A, Example 46- B, Example 47-A, Example 47-B, Example 48-A, Example 48-B for the corresponding active forms, Compound 1e, Compound 1e-A, Compound 1e-B, Compound 34e-A, Compound 34e-B, Compound 36g-A, Compound 36g-B, Compound 36g, Compound 41c, Compound 41c-B, Compound 41c-A, Compound 43e, Compound 43e-A, Compound 43e-B, Compound 45e-A, Compound 45e-B, Compound 47e-A, and Compound 47e-B in the presence of human liver microsomes. The results have been summarized and are illustrated in Table 2.

TABLE 2 METABOLIC CONVERSION OF PRO-DRUGS IN LIVER MICROSOMES

HUMAN Product concentration Product concentration liver microsomes corresponding liver microsomes (corresponding form (Metabolized product form Metabolized product metabolised to human (μM) human) (μM) Example No. Example No. active) Example 1 Compound 1e 0.0214 Example 31 Compound 1e 0.005 Example 1-A Compound 1e-A 0.018 Example 32 Compound 1e 0.013 Example 1-B Compound 1e-B 0.022 Example 33 Compound 1e 0.59 Compound Example 2 Compound 1e 0.028 Example 34-A 0.2 34e- A Compound Example 2-A Compound 1e-B 0.036 Example 34-B 0.088 34e-B Compound Example 2-B Compound 1e-A 0.029 Example 36-A 0.02 36g-A

Product concentration

Concentration of product liver microsomes corresponding liver microsomes (corresponding form (Metabolized product form

Metabolized product metabolized to metabolized in human (μM)

human (μM) Example No.

Example No. active)

active) Compound Example 3 Compound 1e 0.12 Example 36-B 0.019 36g-B Compound Example 5 Compound 1e 0.078 Example 37-A 0.004 36g-A Compound Example 6 Compound 1e 0.074 Example 37-B 0.002 36g-B Compound Example 7 Compound 1e 0.15 Example 38-A 0.026 36g-A Compound Example 8 Compound 1e 0.043 Example 38-B 0.034 36g-B Compound Example 9 Compound 1e 0.002 Example 40 0.032 36g Compound Example 10 Compound 1e 0.005 Example 41-A 0.38 41c -B Compound Example 11 Compound 1e 0.001 Example 41-B 0.36 41c-A Compound Example 12 Compound 1e 0.018 Example 42-A 0.14 41c-A Compound Example 13 Compound 1e 0.04 Example 42-B 0.004 41c-B Compound Example 14 Compound 1e 0.026 Example 43-A 0.014 43e-A Compound Example 15 Compound 1e 0.002 Example 43-B 0.016 43e-B Compound Example 16 Compound 1e 0.024 Example 44-A 0.002 43e-B Compound Example 17 Compound 1e 0.075 Example 44 -B 0.002 43e-A Compound 45e-B or Example 21 Compound 1e 0.48 Example 45-A 0.41 Compound 45e-A

Compound 45e-A or Example 22 Compound 1e 0.42 Example 46-A 0.039 Compound 45e-B

Example 23 Compound 1e 0.42 Example 46-B Compound 0.18

Product concentration Product concentration liver microsomes corresponding liver microsomes (corresponding form (Metabolized product form Metabolized product metabolised to human (μM) human) (μM) Example No. Example No. active) active 45e-B or 45e-A compound Compound 47e-A or Example 25 Compound 1e 0.018 Example 47-A 0.36 Compound 47e-B Compound 47e-B or Example 26 Compound 1e 0.042 Example 47-B 0.41 Compound 47e-A Compound 47e-A Example 27 Compound 1e 0.11 Example 48-A or 0.11 Compound 47e-B Compound 47e-B Example 28 Compound 1e 0.084 Example 48-B or 0.053 Compound 47e-A Example 29 Compound 1e 0.009 EXAMPLE 51 COMBINED IN VIVO EFFECTIVENESS (MICE WITHOUT TUMOR) OF A PRO-DRUG FORM OF COMPOUNDS OF THE PRESENT INVENTION (COMPOUND 41-A) AND

SORAFENIBE IN A HIGH HEPATOCELLULAR CARCINOMA MODEL AGGRESSIVE

[407] Tumorigenesis in iAST mice was initiated by intravenous injection of 5x108 IFU of adenovirus expressing Cre recombinase (in vivo application of Ad-CMV-iCre vector, Vector Biolabs) in transgenic mice that express the hepatocyte-specific albumin promoter, a stop cassette flanked by loxP, and the large SV40 T antigen (Runge A,

et al., Cancer Res. 74 (2014) 4157-69). Cre recombinase excises the stopping cassette in the transduced cells and leads to transient viral hepatitis,

resulting in multinodular tumorigenesis in 8 weeks.

Female mice were treated with vehicle (7.5% gelatin / 0.22% NaCl for sorafenib; or 2% hydroxypropylcellulose LF Klucel® (Asland), 0.5% D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS, Sigma), 0.09% methylparaben (Sigma), 0.01% propylparaben (Sigma) in water for 41-A)

or 90 mg / kg in Sorafenib (Nexavar®, Bayer HealthCare) daily or were treated with compound 41-A (10 mg / kg) once a week by gavage.

Vehicle or Sorafenib treatment started at week 7.5 after the administration of adenovirus and 3 days before the administration of compound 41-A.

The animals were sacrificed on day 12 after the start of treatment and the total weights of the livers and tumors were determined.

The results by group n = 10 were analyzed by ANOVA of correction of

Tukey shown as individual points with mean ± EPM using GraphPad Prism version 6 statistical software. Although Sorafenib was highly effective as monotherapy, the combination with an active form of the compounds of the present invention (compound 41-A) resulted in 2/10 mice without tumors by superficial examination of the livers in this highly aggressive model of hepatocellular carcinoma.

The results are shown in the table below and in Figures 1A and 1B

SYNERGIC EFFECT OF COMPOUND 41-A AND SORAFENIBE ON TUMOR LOAD

(TUMOR FREE MICE) Examination of the liver for tumor nodules Superficial treatment Vehicle 0/10 without tumor nodule Compound 41-A 0/10 without tumor nodule Sorafenib 0/10 without tumor nodule

Examination of the liver for tumor nodules Superficial treatment Compound 41-A + Sorafenib 2/10 without tumor nodule EXAMPLE 52 TREATMENT WITH A PRO-DRUG FORM OF THE COMPOUNDS OF THE PRESENT INVENTION (COMPOUND 41-A) INDUCES THE EXPRESSION OF PD-L1 IN

TUMOR CELLS IN HEPATOCELLULAR CARCINOMA MODEL

[408] The tumors of iAST mice were treated as described in Figure 1. Animals were sacrificed on day 12 after the start of treatment and the tumors analyzed by flow cytometry. For flow cytometry, tumors were excised and suspensions of single cells were obtained by mechanical processing and enzymatic digestion (DNAse 0.01%, collagenase IV 1mg / ml). Staining procedures started with blocking the Fc receptor using the clone 2.4G2 antibody (dilution 1: 200, BD Bioscience) and the following antibodies (clones) were used to analyze the leukocyte infiltrate: CD45-FITC (30-F11, BioLegend) and CD11b-BUV737 (M1 / 70, BD Bioscience). The samples were acquired using an LSRFortessa instrument (BD Bioscience) and analyzed by FlowJo software version 10 (Treestar). Data are shown by group n = 5, analyzed by unidirectional ANOVA and Tukey's correction, shown as individual points with mean ± EPM using the GraphPad Prism software version 6. Although the absolute infiltrate of immune cells in the iAST tumor has not changed in any way of the treatments described (Fig.2A), significant changes were observed in the lymphoid and general myeloid composition of the tumors (Figs. 2C and 2D). Here, the changes were clearly motivated by sorafenib, which previously demonstrated to also act on immune cells (Martin del Campo, et al., J. Immunol. 195 (2015) 1995-2005). However, treatment with 41-A induced the expression of PD-L1 in tumor cells when monotherapy, as well as in combination treatment with

Sorafenib (Fig. 2 B).

EXAMPLE 53 TRIPLE COMBINATION IN VIVO OF 41-A, SORAFENIBE AND ANTI-PD-1 RESULTS IN INCREASED AVERAGE SURVIVAL.

[409] Multinodular tumors were induced in iAST mice as described for Fig. 1 (see Example 51). Female transgenic mice were treated at week 7.5 after vehicle virus injection (7.5% gelatin / 0.22% NaCl for sorafenib; or 2% hydroxypropylcellulose LF Klucel® (Asland), 0.5 % D-α-Tocopherol succinate polyethylene glycol 1000 (TPGS, Sigma), 0.09% methylparaben (Sigma), 0.01% propylparaben (Sigma) in water for 41-A) or 90 mg / kg in Sorafenib (Nexavar®, Bayer HealthCare) daily or were treated with compound 41-A (10 mg / kg) once a week by gavage. Vehicle or Sorafenib treatment started at week 7.5 after the administration of adenovirus and 3 days before the administration of compound 41-A. The mouse anti-PD-1 antibody (clone RPM1-14, BioXCell) was administered every 3 days intraperitoneally at 250 µg / mouse. The total treatment period was 2 weeks (and 3 days + 2 weeks for Sorafenib) and the survival of the iAST mice was monitored. Mice were euthanized after showing signs of distress, such as> 20% body weight gain, bristly coat and shocked position. Kaplan-Meier curves were analyzed using the paired Log-Rank test (see table). In the survival scenario, neither Sorafenib nor 41-A was effective as a monotherapy. Anti-PD-1 monotherapy resulted in significantly reduced survival compared to vehicle control (VEH). The median survival of the iAST mice was significantly increased in the sorafenib and anti-PD-1 antibody combination group. However, the triple combination of 41-A with Sorafenib and anti-PD-1 led to a greater and more significant increase in mean survival from 71 days (VEH) to 104 days (41-A + PD-1 + sorafenib) in this model of Highly aggressive HCC. The results are shown in Figure 3 and the table below

PAIRED LOG-RANK TEST TABLE (MULTIPLE TEST LEVEL = 0.00179) 41-A + PD-1 + 41-A + PD-1 Sorafenibe Sorafenibe Sorafenibe Sorafenibe PD-1 + 41-A + PD-1 41-A Group VEH VEH 1.0 0.1580 0.2309 0.0004 * 0.8759 0.1465 0.0192 * 0.0001 * EXAMPLE 54 TREATMENT WITH A PRO-DRUG FORM OF THE COMPOUNDS OF THE PRESENT INVENTION (COMPOUND 41-A) IN THE HEPATOCELLULAR CARCINOMA MODEL OF HEP55.1C TRANSPLANTED MICE

[410] Female C57BL / 6N mice (Jackson Laboratories) were injected intrahepathically with the Hep55.1c tumor cell line (5x105) together with Matrigel (Matrigel Basement Membrane Matrix, Corning, Cat. No.: 354234) in one volume total of 20 µL (10 µL of cell suspension plus 10 µL of Martigel). Tumor volume was monitored weekly using µCT (TomoScope Synergy Twin, CT Imaging GmbH) after a single intravenous administration of the contrast agent Exitron 6000 (Viscovert). The image data were reconstructed using the TomoScope software and analyzed using the Osirix software. When the tumors reached 80 mm3, the mice were treated weekly with 10 mg / kg of compound 41-A or vehicle (2% Hydroxypropylcellulose LF Klucel® (Asland), 0.5% D-α-Tocopherol polyethylene glycol 1000 succinate ( TPGS, Sigma), 0.09% methylparaben (Sigma), 0.01% propylparaben (Sigma) in water) by oral probe. To compare with another agonist, immunostimulating agent, a single dose of anti-CD40 antibody (4 mg / kg; FGK.45 clone, BioXCell) was administered. The data represented are means ± SEM for a minimum of n = 9 animals per group.

[411] Weekly administration of compound 41-A resulted in inhibition of tumor growth in mice bearing Hep55.1c tumor when compared to vehicle treatment. As previously published, a single dose of anti-CD40 antibody can lead to tumor eradication in subcutaneous MC38 tumors and the anti-CD40 antibody has been shown to have an inflammatory effect on the liver (Hoves S, et al., Exp Med., DOI : 10.1084 / jem.20171440; published on February 7, 2018). However, no beneficial effect of treatment was observed in mice bearing Hep55.1c tumor with anti-CD40 antibody. The results are shown in Figure 5 A.

EXAMPLE 55 IN VIVO EFFECTIVENESS OF COMPOUND 42-A (6-AMINO-9 - [(4-CHLOROPHENYL) METHIL] -N-ETHYL-2 [S (S) -ETHYLSULFONIMIDOIL] -N-METHYL-8-OXO-PURINE- 7-CARBOXAMIDE), ISOLATED AND IN COMBINATION WITH ANTI-PD-1 RESULTS IN BENEFIT OF

SURVIVAL IN THE HEPATOCELLULAR CARCINOMA MOUNTAIN MODEL WITH HEP55.1C CELLS

[412] Female C57BL / 6N mice (Jackson Laboratories) were injected intrahepathically with the Hep55.1c tumor cell line (5x105) together with Matrigel (Matrigel Basement Membrane Matrix, Corning, Cat.: 354234) in one volume total of 20 µL (10 µL of cell suspension plus 10 µL of Martigel). Observation animals were sacrificed to determine the time point at which treatment started at a tumor volume of about 80 mm3. The mice were treated with compound 42-A 10 mg / kg or vehicle (2% Hydroxypropylcellulose LF Klucel ®

(Asland), 0.5% D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS, Sigma), 0.09% methylparaben (Sigma), 0.01% propylparaben (Sigma) in water) by gavage or intraperitoneal administration 250 µg anti-PD-1 antibody (clone RPM1-14, BioXCell) or a combination of compound 42-A plus anti-PD-1. 42-A was administered weekly (total 3 times) and indicated on the same day of treatment with anti-PD-1 antibody. Antibody treatment was continued every three to four days for a total of 6 doses. 42-A monotherapy resulted in less tumor volume compared to control (VEH) and PD-1 monotherapy. The combined treatment of 42-A and anti-PD-1 also reduced tumor volume, with 3 out of 9 tumor-free mice. The results are shown in Figure 5 B and the Table below.

COMBINATION EFFECT OF COMPOUND 42-AE ANTI-PD-1 ON TUMOR LOAD (TUMOR FREE MICE) Treatment Liver examination Vehicle 0/7 without tumor αPD-1 1/9 without tumor 42-A 1/7 without tumor 42 -A + αPD-1 3/9 without tumor EXAMPLE 56 COMBINATION OF A PRO-DRUG FORM OF THE COMPOUNDS OF THE PRESENT INVENTION (COMPOUND 41-A) AND ANTI-PD-1 ANTIBODIES IN THE MODEL OF

HEPATOCELLULAR CARCINOMA IN MICE TRANSPLANTED WITH HEP55.1C.

[413] Female C57BL / 6N mice (Jackson Laboratories) were injected intrahepathically with the Hep55.1c tumor cell line (5x105) together with Matrigel (Matrigel Basement Membrane Matrix, Corning, Cat.: 354234) in one volume total of 20 µL (10 µL of cell suspension plus 10 µL of Martigel). After 3 weeks, the animals were sacrificed and the tumors removed from the liver. The excised tumors were cut into 1x1 mm 3 pieces and implanted in the liver of female C57BL / 6N mice. Observation animals were sacrificed to determine the time point of initiation of treatment at a tumor volume of about 80 mm 3. The mice were treated with 41-A or vehicle (2% Hydroxypropylcellulose LF Klucel ® (Asland), 0 , 5% D-α-Tocopherol succinate polyethylene glycol 1000 (TPGS, Sigma), 0.09% methylparaben (Sigma), 0.01% propylparaben (Sigma) in water) by gavage or intraperitoneal administration of 250 µg of antibody anti-PD-1 (clone RPM1-14, BioXCell) or a combination of compound 41-1 plus anti-PD-1. 41-A was administered weekly, while treatment with anti-PD-1 antibody started one day after treatment with 41-A and was continued every three to four days for a total of 8 doses. Treatment with both agents was stopped after the last administration of anti-PD-1. 41-A monotherapy resulted in longer mouse survival (5/10) compared to vehicle-treated control (1/10).

The combined treatment of 41-A and anti-PD-1 increased the survival of mice even more significantly with 8/10 live mice on day 94 after transplantation of the tumor fragment.

EXAMPLE 57

TREATMENT WITH AN ACTIVE FORM OF THE COMPOUNDS OF THE PRESENT INVENTION (COMPOUND 41C-B) DOES NOT INDUCE THE INCREASE IN THE PROLIFERATION OF CELLS

TUMOR IN CELL LINES ORIGINATED FROM HEPATOCELLULAR CARCINOMA AND CHOLANGIOCARCINOMA.

[414] Cell lines derived from hepatocellular carcinoma and cholangiocarcinoma (EGI1 and OZ) were maintained and tested in the following media: Huh7 and EGI1 were cultured in DMEM 4.5 g / L glucose (Gibco, Cat. No.: 31966 -021), 10% SBF (GIBCO, Cat No .: 10500-064 Lot 07G3690K), 2 mM L-glutamine (Thermo Fischer, Cat No .:

25030081), 1mM sodium pyruvate (GIBCO Cat. No.: 11360-039). Hep3B and HepG2 were grown in MEM of Eagle + BSS from Earle (PAN, Cat. No.: P04-08510), 10% SBF, 2 mM L-glutamine, 0.1 mM NEAA (PAN, Cat. .: P08-32100) and 1 mM sodium pyruvate. JHH1, JHH5, JHH6 and OZ were grown in Williams'E medium (PAN, Cat. No.: P04-29050), 10% SBF and 2 mM L-glutamine. JHH2 was grown in Williams'E, 10% SBF and 2 mM L-glutamine. HLE was grown in DMEM, 4.5 g / L glucose, 10% SBF and 2 mM L-glutamine. HLF was grown in DMEM, 4.5 g / L glucose, 5% SBF, 0.1 nM NEAA and 2 mM L-glutamine. JHH4 was grown in MEM from Eagle + BSS from Earle, 10% SBF and 2 mM L-glutamine. The SkHep1 strain was cultured in MEM from Eagle + BSS from Earle, 10% SBF, 2 mM L-glutamine, 0.1 mM NEAA and 1 mM sodium pyruvate. SNU449 was cultured using RPMI 1640 (PAN, Cat. No.: P04-18047) 10% SBF and 2 mM L-glutamine. The cells were seeded in the respective medium overnight at a density of 5,000 cells per well in 96-well polystyrene microplates with black backgrounds treated with TC (Corning, Cat No .: 3904). The next day, logarithmic dilutions of 41c-B starting from 27 µM to 270 pM were added and incubated for 72, 120 and 148 hours, respectively. Tumor cell counts were determined using the Perkin Elmer Operetta Imaging System and the Harmony Software, counting nuclei stained for 20 minutes in complete medium using the Hoechst33342 dye (2 µg / mL, Sigma, Cat. No.: B2261). The data shown are means + SD of wells in triplicates based on the analysis of 9 images per well in relation to the control with DMSO.

[415] None of the tested cell lines showed a significant increase in proliferation after treatment with 41c-B directly at the time points described. The results are shown in

Figure 6A.

EXAMPLE 58

TREATMENT WITH AN ACTIVE FORM OF THE COMPOUNDS OF THE PRESENT INVENTION (COMPOUND 41C-A) DOES NOT INDUCE THE INCREASE IN THE PROLIFERATION OF CELLS

TUMOR IN CELL LINES ORIGINATED FROM HEPATOCELLULAR CARCINOMA AND CHOLANGIOCARCINOMA.

[416] Cell lines derived from hepatocellular carcinoma and cholangiocarcinoma (EGI1) were maintained and tested in the following media: Huh7 and EGI1 were cultured in DMEM 4.5 g / L glucose (Gibco, Cat No .: 31966-021 ), 10% SBF (GIBCO, Cat No .: 10500-064 Lot 07G3690K), 2 mM L-glutamine (Thermo Fischer, Cat No .: 25030081), 1mM sodium pyruvate (GIBCO Cat. : 11360-039). Hep3B and HepG2 were grown in Eagle's MEM + Earle's BSS (PAN, Cat. No.: P04-0885), 10% SBF, 2 mM L-glutamine, 0.1 mM NEAA (PAN, Cat. .: P08-32100) and 1 mM sodium pyruvate. JHH2 was grown in Williams'E, 10% SBF and 2 mM L-glutamine. HLF was grown in DMEM, 4.5 g / L glucose, 5% SBF, 0.1 nM NEAA and 2 mM L-glutamine. The SkHep1 strain was cultured in MEM from Eagle + BSS from Earle, 10% SBF, 2 mM L-glutamine, 0.1 mM NEAA and 1 mM sodium pyruvate. The cells were seeded in the respective medium overnight at a density of 5,000 cells per well in 96-well polystyrene microplates with black backgrounds treated with TC (Corning, Cat No .: 3904). The next day, logarithmic dilutions of compound 41c-A starting from 27 µM to 270 pM were added and incubated for 72 hours. Tumor cell counts were determined using the Perkin Elmer Operetta Imaging System and the Harmony Software, counting nuclei stained for 20 minutes in complete medium using the Hoechst33342 dye (2 µg / mL, Sigma, Cat. No.: B2261). The data shown are means + SD of wells in triplicates based on the analysis of 9 images per well in relation to the control with DMSO.

[417] None of the tested cell lines showed a significant increase in proliferation after treatment with 41c-A directly after 72 hours. The results are shown in Figure 6B.

EXAMPLE 59

TREATMENT OF TUMOR CELLS WITH AN ACTIVE FORM OF THE COMPOUNDS OF THE PRESENT INVENTION (COMPOUND 41C-B) IN THE PRESENCE OF PERIPHERAL BLOOD

RESULTS IN INHIBITION OF TUMOR CELL PROLIFERATION

[418] Heparinized whole blood from 3 different donors was diluted 1: 1 in RPMI medium (PAN, Cat. No .: P04-18047) plus 10% SBF (GIBCO Cat. No .: 10500-064, lot 07G3690K) and incubated at 37ºC and 5% CO2 for 24 hours with compound 41c-B at 2.7 µM. The supernatant was collected and centrifuged at 600 x g for 8 minutes to remove residual leukocytes, platelets and erythrocytes. The supernatants were stored at - 80ºC until further use and thawed gently at room temperature before addition to the cell lines. Cell lines Huh7, JHH2, HLE, HLF, JHH4, Hep3B, HepG2, JHH1, EGI1, JHH5, JHH6, OZ, SkHep1 and SNU449 were seeded in 100 µL of the respective media (as described in Example 57) overnight at a density of 5,000 cells per well of 96-well black polystyrene microplate wells treated with TC (Corning, Cat No .: 3904). The next day, 100 µL of supernatants from whole blood were added to the cell lines. As a control, whole blood supernatant was added without adding compound 41c-B (“whole blood”) or simple RPMI medium plus SBF (“control medium). Cell lines were incubated for 72 hours. Tumor cell counts were determined using the Perkin Elmer Operetta Imaging System and the Harmony computer program,

counting cores stained for 20 minutes in complete medium using Hoechst33342 (2 µg / mL, Sigma, no .: Cat No .: B2261) and viability was assessed by additional detection of propidium iodide (PI, 1 µg / mL, Sigma , Cat. No.: P4864). The data shown are means + SD of wells in triplicates based on the analysis of 9 images per well.

[419] The results are shown in Figures 7A and 7B. For some cell lines (SNU449, JHH2 and SkHep), the addition of unstimulated whole blood supernatant induced proliferation above the level of the control medium, while other lines responded with reduced proliferation (OZ, JHH1, HepG2, JHH4, JHH6, JHH5 and EGI1). However, treatment with supernatants derived from whole blood incubated with 41c-B resulted in reduced cell counts in all tested cases compared to the respective controls (whole blood). The reduced cell counts were mainly attributed to a stop in proliferation, and only the cell lines JHH2, JHH4, JHH6, Hep3B and EGI1 suffered cell death, as determined by the considerable positivity of PI (data not shown).

EXAMPLE 60

FACTORS RELEASED IN THE PERIPHERAL BLOOD AFTER TREATMENT WITH AN ACTIVE FORM OF THE COMPOUNDS OF THE PRESENT INVENTION (COMPOUND 41C-A)

RESULT IN THE INHIBITION OF PROLIFERATION IN TUMOR CELL LINES

[420] Heparinized whole blood from 2 different donors was diluted 1: 1 in RPMI medium (PAN, Cat. No .: P04-18047) plus 10% SBF (GIBCO Cat. No .: 10500-064, lot 07G3690K) and incubated at 37ºC and 5% CO2 for 24 hours with compound 41c-A at 2.7 µM. The supernatant was collected and centrifuged at 600 x g for 8 minutes to remove residual leukocytes, platelets and erythrocytes. The supernatants were stored at -80ºC until further use and gently thawed at room temperature before adding to the cell lines. The cell lines Huh7, JHH2, HLF, Hep3B, HepG2, EGI1 and SkHep1 were seeded in 100 µL of the respective media (as described in Figure 6) overnight at a density of 5,000 cells per well of transparent polystyrene microplates of 96 black bottom wells treated with TC (Corning, Cat. No .: 3904). The next day, 100 µL of supernatants from whole blood were added to the cell lines. As a control, whole blood supernatant was added without adding compound 41c-A (“whole blood”) or simple RPMI medium plus SBF (“control medium). Cell lines were incubated for 72 hours. Tumor cell counts were determined using the Perkin Elmer Operetta Imaging System and the Harmony computer program, counting nuclei stained for 20 minutes in complete medium using Hoechst33342 (2 µg / mL, Sigma, no .: Cat No .: B2261 ) and viability was assessed by additional detection of propidium iodide (PI, 1 µg / mL, Sigma, Cat. No.: P4864). The data shown are means + SD of wells in triplicates based on the analysis of 9 images per well.

[421] The results are shown in Figure 7C - treatment with supernatants derived from whole blood incubated with 41c-A resulted in reduced cell counts in all tested cases compared to the respective controls (“whole blood”). Only in the Hep3B strain, donor # 5 supernatant increased the proliferation of this cell line, while donor # 4 supernatant had no impact on tumor cell proliferation.

EXAMPLE 61 STUDY PHARMACOKINETICS (PK) STUDY IN WISTER-HAN RATS

MACHINES

[422] A single dose PK study was performed on male Wister-Han rats to assess the pharmacokinetic properties of the compounds tested. Two groups of animals received the respective compound via gavage (POE). Blood samples (approximately 20 μL) were collected from the jugular vein or at an alternative location at the times: 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 7 and 24 hours after administration. Blood samples were placed in tubes that contained EDTA-K2 anticoagulant and centrifuged at

5,000 rpm for 6 min at 4ºC to separate the plasma from the samples. After centrifugation, the resulting plasma was transferred to clean tubes for bioanalysis of the prodrug and the active form by LC / MS / MS. In the groups that received prodrug, the concentration of prodrugs in the plasma samples was below the detection limit. The “compound tested” in Table 8 was used as the internal standard to test the metabolite (active form) of “compound dose” in vivo. The pharmacokinetic parameters were calculated using the WinNonlin® Professional 6.2 non-compartmental module. The peak concentration (Cmax) was recorded directly from experimental observations. The area under the plasma concentration versus time curve (AUC0-t) was calculated using the linear trapezoidal rule until the last detectable concentration.

[423] The values of Cmax and AUC0-last. are two critical PK parameters related to the in vivo efficacy of the tested compound. Compounds with Cmax and AUC0-ultima. higher levels will lead to better in vivo efficacy. The results of the pharmacokinetic parameters after oral administration of the active forms and competing compounds are shown in Table 7. The PK parameters of the prodrugs are shown in Table 8.

[424] After oral administration of prodrugs, the active forms were observed in the plasma and thus tested. The exemplified prodrugs of the present invention (Examples 41-B, 42-A, 42-B, 43-A, 45-A and 45-B) showed surprisingly much improved Cmax (5-175-fold increase) and AUC0-ultima. (2.5-56 fold increase) compared to the reference compound (GS9620, S-2 and S-3) and the compound mentioned in the present invention (Compound 41c-A, 41c-B and 43e-A) which they are all active forms. The results clearly demonstrated the unexpected superiority of prodrugs over the active forms in the PK parameters that led to the best efficacy in vivo.

TABLE 7

AVERAGE PLASMATIC CONCENTRATION AND PHARMACOKINETIC PARAMETERS OF THE ACTIVE FORMS AFTER ORAL ADMINISTRATION OF 5 MG / KG Compound dose GS9620 S-2 S-3 Compound 41c-A Time (h) Average Plasma Concentration (nM) 0.25 56.3 9.49 8.89 16.75 0.5 33.2 16.74 9.99 27.48 1 83.4 19.33 10.16 32.33 2 136 24.89 8.40 27.34 4 16.7 47 , 55 11.54 27.38 8 * 9.49 52.72 8.17 18.02 24 ND 4.90 ND 5.60 Cmax (nM) 164 52.72 11.54 32.33 AUC0-last. (nMh) 316 748 95 242.5 Compound Compound Compound Compound Dose of compound 41c-B 43e-A 45e-A 45e-B Time (h) Mean plasma concentration (nM) 0.25 3.41 12.60 64 , 6 42.8 0.5 0.75 15.22 80.0 52.2 1 2.04 13.01 58.1 37.6 2 5.46 11.98 42.5 24.2 4 2.52 8.20 77.8 53.9 8 * 1.21 6.31 34.6 29 24 ND ND 8.6 5.7 Cmax (nM) 5.46 15.22 80.0 53.9 AUC0-last. (nMh) 55.8 77 767 568 * 7 h for Compound 41c-A, Compound 41c-B and Compound 43e-A.

TABLE 8 PK PARAMETERS OF PRO-DRUGS AFTER ORAL ADMINISTRATION OF 5 MG / KG Compound dose tested Compound Cmax (nM) AUC0-last. (nMh) Example 41-B Compound 41c-A 1315 3658

Example 42-A Compound 41c-A 1742 4867 Example 42-B Compound 41c-B 956 3148 Example 43-A Compound 43e-A 77 229 Example 45-A Compound 45e-B 922 1914 Example 45-B Compound 45e-A 1436 2619 EXAMPLE 62

LYSA SOLUBILITY STUDY

[425] The LYSA study is used to determine the aqueous solubility of the tested compound. The samples were prepared in duplicates from a stock solution in 10 mM DMSO. After evaporating DMSO with a centrifugal vacuum evaporator, the compounds were dissolved in 0.05 M phosphate buffer (pH 6.5), stirred for 1 h and subjected to stirring for two hours. After one night, the solutions were filtered using a microtiter plate. Then the filtrate and its 1/10 dilution were analyzed by HPLC-UV. In addition, a four-point calibration curve was prepared from the 10 mM stock solutions used to determine the solubility of the compounds. The results were in μg / mL. In the event that the percentage of the sample measured in solution after evaporation divided by the calculated maximum value of the sample was greater than 80%, the solubility was reported to be greater than that value.

[426] The results of LYSA are illustrated in Table 9. It was evident that the solubility of the active forms was surprisingly improved 10 to over 200 times when converted to the various prodrugs.

TABLE 9

SOLUBILITY DATA OF SPECIFIC COMPOUNDS LYSA of Pro-LYSA of Active Forms Pro-drugs corresponding active forms (µg / mL) (µg / mL) Example 1 290 Compound 1e 21 Example 1-A 315 Compound 1e-A 56 Example 1- B 200 Compound 1e-B 50 Example 2 615 Compound 1e 21 Example 2-A> 600 Compound 1e-B 50 Example 2-B> 590 Compound 1e-A 56 Example 3 240 Compound 1e 21 Example 4 695 Compound 1e 21 Example 5> 595 Compound 1e 21 Example 6 140 Compound 1e 21 Example 7 615 Compound 1e 21 Example 8 620 Compound 1e 21 Example 9> 520 Compound 1e 21 Example 10 120 Compound 1e 21 Example 11> 618 Compound 1e 21 Example 12 120 Compound 1e 21 Example 13 155 Compound 1e 21 Example 14 225 Compound 1e 21 Example 15 405 Compound 1e 21 Example 16 205 Compound 1e 21 Example 17 190 Compound 1e 21 Example 25> 670 Compound 1e 21 Example 26> 690 Compound 1e 21 Example 27> 380 Compound 1e 21

LYSA of Pro- LYSA of Active Forms Pro-drugs corresponding active forms (µg / mL) (µg / mL)

Example 28 695 Compound 1e 21

Example 29 395 Compound 1e 21

Example 32 125 Compound 1e 21

Example 36-A 168 Compound 36g-A 6

Example 36-B 209 Compound 36g-B 11

Example 41-A 260 Compound 41c-B 5

Example 41-B 250 Compound 41c-A 1

Example 42-A 225 Compound 41c-A 1

Example 42-B 335 Compound 41c-B 5

Example 43-A 203 Compound 43e-A 13

Example 43-B 170 Compound 43e-B 13

Example 45 172 Compound 45e 152

Compound 45e-A or Example 45-A> 560 90 or 115 Compound 45e-B

Compound 45e-B or Example 45-B 420 115 or 90 Compound 45e-A

Compound 45e-A or Example 46-A 205 90 or 115 Compound 45e-B

Compound 45e-B or Example 46-B> 580 115 or 90 Compound 45e-A

Compound 47e-A or Example 47-A 154 <1.0 or <1.0 Compound 47e-B

Compound 47e-B or Example 47-B 128 <1.0 or <1.0 Compound 47e-A

Compound 47e-A or Example 48-A 305 <1.0 or <1.0 Compound 47e-B

LYSA of Pro- LYSA of Active Forms Pro-drugs corresponding active form (µg / mL) (µg / mL) Compound 47e-B or Example 48-B 275 <1.0 or <1.0 Compound 47e-AE XEMPLO 63 Door Vein Study

[427] The aim of this study was to understand whether the prodrug remained unchanged as it was absorbed through the intestine into the portal circulation and to demonstrate the primary site of conversion.

SURGICAL P ROCEDURE FOR CANCULATION OF THE DOOR VEIN (PVC) AND CANOTATION OF THE CAROTID ARTERY (CAC)

[428] The surgery was performed under anesthesia with pentobarbital / isoflurane. Briefly, after disinfecting the abdominal area with betadine and 70% isopropyl alcohol, a small incision was made in the abdominal midline. The cecum was externalized and the mesenteric vein was identified and isolated by about 5 mm from the vessel. A loose ligature was placed in the vicinity and the distal end of the vein was ligated. A small incision (just enough to allow the catheter to be inserted) was made in the isolated vein and the PU catheter was inserted towards the liver for the appropriate length. The catheter was fixed in position by tying the loose ligature around the cannulated vessel. The cecum was replaced in the abdominal cavity. An opening was made in the right abdominal wall to allow the end of the catheter to pass freely. The catheter was fixed by suture to the abdominal wall. The abdominal muscle incision was closed with a suture. A small incision was made in the scapular area to serve as the catheter exit site. The catheter was tunneled subcutaneously and externalized through the scapular incision.

A fixed suture was placed in the scapular region. The patency of the catheter was checked and then externalized from the subcutaneous space to the dorsal region of the neck. After gently cleaning the area, the abdominal cavity was sutured. The left carotid artery was then cannulated by inserting a PE50 catheter. Both external catheters were sutured firmly in the dorsal neck and fixed. The animals were then left to recover in their cages and used for study at least 3 days after surgery. All catheters were washed once a day with heparinized saline to maintain patency.

AND ORAL PK STUDY IN RAT WITH DOUBLE CANNULATION PVC / CAC

[429] The animals were fasted overnight (n = 3) and received gavage administration (10 mg / kg, 10 ml / kg).

Blood samples (60 μL) were collected simultaneously from the catheters of the carotid artery and portal vein at times 0.083, 0.25, 0.5, 1, 2, 4, 7, 24h. All blood samples will be transferred to microcentrifuge tubes containing 2 μL of K 2EDTA (0.5 M) as anticoagulant and placed in an ice bath. Then, the blood samples will be processed for plasma separation by centrifugation at approximately 4ºC, 3,000 g within half an hour after collection. The plasma samples will be stored in polypropylene tubes, quickly frozen in dry ice and kept at -70 ± 10ºC until analysis by LC / MS / MS.

[430] Pharmacokinetic parameters (mean ± SD, n = 3) of prodrugs and were active in portal and carotid samples after oral administration of prodrugs (10 mg / kg) in rats with cannulated portal veins were detected and analyzed . The test results from Example 1-B, 41-A, 41-B, 42-A and 43-A were summarized below.

TABLE 10 P PHARMACOKINETIC ARAMETERS OF EXAMPLE 41-A AND ITS CORRESPONDING ACTIVE FORM COMPOUND 41 C-B IN SAMPLES OF THE CAROTID AND VEIN P ORTA AFTER ORAL ADMINISTRATION OF EXAMPLE 41-A (10 MG / KG) AND M RAT

WITH CANNULATED DOOR VEIN Pro-drug Example 41-A Corresponding active form Compound 41c-B Portal sampling Carotid sampling PK parameter pro-drug active form pro-drug active form Tmax (h) 0.14 0.4 0.19 0, 42 Cmax (nM) 9703 2223 210 2185 AUC0-2 (nMh) 2188 2246 114 2108 AUCativa / AUCtotal 51% 95% TABLE 11 PHARMACOKINETIC PARAMETERS OF EXAMPLE 43-A AND ITS CORRESPONDENT ACTIVE FORM COMPOUND 43E-A IN THE CARTRIDGE SAMPLES VEIN DOOR AFTER ORAL ADMINISTRATION OF EXAMPLE 43-A (10 MG / KG) IN RAT WITH VEIN

CANULATED DOOR Prodrug Example 43-A Corresponding active form Compound 43e-A Portal sampling Carotid sampling PK parameter prodrug active form prodrug active form Tmax (h) 0.28 0.33 0.22 0.28 Cmax (nM) 4110 818 191 691 AUC0-2 (nMh) 2067 679 124 564

Prodrug Example 43-A Corresponding active form Compound 43e-A AUCactive / AUCtotal 25% 82% TABLE 12 PHARMACOKINETIC PARAMETERS OF EXAMPLE 1-B AND ITS COMPARED ACTIVE FORM COMPOUND 1E-A IN VESSEL AND SYSTEMIC SAMPLES AFTER ORAL ADMINISTRATION -B (10 MG / KG) IN RAT WITH VEIN DOOR

CANULATED Prodrug Example 1-B Corresponding active form Compound 1e-A Portal sampling Carotid sampling PK parameter prodrug active form prodrug active form Tmax (h) 0.083 0.25 0.083 0.5 Cmax (nM) 670 192 70 174 AUC0-2 (nMh) 266 164 40 184 AUCativa / AUCtotal 38% 82% TABLE 13 PHARMACOKINETIC PARAMETERS OF EXAMPLE 42-A AND ITS CORRESPONDING ACTIVE FORM COMPOUND 41C-A IN SAMPLES OF THE CAROTID AND VEHICLE THROUGH ORAL ADMINISTRATION 42-A (10 MG / KG) IN RAT WITH VEIN

CANULATED DOOR Prodrug Example 42-A Corresponding active form Compound 41c-A PK parameter Portal sampling Pro-drug carotid sampling active form prodrug active form Tmax (h) 0.19 0.42 0.22 0.36 Cmax (nM) 8917 3162 286 3326

Prodrug Example 42-A Corresponding active form Compound 41c-A AUC0-2 (nMh) 3461 3199 286 3326 AUCativa / AUCtotal 48% 96% TABLE 14 PHARMACOKINETIC PARAMETERS OF EXAMPLE 41-B AND ITS COMPOSITE ACTIVE FORM 41C-A IN CAROTID SAMPLES AND PORT VEIN AFTER ORAL ADMINISTRATION OF EXAMPLE 41-B (10 MG / KG) IN RAT WITH VEIN

CANULATED DOOR Prodrug Example 41-B Corresponding active form Compound 41c-A Portal sampling Carotid sampling PK parameter prodrug active form prodrug active form Tmax (h) 0.19 0.5 0.25 0.5 Cmax (nM) 7068 3315 29.6 3432 AUC0-2 (nMh) 1444 3211 22.5 3301 AUCativa / AUCtotal 69% 99%

[431] Based on the results set out above, it was concluded that the primary prodrug conversion site was the liver rather than the intestine, since AUCativa / AUCtotal was greater in the carotid artery sampling compared to AUCativa / AUCtotal in portal vein sampling.

Claims (38)

1. COMPOUND, of Formula (I): (I), characterized by: - R1 is C1-6 alkyl; - R2 is benzyl, said benzyl not substituted or substituted by one, two or three substituents, independently selected from halogen and C1-6 alkyl; - R3 is -NR4R5, where - R4 is C1-6 alkyl or C1-6 alkoxy-C1-6 alkyl; - R5 is (C1-6alkyl) 2NCOO-C1-6alkyl, C1-6alkoxy-C1-6alkyl, C1-6 alkoxycarbonyl (C1-6alkyl) amino C1-6alkyl, C1-6 alkoxycarbonyl (phenyl) C1alkyl -6, C1-6 alkoxycarbonyl C1-6alkyl, C1-6 alkoxycarbonyl C1-6alkyl, C1-6alkyl, C1-6alkyl (C1-6alkyl) amino C1-6alkyl or pyrrolidinylcarbamoyloxy C1-6alkyl; or - R4 and R5 together with the nitrogen to which they are attached form a heterocyclyl; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof; - for use in the treatment or prophylaxis of liver cancer; - on the condition that they are excluded; -6-amino-9-benzyl-2- (propylsulfonimidoyl) -7- (pyrrolidine-1-carbonyl) purin-8-one; -6-amino-9-benzyl-7- (piperidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (morpholine-4-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (3,3-dimethylpyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; Ethyl -1- [6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] pyrrolidine-2-carboxylate; -6-amino-7- (2-azospiro [3.3] heptane-2-carbonyl) -9-benzyl-2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (2-oxa-6-azospiro [3.3] heptane-6-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (3,3-difluoropyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-amino-9-benzyl-7- (3-fluoro-3-methyl-pyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; - and their enantiomers or diastereomers. 2. COMPOUND, for use according to claim 1, characterized in that - R1 is C1-6 alkyl; - R2 is benzyl, said benzyl not substituted or substituted by halogen or C1-6 alkyl; - R3 is azetidinyl; - piperazinyl substituted by C1-6 alkyl; - piperidinyl replaced by piperidinyl; - pyrrolidinyl; or -NR4R5, wherein: - R4 is C1-6 alkyl or C1-6 alkoxy-C1-6 alkyl; and - R5 is (C1-6alkyl) 2NCOO-C1-6alkyl, C1-6 alkoxy-C1-6alkyl, C1-6 alkoxycarbonyl (C1-6 alkyl) C1-6 alkylalkyl, C1-6 alkoxycarbonyl (phenyl) C1-6 alkyl, C1-6 alkoxycarbonyl C1-6 alkyl, C1-6 alkoxycarbonyl C1-6 alkyl, C1-6 alkyl, C1-6alkyl-carbonyl (C1-6alkyl) amino C1-6alkyl or pyrrolidinylcarbamoyloxy C1-6alkyl. 3. COMPOUND, for use according to claim 1 or 2, characterized in that: - R1 is ethyl or propyl; - R2 is benzyl, bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl; - R3 is azetidinyl; - 4-methylpiperazinyl; - piperidinylpiperidinyl; - pyrrolidinyl; or -NR4R5, where - R4 is methyl, ethyl, propyl or methoxyethyl; and - R5 is acetyl (methyl) aminoethyl, butyl, butyl (methyl) carbamoyloxyethyl, diethylcarbamoyloxyethyl, ethoxycarbonyl (methyl) aminoethyl, ethoxycarbonylethyl, ethoxycarbonylisobutyl, ethoxycarbonylisopentyl, ethoxycarbonylmethyl, ethoxycarbonyloxy (ethyl), ethoxycarbonyloxy (ethyl) phenyl) ethyl, isopropyl, methoxycarbonyl (methyl) aminoethyl, methoxyethyl, methoxypropyl, propyl, propyl (methyl) carbamoyloxyethyl, pyrrolidinylcarbamoyloxyethyl, tert-butoxycarbonyl (methyl) aminoethyl, tert-butoxycarbonylethyl, tert-butoxycarbonyl, tert-butoxycarbonyl, tertiary-butylcarbonyl). COMPOUND, for use according to claim 3, characterized in that R3 is azetidinyl, 4-methylpiperazinyl, piperidinylpiperidinyl, pyrrolidinyl, acetyl (methyl) aminoethyl (methyl) amino, bis (methoxyethyl) amino, butyl (ethyl) amino, butyl (methyl) amino, butyl (methyl) carbamoyloxyethyl (methyl) amino, diethylcarbamoyloxyethyl (methyl) amino, ethoxycarbonyl (methyl) aminoethyl (methyl) amino, ethoxycarbonylethyl (methyl) amino, ethoxycarbonylisobutyl (methyl) amino, ethoxycarbonylisopentyl (methyl) amino, ethoxycarbonylmethyl (methyl) amino, ethoxycarbonyloxyethyl) ethyl (methyl) amino, ethyl (methyl) amino, isobutyl (methyl) amino, isopropoxycarbonylisopentyl (methyl) amino, isopropoxycarbonyl (phenyl) ethyl (methyl) amino, isopropyl (methyl) amino, methoxycarbonyl (methyl) aminoethyl (methyl) amino, methoxyethyl (ethyl) amino, methoxyethyl (methyl) amino, methoxyethyl (propyl) amino, methoxypropyl (methyl) amino, propyl (ethyl) amino, propyl (methyl) amino, propyl (methyl) carbamoyloxyethyl (methyl) amino, pyrrolidinylcarbamoyloxyethyl (methyl) amino, tert-butoxycarbonyl (methyl) aminoethyl (methyl) amino, tert-butoxycarbonylethyl (methyl) amino, tert-butoxycarbonylisopentyl (methyl) amino or tert-butoxycarbonyl (phenyl) ethyl (methyl) amino. COMPOSITE, for use according to any one of claims 1 to 4, characterized in that R1 is ethyl. 6. COMPOUND, for use according to claim 1 or 2, characterized in that R2 represents a benzyl group substituted by halogen or C1-6-alkyl. 7. COMPOUND, for use according to any one of claims 2 to 6, characterized in that R2 represents bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl. 8. COMPOUND, for use according to claim 7, characterized in that R2 represents bromobenzyl, chlorobenzyl or fluorobenzyl. 9. COMPOUND, for use according to claim 1 or 2, characterized in that R3 represents -NR4R5, where R4 is C1-6 alkyl, R5 is C1-6 alkyl. 10. COMPOUND, for use according to claim 9, characterized in that R3 is propyl (methyl) amino or ethyl (methyl) amino. 11. COMPOUND, for use according to any one of claims 1, 2, 6 and 9, characterized in that: - R1 is C1-6 alkyl; - R2 is benzyl, said benzyl being replaced by halogen or C1-6 alkyl; and - R3 is -NR4R5, where R4 is C1-6 alkyl, R5 is C1-6 alkyl. 12. COMPOUND, for use according to claim 11, characterized in that: - R1 is ethyl; - R2 is methylbenzyl, bromobenzyl, chlorobenzyl or fluorobenzyl; and - R3 is propyl (methyl) amino or ethyl (methyl) amino. 13. COMPOUND FOR USE IN THE TREATMENT OR PROPHYLAXIS OF LIVER CANCER, characterized by being selected from: -6-Amino-9-benzyl-N-methyl-8-oxo-N-propyl-2- (propylsulfonimidoil) purine- 7-carboxamide; -6-Amino-9-benzyl-N- (2-methoxyethyl) -N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N-ethyl-8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-7- [4- (1-piperidyl) piperidine-1-carbonyl] -2- (propylsulfonimidoyl) purin-8-one; -6-Amino-9-benzyl-N-ethyl-N- (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N-butyl-N-ethyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-7- (azetidine-1-carbonyl) -9-benzyl-2- (propylsulfonimidoyl) purin-8-one; -6-Amino-9-benzyl-N-isopropyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-7- (4-methylpiperazine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one; -6-Amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-9-benzyl-N-isobutyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide; -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7- carbonyl] -methyl-amino] ethyl acetate; -3 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7- ethyl carbonyl] -methyl-amino] propanoate; -3 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7- tert-butyl carbonyl] -methyl-amino] propanoate; - (2S) -2 - [[6Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7- ethyl carbonyl] -methyl-amino] propanoate; - (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7- tert-butyl carbonyl] -methyl-amino] -4-methyl pentanoate; - (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7- carbonyl] -methyl-amino] -4-methyl-isopropyl pentanoate; - ethyl (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] -3-methyl-butanoate; - (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7- carbonyl] -methyl-amino] -4-methyl-pentanoate; - (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7- ethyl carbonyl] -methyl-amino] -3-phenyl-propanoate; - (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7- isopropyl carbonyl] -methyl-amino] -3-phenyl-propanoate; - (2S) -2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7- tert-butyl carbonyl] -methyl-amino] -3-phenyl-propanoate; -N- [2- [Acetyl (methyl) amino] ethyl] -6-amino-9-benzyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide; -N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7- methyl carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate; -N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7- tert-butyl carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate; -N- [2 - [[6-Amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7- ethyl carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate; -N-Butyl-N-methyl-carbamate of 2 - [[6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl; -Pyrrolidine-1-carboxylate of 2 - [[6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl; -N-Methyl-N-propyl-carbamate of 2 - [[6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl; -N, 2 - [[6-amino-9-benzyl-8-oxo-2- N-diethylcarbamate (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl; -Ethyl carbonate of 2 - [[6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl] -methyl-amino] ethyl; -6-Amino-N-butyl-9 - [(4-chlorophenyl) methyl] -N-methyl-8-oxo-2- [S (S) -propylsulfonimidoyl] purine-7-carboxamide; -6-amino-N-butyl-9 - [(4-chlorophenyl) methyl] -N-methyl-8-oxo-2- [S (S) - propylsulfonimidoyl] purine-7-carboxamide; -6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide; -6-Amino-N-methyl-8-oxo-N-propyl-2 [S (S) -propylsulfonimidoyl] -9- (p- tolylmethyl) purine-7-carboxamide; -6-Amino-N-methyl-8-oxo-N-propyl-2 [S (R) -propylsulfonimidoyl] -9- (p- tolylmethyl) purine-7-carboxamide; -6-Amino-2- [S (S) -propylsulfonimidoyl] -9- (p-tolylmethyl) -7- (pyrrolidine- 1-carbonyl) purin-8-one; -6-Amino-2- [S (R) -propylsulfonimidoyl] -9- (p-tolylmethyl) -7- (pyrrolidine- 1-carbonyl) purin-8-one; -6-Amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [S (S) - propylsulfonimidoyl] -9- (p-tolylmethyl) purine-7-carboxamide; -6-Amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [S (R) - propylsulfonimidoyl] -9- (p-tolylmethyl) purine-7-carboxamide; -6-Amino-N-ethyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) -9- (p- tolylmethyl) purine-7-carboxamide; -6-Amino-N-butyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) -9- (p- tolylmethyl) purine-7-carboxamide; -6-Amino-9 - [(4-chlorophenyl) methyl] -2- [S (R) -ethylsulfonimidoyl] -N-methyl-8- oxo-N-propyl-purine-7-carboxamide; -6-Amino-9 - [(4-chlorophenyl) methyl] -2- [S (S) -ethylsulfonimidoyl] -N-methyl-8- oxo-N-propyl-purine-7-carboxamide; -6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N- methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-2- [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-9- (p- tolylmethyl) purine-7-carboxamide; -6-Amino-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-N-propyl-9- (p- tolylmethyl) purine-7-carboxamide; -6-Amino-N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-9- (p- tolylmethyl) purine-7-carboxamide; -6-Amino-N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-9- (p- tolylmethyl) purine-7-carboxamide; -6-Amino-2- [S (S) ethylsulfonimidoyl] -9 - [(4-fluorophenyl) methyl] -N-methyl-8- oxo-N-propyl-purine-7-carboxamide; -6-Amino-2- [S (R) ethylsulfonimidoyl] -9 - [(4-fluorophenyl) methyl] -N-methyl-8- oxo-N-propyl-purine-7-carboxamide; -6-Amino-N-ethyl-2- (ethylsulfonimidoyl) -9 - [(4-fluorophenyl) methyl] -N-methyl- 8-oxo-purine-7-carboxamide; -6-Amino-N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - 9 - [(4-fluorophenyl) methyl] -N- methyl-8-oxo-purine-7-carboxamide; -6-Amino-N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - 9 - [(4-fluorophenyl) methyl] -N- methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -2- (ethylsulfonimidoyl) -N-methyl-8-oxo- N-propyl-purine-7-carboxamide; -6-Amino-2- [S (R) -ethylsulfonimidoyl] -9 - [(4-bromophenyl) methyl] -N-methyl- 8-oxo-N-propyl-purine-7-carboxamide; -6-Amino-2- [S (S) -ethylsulfonimidoyl] -9 - [(4-bromophenyl) methyl] -N-methyl- 8-oxo-N-propyl-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimidoyl) -N-methyl- 8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; and -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof. 14. COMPOUND, for use according to claim 13, characterized by being selected from; -6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimidoyl] -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimidoyl) -N-methyl-8-oxo-purine-7-carboxamide; -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (S) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; and -6-Amino-9 - [(4-bromophenyl) methyl] -N-ethyl-2- [S (R) - (ethylsulfonimidoyl)] - N-methyl-8-oxo-purine-7-carboxamide; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof. 15. COMPOUND, for use according to claim 13, characterized in that the compound is: - 6-Amino-9 - [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] -N- methyl-8-oxo-purine-7-carboxamide; - or the enantiomer or diastereomer or pharmaceutically acceptable salt thereof. 16. COMPOUND or enantiomer or diastereomer or pharmaceutically acceptable salt thereof, for use according to any one of claims 1 to 15, characterized in that the liver cancer is hepatocellular carcinoma, hepatoma, cholangiocarcinoma, hepatoblastoma, liver carcinoma, liver angiosarcoma, or metastatic liver cancer. 17. COMPOUND or enantiomer or diastereomer or pharmaceutically acceptable salt thereof, for use according to any one of claims 1 to 15, characterized in that liver cancer is hepatocellular carcinoma. 18. PHARMACEUTICAL OR MEDICINE COMPOSITION, characterized in that it comprises a compound according to any one of claims 1 to 15 and a therapeutically inert vehicle, for use in the treatment or prophylaxis of liver cancer. 19. Use of a compound according to any one of claims 1 to 15, characterized in that it is for the preparation of a medicament for the treatment or prophylaxis of liver cancer. 20. METHOD FOR THE TREATMENT OR PROPHYLAXIS OF LIVER CANCER, characterized in that it comprises the administration of a therapeutically effective amount of a compound as defined in any one of claims 1 to 15. 21. A COMPOUND according to any one of claims 1 to 15, or a pharmaceutical composition or a medicament comprising such a compound: - characterized in that it is for use; a) in the treatment or prophylaxis of liver cancer in combination with a PD1 antagonist or PD-L1 antagonist antibody; or b) in the treatment of a patient suffering from liver cancer in combination with a PD1 antagonist or PD-L1 antagonist antibody. 22. COMPOUND, according to any of the realization examples 1 to 15, or a pharmaceutical composition or a medicine comprising such a compound: - characterized for being for use in the treatment or prophylaxis of liver cancer; and - wherein the treatment is combined with a PD1 antagonist antibody or PD-L1 antagonist antibody. 23. USE of a compound according to any of the realization examples 1 to 15: - characterized for being for the preparation of a medicine for the treatment or prophylaxis of liver cancer; and - wherein the treatment is combined with a PD1 antagonist antibody or PD-L1 antagonist antibody. 24. COMPOUND, COMPOSITION, MEDICINE OR USE, according to any one of claims 21 to 23, characterized in that the treatment is combined with a PD1 antagonist antibody. 25. COMPOUND, COMPOSITION, MEDICINE OR USE, according to claim 24, characterized in that the PD1 antagonist antibody is nivolumab or pemprolizumab. 26. COMPOUND, COMPOSITION, MEDICINE OR USE, according to claim 25, characterized in that the compound is 6-Amino-9- [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] - N-methyl-8-oxo-purine-7-carboxamide. 27. COMPOUND, COMPOSITION, MEDICINE OR USE, according to claim 24, characterized in that the PD1 antagonist antibody comprises a VH heavy chain variable domain with an amino acid sequence of SEQ ID NO: 5 and a VL light chain variable domain with an amino acid sequence of SEQ ID NO: 6. 28. COMPOUND, COMPOSITION, MEDICINE OR USE, according to claim 26, characterized in that the compound is 6-Amino-9- [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] - N-methyl-8-oxo-purine-7-carboxamide. 29. COMPOUND, COMPOSITION, MEDICINE OR USE, according to any of claims 21 to 23, characterized in that the treatment is combined with a PD-L1 antagonist antibody. 30. COMPOUND, COMPOSITION, MEDICINE OR USE, according to claim 29, characterized in that the PD-L1 antagonist antibody used in the combined therapy is atezolizumab or durvalumab or avelumab (in an example of a preferred embodiment is atezolizumab). 31. COMPOUND, COMPOSITION, MEDICINE OR USE, according to claim 30, characterized in that the compound is 6-Amino-9- [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] - N-methyl-8-oxo-purine-7-carboxamide. 32. COMPOUND, COMPOSITION, MEDICINE OR USE, according to any one of claims 21 to 31, characterized in that an antiangiogenic agent is additionally used in combination therapy. 33. COMPOUND, COMPOSITION, MEDICINE OR USE, according to any one of claims 21 to 31, characterized by an additional antiangiogenic agent selected from sorafenib, regorafenib, sunitinib or bevacizumab (in an example of preferred embodiment the antiangiogenic agent is sorafenib; in one preferred embodiment the antiangiogenic agent is bevacizumab) to be used in combination therapy. 34. A COMPOUND according to any one of claims 1 to 15, or a pharmaceutical composition or a medicament comprising such a compound: - characterized in that it is for use; a) in the treatment or prophylaxis of liver cancer in combination with an antiangiogenic agent; or b) in the treatment of a patient suffering from liver cancer in combination with an antiangiogenic agent. 35. COMPOUND, according to any of the realization examples 1 to 15, or a pharmaceutical composition or a drug comprising such compound: - characterized for being for use in the treatment or prophylaxis of liver cancer; - where the treatment is combined with an antiangiogenic agent. 36. USE, of a compound according to any one of claims 1 to 15: - for the preparation of a medicament for the treatment or prophylaxis of liver cancer; and - characterized by the treatment being combined with an antiangiogenic agent. 37. COMPOUND, COMPOSITION, MEDICINE OR USE, according to any one of claims 34 to 36, characterized in that the antiangiogenic agent is selected from sorafenib, regorafenib, sunitinib or bevacizumab (in a preferred embodiment the antiangiogenic agent is sorafenib in an example of a preferred embodiment the antiangiogenic agent is bevacizumab). 38. COMPOUND, COMPOSITION, MEDICINE OR USE, according to claim 37, characterized in that the compound is 6-Amino-9- [(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimidoyl] - N-methyl-8-oxo-purine-7-carboxamide.