JP2021514972A - 7-substituted sulfonimideylprinone compounds and derivatives for the treatment and prevention of liver cancer - Google Patents

Abstract

The present invention is a compound of formula (I): [where R1, R2 and R3 are as described herein] for the treatment and / or prevention (use in) of liver cancer, and the like. With respect to prodrugs or pharmaceutically acceptable salts thereof, enantiomers or diastereomers. [Selection diagram] Fig. 3

Description

The present invention relates to novel sulfonimide ylprinone derivatives having Toll-like receptor agonist activity in vivo for the treatment and / or prevention (use in) of liver cancer.

Liver cancer is the fifth most common form of cancer. Approximately 750,000 cases are diagnosed each year, and approximately 700,000 people die from the disease each year, the third most common cause of cancer death in the world (Ferry et al. , Int. J. Cancer 127: 2893-2917 (2010)). In the United States, the incidence of primary liver cancer is rising, and despite some advances in the detection and treatment of local diseases, the 5-year survival rate for late-stage liver cancer is still well below 10%. (American-Cancer-Society. 2012. Cancer Factors & Diseases 2012. Atlanta: American Cancer Society).

Established treatments for liver cancer include surgical resection of the part of the liver that contains the tumor (partial liver resection), liver transplantation, transcatheter arterial chemoembolization (TACE), radiofrequency ablation (RFA), or Tumor destruction in situ by various methods such as cryoresection, and administration of sorafenib are included. Treatment options for late-stage liver patients are limited. Therefore, effective treatment of liver cancer is a major unmet medical need.

［式中、Ｒ^１からＲ^３は後述の通りである］の化合物、又はその薬学的に許容される塩、エナンチオマー又はジアステレオマーに関する。 The present invention has the formula (I) :.

In the formula, R ¹ to R ³ are as described below], or pharmaceutically acceptable salts thereof, enantiomers or diastereomers thereof.

Toll-like receptors (TLRs) detect a wide range of conserved pathogen-associated molecular patterns (PAMPs). It plays an important role in sensing the infiltration of pathogens and the subsequent initiation of the innate immune response. There are 10 known members in the human TLR family, which are cytoplasmic ends containing an extracellular leucine-rich domain and a conserved Toll / interleukin (IL) -1 receptor (TIR) domain. It is a type I transmembrane protein characterized by. Within this family, TLR3, TLR7, TLR8 and TLR9 are located inside endosomes.

TLR7 can be activated by binding to a specific small molecule ligand (ie, TLR7 agonist) or its native ligand (ie, single-strand RNA, ssRNA). Following the binding of ssRNA to TLR7, the receptor in dimeric form undergoes structural changes and then recruits adapter proteins in its cytoplasmic domain, including the myeloid differentiation primary response gene 88 (MyD88). It is thought to bring. Following initiation of the receptor signaling cascade via the MyD88 pathway, cytoplasmic transcription factors such as interferon regulator 7 (IRF-7) and nuclear factor kappa B (NF-κB) are activated. These transcription factors then translocate into the nucleus and initiate transcription of various genes, such as IFN-α and other antiviral cytokine genes.

WO 201772662 relates to a TLR7 agonist-anti-HER2 conjugate for the treatment of HER2-positive cancer. Hotz et al, Oncoimmunology 2012, 227-228 relates to cancer treatment with TLR7 agonists. However, so far, no TLR7 agonist has been used systemically for the treatment of cancer. The topical TLR7 agonist imiquimod is only known to induce immune-mediated rejection of skin metastases in patients with breast cancer (Adams s., Kozhaya L., Martiniuk F., Meng T. et al. C., Chiriboga L., Leebes L., Hochman T., Shuman N., Axelrod D., Speyer J., et al. Clin. Cancer Res. 2012; 18: 6748-6757).

The present invention is a series of novel 6-amino-2-sulfonimideyl-9-substitution-7-substitutions with Toll-like receptor agonist activity for use in the treatment or prevention (prevention) of liver cancer. With respect to purine-8-one compounds and their prodrugs.

The potent and safe TLR7 agonist prodrugs described herein have been found to be effective in the treatment of liver cancer alone or in combination with other agents.

The present invention provides a series of novel 6-amino-2-sulfonimideyl-9-substituted-7-substituted-purine-8-one compounds with Toll-like receptor agonist activity and prodrugs thereof. The invention also presents the bioactivity of such compounds that induce cytokine / chemokine release, elevated SEAP levels by activating Toll-like receptors such as TLR7 receptors, and the parental of the prodrug in the presence of human hepatocytes. Provided are metabolic conversions to compounds and therapeutic or prophylactic use of such compounds and their pharmaceutical compositions containing these compounds and their prodrugs to treat or prevent liver cancer. The present invention also provides compounds with excellent activity. In addition, the compounds of formula (I) also exhibit good solubility and PK profile.

［式中、
Ｒ^１はＣ_１−６アルキルであり；
Ｒ^２はベンジルであり、前記ベンジルは、無置換であるか又はハロゲン及びＣ_１−６アルキルより独立して選択された一つ、二つ、又は三つの置換基で置換されており；
Ｒ^３は、−ＮＲ^４Ｒ^５であって、ここで
Ｒ^４は、Ｃ_１−６アルキル又はＣ_１−６アルコキシＣ_１−６アルキルであり；
Ｒ^５は、（Ｃ_１−６アルキル）_２ＮＣＯＯＣ_１−６アルキル、Ｃ_１−６アルコキシＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニル（Ｃ_１−６アルキル）アミノＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニル（フェニル）Ｃ_１−６アルキル、Ｃ_１−６アルコキシカルボニルＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニルオキシＣ_１−６アルキル、Ｃ_１−６アルキル、Ｃ_１−６アルキルカルボニル（Ｃ_１−６アルキル）アミノＣ_１−６アルキル又はピロリジニルカルバモイルオキシＣ_１−６アルキルであるか；又は
Ｒ^４及びＲ^５は、それらが結合する窒素と共にヘテロシクリルを形成する］
の新規化合物、又はその薬学的に許容される塩、エナンチオマー若しくはジアステレオマーに関し；
但し、
６−アミノ−９−ベンジル−２−（プロピルスルホンイミドイル）−７−（ピロリジン−１−カルボニル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（ピぺリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（モルホリン−４−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３，３−ジメチルピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
エチル １−［６−アミノ−９−ベンジル−８−オキソ−２−（プロピルスルホンイミドイル）プリン−７−カルボニル］ピロリジン−２−カルボキシレート；
６−アミノ−７−（２−アザスピロ［３．３］ヘプタン−２−カルボニル）−９−ベンジル−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（２−オキサ−６−アザスピロ［３．３］ヘプタン−６−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３，３−ジフルオロピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３−フルオロ−３−メチル−ピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
及びこれらのエナンチオマー又はジアステレオマーは除外される。 The present invention has formula (I): for use in the treatment or prevention of liver cancer.

[During the ceremony,
R ¹ is C _1-6 alkyl;
R ² is benzyl, which is unsubstituted or substituted with one, two, or three substituents independently selected from _{halogens and C 1-6 alkyls;}
R ³ is -NR ⁴ R ⁵ , where R ⁴ is C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl;
R ⁵ is (C _1-6 alkyl) ₂ NCOCOC _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxycarbonyl (C _1-6 alkyl) amino C _1-6 alkyl, C _1-6 Alkoxycarbonyl (Phenyl) C _1-6 Alkyl, C _1-6 Alkoxycarbonyl C _1-6 Alkyl, C _1-6 Alkoxycarbonyloxy C _1-6 Alkyl, C _1-6 Alkyl, C _1-6 Alkyl Is it a carbonyl (C _1-6 alkyl) amino C _1-6 alkyl or pyrrolidinyl carbamoyloxy C _1-6 alkyl; or R ⁴ and R ⁵ form heterocyclyls with the nitrogen they bind to]
With respect to the novel compound of, or its pharmaceutically acceptable salt, enantiomer or diastereomer;
However,
6-Amino-9-Benzyl-2- (propylsulfonimideyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-9-benzyl-7- (piperidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (Morpholine-4-carbonyl) -2- (Propylsulfonimideyl) Purine-8-one;
6-Amino-9-benzyl-7- (3,3-dimethylpyrrolidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
Ethyl 1- [6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] pyrrolidine-2-carboxylate;
6-Amino-7- (2-azaspiro [3.3] heptane-2-carbonyl) -9-benzyl-2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (2-oxa-6-azaspiro [3.3] heptane-6-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (3,3-difluoropyrrolidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (3-Fluoro-3-methyl-pyrrolidin-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
And these enantiomers or diastereomers are excluded.

These prodrug compounds are particularly useful for the treatment of liver cancer because they are activated (converted to their active form) in the liver. They are used in vivo in a cell model of liver cancer (alone or in combination with anti-PD1 / PD1 antibodies or anti-angiogenic agents) and in vitro against liver cancer cells (peripheral blood cells and /). It exhibits a beneficial antitumor effect (or by activation of factors).

The present invention also relates to their use for the manufacture of medicaments for the treatment or prevention of liver cancer, and formulations based on the compounds according to the invention for the treatment or prevention of liver cancer. Thus, the compound of formula (I) can be used to treat or prevent liver cancer, especially hepatocellular carcinoma, hepatoma, cholangiocarcinoma, lung blastoma, liver cancer, hepatoangisarcoma, or metastatic liver cancer. It is useful for.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. In addition, the following definitions are given to illustrate and define the meaning and scope of the various terms used to describe the invention.

The term "C _1-6 alkyl" is saturated, direct containing 1 to 6, especially 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. It means a chain or branched chain alkyl group. Specific "C _1-6 alkyl" groups are methyl, ethyl and n-propyl.

The term "C _1-6 alkoxy" means a group of _{formula C 1-6 alkyl-O-.} Examples of C _1-6 alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Specific "C _1-6 alkoxy" groups are methoxy, ethoxy and isopropoxy. The more specific C _1-6 alkoxy group is ethoxy.

The terms "halogen" and "halo" are used interchangeably here to mean fluoro, chloro, bromo, or iodine.

The term "heterocyclyl" is monovalently saturated or partially unsaturated, comprising 1 to 5 ring heteroatoms selected from N, O, and S, and consisting of 3 to 10 ring atoms with the remaining ring atoms being carbon. Refers to a saturated monocyclic or bicyclic system. In certain embodiments, the heterocyclyl comprises 1, 2 or 3 ring heteroatoms selected from N, O, and S and consists of 4 to 7 ring atoms in which the remaining ring atoms are carbon monovalent. It is a saturated monocyclic system. Examples of monocyclic saturated heterocyclyls are aziridinyl, oxylanyl, azetidinyl, oxetanyl, pyrrolidinyl, dimethylpyrrolidinyl, ethoxycarbonylpyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolydinyl, imidazolidinyl, oxazolidinyl, isooxazolidinyl, thiazolidinyl. , Piperidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. The monocyclic saturated heterocyclyl can be further substituted with one to three substituents independently selected from _{halogen, C 1-6} alkyl and C _{1-6 alkoxycarbonyl.} Examples of substituted monocyclic saturated heterocyclyls are 4-methylpiperazinyl, dimethylpyrrolidinyl, ethoxycarbonylpyrrolidinyl, difluoropyrrolidinyl, fluoro (methyl) pyrrolidinyl. Examples of bicyclic saturated heterocyclyls are azabicyclo [3.2.1] octyl, quinucridinyl, oxaazabicyclo [3.2.1] octyl, azabicyclo [3.3.1] nonyl, oxaazabicyclo [3.3]. .1] Nonyl, thiaazabicyclo [3.3.1] nonyl, azaspiro [3.3] heptanyl and oxaazaspiro [3.3] heptanyl. Examples of partially unsaturated heterocyclyls are dihydrofuryl, imidazolinyl, dihydrooxazolyl, tetrahydropyridinyl and dihydropyranyl.

The term "carbonyl", alone or in combination, refers to the group -C (O)-.

The term "C _1-6 alkylcarbonyl" refers to the group C _1-6 alkyl-C (O) _-where "C 1-6 alkyl" is as defined above. The particular "C _1-6 alkylcarbonyl" group is acetyl.

The term "enantiomer" means two stereoisomers of a compound that are mirror images of each other that cannot be superimposed.

The term "diastereomer" means a steric isomer having two or more chirality centers whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectroscopic properties and reactivity.

The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acids and base addition salts.

The term "pharmaceutically acceptable acid addition salt" refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitrate, carbonic acid, phosphoric acid, as well as aliphatic, cyclic aliphatic, aromatic, aromatic fats of organic acids. Organic acids selected from the family, heterocyclic, carboxylic acid and sulfonic acid classes, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvate, oxalic acid, malic acid, maleic acid, malon. (Maloneic) acid, succinic acid, fumaric acid, tartrate acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranic acid, benzoic acid, silicate acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid , Ethan sulfonic acid, p-toluene sulfonic acid and salicyl acid, which means a pharmaceutically acceptable salt.

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

The compounds of general formula (I) and their prodrugs containing one or more chiral centers can be either racemic, diastereomeric mixtures, or optically active monoisomers. Racemates can be separated into enantiomers according to known methods. In particular, diastereomeric salts that can be separated by crystallization are formed from the racemic mixture by reaction with optically active acids such as D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphor-sulfonic acid. To.

The term "prodrug" means a form or derivative of a compound that is metabolized in vivo, eg, by a biological fluid or enzyme by the subject after administration, to a pharmacologically active form of the compound in order to produce the desired pharmacological effect. To do. Prodrugs include, for example, "The Organic Chemistry of Drug Design and Drug Action", by Richard B. et al. Silverman, Academic Press, San Diego, 2004, Chapter 8 Prodrugs and Drug Delivery Systems, pp. 497-558.

By "pharmacologically active metabolite" is intended to mean a pharmacologically active product produced through metabolism in the body of a particular compound or salt thereof. After entering the body, most drugs become substrates for chemical reactions that can alter their physical properties and biological effects. These metabolic transformations, which usually affect the polarity of the compounds of the invention, alter the way the drug is distributed and excreted from the body. However, in some cases, drug metabolism is necessary for a therapeutic effect.

The term "therapeutically effective amount (therapeutically effective amount)", when administered to a subject, is described herein (i) treating or preventing a particular disease, condition, or disorder, (ii). The present invention alleviates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder. Means the amount of compound or molecule of. Therapeutically effective amounts depend on the compound, the condition being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors. It will change accordingly.

The term "pharmaceutical composition" means a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient that is administered to a mammal (eg, human) in need thereof with a pharmaceutically acceptable additive.

［式中、
Ｒ^１はＣ_１−６アルキルであり；
Ｒ^２はベンジルであり、前記ベンジルは、無置換であるか又はハロゲン及びＣ_１−６アルキルより独立して選択された一つ、二つ、又は三つの置換基で置換されており；
Ｒ^３は、−ＮＲ^４Ｒ^５であって、ここで
Ｒ^４は、Ｃ_１−６アルキル又はＣ_１−６アルコキシＣ_１−６アルキルであり；
Ｒ^５は、（Ｃ_１−６アルキル）_２ＮＣＯＯＣ_１−６アルキル、Ｃ_１−６アルコキシＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニル（Ｃ_１−６アルキル）アミノＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニル（フェニル）Ｃ_１−６アルキル、Ｃ_１−６アルコキシカルボニルＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニルオキシＣ_１−６アルキル、Ｃ_１−６アルキル、Ｃ_１−６アルキルカルボニル（Ｃ_１−６アルキル）アミノＣ_１−６アルキル又はピロリジニルカルバモイルオキシＣ_１−６アルキルである；か又は
Ｒ^４及びＲ^５はそれらが結合する窒素と共にヘテロシクリルを形成する］
の新規化合物、又はその薬学的に許容される塩、エナンチオマー若しくはジアステレオマーに関し；
但し、
６−アミノ−９−ベンジル−２−（プロピルスルホンイミドイル）−７−（ピロリジン−１−カルボニル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（ピぺリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（モルホリン−４−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３，３−ジメチルピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
エチル １−［６−アミノ−９−ベンジル−８−オキソ−２−（プロピルスルホンイミドイル）プリン−７−カルボニル］ピロリジン−２−カルボキシレート；
６−アミノ−７−（２−アザスピロ［３．３］ヘプタン−２−カルボニル）−９−ベンジル−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（２−オキサ−６−アザスピロ［３．３］ヘプタン−６−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３，３−ジフルオロピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３−フルオロ−３−メチル−ピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
及びこれらのエナンチオマー又はジアステレオマーは除外される。 TLR7 Agonists and Prodrugs The present invention has formula (I): for use in the treatment or prevention of liver cancer.

[During the ceremony,
R ¹ is C _1-6 alkyl;
R ² is benzyl, which is unsubstituted or substituted with one, two, or three substituents independently selected from _{halogens and C 1-6 alkyls;}
R ³ is -NR ⁴ R ⁵ , where R ⁴ is C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl;
R ⁵ is (C _1-6 alkyl) ₂ NCOCOC _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxycarbonyl (C _1-6 alkyl) amino C _1-6 alkyl, C _1-6 Alkoxycarbonyl (Phenyl) C _1-6 Alkyl, C _1-6 Alkoxycarbonyl C _1-6 Alkyl, C _1-6 Alkoxycarbonyloxy C _1-6 Alkyl, C _1-6 Alkyl, C _1-6 Alkyl Carbonyl (C _1-6 alkyl) Amino C _1-6 alkyl or pyrrolidinyl carbamoyloxy C _1-6 alkyl; or R ⁴ and R ⁵ form heterocyclyls with the nitrogen to which they bind]
With respect to the novel compound of, or its pharmaceutically acceptable salt, enantiomer or diastereomer;
However,
6-Amino-9-Benzyl-2- (propylsulfonimideyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-9-benzyl-7- (piperidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (Morpholine-4-carbonyl) -2- (Propylsulfonimideyl) Purine-8-one;
6-Amino-9-benzyl-7- (3,3-dimethylpyrrolidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
Ethyl 1- [6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] pyrrolidine-2-carboxylate;
6-Amino-7- (2-azaspiro [3.3] heptane-2-carbonyl) -9-benzyl-2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (2-oxa-6-azaspiro [3.3] heptane-6-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (3,3-difluoropyrrolidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (3-Fluoro-3-methyl-pyrrolidin-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
And these enantiomers or diastereomers are excluded.

A further embodiment of the invention is (ii) formula (I) for use in the treatment or prevention of liver cancer.
[During the ceremony,
R ¹ is C _1-6 alkyl;
R ² is benzyl, said benzyl being unsubstituted or substituted with halogen or C _1-6 alkyl;
R ³ is azetidinyl;
Piperazinyl substituted with C _{1-6 alkyl;}
Piperidinyl substituted with piperidinyl;
Pyrrolidinyl; or −NR ⁴ R ⁵ , where R ⁴ is C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl;
R ⁵ is (C _1-6 alkyl) ₂ NCOCOC _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxycarbonyl (C _1-6 alkyl) amino C _1-6 alkyl, C _1-6 Alkoxycarbonyl (Phenyl) C _1-6 Alkyl, C _1-6 Alkoxycarbonyl C _1-6 Alkyl, C _1-6 Alkoxycarbonyloxy C _1-6 Alkyl, C _1-6 Alkyl, C _1-6 Alkyl Carbonyl (C _1-6 alkyl) Amino C _1-6 alkyl or pyrrolidinyl carbamoyloxy C _1-6 alkyl]
Or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

A further embodiment of the invention is (iii) formula (I) for use in the treatment or prevention of liver cancer.
[During the ceremony,
R ¹ is ethyl or propyl;
R ² is benzyl, bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl;
R ³ is azetidinyl;
4-Methylpiperazinyl;
Piperidinyl Piperidinil;
Pyrrolidinyl; or -NR ⁴ R ⁵ , where R ⁴ is methyl, ethyl, propyl or methoxyethyl;
R ⁵ is acetyl (methyl) aminoethyl, butyl, butyl (methyl) carbamoyloxy ethyl, diethylcarbamoyloxy ethyl, ethoxycarbonyl (methyl) aminoethyl, ethoxycarbonylethyl, ethoxycarbonyl isobutyl, ethoxycarbonyl isopentyl, ethoxycarbonylmethyl , Ethoxycarbonyloxyethyl, ethoxycarbonyl (phenyl) ethyl, ethyl, isobutyl, isopropoxycarbonyl isopentyl, isopropoxycarbonyl (phenyl) ethyl, isopropyl, methoxycarbonyl (methyl) aminoethyl, methoxyethyl, methoxypropyl, propyl, propyl (Methyl) carbamoyloxyethyl, pyrrolidinyl carbamoyloxyethyl, tert-butoxycarbonyl (methyl) aminoethyl, tert-butoxycarbonylethyl, tert-butoxycarbonyl isopentyl or tert-butoxycarbonyl (phenyl) ethyl]
Or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

A further embodiment of the present invention is the formula (I) for use in the treatment or prevention of (iii-1) liver cancer.
[During the ceremony,
R ¹ is ethyl or propyl;
R ² is benzyl, chlorobenzyl, fluorobenzyl or methylbenzyl;
R ³ is azetidinyl;
4-Methylpiperazinyl;
Piperidinyl Piperidinil;
Pyrrolidinyl; or -NR ⁴ R ⁵ , where R ⁴ is methyl, ethyl, propyl or methoxyethyl;
R ⁵ is acetyl (methyl) aminoethyl, butyl, butyl (methyl) carbamoyloxy ethyl, diethylcarbamoyloxy ethyl, ethoxycarbonyl (methyl) aminoethyl, ethoxycarbonylethyl, ethoxycarbonyl isobutyl, ethoxycarbonyl isopentyl, ethoxycarbonylmethyl , Ethoxycarbonyloxyethyl, ethoxycarbonyl (phenyl) ethyl, ethyl, isobutyl, isopropoxycarbonyl isopentyl, isopropoxycarbonyl (phenyl) ethyl, isopropyl, methoxycarbonyl (methyl) aminoethyl, methoxyethyl, methoxypropyl, propyl, propyl (Methyl) carbamoyloxyethyl, pyrrolidinyl carbamoyloxyethyl, tert-butoxycarbonyl (methyl) aminoethyl, tert-butoxycarbonylethyl, tert-butoxycarbonyl isopentyl or tert-butoxycarbonyl (phenyl) ethyl]
Or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

A further embodiment of the invention is (iv) formula (I) for use in the treatment or prevention of liver cancer.
[In the formula, R ³ is azetidinyl, 4-methylpiperazinyl, piperidinyl piperidinyl, 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, isopropoxycarbonyl isopentyl (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, pyrrolidinyl carbamoyloxyethyl (Methyl) amino, tert-butoxycarbonyl (methyl) aminoethyl (methyl) amino, tert-butoxycarbonylethyl (methyl) amino, tert-butoxycarbonyl isopentyl (methyl) amino or tert-butoxycarbonyl (phenyl) ethyl (methyl) ) Amino]
Or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Further embodiment of the present invention is a compound of (v) for use in the treatment or prevention of liver cancer, the formula (I) [wherein, R ¹ is ethyl.

Further embodiment of the invention, (vi) for use in the treatment or prevention of liver cancer, the formula (I) [wherein, R ² is benzyl substituted with halogen or C _1-6 alkyl There is] compound.

Further embodiment of the present invention, (vii) for use in the treatment or prevention of liver cancer, the formula (I) [wherein, R ² is a bromobenzyl, chlorobenzyl, fluorobenzyl or methyl benzyl ] Compound.

Further embodiment of the present invention, (vii-1) for use in the treatment or prevention of liver cancer, the formula (I) [wherein, R ² is chloro benzyl, fluorobenzyl or methylbenzyl] It is a compound of.

Further embodiment of the present invention, for use in the treatment or prevention of (viii) liver cancer, formula (I) [wherein, R ² is bromo benzyl, chlorobenzyl or fluorobenzyl] compounds of Is.

Further embodiment of the present invention, (viii-1) for use in the treatment or prevention of liver cancer, the formula (I) [wherein, R ² is chlorobenzyl or fluorobenzyl] with a compound of is there.

A further embodiment of the invention is (ix) for use in the treatment or prevention of liver cancer, in formula (I) [where R ³ is -NR ⁴ R ⁵ , where R ⁴ is C. a _1-6 alkyl, ^{R 5} is a compound of _{C 1-6} alkyl.

Further embodiment of the present invention is a (x) for use in the treatment or prevention of liver cancer, the formula (I) [wherein, R ³ is propyl (methyl) amino or (methyl) amino ] Compound.

A further embodiment of the invention is (xi) formula (I) for use in the treatment or prevention of liver cancer.
[During the ceremony,
R ¹ is C _1-6 alkyl;
R ² is benzyl, said benzyl substituted with _{halogen or C 1-6 alkyl;}
R ³ is -NR ⁴ R ⁵ , where R ⁴ is C _1-6 alkyl and R ⁵ is C _1-6 alkyl]
Or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

A further embodiment of the invention is (xii) formula (I) for use in the treatment or prevention of liver cancer
[During the ceremony,
R ¹ is ethyl;
R ² is methyl benzyl, bromobenzyl, chlorobenzyl or fluorobenzyl;
R ³ is propyl (methyl) amino or ethyl (methyl) amino]
Or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

A further embodiment of the present invention is the formula (I) for use in the treatment or prevention of (xii-1) liver cancer.
[During the ceremony,
R ¹ is ethyl;
R ² is methyl benzyl, chlorobenzyl or fluorobenzyl;
R ³ is propyl (methyl) amino or ethyl (methyl) amino]
Or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment of the invention is a specific compound of formula (I) listed below for use in the treatment or prevention of (xiii) liver cancer:
6-Amino-9-Benzyl-N-Methyl-8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N- (2-methoxyethyl) -N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N-Ethyl-8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-Benzyl-7- [4- (1-piperidyl) piperidine-1-carbonyl] -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-benzyl-N-Ethyl-N- (2-Methoxyethyl) -8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N-Butyl-N-Ethyl-8-oxo-2- (propylsulfoneimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-7- (azetidine-1-carbonyl) -9-benzyl-2- (propylsulfoneimideyl) purine-8-one;
6-Amino-9-benzyl-N-isopropyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-7- (4-methylpiperazin-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N-isobutyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
Ethyl 2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] acetate;
Ethyl 3-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate;
tert-Butyl 3-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate;
tert-Butyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate;
Isopropyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-methyl-butanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate;
Isopropyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanol;
tert-Butyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate;
N- [2- [Acetyl (Methyl) Amino] Ethyl] -6-Amino-9-Benzyl-N-Methyl-8-oxo-2- (propylsulfonimideyl) Purine-7-Carboxamide;
Methyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;
tert-butyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;
Ethyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N-butyl-N-methyl-carbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl pyrrolidine-1-carboxylate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N-methyl-N-propyl-carbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N, N-diethylcarbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl ethyl carbonate;
6-Amino-N-Butyl-9-[(4-Chlorophenyl) Methyl] -N-Methyl-8-oxo-2- [S (S) -propylsulfonimideyl] Purine-7-Carboxamide;
6-Amino-N-Butyl-9-[(4-Chlorophenyl) Methyl] -N-Methyl-8-oxo-2- [S (S) -propylsulfonimideyl] Purine-7-Carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-N-Methyl-8-oxo-N-propyl-2 [S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Methyl-8-oxo-N-propyl-2 [S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- [S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-2- [S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-N- (2-Methoxyethyl) -N-Methyl-8-oxo-2-[S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N- (2-Methoxyethyl) -N-Methyl-8-oxo-2-[S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-N-Methyl-8-oxo-2- (propylsulfoneimideyl) -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Butyl-N-Methyl-8-oxo-2- (propylsulfoneimideyl) -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -2- [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-2- [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-2 [S (S) -Ethylsulfonimideyl] -N-Methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-2- [S (R) -Ethylsulfonimideyl] -N-Methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- [S (S) ethylsulfonimideyl] -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-2- [S (R) Ethylsulfonimideyl] -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-N-Ethyl-2- (Ethylsulfonimideyl) -9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Prince-7-Carboxamide;
6-Amino-N-Ethyl-2- [S (S)-(Ethylsulfonimideyl)]-9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Purin-7-Carboxamide;
6-Amino-N-Ethyl-2- [S (R)-(Ethylsulfonimideyl)]-9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Purin-7-Carboxamide;
6-Amino-9-[(4-Bromophenyl) Methyl] -2- (Ethylsulfonimideyl) -N-Methyl-8-oxo-N-propyl-Prin-7-Carboxamide;
6-Amino-2- [S (R) -ethylsulfonimideyl] -9-[(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-2- [S (S) -ethylsulfonimideyl] -9-[(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimideyl) -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (S)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide; And 6-amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (R)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide ;
Or its pharmaceutically acceptable salt, enantiomer or diastereomer.

Another embodiment of the present invention is a more specific compound of formula (I) listed below for use in the treatment or prevention of (xiv) liver cancer:
6-Amino-9-Benzyl-N-Methyl-8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -2- [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-2- [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-2 [S (S) -Ethylsulfonimideyl] -N-Methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-2- [S (R) -Ethylsulfonimideyl] -N-Methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- (ethylsulfonimideyl) -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-2- [S (S) ethylsulfonimideyl] -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-2- [S (R) Ethylsulfonimideyl] -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-N-Ethyl-2- (Ethylsulfonimideyl) -9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Prince-7-Carboxamide;
6-Amino-N-Ethyl-2- [S (S)-(Ethylsulfonimideyl)]-9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Purin-7-Carboxamide;
6-Amino-N-Ethyl-2- [S (R)-(Ethylsulfonimideyl)]-9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Purin-7-Carboxamide;
6-Amino-9-[(4-Bromophenyl) Methyl] -2- (Ethylsulfonimideyl) -N-Methyl-8-oxo-N-propyl-Prin-7-Carboxamide;
6-Amino-2- [S (R) -ethylsulfonimideyl] -9-[(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-2- [S (S) -ethylsulfonimideyl] -9-[(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimideyl) -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (S)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide; And 6-amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (R)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide ;
Or its pharmaceutically acceptable salt, enantiomer or diastereomer.

Another embodiment of the invention is a more specific compound of formula (I) listed below for use in the treatment or prevention of (xv) liver cancer:
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimideyl) -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (S)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide; And 6-amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (R)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide ;
Or its pharmaceutically acceptable salt, enantiomer or diastereomer.

In some embodiments, the compounds of the invention have been tested and compared to the following reference compounds. As the most successful biopharmacy company focused on discovering and developing TLR7 agonists for the treatment of liver disease, Gilead is one of the most advanced TLR7 agonists, including major compounds such as GS-9620 that have entered Phase II trials. Has a pipeline of Gilead's compound GS-9620, disclosed in JP 1999-193282, and compound S-2 and compound S-3, all disclosed as Example 49 in U.S. Patent Application Publication No. 2010143301, were all selected as reference compounds in this application. :

Synthesis The compounds of the present invention can be prepared by any common method. Suitable methods for synthesizing these compounds and their starting materials are provided in the schemes and examples below. All substituents, in particular R ¹ to R ¹⁴ , are as defined above unless otherwise indicated. Moreover, unless otherwise stated, all reactions, reaction conditions, abbreviations and symbols have meanings familiar to those skilled in the art of organic chemistry.
Scheme 1

Compounds of formula VI are prepared by cyclization of isocyanate VII with aminomalononitrile p-toluenesulfonate. Bicycle V is then synthesized by the reaction of a compound of formula VI with a benzoyl isothiocyanate in the presence of an inorganic base such as NaOH or KOH. Alkylation of the vehicle V with an alkyl halide in the presence of a base such as K ₂ CO ₃ , NaH or Cs ₂ CO _{3 gives the compound of formula IV.} Compounds of formula III are prepared by oxidation of compounds of formula IV with oxidizing agents such as metachloroperbenzoic acid, urea-hydrogen peroxide adduct and HIO _4. The compound of formula II is obtained by imitation of the compound of formula III with an imitation reagent such as sodium azide contained in the acid, the acid being, 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

The compound of formula II can also be prepared as Scheme 2.

The compound of formula X is prepared by the reaction of the compound of formula XI with R ² NH _2. Reduction of compound X with a reducing agent such as zinc or iron powder in AcOH gives compound of formula IX. Cyclization of compounds of formula IX with cyclizers such as phosgene, carbonyldiimidazole, diethyl carbonate and triphosgene yields compounds of formula VIII. Compounds of formula IVa are prepared by treating compounds of formula VIII with PMBNH _2. Compounds of formula III are prepared by deprotection of compounds of formula IVa with acids such as _{CF 3} COOH followed by oxidation with oxidizing agents such as _{meta-chloroperbenzoic acid, urea-hydrogen peroxide adduct and HIO 4.} .. The compound of formula II is obtained by imitating the compound of formula III with an imitation reagent such as sodium azide contained in the acid, the acid being, for example, Eaton's reagent or PPA.

の化合物と、塩化カルバモイルとの反応を含み；
ここでＲ^１とＲ^２は上記に定義される通りである。 In addition, a process for the preparation of the compound of formula (I) is described, which process is:
Formula (II) in the presence of mixed bases

Including the reaction of the compound with carbamoyl chloride;
Here, R ¹ and R ² are as defined above.

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

Compounds of formula (I) for use in the treatment or prevention of liver cancer, when manufactured according to the above process, are also objects of the invention.

Pharmaceutical Compositions and Administration Another embodiment is a pharmaceutical composition or medicament comprising the compounds of the invention and therapeutically inert carriers, diluents or additives for use in the treatment or prevention of liver cancer. , And methods of using the compounds of the invention for preparing such compositions and pharmaceuticals. In one example, the compound of formula (I) is a physiologically acceptable carrier at ambient temperature, at an appropriate pH and desired purity, i.e., a carrier that is non-toxic to the recipient at the dose and concentration used. Can be formulated into a galenical dosage form by mixing with. The pH of the pharmaceutical product depends mainly on the specific use and the concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula (I) is formulated at pH 5 in acetate buffer. In another embodiment, the compound of formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

The composition is formulated, dosed and administered in a manner consistent with the Code of Conduct. Factors to consider in this regard include the particular disease being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disease, the site of drug delivery, the method of administration, the schedule of administration and the healthcare professional. Other factors to know are included. The "effective amount" of the compound administered will depend on these considerations, which is the minimum required to activate the TLR7 receptor and result in the production of INF-α and other cytokines. Amounts, but not limited to, can be used for the treatment or prevention of patients infected with hepatitis B and / or C virus.

In one example, the pharmaceutically effective amount of a compound of the invention in parenteral administration per dose is from about 0.1 to 50 mg / kg, or from about 0.1, per kg body weight of the patient per day. It is 30 mg / kg and the typical initial range of compounds used is 0.3 to 15 mg / kg / day. In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain from about 20 to about 1000 mg of the compound of the invention.

The compounds of the present invention are oral, topical (including oral and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and nasal. It can be administered internally and, if desired, by any suitable method, including topical treatment, intralesional administration. Parenteral injections include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

The compounds of the present invention can be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. Such compositions include ingredients useful in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, bulking agents, and additional activators.

A typical preparation is prepared by mixing the compound of the present invention with a carrier or an additive. Suitable carriers and additives are well known to those of skill in the art and are described, for example, in Ansel, Howard C.I. , Et al. , Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems . Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al. , Et al. Remington: The Science and Practice of Pharmacy . Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C.I. Handbook of Pharmaceutical Excipients . A detailed description can be found in Chicago, Pharmaceutical Press, 2005. The pharmaceutical product is also one or more buffers, stabilizing, to provide a good-looking agent (ie, the compound of the invention or a pharmaceutical composition thereof) or to assist in the production of a pharmaceutical product (ie, pharmaceutical). Agents, surfactants, wetting agents, smoothing agents, emulsifiers, suspending agents, preservatives, antioxidants, opacity agents, flow promoters, processing aids, coloring agents, sweeteners, flavors, flavors, dilutions Agents and other known additives may also be included.

An example of a suitable oral dosage form comprises about 30 to 90 mg anhydrous lactose, about 5 to 40 mg sodium croscarmellose, about 5 to 30 mg polyvinylpyrrolidone (PVP) K30, and about 1 to 10 mg magnesium stearate. It is a tablet containing about 20 mg to 1000 mg of the compound of the present invention. The powder components are mixed first and then with the solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate and compressed into tablet form using common equipment. An example of an aerosol preparation is to dissolve, for example, 20 to 1000 mg of a compound of the present invention in a suitable buffer such as a phosphate buffer solution, and if necessary, a tonicifier, for example, a salt such as sodium chloride. Can be prepared by adding. The solution may be filtered using, for example, a 0.2 micron filter to remove impurities and contaminants.

Thus, one embodiment comprises a compound of formula (I) or a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof or an enantiomer or diastereomer.

A further embodiment comprises a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or enantiomer or diastereomer thereof, together with a pharmaceutically acceptable carrier or additive.

Another embodiment comprises a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition comprising an enantiomer or diastereomer for use in the treatment of hepatitis B virus infection.

Indications and Therapeutic Methods The present invention provides methods for treating or preventing liver cancer in patients in need of treatment or prevention of liver cancer. In some embodiments, the liver cancer is hepatocellular carcinoma, hepatoma, cholangiocarcinoma, lung blastoma, liver cancer, hepatoangiosarcoma, or metastatic liver cancer. In some embodiments, liver cancer is a refractory cancer.

The terms "cancer" and "cancerous" refer to or describe physiological conditions in mammals that are typically characterized by uncontrolled cell growth / proliferation. Examples of liver cancer include, but are not limited to, hepatocellular carcinoma, hepatoma, alveolar blastoma, cholangiocarcinoma, alveolar blastoma, liver cancer, sarcoma, lymphoma and hepatic angiosarcoma. In various embodiments, liver cancer (eg, HCC) can be mid-stage, advanced-stage, or end-stage. Liver cancer (eg, HCC) can be metastatic or non-metastatic. Liver cancer (eg, HCC) can be resectable or unresectable. Liver cancer (eg, HCC) can include a single tumor, multiple tumors, or unclear tumors with an invasive growth pattern (to the portal vein or hepatic veins). Liver cancer (eg, HCC) can include a fibrous lamellar, pseudoglandular (glandular proliferative), polymorphic (giant cell), or clear cell pattern. Liver cancer (eg, HCC) can include well-differentiated morphology, tumor cells resemble hepatocytes, form palisade, cords, and nests, and / or bile pigment in the cytoplasm including. Liver cancer (eg, HCC) can contain poorly differentiated forms, and malignant epithelial cells are non-aggregating, polymorphic, undifferentiated, and / or large. In some embodiments, liver cancer (eg, HCC) is associated with hepatitis B, hepatitis C, cirrhosis, or type 2 diabetes. The terms "cell proliferation disorders" and "proliferative disorders" refer to disorders associated with some degree of abnormal cell proliferation. In one embodiment, the cell proliferation disease is cancer.

In one embodiment of the invention, the compounds described herein (and their pharmaceutical compositions and pharmaceuticals) are used in the prevention / prevention of liver cancer in patients at high risk of developing liver cancer.

［式中、
Ｒ^１はＣ_１−６アルキルであり；
Ｒ^２はベンジルであり、前記ベンジルは、無置換であるか又はハロゲン及びＣ_１−６アルキルより独立して選択された一つ、二つ、又は三つの置換基で置換されており；
Ｒ^３は、−ＮＲ^４Ｒ^５であって、ここで
Ｒ^４は、Ｃ_１−６アルキル又はＣ_１−６アルコキシＣ_１−６アルキルであり；
Ｒ^５は、（Ｃ_１−６アルキル）_２ＮＣＯＯＣ_１−６アルキル、Ｃ_１−６アルコキシＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニル（Ｃ_１−６アルキル）アミノＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニル（フェニル）Ｃ_１−６アルキル、Ｃ_１−６アルコキシカルボニルＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニルオキシＣ_１−６アルキル、Ｃ_１−６アルキル、Ｃ_１−６アルキルカルボニル（Ｃ_１−６アルキル）アミノＣ_１−６アルキル又はピロリジニルカルバモイルオキシＣ_１−６アルキルである；か又は
Ｒ^４及びＲ^５はそれらが結合する窒素と共にヘテロシクリルを形成する］
のプロドラッグ、又はその薬学的に許容される塩、エナンチオマー若しくはジアステレオマーであり；
但し、
６−アミノ−９−ベンジル−２−（プロピルスルホンイミドイル）−７−（ピロリジン−１−カルボニル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（ピぺリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（モルホリン−４−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３，３−ジメチルピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
エチル １−［６−アミノ−９−ベンジル−８−オキソ−２−（プロピルスルホンイミドイル）プリン−７−カルボニル］ピロリジン−２−カルボキシレート；
６−アミノ−７−（２−アザスピロ［３．３］ヘプタン−２−カルボニル）−９−ベンジル−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（２−オキサ−６−アザスピロ［３．３］ヘプタン−６−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３，３−ジフルオロピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３−フルオロ−３−メチル−ピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
及びこれらのエナンチオマー又はジアステレオマーは除外され、
式Ｉのプロドラッグ化合物は、ヒトの肝臓において式ＩＩ

［式中、Ｒ^１及びＲ^２は上記に規定される通りである］の活性薬物に変換される。 In one preferred embodiment of the invention, the compounds described herein are particularly useful as prodrugs that are converted primarily into active drugs in the liver. One embodiment of the invention is a prodrug compound described herein for use in the treatment of liver cancer, which compound is of formula (I).

[During the ceremony,
R ¹ is C _1-6 alkyl;
R ² is benzyl, which is unsubstituted or substituted with one, two, or three substituents independently selected from _{halogens and C 1-6 alkyls;}
R ³ is -NR ⁴ R ⁵ , where R ⁴ is C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl;
R ⁵ is (C _1-6 alkyl) ₂ NCOCOC _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxycarbonyl (C _1-6 alkyl) amino C _1-6 alkyl, C _1-6 Alkoxycarbonyl (Phenyl) C _1-6 Alkyl, C _1-6 Alkoxycarbonyl C _1-6 Alkyl, C _1-6 Alkoxycarbonyloxy C _1-6 Alkyl, C _1-6 Alkyl, C _1-6 Alkyl Carbonyl (C _1-6 alkyl) Amino C _1-6 alkyl or pyrrolidinyl carbamoyloxy C _1-6 alkyl; or R ⁴ and R ⁵ form heterocyclyls with the nitrogen to which they bind]
Prodrug, or its pharmaceutically acceptable salt, enantiomer or diastereomer;
However,
6-Amino-9-Benzyl-2- (propylsulfonimideyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-9-benzyl-7- (piperidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (Morpholine-4-carbonyl) -2- (Propylsulfonimideyl) Purine-8-one;
6-Amino-9-benzyl-7- (3,3-dimethylpyrrolidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
Ethyl 1- [6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] pyrrolidine-2-carboxylate;
6-Amino-7- (2-azaspiro [3.3] heptane-2-carbonyl) -9-benzyl-2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (2-oxa-6-azaspiro [3.3] heptane-6-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (3,3-difluoropyrrolidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (3-Fluoro-3-methyl-pyrrolidin-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
And these enantiomers or diastereomers are excluded
Prodrug compounds of formula I have formula II in the human liver.

In the formula, R ¹ and R ² are converted to the active drug [as defined above].

An exemplary conversion rate using human liver microsomes is shown in Example 50. Also, Example 61 shows the liver as the major site of conversion of the prodrug to its active form.

A preferred embodiment of the invention is the (prodrug) compound described herein, which undergoes conversion to its active form by the liver enzymes CYP2C9 and CYP2C19. A preferred embodiment of the invention is the (prodrug) compound described herein, which is ≥10 nmol / min per 1 mg protein in human hepatocytes and ≤2 nmol / min per 1 mg protein in human hepatocytes. Minutes (as measured in a suitable assay using human hepatocytes and human enterosites) are shown for conversion to active compounds.

Combination therapy One aspect of the present invention is combination therapy (combination therapy) for a liver cancer patient using a compound of formula I.

Surprisingly, we have found that the combination therapy of compounds of formula I and anti-PD-L1 / PD1 axis therapy are highly effective for liver tumors.

［式中、
Ｒ^１はＣ_１−６アルキルであり；
Ｒ^２はベンジルであり、前記ベンジルは、無置換であるか又はハロゲン及びＣ_１−６アルキルより独立して選択された一つ、二つ、又は三つの置換基で置換されており；
Ｒ^３は、−ＮＲ^４Ｒ^５であって、ここで
Ｒ^４は、Ｃ_１−６アルキル又はＣ_１−６アルコキシＣ_１−６アルキルであり；
Ｒ^５は、（Ｃ_１−６アルキル）_２ＮＣＯＯＣ_１−６アルキル、Ｃ_１−６アルコキシＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニル（Ｃ_１−６アルキル）アミノＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニル（フェニル）Ｃ_１−６アルキル、Ｃ_１−６アルコキシカルボニルＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニルオキシＣ_１−６アルキル、Ｃ_１−６アルキル、Ｃ_１−６アルキルカルボニル（Ｃ_１−６アルキル）アミノＣ_１−６アルキル又はピロリジニルカルバモイルオキシＣ_１−６アルキルである；か又は
Ｒ^４及びＲ^５はそれらが結合する窒素と共にヘテロシクリルを形成する］
の化合物（又はそのような化合物を含む医薬若しくは薬学的組成物）、又はその薬学的に許容される塩、エナンチオマー若しくはジアステレオマーであり；
但し、
６−アミノ−９−ベンジル−２−（プロピルスルホンイミドイル）−７−（ピロリジン−１−カルボニル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（ピぺリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（モルホリン−４−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３，３−ジメチルピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
エチル １−［６−アミノ−９−ベンジル−８−オキソ−２−（プロピルスルホンイミドイル）プリン−７−カルボニル］ピロリジン−２−カルボキシレート；
６−アミノ−７−（２−アザスピロ［３．３］ヘプタン−２−カルボニル）−９−ベンジル−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（２−オキサ−６−アザスピロ［３．３］ヘプタン−６−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３，３−ジフルオロピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３−フルオロ−３−メチル−ピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
及びこれらのエナンチオマー又はジアステレオマーは除外される、
ａ）アンタゴニストＰＤ１又はＰＤ−Ｌ１抗体と組み合わせた肝がんの治療
又は
ｂ）アンタゴニストＰＤ１又はアンタゴニストＰＤ−Ｌ１抗体と組み合わせた肝がん患者の治療
のための化合物（又はそのような化合物を含む医薬若しくは薬学的組成物）、又はその薬学的に許容される塩、エナンチオマー若しくはジアステレオマーである。 Therefore, one aspect of the present invention is the formula (I).

[During the ceremony,
R ¹ is C _1-6 alkyl;
R ² is benzyl, which is unsubstituted or substituted with one, two, or three substituents independently selected from _{halogens and C 1-6 alkyls;}
R ³ is -NR ⁴ R ⁵ , where R ⁴ is C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl;
R ⁵ is (C _1-6 alkyl) ₂ NCOCOC _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxycarbonyl (C _1-6 alkyl) amino C _1-6 alkyl, C _1-6 Alkoxycarbonyl (Phenyl) C _1-6 Alkyl, C _1-6 Alkoxycarbonyl C _1-6 Alkyl, C _1-6 Alkoxycarbonyloxy C _1-6 Alkyl, C _1-6 Alkyl, C _1-6 Alkyl Carbonyl (C _1-6 alkyl) Amino C _1-6 alkyl or pyrrolidinyl carbamoyloxy C _1-6 alkyl; or R ⁴ and R ⁵ form heterocyclyls with the nitrogen to which they bind]
Compound (or pharmaceutical or pharmaceutical composition containing such compound), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof;
However,
6-Amino-9-Benzyl-2- (propylsulfonimideyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-9-benzyl-7- (piperidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (Morpholine-4-carbonyl) -2- (Propylsulfonimideyl) Purine-8-one;
6-Amino-9-benzyl-7- (3,3-dimethylpyrrolidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
Ethyl 1- [6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] pyrrolidine-2-carboxylate;
6-Amino-7- (2-azaspiro [3.3] heptane-2-carbonyl) -9-benzyl-2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (2-oxa-6-azaspiro [3.3] heptane-6-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (3,3-difluoropyrrolidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (3-Fluoro-3-methyl-pyrrolidin-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
And these enantiomers or diastereomers are excluded,
a) Treatment of liver cancer in combination with antagonist PD1 or PD-L1 antibody or b) Compound for treatment of liver cancer patients in combination with antagonist PD1 or antagonist PD-L1 antibody (or pharmaceuticals containing such compounds Or a pharmaceutical composition), or a pharmaceutically acceptable salt thereof, enantiomer or diastereomeric.

［式中、
Ｒ^１はＣ１−６アルキルであり；
Ｒ^２はベンジルであり、前記ベンジルは、無置換であるか又はハロゲン及びＣ_１−６アルキルより独立して選択された一つ、二つ、又は三つの置換基で置換されており；
Ｒ^３は、−ＮＲ^４Ｒ^５であって、ここで
Ｒ^４は、Ｃ_１−６アルキル又はＣ_１−６アルコキシＣ_１−６アルキルであり；
Ｒ^５は、（Ｃ_１−６アルキル）_２ＮＣＯＯＣ_１−６アルキル、Ｃ_１−６アルコキシＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニル（Ｃ_１−６アルキル）アミノＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニル（フェニル）Ｃ_１−６アルキル、Ｃ_１−６アルコキシカルボニルＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニルオキシＣ_１−６アルキル、Ｃ_１−６アルキル、Ｃ_１−６アルキルカルボニル（Ｃ_１−６アルキル）アミノＣ_１−６アルキル又はピロリジニルカルバモイルオキシＣ_１−６アルキルであるか；又は
Ｒ^４及びＲ^５は、それらが結合する窒素と共にヘテロシクリルを形成する］
の化合物（又は医薬若しくはこのような化合物を含む薬学的組成物）、又はその薬学的に許容される塩、エナンチオマー若しくはジアステレオマーであり；
但し、
６−アミノ−９−ベンジル−２−（プロピルスルホンイミドイル）−７−（ピロリジン−１−カルボニル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（ピぺリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（モルホリン−４−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３，３−ジメチルピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
エチル １−［６−アミノ−９−ベンジル−８−オキソ−２−（プロピルスルホンイミドイル）プリン−７−カルボニル］ピロリジン−２−カルボキシレート；
６−アミノ−７−（２−アザスピロ［３．３］ヘプタン−２−カルボニル）−９−ベンジル−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（２−オキサ−６−アザスピロ［３．３］ヘプタン−６−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３，３−ジフルオロピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３−フルオロ−３−メチル−ピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
及びこれらのエナンチオマー又はジアステレオマーは除外され、
アンタゴニストＰＤ１又はアンタゴニストＰＤ−Ｌ１抗体が共投与される（治療はアンタゴニストＰＤ１又はアンタゴニストＰＤ−Ｌ１抗体と組み合わせられる）。 One embodiment of the invention is of formula (I) for use in the treatment or prevention of liver cancer.

[During the ceremony,
R ¹ is C1-6 alkyl;
R ² is benzyl, which is unsubstituted or substituted with one, two, or three substituents independently selected from _{halogens and C 1-6 alkyls;}
R ³ is -NR ⁴ R ⁵ , where R ⁴ is C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl;
R ⁵ is (C _1-6 alkyl) ₂ NCOCOC _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxycarbonyl (C _1-6 alkyl) amino C _1-6 alkyl, C _1-6 Alkoxycarbonyl (Phenyl) C _1-6 Alkyl, C _1-6 Alkoxycarbonyl C _1-6 Alkyl, C _1-6 Alkoxycarbonyloxy C _1-6 Alkyl, C _1-6 Alkyl, C _1-6 Alkyl Is it a carbonyl (C _1-6 alkyl) amino C _1-6 alkyl or pyrrolidinyl carbamoyloxy C _1-6 alkyl; or R ⁴ and R ⁵ form heterocyclyls with the nitrogen they bind to]
Compounds (or pharmaceuticals or pharmaceutical compositions containing such compounds), or pharmaceutically acceptable salts thereof, enantiomers or diastereomers;
However,
6-Amino-9-Benzyl-2- (propylsulfonimideyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-9-benzyl-7- (piperidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (Morpholine-4-carbonyl) -2- (Propylsulfonimideyl) Purine-8-one;
6-Amino-9-benzyl-7- (3,3-dimethylpyrrolidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
Ethyl 1- [6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] pyrrolidine-2-carboxylate;
6-Amino-7- (2-azaspiro [3.3] heptane-2-carbonyl) -9-benzyl-2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (2-oxa-6-azaspiro [3.3] heptane-6-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (3,3-difluoropyrrolidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (3-Fluoro-3-methyl-pyrrolidin-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
And these enantiomers or diastereomers are excluded
Antagonist PD1 or antagonist PD-L1 antibody is co-administered (treatment is combined with antagonist PD1 or antagonist PD-L1 antibody).

［式中、
Ｒ^１はＣ_１−６アルキルであり；
Ｒ^２はベンジルであり、前記ベンジルは、無置換であるか又はハロゲン及びＣ_１−６アルキルより独立して選択された一つ、二つ、又は三つの置換基で置換されており；
Ｒ^３は−ＮＲ^４Ｒ^５であって、ここで
Ｒ^４は、Ｃ_１−６アルキル又はＣ_１−６アルコキシＣ_１−６アルキルであり；
Ｒ^５は、（Ｃ_１−６アルキル）_２ＮＣＯＯＣ_１−６アルキル、Ｃ_１−６アルコキシＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニル（Ｃ_１−６アルキル）アミノＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニル（フェニル）Ｃ_１−６アルキル、Ｃ_１−６アルコキシカルボニルＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニルオキシＣ_１−６アルキル、Ｃ_１−６アルキル、Ｃ_１−６アルキルカルボニル（Ｃ_１−６アルキル）アミノＣ_１−６アルキル又はピロリジニルカルバモイルオキシＣ_１−６アルキルであるか；又は
Ｒ^４及びＲ^５は、それらが結合する窒素と共にヘテロシクリルを形成する］
の化合物；
又はその薬学的に許容される塩、エナンチオマー若しくはジアステレオマーであって；
但し、
６−アミノ−９−ベンジル−２−（プロピルスルホンイミドイル）−７−（ピロリジン−１−カルボニル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（ピぺリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（モルホリン−４−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３，３−ジメチルピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
エチル １−［６−アミノ−９−ベンジル−８−オキソ−２−（プロピルスルホンイミドイル）プリン−７−カルボニル］ピロリジン−２−カルボキシレート；
６−アミノ−７−（２−アザスピロ［３．３］ヘプタン−２−カルボニル）−９−ベンジル−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（２−オキサ−６−アザスピロ［３．３］ヘプタン−６−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３，３−ジフルオロピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３−フルオロ−３−メチル−ピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
及びこれらのエナンチオマー又はジアステレオマーは除外される、
化合物；
又はその薬学的に許容される塩、エナンチオマー若しくはジアステレオマーの使用であり、
アンタゴニストＰＤ１又はアンタゴニストＰＤ−Ｌ１抗体が共投与される（治療はアンタゴニストＰＤ１又はアンタゴニストＰＤ−Ｌ１抗体と組み合わせられる）。 One embodiment of the present invention is the formula (I) for the preparation of a medicament for the treatment or prevention of liver cancer.

[During the ceremony,
R ¹ is C _1-6 alkyl;
R ² is benzyl, which is unsubstituted or substituted with one, two, or three substituents independently selected from _{halogens and C 1-6 alkyls;}
R ³ is -NR ⁴ R ⁵ , where R ⁴ is C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl;
R ⁵ is (C _1-6 alkyl) ₂ NCOCOC _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxycarbonyl (C _1-6 alkyl) amino C _1-6 alkyl, C _1-6 Alkoxycarbonyl (Phenyl) C _1-6 Alkyl, C _1-6 Alkoxycarbonyl C _1-6 Alkyl, C _1-6 Alkoxycarbonyloxy C _1-6 Alkyl, C _1-6 Alkyl, C _1-6 Alkyl Is it a carbonyl (C _1-6 alkyl) amino C _1-6 alkyl or pyrrolidinyl carbamoyloxy C _1-6 alkyl; or R ⁴ and R ⁵ form heterocyclyls with the nitrogen they bind to]
Compound;
Or its pharmaceutically acceptable salt, enantiomer or diastereomer;
However,
6-Amino-9-Benzyl-2- (propylsulfonimideyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-9-benzyl-7- (piperidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (Morpholine-4-carbonyl) -2- (Propylsulfonimideyl) Purine-8-one;
6-Amino-9-benzyl-7- (3,3-dimethylpyrrolidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
Ethyl 1- [6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] pyrrolidine-2-carboxylate;
6-Amino-7- (2-azaspiro [3.3] heptane-2-carbonyl) -9-benzyl-2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (2-oxa-6-azaspiro [3.3] heptane-6-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (3,3-difluoropyrrolidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (3-Fluoro-3-methyl-pyrrolidin-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
And these enantiomers or diastereomers are excluded,
Compound;
Or the use of its pharmaceutically acceptable salt, enantiomer or diastereomer,
Antagonist PD1 or antagonist PD-L1 antibody is co-administered (treatment is combined with antagonist PD1 or antagonist PD-L1 antibody).

In another embodiment of the invention, the specific compound of formula (I) used in combination therapy with antagonist PD1 or antagonist PD-L1 antibody is:
6-Amino-9-Benzyl-N-Methyl-8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N- (2-methoxyethyl) -N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N-Ethyl-8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-Benzyl-7- [4- (1-piperidyl) piperidine-1-carbonyl] -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-benzyl-N-Ethyl-N- (2-Methoxyethyl) -8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N-Butyl-N-Ethyl-8-oxo-2- (propylsulfoneimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-7- (azetidine-1-carbonyl) -9-benzyl-2- (propylsulfoneimideyl) purine-8-one;
6-Amino-9-benzyl-N-isopropyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-7- (4-methylpiperazin-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N-isobutyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
Ethyl 2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] acetate;
Ethyl 3-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate;
tert-Butyl 3-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate;
tert-Butyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate;
Isopropyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-methyl-butanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate;
Isopropyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanol;
tert-Butyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate;
N- [2- [Acetyl (Methyl) Amino] Ethyl] -6-Amino-9-Benzyl-N-Methyl-8-oxo-2- (propylsulfonimideyl) Purine-7-Carboxamide;
Methyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;
tert-butyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;
Ethyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N-butyl-N-methyl-carbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl pyrrolidine-1-carboxylate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N-methyl-N-propyl-carbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N, N-diethylcarbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl ethyl carbonate;
6-Amino-N-Butyl-9-[(4-Chlorophenyl) Methyl] -N-Methyl-8-oxo-2- [S (S) -propylsulfonimideyl] Purine-7-Carboxamide;
6-Amino-N-Butyl-9-[(4-Chlorophenyl) Methyl] -N-Methyl-8-oxo-2- [S (S) -propylsulfonimideyl] Purine-7-Carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-N-Methyl-8-oxo-N-propyl-2 [S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Methyl-8-oxo-N-propyl-2 [S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- [S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-2- [S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-N- (2-Methoxyethyl) -N-Methyl-8-oxo-2-[S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N- (2-Methoxyethyl) -N-Methyl-8-oxo-2-[S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-N-Methyl-8-oxo-2- (propylsulfoneimideyl) -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Butyl-N-Methyl-8-oxo-2- (propylsulfoneimideyl) -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -2- [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-2- [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-2 [S (S) -Ethylsulfonimideyl] -N-Methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-2- [S (R) -Ethylsulfonimideyl] -N-Methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- [S (S) ethylsulfonimideyl] -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-2- [S (R) Ethylsulfonimideyl] -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-N-Ethyl-2- (Ethylsulfonimideyl) -9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Prince-7-Carboxamide;
6-Amino-N-Ethyl-2- [S (S)-(Ethylsulfonimideyl)]-9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Purin-7-Carboxamide;
6-Amino-N-Ethyl-2- [S (R)-(Ethylsulfonimideyl)]-9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Purin-7-Carboxamide;
6-Amino-9-[(4-Bromophenyl) Methyl] -2- (Ethylsulfonimideyl) -N-Methyl-8-oxo-N-propyl-Prin-7-Carboxamide;
6-Amino-2- [S (R) -ethylsulfonimideyl] -9-[(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-2- [S (S) -ethylsulfonimideyl] -9-[(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimideyl) -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (S)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide; And 6-amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (R)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide ;
Or it is selected from its pharmaceutically acceptable salts, enantiomers or diastereomers.

In another embodiment of the invention, the specific compound of formula (I) used in combination therapy with antagonist PD1 or antagonist PD-L1 antibody is:
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimideyl) -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (S)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide; And 6-amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (R)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide ;
Or it is selected from its pharmaceutically acceptable salts, enantiomers or diastereomers.

In another embodiment of the invention, the compound of specific formula (I) used in combination therapy with antagonist PD1 or antagonist PD-L1 antibody is: 6-amino-9-[(4-chlorophenyl) methyl]-. It is N-ethyl-2 [S (S) -ethylsulfoneimideyl] -N-methyl-8-oxo-purine-7-carboxamide.
In one embodiment, co-administration (or combination therapy or combination therapy) of a compound of formula I with an antagonist PD1 or antagonist PD-L1 antibody is performed simultaneously. In one embodiment, co-administration (or combination therapy or combination therapy) of a compound of formula I with an antagonist PD1 or antagonist PD-L1 antibody is performed sequentially.

The terms "administered in combination with" or "co-administered", "co-administered", "combination therapy", "treatment in combination with", or "combination therapy" are the expressions described herein. Refers to the administration of the compound I and the antagonist PD1 or PD-L1 antibody described herein, eg, as a separate formulation / usage (or as a single formulation / usage). Co-administration may be simultaneous or sequential in any order, and there is a period during which both (or all) activators exert their biological activity simultaneously. Co-administration is simultaneous or sequential (eg, intravenous injection by continuous infusion (iv)). In one embodiment, co-administration is simultaneous. In one embodiment, co-administration is sequential. Co-administration is simultaneous or sequential (eg, intravenous injection by continuous infusion (iv)).

The amount or combination of each compound is the amount that will elicit the biological or medical response of the tissue, system, animal or human required by researchers, veterinarians, physicians or other clinicians, "therapeutically effective". It is self-evident that the antibody is administered to the patient in "amount" (or simply "effective amount").

The amount of co-administration and the timing of co-administration depend on the type and condition of the patient being treated (race, gender, age, weight, etc.) and the severity of the disease or condition being treated. The compound of formula I and the antibody are appropriately co-administered to the patient at one time or over a series of treatments, eg, on the same day or the next day.

PD-1 / PD-L1 / PD-L2 route:
Important negative co-stimulatory signals that regulate T cell activation are programmed death-1 receptor (PD-1) (CD279), its ligand-binding partners PD-L1 (B7-H1, CD274; SEQ ID NO: 13) and PD. -L2 (B7-DC, CD273). The negative regulatory role of PD-1 was revealed by the knockout of PD-1 (Pdcd1-/-), which tends to give rise to autoimmunity. Nishimura et al. , Immunoty 11: 141-51 (1999); Nishimura et al. , Science 291: 319-22 (2001). PD-1 is associated with CD28 and CTLA-4, but lacks near-membrane cysteine, which allows homodimerization. The cytoplasmic domain of PD-1 contains an immunoreceptor tyrosine-based inhibitory 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); Ratchman et al. , Nature Immunology. 2: 261-268 (2001); Tseng et al. , J. Exp. Med. 193: 839-846 (2001).

PD-1 can be expressed on T cells, B cells, natural killer T cells, activated monocytes and dendritic cells (DCs). PD-1 is expressed by activated but unstimulated human CD4 + and CD8 + T cells, B cells, and bone marrow. This is in contrast to 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 four PD-1 variants cloned from activated human T cells, which include (i) exon 2, (ii) exon 3, (iii) exon 2 and 3 or (iv) exon 2. Includes transcriptions lacking ~ 4. Nielsen et al. , Cell. Immunol. 235: 109-16 (2005). With the exception of PD-1 delta ex3, all mutants are expressed in resting peripheral blood mononuclear cells (PBMC) at levels similar to full-length PD-1. Expression of all mutants is markedly induced by anti-CD3 and anti-CD28 upon activation of human T cells. The PD-1delta ex3 mutant lacks a transmembrane domain and resembles soluble CTLA-4, which plays an important role in autoimmunity. Ueda et al. , Nature 423: 506-11 (2003). This variant is concentrated in the synovial fluid and serous fluid of patients with rheumatoid arthritis. Wan et al. , J. Immunol. 177: 8844-50 (2006).

The two PD-1 ligands have different expression patterns. PD-L1 is constitutively expressed on mouse T and B cells, CDs, macrophages, mesenchymal stem cells and bone marrow-derived mast cells. Yamazaki et al. , J. Immunol. 169: 5538-45 (2002). PD-L1 is expressed on a wide range of non-hematopoietic cells (eg, corneal cells, lung cells, vascular epithelial cells, liver nonparenchymal cells, mesenchymal stem cells, pancreatic islets, placental syncytium vegetative blasts, keratinocytes, etc.) [Ker et al. , Annu. Rev. Immunol. 26: 677-704 (2008)], upregulated in multiple cell types after activation. Both type I and type II interferon IFNs upregulate PD-L1. Epihimer et al. , Microcyclation 9: 133-45 (2002); Schreiner et al. , J. Neuroimmul. 155: 172-82 (2004). Expression of PD-L1 in cell lines decreases when MyD88, TRAF6 and MEK are suppressed. Liu et al. , Blood 110: 296-304 (2007). JAK2 is also involved in PD-L1 induction. Lee et al. , FEBS Lett. 580: 755-62 (2006); Liu et al. , Blood 110: 296-304 (2007). Deletion or suppression of phosphatase-tensin homologue (PTEN), a cellular phosphatase that modifies phosphatidylinositol 3-kinase (PI3K) and Akt signaling, increased post-transcriptional PD-L1 expression in cancer. Parasa et al. , Nat. Med. 13: 84 / -88 (2007).

Expression of PD-L2 is more restricted than PD-L1. PD-L2 is inducibly expressed on DC, macrophages, and bone marrow-derived mast cells. PD-L2 also expresses about half to two-thirds of resting peritoneal B1 cells, but not on conventional B2B cells. Zhong et al. , Euro. J. Immunol. 37: 2405-10 (2007). PD-L2 + B1 cells bind to phosphatidylcholine and may be important for the innate immune response to bacterial antigens. The induction of PD-L2 by IFN-gamma is partially dependent on NF-κB. Liang et al. , Euro. 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); Look et al. , PNAS 100: 5336-41 (2003).

PD-1 signaling typically has a greater effect on cytokine production than cell proliferation and has a greater effect on IFN-gamma, TNF-alpha and IL-2 production. PD-1 mediated inhibitory signaling also depends on the intensity of TCR signaling, and lower levels of TCR stimulation deliver greater inhibition. Such reduction is due to co-stimulation with CD28 [Freeman et al. , J. Exp. Med. 192: 1027-34 (2000)] or due to the presence of IL-2 [Carter et al. , Euro. J. Immunol. 32: 634-43 (2002)] Can be overcome.

Evidence has accumulated that signal transduction by PD-L1 and PD-L2 is bidirectional. That is, in addition to regulating TCR or BCR signaling, signaling is also delivered back to cells expressing PD-L1 and PD-L2. Treatment of dendritic cells with native human anti-PD-L2 antibody isolated from Waldenström gamma globulinemia patients did not upregulate MHC II or B7 costimulatory molecules. The cells produced more pro-inflammatory cytokines, especially TNF-alpha and IL-6, which stimulated T cell proliferation. Nguyen et al. , J. Exp. Med. 196: 1393-98 (2002). In addition, treatment of mice with this antibody (1) enhances resistance to transplanted b16 melanoma and rapidly induces tumor-specific CTL; Radhakrishanan et al. , J. Immunol. 170: 1830-38 (2003); Radhaklishnan et al. , Cancer Res. 64: 4965-72 (2004); Heckman et al. , Euro. J. Immunol. 37: 1827-35 (2007); (2) Prevented the development of airway inflammatory disease in a mouse model of allergic asthma; , J. Immunol. 173: 1360-65 (2004); Radhaklishnan et al. , J. Allergy Clin. Immunol. 116: 668-74 (2005).

Further evidence of reverse signaling to dendritic cells (“DC”) was obtained from studies of bone marrow-derived DCs cultured with soluble PD-1 (PD-1 fused to Ig constant regions). EC domain- "s-PD-1"). Kuipers et al. , Euro. J. Immunol. 36: 2472-82 (2006). This sPD-1 reversibly inhibited DC activation by administration of anti-PD-1, and increased the production of IL-10.

In addition, multiple studies have shown PD-L1 or PD-L2 receptors that are independent of PD-1. B7.1 has already been identified as a binding partner for PD-L1. Butte et al. , Immunoty 27: 111-22 (2007). Studies of chemical cross-linking suggest that PD-L1 and B7.1 can interact through their IgV-like domains. The B7.11: PD-L1 interaction can induce an inhibitory signal into T cells. B7.1 ligation of PD-L1 on CD4 + T cells or PD-L1 ligation of B7.1 on CD4 + T cells delivers an inhibitory signal. T cells lacking CD28 and CTLA-4 show reduced proliferation and cytokine production when stimulated with anti-CD3-positive B7.1 coated beads. In T cells lacking all B7.1 receptors (ie, CD28, CTLA-4 and PD-L1), T cell proliferation and cytokine production are no longer inhibited by anti-CD3-positive B7.1 coated beads. This indicates that B7.1 acts more specifically on PD-L1 on T cells in the absence of CD28 and CTLA-4. Similarly, PD-1 deficient T cells showed reduced proliferation and cytokine production when stimulated in the presence of anti-CD3-positive PD-L1 coated beads, which was B7. This is to demonstrate the inhibitory effect of PD-L1 ligation on 1. When T cells lacked all known receptors for PD-L1 (ie, in the absence of PD-1 and B7.1), T cell proliferation was no longer reduced by anti-CD3-positive PD-L1 coding beads. .. Therefore, PD-L1 can exert an inhibitory effect on T cells by B7.1 or PD-1.

The direct interaction between B7.1 and PD-L1 suggests that the current understanding of co-stimulation is inadequate and underestimates the importance of these molecules on T cell expression. Studies of PD-L1-/-T cells show that PD-L1 on T cells can down-regulate T cell cytokine production. Latchman et al. , Proc. Natl. Acad. Sci. USA 101: 10691-96 (2004). Since both PD-L1 and B7.1 are expressed on T cells, B cells, DCs and macrophages, it is possible that B7.1 and PD-L1 have directional interactions in these cell types. There is. In addition, PD-L1 on non-hematopoietic cells can interact with B7.1 and PD-1 on T cells, raising the question of whether PD-L1 is involved in their regulation. .. One possible explanation for the inhibitory effect of B7.1: PD-L1 interaction is that T cell PD-L1 can capture or isolate APC B7.1 from its interaction with CD28.

As a result, PD-L1 sends a negative co-stimulation signal to T cells and other antigen-presenting cells by blocking PD-L1 from interacting with PD-1, B7.1, or both. The antagonism of PD-L1 signaling, including prevention, appears to enhance immunity to infectious diseases (eg, acute and chronic) and tumor immunity.

One exemplary PD-L1 antagonist is the anti-PD-L1 antibody atezolizumab. Other antagonist PD-L1 antibodies are durvalumab and avelumab.

In another embodiment, the anti-PD-L1 / PD1 interaction comprises an antagonist anti-PD-1 antibody such as the antagonist PD1 antibody pembrolizumab or nivolumab, or the variable heavy and light chain domains of PD1-0103-0312. It can be blocked by anti-PD1 antibody.

The term "human PD-L1" refers to the human protein PD-L1 (SEQ ID NO: 13, typically PD-1 signaling). As used herein, "binding to human PD-L1" or "specifically binding to human PD-L1" or "binding to human PD-L1" or "anti-PD-L1 antibody" or "antigen PD-L1". An "antibody" is an antibody that specifically binds to a human PD-L1 antigen with a binding affinity of KD value of 1.0 x 10-8 mol / l or less, and in one embodiment, KD value of 1.0 x 10-9 mol / l or less. Point to. Binding affinity is determined by standard binding assays such as, for example, surface plasmon resonance (BIAcore® of GE-Healthcare, Uppsala, Sweden). Therefore, the “antibody that binds to human PD-L1” used here is KD 1.0 × 10-8 mol / l or less (1.0 × 10-8 mol / l-1.0 × 10 in one embodiment). -13 mol / l), KD 1.0x10-9 mol / l or less in one embodiment (1.0 × 10-9 mol / l-1.0 × 10-13 mol / l in one embodiment) human Refers to an antibody that specifically binds to the PD-L1 antigen.

The term "human PD1" refers to the human protein PD1 (SEQ ID NO: 14, typically PD-1 signaling). The "binding to human PD1" or "specifically binding to human PD1" or "binding to human PD1" or "anti-PD1 antibody" or "antagonist PD1 antibody" used herein has a KD value of 1.0 ×. An antibody that specifically binds to a human PD1 antigen with a binding affinity of 10-8 mol / l or less, in one embodiment a KD value of 1.0x10-9 mol / l or less. Binding affinity is determined by standard binding assays such as, for example, surface plasmon resonance (BIAcore® of GE-Healthcare, Uppsala, Sweden). Therefore, the “antibody that binds to human PD1” used here is KD 1.0 × 10-8 mol / l or less (1.0 × 10-8 mol / l-1.0 × 10-13 mol in one embodiment). / L), human PD1 antigen with binding affinity of KD 1.0x10-9 mol / l or less in one embodiment (1.0 × 10-9 mol / l-1.0 × 10-13 mol / l in one embodiment) Refers to an antibody that specifically binds to.

As used herein, "variable domain" (the variable domain of the light chain (VL), the variable domain of the heavy chain (VH) refers to each pair of light chain and heavy chain that is directly involved in the binding of the antibody to the antigen. Means. Variable human light chain and heavy chain domains have the same general structure, and each domain is widely conserved in sequence, connected by three "hypervariable regions" (or complementarity determination regions, CDRs). Includes four framework (FR) regions. The framework regions take a β-sheet conformation and the CDRs can form loops connecting the β-sheet structures. The CDRs in each chain are frameworks. It is retained in its three-dimensional structure by the region and forms an antigen-binding site with the CDR of the other chain. The CDR3 regions of the heavy and light chains of the antibody are particularly important in the binding specificity / affinity of the antibody according to the present invention. It serves a role and thus provides a further object of the invention.

As used herein, the term "constant region" means the sum of domains other than the variable region of an antibody. The constant region does not directly participate in antigen binding, but exhibits various effector functions. Antibodies are classified into IgA, IgD, IgE, IgG and IgM classes according to the amino acid sequence of their heavy chain constant region, some of which are such as IgG1, IgG2, IgG3 and IgG4, IgA1 and IgA2. It can be further subclassed. The heavy chain constant regions corresponding to different classes of antibodies are called α, δ, ε, γ, and μ, respectively. The light chain constant regions found in all five antibody classes are called κ (kappa) and λ (lambda).

As used herein, the term "constant region of human origin" or "human constant region" refers to the constant heavy chain region of a human antibody in the subclass IgG1, IgG2, IgG3, or IgG4 and / or the constant light chain kappa or lambda region. Means. Such constant regions are well known in the art and are described, for example, in Kabat, E. et al. A. , Et al. , Sequences of Proteins of Immunological Interest, 5th ed. , Public Health Service, National Institutes of Health, Bethesda, MD (1991) (eg, Johnson, G., and Wu, TT, Nucleic Acids Res. 28 (2000) 214-218; A., et al., Proc. Natl. Acad. Sci. USA 72 (1975) 2785-2788). In this application, Kabat, E. et al. A. , Et al. , Sequences of Proteins of Immunological Interest, 5th ed. , Public Health Service, National Institutes of Health, Bethesda, MD (1991) EU numbering system (EU Index) is used, which is referred to as "Kabat's EU Index numbering".

In one embodiment, the agonist anti-PD1 antibody that binds to human PD1 used in the combination therapies described herein is nivolumab or pembrolizumab and is characterized by comprising the following VH and VL sequences described herein. To:
table:

In one preferred embodiment of the invention, the compounds of formula I used in the combination therapies described herein are:
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimideyl) -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (S)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide; Alternatively, 6-amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (R)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide ;
Or a pharmaceutically acceptable salt thereof, enantiomer or diastereomer; (in one preferred embodiment, 6-amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfone]. Imidyl] -N-methyl-8-oxo-purine-7-carboxamide);
Selected from
The antagonist PD1 antibody used in the combination therapy is nivolumab or pembrolizumab.
In one embodiment, the agonist anti-PD1 antibody that binds to human PD1 used in the combination therapies described herein is a mono- or multispecific antagonist PD1 antibody, the following heavy chain variable described herein. Includes domain VH and light chain variable domain VL sequences:
table:

Preferably, such anti-PD1 antibodies based on the heavy chain variable domain VH and light chain variable domain VL sequences of PD1-0103-0312 are such anti-PD1 antibodies as heavy chain constant regions of the IgG1 subtype (eg, SEQ ID NO: 16 or SEQ ID NO: 17, over time. Includes (see, Bispecific Embodiments below) and the human kappa light chain constant region (eg, SEQ ID NO: 15), which also have additional mutations.

In one embodiment, such anti-PD1 antibodies based on the heavy chain variable domain VH and light chain variable domain VL sequences of PD1-0103-0312 are, for example, bispecific, i) the bispecific antibody. , Includes constant heavy chain regions of the human IgG1 subclass, including variants L234A, L235A and P329G (numbered by EU Index of Kabat); ii)) In constant heavy chain regions, mutations in S354C and T366W are contained in one CH3 domain. Thus, mutations in Y349C, T366S, L368A and Y407V are contained in the other CH3 domain (Kabat's EU Index numbering).

In another preferred embodiment of the invention, the compounds of formula I used in the combination therapies described herein are:
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimideyl) -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (S)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide; Alternatively, 6-amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (R)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide ;
Or a pharmaceutically acceptable salt thereof, enantiomer or diastereomer; (in one preferred embodiment, 6-amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfone]. Imidyl] -N-methyl-8-oxo-purine-7-carboxamide);
More selected,
The antagonist PD1 antibody used in the combination therapy comprises a heavy chain variable domain VH containing the amino acid sequence of SEQ ID NO: 5 and a light chain variable domain VL containing the amino acid sequence of SEQ ID NO: 6.

In one embodiment, the antibody that binds to human PD-L1 used in the combination therapies described herein is atezolizumab, durvalumab or avelumab characterized by comprising the following VH and VL sequences described herein. is there.
table:

In another preferred embodiment of the invention, the compounds of formula I used in the combination therapies described herein are:
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimideyl) -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (S)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide; Or 6-amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (R)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide ;
Or a pharmaceutically acceptable salt thereof, enantiomer or diastereomer; (in one preferred embodiment, 6-amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfone]. Imidyl] -N-methyl-8-oxo-purine-7-carboxamide)
More selected;
The antagonist PD-L1 antibody used in the combination therapy is atezolizumab or durvalumab or avelumab (atezolizumab in one preferred embodiment).

Another aspect of the present invention is a combined treatment (combination treatment) of a liver cancer patient using the compound of the above formula I in combination with an anti-angiogenic agent. The anti-angiogenic agent can be co-administered with the compound of formula I alone or in combination with the compound of formula I and anti-PD-L1 / PD uniaxial therapy. The anti-angiogenic agents used herein include, for example, sorafenib (4- {4- [3- (4-chloro-3-trifluoromethylphenyl) ureido] phenoxy} pyridine-2-carboxylic. Acid methylamide; Nexavar ^TM ), regorafenib (4- [4-({[4-chloro-3- (trifluoromethyl) phenyl] carbamoyl} amino) -3-fluorophenoxy] -N-methylpyridine-2-carboxamide- Hydrat; Stivalga ^TM ) and sunitinib (N- [2- (diethylamino) ethyl] -5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-iriden)) - methyl] -2,4-dimethyl -1H- pyrrole-3-carboxamide; Sutent ^TM), such as, VEGF, PDGF, and other small molecules that competitively bind to the intracellular receptor domains of angiogenic growth factors contains a tyrosine kinase inhibitor (TKI) is, furthermore, for example, bevacizumab anti-VEGF or anti-VEGF receptor antibody such as (Avastin ^TM) is also included.

In one preferred embodiment of the invention, the compounds of formula I used in combination therapy with the anti-angiogenic agents described herein are:
6-Amino-9-Benzyl-N-Methyl-8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N- (2-methoxyethyl) -N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N-Ethyl-8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-Benzyl-7- [4- (1-piperidyl) piperidine-1-carbonyl] -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-benzyl-N-Ethyl-N- (2-Methoxyethyl) -8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N-Butyl-N-Ethyl-8-oxo-2- (propylsulfoneimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-7- (azetidine-1-carbonyl) -9-benzyl-2- (propylsulfoneimideyl) purine-8-one;
6-Amino-9-benzyl-N-isopropyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-7- (4-methylpiperazin-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N-isobutyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
Ethyl 2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] acetate;
Ethyl 3-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate;
tert-Butyl 3-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate;
tert-Butyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate;
Isopropyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-methyl-butanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate;
Isopropyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanol;
tert-Butyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate;
N- [2- [Acetyl (Methyl) Amino] Ethyl] -6-Amino-9-Benzyl-N-Methyl-8-oxo-2- (propylsulfonimideyl) Purine-7-Carboxamide;
Methyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;
tert-butyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;
Ethyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N-butyl-N-methyl-carbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl pyrrolidine-1-carboxylate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N-methyl-N-propyl-carbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N, N-diethylcarbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl ethyl carbonate;
6-Amino-N-Butyl-9-[(4-Chlorophenyl) Methyl] -N-Methyl-8-oxo-2- [S (S) -propylsulfonimideyl] Purine-7-Carboxamide;
6-Amino-N-Butyl-9-[(4-Chlorophenyl) Methyl] -N-Methyl-8-oxo-2- [S (S) -propylsulfonimideyl] Purine-7-Carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-N-Methyl-8-oxo-N-propyl-2 [S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Methyl-8-oxo-N-propyl-2 [S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- [S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-2- [S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-N- (2-Methoxyethyl) -N-Methyl-8-oxo-2-[S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N- (2-Methoxyethyl) -N-Methyl-8-oxo-2-[S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-N-Methyl-8-oxo-2- (propylsulfoneimideyl) -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Butyl-N-Methyl-8-oxo-2- (propylsulfoneimideyl) -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -2- [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-2- [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-2 [S (S) -Ethylsulfonimideyl] -N-Methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-2- [S (R) -Ethylsulfonimideyl] -N-Methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- [S (S) ethylsulfonimideyl] -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-2- [S (R) Ethylsulfonimideyl] -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-N-Ethyl-2- (Ethylsulfonimideyl) -9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Prince-7-Carboxamide;
6-Amino-N-Ethyl-2- [S (S)-(Ethylsulfonimideyl)]-9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Purin-7-Carboxamide;
6-Amino-N-Ethyl-2- [S (R)-(Ethylsulfonimideyl)]-9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Purin-7-Carboxamide;
6-Amino-9-[(4-Bromophenyl) Methyl] -2- (Ethylsulfonimideyl) -N-Methyl-8-oxo-N-propyl-Prin-7-Carboxamide;
6-Amino-2- [S (R) -ethylsulfonimideyl] -9-[(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-2- [S (S) -ethylsulfonimideyl] -9-[(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimideyl) -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (S)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide; And 6-amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (R)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide ;
Or selected from its pharmaceutically acceptable salts, enantiomers or diastereomers;
The anti-angiogenic agent used in the combination therapy is sorafenib, regorafenib, sunitinib or bevacizumab (preferably sorafenib or bevacizumab).

In one preferred embodiment of the invention, the compounds of formula I used in combination therapy with the anti-angiogenic agents described herein are:
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimideyl) -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (S)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide; Alternatively, 6-amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (R)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide ;
Or a pharmaceutically acceptable salt thereof, enantiomer or diastereomer; (in one preferred embodiment, 6-amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfone]. Imidyl] -N-methyl-8-oxo-purine-7-carboxamide)
More selected;
The anti-angiogenic agent used in the combination therapy is sorafenib, regorafenib, sunitinib or bevacizumab (preferably sorafenib or bevacizumab).

In one preferred embodiment of the invention, the compounds of formula I used in combination therapy with antagonist PD1 or antagonist PD-L1 antibodies and the anti-angiogenic agents described herein are:
6-Amino-9-Benzyl-N-Methyl-8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N- (2-methoxyethyl) -N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N-Ethyl-8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-Benzyl-7- [4- (1-piperidyl) piperidine-1-carbonyl] -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-benzyl-N-Ethyl-N- (2-Methoxyethyl) -8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N-Butyl-N-Ethyl-8-oxo-2- (propylsulfoneimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-7- (azetidine-1-carbonyl) -9-benzyl-2- (propylsulfoneimideyl) purine-8-one;
6-Amino-9-benzyl-N-isopropyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-7- (4-methylpiperazin-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N-isobutyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
Ethyl 2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] acetate;
Ethyl 3-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate;
tert-Butyl 3-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate;
tert-Butyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate;
Isopropyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-methyl-butanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate;
Isopropyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanol;
tert-Butyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate;
N- [2- [Acetyl (Methyl) Amino] Ethyl] -6-Amino-9-Benzyl-N-Methyl-8-oxo-2- (propylsulfonimideyl) Purine-7-Carboxamide;
Methyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;
tert-butyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;
Ethyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N-butyl-N-methyl-carbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl pyrrolidine-1-carboxylate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N-methyl-N-propyl-carbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N, N-diethylcarbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl ethyl carbonate;
6-Amino-N-Butyl-9-[(4-Chlorophenyl) Methyl] -N-Methyl-8-oxo-2- [S (S) -propylsulfonimideyl] Purine-7-Carboxamide;
6-Amino-N-Butyl-9-[(4-Chlorophenyl) Methyl] -N-Methyl-8-oxo-2- [S (S) -propylsulfonimideyl] Purine-7-Carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-N-Methyl-8-oxo-N-propyl-2 [S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Methyl-8-oxo-N-propyl-2 [S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- [S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-2- [S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-N- (2-Methoxyethyl) -N-Methyl-8-oxo-2-[S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N- (2-Methoxyethyl) -N-Methyl-8-oxo-2-[S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-N-Methyl-8-oxo-2- (propylsulfoneimideyl) -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Butyl-N-Methyl-8-oxo-2- (propylsulfoneimideyl) -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -2- [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-2- [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-2 [S (S) -Ethylsulfonimideyl] -N-Methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-2- [S (R) -Ethylsulfonimideyl] -N-Methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- [S (S) ethylsulfonimideyl] -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-2- [S (R) Ethylsulfonimideyl] -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-N-Ethyl-2- (Ethylsulfonimideyl) -9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Prince-7-Carboxamide;
6-Amino-N-Ethyl-2- [S (S)-(Ethylsulfonimideyl)]-9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Purin-7-Carboxamide;
6-Amino-N-Ethyl-2- [S (R)-(Ethylsulfonimideyl)]-9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Purin-7-Carboxamide;
6-Amino-9-[(4-Bromophenyl) Methyl] -2- (Ethylsulfonimideyl) -N-Methyl-8-oxo-N-propyl-Prin-7-Carboxamide;
6-Amino-2- [S (R) -ethylsulfonimideyl] -9-[(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-2- [S (S) -ethylsulfonimideyl] -9-[(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimideyl) -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (S)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide; And 6-amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (R)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide ;
Or selected from its pharmaceutically acceptable salts, enantiomers or diastereomers;
i) The antagonist PD1 antibody is either nivolumab or pembrolizumab, or the heavy chain variable domain VH of SEQ ID NO: 5 and the light chain variable domain VL of SEQ ID NO: 6;
ii) The antagonist PD-L1 antibody is atezolizumab or durvalumab or avelumab (atezolizumab in one preferred embodiment).
The anti-angiogenic agent used in the combination therapy is sorafenib, regorafenib, sunitinib or bevacizumab (preferably sorafenib or bevacizumab).

In one preferred embodiment of the invention, the compounds of formula I used in the combination therapy of the antagonist PD1 or antagonist PD-L1 antibody with the anti-angiogenic agents described herein are:
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimideyl) -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (S)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide; Or 6-amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (R)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide ;
Or a pharmaceutically acceptable salt thereof, enantiomer or diastereomer; (in one preferred embodiment, 6-amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfone]. Imidyl] -N-methyl-8-oxo-purine-7-carboxamide)
More selected;
i) Antagonist PD1 antibody is nivolumab or pembrolizumab or comprises heavy chain variable domain VH of SEQ ID NO: 5 and light chain variable domain VL of SEQ ID NO: 6;
ii) The antagonist PD-L1 antibody is atezolizumab or durvalumab or avelumab (atezolizumab in one preferred embodiment).
The anti-angiogenic agent used in the combination therapy is sorafenib, regorafenib, sunitinib or bevacizumab (preferably sorafenib or bevacizumab).

［式中、
Ｒ^１はＣ_１−６アルキルであり；
Ｒ^２はベンジルであり、前記ベンジルは、無置換であるか又はハロゲン及びＣ_１−６アルキルより独立して選択された一つ、二つ、又は三つの置換基で置換されており；
Ｒ^３は、−ＮＲ^４Ｒ^５であって、ここで
Ｒ^４は、Ｃ_１−６アルキル又はＣ_１−６アルコキシＣ_１−６アルキルであり；
Ｒ^５は、（Ｃ_１−６アルキル）_２ＮＣＯＯＣ_１−６アルキル、Ｃ_１−６アルコキシＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニル（Ｃ_１−６アルキル）アミノＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニル（フェニル）Ｃ_１−６アルキル、Ｃ_１−６アルコキシカルボニルＣ_１−６アルキル、Ｃ_１−６アルコキシカルボニルオキシＣ_１−６アルキル、Ｃ_１−６アルキル、Ｃ_１−６アルキルカルボニル（Ｃ_１−６アルキル）アミノＣ_１−６アルキル又はピロリジニルカルバモイルオキシＣ_１−６アルキルである；か又は
Ｒ^４及びＲ^５はそれらが結合する窒素と共にヘテロシクリルを形成する］
の化合物、又はその薬学的に許容される塩、エナンチオマー若しくはジアステレオマー（又はその薬学的組成物若しくは医薬）であって；
但し、
６−アミノ−９−ベンジル−２−（プロピルスルホンイミドイル）−７−（ピロリジン−１−カルボニル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（ピぺリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（モルホリン−４−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３，３−ジメチルピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
エチル １−［６−アミノ−９−ベンジル−８−オキソ−２−（プロピルスルホンイミドイル）プリン−７−カルボニル］ピロリジン−２−カルボキシレート；
６−アミノ−７−（２−アザスピロ［３．３］ヘプタン−２−カルボニル）−９−ベンジル−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（２−オキサ−６−アザスピロ［３．３］ヘプタン−６−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３，３−ジフルオロピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
６−アミノ−９−ベンジル−７−（３−フルオロ−３−メチル−ピロリジン−１−カルボニル）−２−（プロピルスルホンイミドイル）プリン−８−オン；
及びこれらのエナンチオマー又はジアステレオマーは除外される、
化合物。 Specific embodiments of the present invention include:
1. 1. Formula (I) for use in the treatment or prevention of liver cancer

[During the ceremony,
R ¹ is C _1-6 alkyl;
R ² is benzyl, which is unsubstituted or substituted with one, two, or three substituents independently selected from _{halogens and C 1-6 alkyls;}
R ³ is -NR ⁴ R ⁵ , where R ⁴ is C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl;
R ⁵ is (C _1-6 alkyl) ₂ NCOCOC _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxycarbonyl (C _1-6 alkyl) amino C _1-6 alkyl, C _1-6 Alkoxycarbonyl (Phenyl) C _1-6 Alkyl, C _1-6 Alkoxycarbonyl C _1-6 Alkyl, C _1-6 Alkoxycarbonyloxy C _1-6 Alkyl, C _1-6 Alkyl, C _1-6 Alkyl Carbonyl (C _1-6 alkyl) Amino C _1-6 alkyl or pyrrolidinyl carbamoyloxy C _1-6 alkyl; or R ⁴ and R ⁵ form heterocyclyls with the nitrogen to which they bind]
Compound, or a pharmaceutically acceptable salt, enantiomer or diastereomer (or its pharmaceutical composition or pharmaceutical) thereof;
However,
6-Amino-9-Benzyl-2- (propylsulfonimideyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-9-benzyl-7- (piperidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (Morpholine-4-carbonyl) -2- (Propylsulfonimideyl) Purine-8-one;
6-Amino-9-benzyl-7- (3,3-dimethylpyrrolidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
Ethyl 1- [6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] pyrrolidine-2-carboxylate;
6-Amino-7- (2-azaspiro [3.3] heptane-2-carbonyl) -9-benzyl-2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (2-oxa-6-azaspiro [3.3] heptane-6-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (3,3-difluoropyrrolidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (3-Fluoro-3-methyl-pyrrolidin-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
And these enantiomers or diastereomers are excluded,
Compound.

2. R ¹ is C _1-6 alkyl;
R ² is benzyl, said benzyl being unsubstituted or substituted with halogen or C _1-6 alkyl;
R ³ is azetidinyl;
Piperazinyl substituted with C _{1-6 alkyl;}
Piperidinyl substituted with piperidinyl;
Pyrrolidinyl; or −NR ⁴ R ⁵ , where R ⁴ is C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl;
R ⁵ is (C _1-6 alkyl) ₂ NCOCOC _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxycarbonyl (C _1-6 alkyl) amino C _1-6 alkyl, C _1-6 Alkoxycarbonyl (Phenyl) C _1-6 Alkyl, C _1-6 Alkoxycarbonyl C _1-6 Alkyl, C _1-6 Alkoxycarbonyloxy C _1-6 Alkyl, C _1-6 Alkyl, C _1-6 Alkyl Carbonyl (C _1-6 Alkoxy) Amino C _1-6 Alkoxy or Pyrrolidinyl Carbamoyloxy C _1-6 Alkoxy,
The compound for use according to embodiment 1.

3. 3. R ¹ is ethyl or propyl;
R ² is benzyl, bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl;
R ³ is azetidinyl;
4-Methylpiperazinyl;
Piperidinyl Piperidinil;
Pyrrolidinyl; or -NR ⁴ R ⁵ , where R ⁴ is methyl, ethyl, propyl or methoxyethyl;
R ⁵ is acetyl (methyl) aminoethyl, butyl, butyl (methyl) carbamoyloxy ethyl, diethylcarbamoyloxy ethyl, ethoxycarbonyl (methyl) aminoethyl, ethoxycarbonylethyl, ethoxycarbonyl isobutyl, ethoxycarbonyl isopentyl, ethoxycarbonylmethyl , Ethoxycarbonyloxyethyl, ethoxycarbonyl (phenyl) ethyl, ethyl, isobutyl, isopropoxycarbonyl isopentyl, isopropoxycarbonyl (phenyl) ethyl, isopropyl, methoxycarbonyl (methyl) aminoethyl, methoxyethyl, methoxypropyl, propyl, propyl (Methyl) carbamoyloxyethyl, pyrrolidinyl carbamoyloxyethyl, tert-butoxycarbonyl (methyl) aminoethyl, tert-butoxycarbonylethyl, tert-butoxycarbonyl isopentyl or tert-butoxycarbonyl (phenyl) ethyl.
The compound for use according to embodiment 1 or 2.

4. R ³ is azetidinyl, 4-methylpiperazinyl, piperidinyl piperidinyl, 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, iso Propoxycarbonyl Isopentyl (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, pyrrolidinyl carbamoyloxyethyl (methyl) amino , Tert-Butoxycarbonyl (methyl) aminoethyl (methyl) amino, tert-butoxycarbonylethyl (methyl) amino, tert-butoxycarbonyl isopentyl (methyl) amino or tert-butoxycarbonyl (phenyl) ethyl (methyl) amino. ,
The compound for use according to embodiment 3.

5. The compound for use according to any one of embodiments 1 to 4, wherein R ^{1 is ethyl.}

6. The compound for use according to embodiment 1 or 2, wherein R ² is a benzyl substituted with a halogen or C _{1-6 alkyl.}

7. R ² is, bromobenzyl, chlorobenzyl, fluoro benzyl or methylbenzyl, compounds for use according to any one of embodiments 2 6.

8. R ² is bromo benzyl, chlorobenzyl or fluorobenzyl, the compounds for use according to claim 7.

9. The compound for use according to embodiment 1 or 2, wherein R ³ is -NR ⁴ R ⁵ , where R ⁴ is C _1-6 alkyl and R ⁵ is C _{1-6 alkyl.}

10. The compound for use according to embodiment 9, wherein R ³ is propyl (methyl) amino or ethyl (methyl) amino.

11. R ¹ is C _1-6 alkyl;
R ² is benzyl and said benzyl is substituted with _{halogen or C 1-6 alkyl;}
R ³ is -NR ⁴ R ⁵ , where R ⁴ is C _1-6 alkyl and R ⁵ is C _1-6 alkyl.
The compound for use according to any one of embodiments 1, 2, 6 and 9.

12. R ¹ is ethyl;
R ² is methyl benzyl, bromobenzyl, chlorobenzyl or fluorobenzyl;
R ³ is propyl (methyl) amino or ethyl (methyl) amino,
The compound for use according to embodiment 11.

13.
6-Amino-9-Benzyl-N-Methyl-8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N- (2-methoxyethyl) -N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N-Ethyl-8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-Benzyl-7- [4- (1-piperidyl) piperidine-1-carbonyl] -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-benzyl-N-Ethyl-N- (2-Methoxyethyl) -8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N-Butyl-N-Ethyl-8-oxo-2- (propylsulfoneimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-7- (azetidine-1-carbonyl) -9-benzyl-2- (propylsulfoneimideyl) purine-8-one;
6-Amino-9-benzyl-N-isopropyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-7- (4-methylpiperazin-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N-isobutyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
Ethyl 2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] acetate;
Ethyl 3-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate;
tert-Butyl 3-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate;
tert-Butyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate;
Isopropyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-methyl-butanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate;
Isopropyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanol;
tert-Butyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate;
N- [2- [Acetyl (Methyl) Amino] Ethyl] -6-Amino-9-Benzyl-N-Methyl-8-oxo-2- (propylsulfonimideyl) Purine-7-Carboxamide;
Methyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;
tert-butyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;
Ethyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N-butyl-N-methyl-carbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl pyrrolidine-1-carboxylate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N-methyl-N-propyl-carbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N, N-diethylcarbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl ethyl carbonate;
6-Amino-N-Butyl-9-[(4-Chlorophenyl) Methyl] -N-Methyl-8-oxo-2- [S (S) -propylsulfonimideyl] Purine-7-Carboxamide;
6-Amino-N-Butyl-9-[(4-Chlorophenyl) Methyl] -N-Methyl-8-oxo-2- [S (S) -propylsulfonimideyl] Purine-7-Carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-N-Methyl-8-oxo-N-propyl-2 [S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Methyl-8-oxo-N-propyl-2 [S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- [S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-2- [S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-N- (2-Methoxyethyl) -N-Methyl-8-oxo-2-[S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N- (2-Methoxyethyl) -N-Methyl-8-oxo-2-[S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-N-Methyl-8-oxo-2- (propylsulfoneimideyl) -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Butyl-N-Methyl-8-oxo-2- (propylsulfoneimideyl) -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -2- [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-2- [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-2 [S (S) -Ethylsulfonimideyl] -N-Methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-2- [S (R) -Ethylsulfonimideyl] -N-Methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- [S (S) ethylsulfonimideyl] -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-2- [S (R) Ethylsulfonimideyl] -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-N-Ethyl-2- (Ethylsulfonimideyl) -9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Prince-7-Carboxamide;
6-Amino-N-Ethyl-2- [S (S)-(Ethylsulfonimideyl)]-9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Purin-7-Carboxamide;
6-Amino-N-Ethyl-2- [S (R)-(Ethylsulfonimideyl)]-9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Purin-7-Carboxamide;
6-Amino-9-[(4-Bromophenyl) Methyl] -2- (Ethylsulfonimideyl) -N-Methyl-8-oxo-N-propyl-Prin-7-Carboxamide;
6-Amino-2- [S (R) -ethylsulfonimideyl] -9-[(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-2- [S (S) -ethylsulfonimideyl] -9-[(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimideyl) -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (S)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide; And 6-amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (R)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide ;
More selected compounds for use in the treatment or prevention of liver cancer, or pharmaceutically acceptable salts thereof, enantiomers or diastereomers.

14.
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimideyl) -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (S)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide; And 6-amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (R)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide More selected, the compound according to embodiment 13, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

14.6-amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide, The compound for use according to embodiment 13.

16. For use according to any one of embodiments 1 to 15, wherein the liver cancer is hepatocellular carcinoma, hepatoma, cholangiocarcinoma, lung blastoma, liver cancer, hepatic angiosarcoma, or metastatic liver cancer. Compounds, or pharmaceutically acceptable salts, enantiomers or diastereomers.

17. The compound for use according to any one of embodiments 1 to 15, or a pharmaceutically acceptable salt, enantiomer or diastereomer, wherein the liver cancer is hepatocellular carcinoma.

18. A pharmaceutical composition or medicament comprising the compound according to any one of embodiments 1 to 15 and a therapeutically inert carrier for use in the treatment or prevention of liver cancer.

19. Use of the compound according to any one of embodiments 1 to 14 for the preparation of a medicament for the treatment or prevention of liver cancer.

20. A method for treating or preventing liver cancer, which comprises administering a therapeutically effective amount of the compound according to any one of embodiments 1 to 15.

21.
a) Treatment or prevention of liver cancer in combination with antagonist PD1 antibody or antagonist PD-L1 antibody, or b) Use in treatment of liver cancer patients in combination with antagonist PD1 antibody or antagonist PD-L1 antibody The compound according to any one of embodiments 1 to 15, or a pharmaceutical composition or medicine containing such a compound.

22. The compound according to any one of embodiments 1 to 15, or such a compound, for use in the treatment or prevention of liver cancer, wherein the treatment is combined with an antagonist PD1 antibody or an antagonist PD-L1 antibody. Pharmaceutical composition or pharmaceutical.

23. Use of the compound according to any one of embodiments 1 to 15 for the preparation of a medicament for the treatment or prevention of liver cancer, wherein the treatment is combined with an antagonist PD1 antibody or an antagonist PD-L1 antibody.

24. The compound, composition, medicament or use according to any one of embodiments 21 to 23, wherein the treatment is combined with an antagonist PD1 antibody.

25. The compound, composition, medicament or use according to embodiment 24, wherein the antagonist PD1 antibody is nivolumab or penprolizumab.

26. The compound is 6-amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide. , The compound, composition, medicament or use according to embodiment 24.

27. The compound, composition, medicament or drug according to embodiment 23, wherein the agonist PD1 antibody comprises a heavy chain variable region VH comprising the amino acid sequence of SEQ ID NO: 5 and a light chain variable region VL containing the amino acid sequence of SEQ ID NO: 6. use.

28. The compound is 6-amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide. , The compound, composition, medicament or use according to embodiment 27.

29. The compound, composition, medicament or use according to any one of embodiments 21 to 23, wherein the treatment is combined with an antagonist PD-L1 antibody.

30. The compound, composition, medicament or use according to embodiment 29, wherein the antagonist PD-L1 antibody used in the combination therapy is atezolizumab or durvalumab or avelumab (atezolizumab in one preferred embodiment).

31. The compound is 6-amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide. , The compound, composition, medicament or use according to embodiment 30.

32. The compound, composition, medicament or use according to any one of embodiments 21 to 31, wherein an anti-angiogenic agent is further used in the combination therapy.

33. The combination therapy further uses an anti-angiogenic agent selected from sorafenib, regorafenib, sunitinib or bevacizumab (in one preferred embodiment the anti-angiogenic agent is sorafenib; in one preferred embodiment the anti-angiogenic agent is Bevacizumab), the compound, composition, medicament or use according to any one of embodiments 21-31.

34.
Any of embodiments 1 to 15 for use in a) treatment or prevention of liver cancer in combination with an anti-angiogenic agent, or b) treatment of a liver cancer patient in combination with an anti-angiogenic agent. The compound according to any one, or a pharmaceutical composition or medicine containing such a compound.

35. The compound according to any one of embodiments 1 to 15, or a pharmaceutical composition comprising such a compound, for use in the treatment or prevention of liver cancer, the treatment of which is combined with an anti-angiogenic agent. Medicine.

36. Use of the compound according to any one of embodiments 1 to 15 for the preparation of a medicament for the treatment or prevention of liver cancer, the treatment of which is combined with an anti-angiogenic agent.

37. The anti-angiogenic agent is selected from sorafenib, regorafenib, sunitinib or bevacizumab (in one preferred embodiment the anti-angiogenic agent is sorafenib; in one preferred embodiment the anti-angiogenic agent is bevacizumab), embodiment 34. The compound, composition or use according to any one of 36 to 36.

38. The compound is 6-amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide. , The compound, composition, medicament or use according to embodiment 37.

39. The invention described above.

Description of Amino Acid Sequence SEQ ID NO: 1 Heavy chain variable domain of anti-PD1 antibody nibolumab SEQ ID NO: 2 Light chain variable domain of anti-PD1 antibody nibolumab SEQ ID NO: 3 Heavy chain variable domain of anti-PD1 antibody penbrolizumab Variable domain SEQ ID NO: 5 Heavy chain variable domain of anti-PD1 antibody PD1-0103-0312 SEQ ID NO: 6 Light chain variable domain of anti-PD1 antibody PD1-0103-0312 SEQ ID NO: 7 Heavy chain variable domain of anti-PD-L1 antibody atezolizumab SEQ ID NO: 8 Anti-PD-L1 antibody atezolizumab light chain variable domain SEQ ID NO: 9 Anti-PD-L1 antibody durvalumab heavy chain variable domain SEQ ID NO: 10 Anti-PD-L1 antibody durvalumab light chain variable domain SEQ ID NO: 11 Anti-PD-L1 antibody durvalumab Heavy Chain Variable Domain SEQ ID NO: 12 Light chain variable domain of anti-PD-L1 antibody Avelumab SEQ ID NO: 13 Exemplary human PD-L1
SEQ ID NO: 14 Exemplary human PD1
SEQ ID NO: 15 Human kappa light chain constant region SEQ ID NO: 16 Human heavy chain constant region derived from IgG1 SEQ ID NO: 17 Human heavy chain constant region derived from IgG1 mutated with L234A, L235A and P329G

The combination of the prodrug form of the compound of the present invention (Compound 41-A) with sorafenib gave two tumor-free mice in the iAST mouse model of hepatocellular carcinoma. 1A shows the synergistic effect of compound 41-A and sorafenib on tumor loading (tumor-free mice), and 1B shows the total weight of liver and tumor after treatment. Treatment with the prodrug form of the compound of the invention (Compound 41-A) induces PD-L1 expression in tumor cells in an iAST mouse model of hepatocellular carcinoma. 2A indicates CD45 + total immune cell infiltration, 2B indicates PD-L1 on CD45-, 2C indicates CD11b-lymphocytes, and 2D indicates CD11b + bone marrow cells. The three combinations of the prodrug form of the compound of the invention (Compound 41-A), sorafenib and anti-PD-1, result in an increase in median survival. Treatment with the prodrug form of the compound of the invention (Compound 41-A) results in tumor progression and quiescence in a transplanted Hep55.1c mouse model of hepatocellular carcinoma. The combination of the prodrug form of the compound of the present invention (Compound 41-A) with an anti-PD-1 antibody serves beneficially for the survival rate of the Hep55.1c mouse model of hepatocellular carcinoma. Compound 42-A (6-amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-] in hepatocellular carcinoma It shows the efficacy of purine-7-carboxamide) alone and in combination with anti-PD-1. Treatment with the active form of the compounds of the invention does not induce hyperproliferation of tumor cells in cell lines originating from hepatocellular carcinoma and cholangiocarcinoma. Compound 41c-B. Treatment with the active form of the compounds of the invention does not induce hyperproliferation of tumor cells in cell lines originating from hepatocellular carcinoma and cholangiocarcinoma. Compound 41c-A. Factors released into peripheral blood upon treatment with the active form of the compound of the invention (Compound 41c-B) inhibit growth in tumor cell lines. Cell lines Hep3B, SNU449, HLF, JHH2, Huh7, OZ, JHH1, HepG2. Factors released into peripheral blood upon treatment with the active form of the compound of the invention (Compound 41c-B) inhibit growth in tumor cell lines. Cell lines JHH4, HLE, JHH6, JHH5, SkHep1, EGI1. Factors released into peripheral blood upon treatment with the active form of the compound of the invention (Compound 41c-A) inhibit growth in tumor cell lines. The single crystal X-ray diffraction of Example 41-B is shown. The single crystal X-ray diffraction of Example 42-A is shown. The single crystal X-ray diffraction of Example 43-B is shown.

The present invention will be more fully understood by reference to the following examples. However, these examples should not be construed as limiting the scope of the invention.

Abbreviation aq. : Aqueous BSA: N, O-bis (trimethylsilyl) acetamide CDI: N, N'-carbonyldiimidazole DIEPA: N, N-diethylpropylamine DBU: 1,8-diazabicycloundec-7-en DPPA: diphenyl Phosphoryl azide EC ₅₀ : Mormo-concentration of agonist that produces 50% of the maximum possible response for that agonist EDC: N1-((ethylimino) methylene) -N3, N3-dimethylpropan-1,3-diamine EtOAc or EA: Ethylacetate HATU: 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate hr (s): time HPLC: high performance liquid chromatography HOBtN-Hydroxybenzotriazole MS (ESI): Mass spectrometry (electron spray ionization)
m-CPBA: 3-chloroperbenzoic acid MTEB: methyl tert-butyl ether NMP: N-methylpyrrolidone obsd. : Measured value PE: Petroleum ether PMB: p-methoxybenzyl PPA: Polyphosphoric acid QOD: Every other day QW: Weekly RT or rt: Room temperature sat. : Saturated TFA: Trifluoroacetic acid TEA: Triethylamine V / V: Volume ratio

General Experimental Conditions Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and Quad 12/25 Cartridge module, ii) ISCO combi-flash chromatography instrument. .. Silica gel brand and pore size: i) KP-SIL 60A, particle size: 40-60 μm; ii) CAS registration NO: Silicona Gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) Qingdao Haiyang Chemical Co .. , Ltd. ZCX, hole: 200-300 or 300-400.

Intermediates and final compounds are ^{preparatively HPLC using an X Bridge TM} Perp C ₁₈ (5 μm, OBD ^TM 30 × 100 mm) column or a SunFire ^TM Perp C ₁₈ (5 μm, OBD ^TM 30 × 100 mm) column. Purified.

LC / MS spectra were acquired using Waters UPLC-SQD Mass. The standard LC / MS conditions were as follows (running time 3 minutes):
Acidic conditions: A: in _{H 2} O, 0.1% formic acid and 1% acetonitrile; B: acetonitrile, 0.1% formic acid.
Basic conditions: A: in _{H 2 O, 0.05% NH 3} · H 2 O; B: acetonitrile.

Mass Spectrum (MS): Normally only ions showing parent mass are reported, and unless otherwise specified, the cited mass ions are positive mass ions (M + H) ⁺ .

The NMR spectrum was acquired using Bruker Avance 400 MHz.

All reactions involving air-sensitive reagents were performed in an argon atmosphere. Unless otherwise noted, reagents used were those received by the supplier without further purification.

Preparation Example Preparation of Intermediate Intermediate AA
N-methyl-N-propyl-carbamoyl chloride

Bis (trichloromethyl) in DCM (30 mL) relative to 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. ) Carbonate (8.11 g, 27.3 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours and filtered. The filtrate was concentrated in vacuo. The resulting N-methyl-N-propyl-carbamoyl chloride (7.2 g, intermediate AA) was used in the next step without further purification.

Intermediate AB
N- (2-Methoxyethyl) -N-methyl-carbamoyl chloride

Intermediate AB was prepared similarly to Intermediate AA using 2-methoxy-N-methyl-ethaneamine instead 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 further purification.

Intermediate AC
N-ethyl-N-propyl-carbamoyl chloride

Intermediate AC was prepared similarly to Intermediate AA, using N-ethylpropane-1-amine instead of N-methylpropane-1-amine. N-ethyl-N-propyl-carbamoyl chloride (12.6 g, intermediate AC) was obtained as a yellow oil, which was used in the next step without further purification.

Intermediate AD
N-Ethyl-N- (2-Methoxyethyl) Carbamoyl Chloride

Intermediate AD was prepared similarly to Intermediate AA using N-ethyl-2-methoxyethaneamine instead of N-methylpropan-1-amine. Crude N-ethyl-N- (2-methoxyethyl) carbamoyl chloride (2.5 g, intermediate AD) was obtained as a bright yellow oil, which was used in the next step without further purification.

Intermediate AE
N-Butyl-N-Ethyl-Carbamic Chloride

Intermediate AE was prepared similarly to Intermediate AA using N-ethylbutane-1-amine (5 g) instead of N-methylpropane-1-amine. Crude N-butyl-N-ethyl-carbamoyl chloride (6.3 g, intermediate AE) was obtained as a bright yellow oil, which was used in the next step without further purification.

Intermediate AF
N- (2-Methoxyethyl) -N-propyl-carbamoyl chloride

Intermediate AF was prepared similarly to Intermediate AA using N- (2-methoxyethyl) propan-1-amine (2 g, 17.1 mmol) instead of N-methylpropane-1-amine. .. Crude N- (2-methoxyethyl) -N-propyl-carbamoyl chloride (2.5 g, intermediate AF) was obtained as a bright yellow oil, which was used in the next step without further purification.

Intermediate AG
N, N-bis (2-methoxyethyl) carbamoyl chloride

Intermediate AG was prepared similarly to Intermediate AA using bis (2-methoxyethyl) amine (2 g, 15 mmol) instead of N-methylpropane-1-amine. The crude product N, N-bis (2-methoxyethyl) carbamoyl chloride (2.6 g, intermediate AG) was obtained as a bright yellow oil, which was used in the next step without further purification.

Intermediate AH
Azetidine-1-carbonyl chloride

Intermediate AH uses azetidine hydrochloride (10.7 g, 107 mmol) and sodium bicarbonate (3 eq) in place of N-methylpropan-1-amine and sodium bicarbonate (2 eq) with Intermediate AA. Prepared in the same manner. Crude azetidine-1-carbonyl chloride (1.5 g, intermediate AH) was obtained as a bright yellow oil, which was used in the next step without further purification.

Intermediate AI
N-isopropyl-N-methyl-carbamoyl chloride

Intermediate AI was prepared similarly to Intermediate AA 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, which was used in the next step without further purification.

Intermediate AL
N-isobutyl-N-methyl-carbamoyl chloride

Intermediate AL was prepared similarly to Intermediate AA using N-2-dimethylpropane-1-amine (4.8 g) instead of N-methylpropane-1-amine. Crude N-isobutyl-N-methyl-carbamoyl chloride (8.1 g, intermediate AL) was obtained as a bright yellow oil, which was used in the next step without further purification.

Intermediate AP
Ethyl 2- [chlorocarbonyl (methyl) amino] acetate

Ethyl 2- (methylamino) acetate hydrochloride (1.3 g, 8.46 mmol) and pyridine (1 mL) in DCM (5 mL) versus a solution of triphosgene (728 mg, 2.45 mmol) in DCM (5 mL). The solution was added dropwise at 0 ° C. The reaction mixture turned orange and a yellow precipitate appeared, then the temperature was raised to room temperature. After stirring for 1 hour, aqueous HCl (0.1N, 25 mL) was added to the reaction mixture, the organic layer was separated, washed twice with 0.1N HCl (10 mL) and with brine (10 mL), Na ₂ SO. _It was dried in No. 4 and concentrated in vacuo to give crude ethyl 2- [chlorocarbonyl (methyl) amino] acetate (2.0 g, intermediate AP) as a light yellow oil. It was used in the next step without further purification.

Intermediate AR
tert-Butyl 3- [chlorocarbonyl (methyl) amino] propanoate

Step 1: Preparation of tert-butyl 3- (methylamino) propanoate (Compound AR-1)

Methylamine hydrochloride (4.74 g, 70 mmol) and DBU (21.4 g, 140 mmol) were added to a solution of tert-butyl acrylate (3 g) in DMF (40 mL) at −45 ° C. The temperature of the reactants was then raised to −10 ° C. The reaction mixture was stirred at the same temperature for 2.5 hours. Et ₂ O (200 mL) was added and the resulting mixture was washed 4 times with brine (50 mL). The separated organic layer was _{dried over Na 2} SO ₄ and concentrated in vacuo to give tert-butyl 3- (methylamino) propanoate (3.5 g, compound AR-1) as a bright yellow oil.

Step 2: Preparation of tert-butyl 3- [chlorocarbonyl (methyl) amino] propanoate (intermediate AR)

Intermediate AR was prepared similarly to Intermediate AP using tert-butyl 3- (methylamino) propanoate (3.4 g, compound AR-1) instead of ethyl 2- (methylamino) acetate hydrochloride. Was done. A crude tert-butyl 3- [chlorocarbonyl (methyl) amino] propanoate (3.5 g, intermediate AR) was obtained, which was used in the next step without further purification.

Intermediate AS
Ethyl (2S) -2- [Chlorocarbonyl (Methyl) Amino] Propanoate

Step 1: Preparation of ethyl (2S) -2- (methylamino) propanoate hydrochloride (Compound AS-1)

_{SOCl 2} (1.50 g, 12.61 mmol) was added dropwise at 0 ° C. for 0.5 hours to a solution of (2S) -2- (methylamino) propanoic acid (1 g, 9.70 mmol) in EtOH (10 mL). did. The reaction mixture was stirred for 15.5 hours at 25 ° C., then diluted with EA (20 _mL), washed with H 2 O (5mL) and brine (5 mL). The organic layer was _{dried over Na 2} SO ₄ and concentrated in vacuo. Ethyl (2S) -2- (methylamino) propanoate hydrochloride (1.8 g, compound AS-1) was obtained as a yellow oil, which was used in the next step without further purification.

Step 2: Preparation of ethyl (2S) -2- (methylamino) propanoate (Compound AS-2)

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 wt% aqueous NaHCO 3.} .. The reaction mixture was stirred at room temperature for 0.5 hours. The organic layer was washed with brine (5 mL), dried over Na ₂ SO ₄ , and concentrated in vacuo. Ethyl (2S) -2- (methylamino) propanoate (620 mg, compound AS-2) was obtained as a yellow oil, which was used in the next step without further purification.

Step 3: Preparation of ethyl (2S) -2- [chlorocarbonyl (methyl) amino] propanoate (intermediate AS)

Intermediate AS was prepared similarly to Intermediate AP using ethyl (2S) -2- (methylamino) propanoate (260 mg, compound AS-2) instead of ethyl 2- (methylamino) acetate hydrochloride. Was done. Crude ethyl (2S) -2- [chlorocarbonyl (methyl) amino] propanoate (200 mg, intermediate AS) was obtained as a yellow oil, which was used in the next step without further purification.

Intermediate AT
tert-butyl (2S) -2- [chlorocarbonyl (methyl) amino] -4-methyl-pentanoate

Step 1: Preparation of tert-butyl (2S) -4-methyl-2- (methylamino) pentanoate (Compound AT-1)

2-Methylpropene (25 g, 446 mmol) was bubbled into DCM (50 mL) at −78 ° C. The 2-methylpropene solution was then added to dioxane (20 mL) in (S) -4-methyl-2- (methylamino) pentanoic acid hydrochloride (500 mg, 2.75 mmol) and H ₂ SO ₄ (3.68 g, 2 mL). , 37.5 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 18 hours in a shielded tube. The reaction solution was poured into ice-cold KOH aqueous solution (8.4 g (30 mL) in water) and the resulting mixture was extracted twice with DCM (50 mL). The mixed organic layer was washed twice with brine (30 mL), dried over Na ₂ SO ₄ , concentrated in vacuo and the crude product tert-butyl (2S) -4-methyl-2- (methylamino) pentanoate. (Compound AT-1) was obtained as a bright yellow oil.

Step 2: Preparation of tert-butyl (2S) -2- [chlorocarbonyl (methyl) amino] -4-methyl-pentanoate (intermediate AT)

Intermediate AT uses tert-butyl (2S) -4-methyl-2- (methylamino) pentanoate (300 mg, compound AT-1) in place of ethyl 2- (methylamino) acetate hydrochloride. Prepared similarly to body AP. Crude tert-butyl (2S) -2- [chlorocarbonyl (methyl) amino] -4-methyl-pentanoate (350 mg, intermediate AT) was obtained as a bright yellow oil, which could be followed without further purification. Used in the process of.

Intermediate AU
Isopropyl (2S) -2- [chlorocarbonyl (methyl) amino] -4-methyl-pentanoate

Step 1: Preparation of isopropyl (2S) -4-methyl-2- (methylamino) pentanoate hydrochloride (Compound AU-1)

Thionyl chloride (655 mg, 402 μL) to a solution of (S) -4-methyl-2- (methylamino) pentanoic acid hydrochloride (0.5 g) in i-PrOH (7.8 g, 10 mL) at room temperature. Dropped. The resulting mixture was stirred, refluxed for 16 hours and then concentrated in vacuo. The residue was basified with saturated _{aqueous NaHCO 3} solution (30 mL) and extracted with DCM (50 mL). The organic layer was washed with brine, dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was chlorinated with HCl / EtOAc (10 mL, 1 mmol / mL) and concentrated to whiten isopropyl (2S) -4-methyl-2- (methylamino) pentanoate hydrochloride (510 mg, compound AU-1). Obtained as a solid.

Step 2: Preparation of isopropyl (2S) -2- [chlorocarbonyl (methyl) amino] -4-methyl-pentanoate (intermediate AU)

Intermediate AU uses isopropyl (2S) -4-methyl-2- (methylamino) pentanoate hydrochloride (500 mg, compound AU-1) in place of ethyl 2- (methylamino) acetate hydrochloride. Prepared similarly to body AP. Crude isopropyl (2S) -2- [chlorocarbonyl (methyl) amino] -4-methyl-pentanoate (650 mg, intermediate AU) was obtained as a bright yellow oil, which could be followed without further purification. Used for.

Intermediate AV
Ethyl (2S) -2- [Chlorocarbonyl (Methyl) Amino] -3-Methyl-Butanoate

Step 1: Preparation of ethyl (2S) -3-methyl-2- (methylamino) butanoate hydrochloride (Compound AV-1)

Thionyl chloride (2.45 g, 21 mmol) was added dropwise to a solution of (2S) -3-methyl-2- (methylamino) butanoic acid (1.0 g, 7.6 mmol) in EtOH (10 mL) at room temperature. .. The resulting mixture was stirred, refluxed for 16 hours and then concentrated in vacuo. The residue was basified with saturated _{aqueous NaHCO 3} solution (30 mL) and extracted twice with DCM (50 mL). The mixed organic layer was washed with brine, dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was dissolved in HCl / EtOAc (10 mL, 1 M) and concentrated to whiten ethyl (2S) -3-methyl-2- (methylamino) butanoate hydrochloride (1.9 g, compound AV-1). Obtained as a solid.

Step 2: Preparation of ethyl (2S) -2- [chlorocarbonyl (methyl) amino] -3-methyl-butanoate (intermediate AV)

Intermediate AV uses ethyl (2S) -3-methyl-2- (methylamino) butanoate hydrochloride (500 mg, compound AV-1) instead of ethyl 2- (methylamino) acetate hydrochloride. Prepared similarly to body AP. Crude ethyl (2S) -2- [chlorocarbonyl (methyl) amino] -3-methyl-butanoate (600 mg, intermediate AV) was obtained as a bright yellow oil, which could be followed without further purification. Used for.

Intermediate AW
Ethyl (2S) -2- [chlorocarbonyl (methyl) amino] -4-methyl-pentanoate

Step 1: Preparation of ethyl (2S) -4-methyl-2- (methylamino) pentanoate hydrochloride (Compound AW-1)

Thionyl chloride (1.07 g, 8.3 mmol) was added dropwise to a solution of (2S) -4-methyl-2- (methylamino) pentanoic acid (1 g, 6.9 mmol) in EtOH (10 mL) at room temperature. .. The resulting mixture was stirred at reflux for 16 hours and then concentrated in vacuo. The residue was basified with saturated _{aqueous NaHCO 3} solution (30 mL) and extracted with DCM (50 mL). The organic layer was washed with brine, dried over Na ₂ SO ₄ , and concentrated in vacuo. Residues were chlorided with HCl / EtOAc (10 mL, 1 mmol / mL) and concentrated to concentrate ethyl (2S) -4-methyl-2- (methylamino) pentanoate hydrochloride (1.8 g, compound AW-1). Was obtained as a white solid.

Step 2: Preparation of ethyl (2S) -2- [chlorocarbonyl (methyl) amino] -4-methyl-pentanoate (intermediate AW)

Intermediate AW uses ethyl (2S) -4-methyl-2- (methylamino) pentanoate hydrochloride (610 mg, AW-1) instead of ethyl 2- (methylamino) acetate hydrochloride. Prepared in the same manner as AP. Crude ethyl (2S) -2- [chlorocarbonyl (methyl) amino] -4-methyl-pentanoate (280 mg, intermediate AW) was obtained as a bright yellow oil, which could be followed without further purification. Used for.

Intermediate AX
Ethyl (2S) -2- [Chlorocarbonyl (Methyl) Amino] -3-Phenyl-Propanoate

Intermediate AX was prepared similarly to Intermediate AP using (S) -ethyl-2- (methylamino) -3-phenylpropanoate instead of ethyl 2- (methylamino) acetate hydrochloride. It was. Crude ethyl (2S) -2- [chlorocarbonyl (methyl) amino] -3-phenyl-propanoate (200 mg, intermediate AX) was obtained as a bright yellow oil, which could be followed without further purification. Used for.

Intermediate AY
Isopropyl (2S) -2- [chlorocarbonyl (methyl) amino] -3-phenyl-propanoate

Intermediate AY was prepared similarly to Intermediate AP using isopropyl (2S) -2- (methylamino) -3-phenyl-propanoate (190 mg) instead of ethyl 2- (methylamino) acetate hydrochloride. Was done. Crude isopropyl (2S) -2- [chlorocarbonyl (methyl) amino] -3-phenyl-propanoate (220 mg, intermediate AY) was obtained as a light brown oil, which could be followed without further purification. Used for.

Intermediate AZ
(S) -tert-Butyl 2-((chlorocarbonyl) (methyl) amino) -3-phenylpropanoid

Step 1: Preparation of tert-butyl (2S) -2- (methylamino) -3-phenyl-propanoate (Compound AZ-1)

2-Methylpropene (25 g, 446 mmol) was bubbled into DCM (50 mL) at −78 ° C. The 2-methylpropene solution was then added to a solution of (S) -2- (methylamino) -3-phenylpropanoic acid (500 mg) and H ₂ SO _{4 (3.68 g, 2 mL) in dioxane (20 mL) at 0 ° C.} Added in. The reaction mixture was stirred at room temperature for 18 hours in a shielded tube. The reaction mixture was poured into ice-cold KOH aqueous solution (8.4 g (30 mL) in water) and the resulting mixture was extracted twice with DCM (50 mL). The organic layer was washed twice with brine (30 mL), dried over Na ₂ SO ₄ , concentrated in vacuo and tert-butyl (2S) -2- (methylamino) -3-phenyl-propanoate (710 mg, Compound AZ-1) was obtained as a bright yellow oil.

Step 2: Preparation of (S) -tert-butyl 2-((chlorocarbonyl) (methyl) amino) -3-phenylpropanoid (intermediate AZ)

Intermediate AZ uses tert-butyl (2S) -2- (methylamino) -3-phenyl-propanoate (Compound AZ-1) in place of ethyl 2- (methylamino) acetate hydrochloride. Prepared in the same manner as AP. Crude tert-butyl (2S) -2- [chlorocarbonyl (methyl) amino] -3-phenyl-propanoate (360 mg, intermediate AZ) was obtained as a bright yellow oil, which could be followed without further purification. Used in the process of.

Intermediate BA
N- [2- [Acetyl (Methyl) Amino] Ethyl] -N-Methyl-Carbamoyl Chloride

Step 1: Preparation of tert-butyl N- [2- [acetyl (methyl) amino] ethyl] -N-methyl-carbamate (Compound BA-1)

Acetic anhydride (3.06 g, 30 mmol) was added dropwise at 0 ° C. to a solution of tert-butyl methyl (2- (methylamino) ethyl) carbamate (1.13 g, 6 mmol) in pyridine (10 mL). The solution was then stirred at room temperature for 0.5 hours. The solvent was removed in vacuo and the residue _{was separated into EtOAc (50 mL) and saturated aqueous NaHCO 3} solution (25 mL). The organic layer is separated, washed with brine (20 mL), dried over Na ₂ SO ₄ , concentrated in vacuo and tert-butyl N- [2- [acetyl (methyl) amino] ethyl] -N-methyl. -Carbamate (1.28 g, compound BA-1) was obtained as a yellow oil.

Step 2: Preparation of N-methyl-N- (2- (methylamino) ethyl) acetamide hydrochloride (Compound BA-2)

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). , Stirred for 2 hours at room temperature, then the mixture was filtered. The collected solid was washed 3 times with EtOAc (5 mL) and dried in vacuo to whiten crude N-methyl-N- (2- (methylamino) ethyl) acetamide hydrochloride (460 mg, compound BA-2). Obtained as a solid.

Step 3: Preparation of N- [2- [acetyl (methyl) amino] ethyl] -N-methyl-carbamoyl chloride (intermediate BA)

Intermediate BA uses N-methyl-N- (2- (methylamino) ethyl) acetamide hydrochloride (200 mg, compound BA-2) in place of ethyl 2- (methylamino) acetate hydrochloride. Prepared similarly to body AP. Crude 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.

Intermediate BB
Methyl N- [2- [chlorocarbonyl (methyl) amino] ethyl] -N-methyl-carbamate

Step 1: Preparation of Methyl N-Methyl-N- [2- (Methylamino) Ethyl] Carbamate (Compound BB-1)

Methyl chloroformate (1.92 g) was added dropwise at −70 ° C. for 1 hour to a solution of N, N'-dimethylethane-1,2-diamine (10 g) in THF (40 mL). The mixture was ^{stirred at 25 ° C.} for 15 hours, then filtered and washed with water and brine. The organic layer was dried and concentrated to give a yellow residue, which was purified by column chromatography to obtain methyl N-methyl-N- [2- (methylamino) ethyl] carbamate (2 g, compound). BB-1) was obtained as a colorless oil.

Step 2: Preparation of methyl N- [2- [chlorocarbonyl (methyl) amino] ethyl] -N-methyl-carbamate (intermediate BB)

Intermediate BB uses methyl N-methyl-N- [2- (methylamino) ethyl] carbamate (2.0 g, compound BB-1) instead of ethyl 2- (methylamino) acetate hydrochloride. It was prepared in the same manner as the intermediate AP. 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. did.

Intermediate BC
tert-butyl N- [2- [chlorocarbonyl (methyl) amino] ethyl] -N-methyl-carbamate

Step 1: Preparation of tert-butyl N-methyl-N- [2- (methylamino) ethyl] carbamate (Compound BC-1)

_{Boc 2} O (10 g, 10.6 mL, 45.8 mmol) in DCM (100 mL) relative to a solution of N, N'-dimethylethane-1,2-diamine (40.4 g) in DCM (300 mL). The solution was added dropwise at 0 ° C. over 1 hour. The reaction mixture was stirred at room temperature for 18 hours. The organic layer was washed with saturated _{aqueous NaHCO 3} solution (50 mL) and brine (50 mL), dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by column chromatography to give tert-butyl N-methyl-N- [2- (methylamino) ethyl] carbamate (6.8 g, compound BC-1) as a yellow oil. ^{1 1} H NMR (400 MHz, 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 tert-butyl N- [2- [chlorocarbonyl (methyl) amino] ethyl] -N-methyl-carbamate (intermediate BC)

Intermediate BC uses tert-butyl N-methyl-N- [2- (methylamino) ethyl] carbamate (1.15 g, compound BC-1) instead of ethyl 2- (methylamino) acetate hydrochloride. Was prepared in the same manner as the intermediate AP. The crude tert-butyl N- [2- [chlorocarbonyl (methyl) amino] ethyl] -N-methyl-carbamate (1.3 g, intermediate BC) was obtained in the next step without further purification. Used for.

Intermediate BD
Ethyl N- [2- [Chlorocarbonyl (Methyl) Amino] Ethyl] -N-Methyl-Carbamate

Step 1: Preparation of Ethyl N-Methyl-N- [2- (Methylamino) Ethyl] Carbamate (Compound BD-1)

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

Step 2: Preparation of ethyl N- [2- [chlorocarbonyl (methyl) amino] ethyl] -N-methyl-carbamate (intermediate BD)

Intermediate BD uses ethyl N-methyl-N- [2- (methylamino) ethyl] carbamate (Compound BD-1) in place of ethyl 2- (methylamino) acetate hydrochloride with Intermediate AA. Prepared in the same manner. 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. did.

Intermediate BE
2- [Chlorocarbonyl (Methyl) Amino] Ethyl N-Butyl-N-Methyl-Carbamate

Step 1: Preparation of tert-butyl N- (2-hydroxyethyl) -N-methyl-carbamate (Compound BE-1)

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

Step 2: Preparation of 2- [tert-butoxycarbonyl (methyl) amino] ethyl N-butyl-N-methyl-carbamate (Compound BE-2)

In DCM (10mL), tert- butyl N-(2-hydroxyethyl) -N- methyl - To a solution of carbamate (880 mg, Compound BE-1) and _{Et 3 N (1g, 10.08mmol)} , N- butyl -N-Methyl-carbamoyl chloride (903 mg, 7.04 mmol) was added dropwise at −10 ° C. for 1 hour. The reaction mixture was stirred at 25 ° C. for 15 hours, then filtered and washed with water and brine. The organic layer was dried and concentrated to give 2- [tert-butoxycarbonyl (methyl) amino] ethyl N-butyl-N-methyl-carbamate (2 g, compound BE-2) as a colorless oil.

Step 3: Preparation of 2- (methylamino) ethyl N-butyl-N-methyl-carbamate hydrochloride (Compound BE-3)

HCl / EA (40 mL, 1 M) was added to a solution of 2- [tert-butoxycarbonyl (methyl) amino] ethyl N-butyl-N-methyl-carbamate (1 g, compound BE-2). The reaction mixture was stirred at 0 ° C. for 0.5 hours, warmed to 25 ° C. and further stirred for 15.5 hours. The reaction mixture was concentrated to give 2- (methylamino) ethyl-N-butyl-N-methyl-carbamate hydrochloride (400 mg, compound BE-3) as a colorless oil.

Step 4: Preparation of 2- [chlorocarbonyl (methyl) amino] ethyl N-butyl-N-methyl-carbamate (intermediate BE)

Intermediate BE uses 2- (methylamino) ethyl N-butyl-N-methyl-carbamate hydrochloride (374 mg, compound BE-3) in place of ethyl 2- (methylamino) acetate hydrochloride. Prepared similarly to body AP. 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
2- [Chlorocarbonyl (methyl) amino] ethyl pyrrolidine-1-carboxylate

Step 1: Preparation of tert-butyl N- (2-hydroxyethyl) -N-methyl-carbamate (Compound BF-1)

_{Boc 2} O (34.87 g, 159.77 mmol) was added to a solution of 2- (methylamino) ethanol (10 g, 133.14 mmol) in DCM (10 mL) at 25 ° C. The mixture was stirred at 25 ° C. for 16 hours. The reaction mixture is concentrated to give a residue, which is purified by column chromatography to make tert-butyl N- (2-hydroxyethyl) -N-methyl-carbamate (20 g, compound BF-1) colorless. Obtained as an oil.

Step 2: Preparation of 2- [tert-butoxycarbonyl (methyl) amino] ethyl pyrrolidine-1-carboxylate (Compound BF-2)

For a solution of tert-butyl N- (2-hydroxyethyl) -N-methyl-carbonyl (300 mg, 1.71 mmol, compound BF-1) and Et _{3 N (578 mg, 5.71 mmol) in DCM (5 mL).} , Pyrrolidine-1-carbonyl chloride (458 mg, 3.4 mmol) was added dropwise at 0 ° C. for 0.5 hours, followed by stirring at 25 ° C. for 15.5 hours. After filtration, the filtrate was washed with water and brine. The organic layer was dried and concentrated to give 2- [tert-butoxycarbonyl (methyl) amino] ethylpyrrolidine-1-carboxylate (335 mg, compound BF-2) as a colorless oil.

Step 3: Preparation of 2- (methylamino) ethyl pyrrolidine-1-carboxylate hydrochloride (Compound BF-3)

2- [tert-Butoxycarbonyl (methyl) amino] ethyl pyrrolidine-1-carboxylate (335 mg, compound BF-2) was added to HCl in EA (12.3 mL, 1 M) and the mixture was added at 0 ° C. at 0 ° C. The mixture was stirred for 5 hours and then at 25 ° C. for an additional 15.5 hours. The reaction mixture was concentrated to give 2- (methylamino) ethyl pyrrolidine-1-carboxylate hydrochloride (300 mg, compound BF-3) as a colorless oil.

Step 4: Preparation of 2- [chlorocarbonyl (methyl) amino] ethyl pyrrolidine-1-carboxylate (intermediate BF)

Intermediate BF uses 2- (methylamino) ethylpyrrolidin-1-carboxylate hydrochloride (299 mg, compound BF-3) in place of ethyl 2- (methylamino) acetate hydrochloride with Intermediate AP. Prepared in the same manner. A crude 2- [chlorocarbonyl (methyl) amino] ethyl pyrrolidine-1-carboxylate (230 mg, intermediate BF) was obtained, which was used in the next step without further purification.

Intermediate BG
2- [Chlorocarbonyl (methyl) amino] ethyl N-methyl-N-propyl-carbamate

Step 1: Preparation of tert-butyl N- (2-hydroxyethyl) -N-methyl-carbamate (Compound BG-1)

_{Boc 2} O (34.87 g, 159.77 mmol) was added to a solution of 2- (methylamino) ethanol (10 g, 133.14 mmol) in DCM (10 mL) at 25 ° C. The reaction mixture was stirred at 25 ° C. for 16 hours and then concentrated to give a residue. This was purified by column chromatography to obtain tert-butyl N- (2-hydroxyethyl) -N-methyl-carbamate (20 g, compound BG-1) as a colorless oil.

Step 2: Preparation of tert-butyl-N-methyl-N- [2- [methyl (propyl) carbamoyl] oxyethyl] carbamate (compound BG-2)

In DCM (5mL), tert- butyl N-(2-hydroxyethyl) -N- methyl - To a solution of carbamate (265 mg, Compound BG-1) and _{Et 3 N (1mL, 5.71mmol)} , N- methyl -N-propyl-carbamoyl chloride (410 mg, 1.83 mmol) was added dropwise at 0 ° C. for 0.5 hours. The reaction mixture was stirred at 25 ° C. for 15.5 hours, then filtered and the filtrate washed with water and brine. The organic layer was dried and concentrated to give tert-butyl N-methyl-N- [2- [methyl (propyl) carbamoyl] oxyethyl] carbamate (380 mg, compound BG-2) as a colorless oil.

Step 3: Preparation of 2- (methylamino) ethyl N-methyl-N-propyl-carbamate hydrochloride (Compound BG-3)

Preparation of tert-butyl N-methyl-N- [2- [methyl (propyl) carbamoyl] oxyethyl] carbamate (380 mg, compound BG-2) was added to HCl (13.7 mL, 1 M) in EA. The mixture was stirred at 0 ° C. for 0.5 hours. The mixture was then stirred at 25 ° C. for an additional 15.5 hours and concentrated to make 2- (methylamino) ethyl N-methyl-N-propyl-carbamate hydrochloride (300 mg, compound BG-3) a colorless oil. Obtained.

Step 4: Preparation of 2- [chlorocarbonyl (methyl) amino] ethyl N-methyl-N-propyl-carbamate (intermediate BG)

Intermediate BG uses 2- (methylamino) ethyl N-methyl-N-propyl-carbamate hydrochloride (330 mg, compound BG-3) in place of ethyl 2- (methylamino) acetate hydrochloride. Prepared similarly to body AP. 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
2- [Chlorocarbonyl (Methyl) Amino] Ethyl N, N-Diethyl Carbamate

Step 1: Preparation of tert-butyl N- (2-hydroxyethyl) -N-methyl-carbamate (Compound BH-1)

_{Boc 2} O (34.87 g, 159.77 mmol) was added to a solution of 2- (methylamino) ethanol (10 g, 133.14 mmol) in DCM (10 mL) at 25 ° C. The mixture was stirred at 25 ° C. for 16 hours, then concentrated and the residue was purified by column chromatography by tert-butyl N- (2-hydroxyethyl) -N-methyl-carbamate (20 g, compound BH-). 1) was obtained as a colorless oil.

Step 2: Preparation of 2- [tert-butoxycarbonyl (methyl) amino] ethyl-N, N-diethylcarbamate (Compound BH-2)

Against a solution of tert-butyl N- (2-hydroxyethyl) -N-methyl-carbamate (200 mg, 1.14 mmol, compound BH-1) and Et _{3 N (578 mg, 5.71 mmol) in DCM (5 mL).} , N, N-diethylcarbamoyl chloride (248 mg, 1.83 mmol) was added dropwise at 0 ° C. for 0.5 hour, and the mixture was stirred at 25 ° C. for 15.5 hours. After filtration, the filtrate was washed with water and brine. The organic layer was dried and concentrated to give 2- [tert-butoxycarbonyl (methyl) amino] ethyl N, N-diethyl carbamate (313 mg, compound BH-2) as a colorless oil.

Step 3: Preparation of 2- (methylamino) ethyl N, N-diethyl carbamate hydrochloride (Compound BH-3)

2- [tert-Butyloxycarbonyl (methyl) amino] ethyl N, N-diethyl carbamate (436 mg, 1.77 mmol, compound BH-2) was added to HCl (17 mL, 1 M) in the EA. The mixture was stirred at 0 ° C. for 0.5 hours. The mixture was then stirred at 25 ° C. for an additional 15.5 hours and concentrated to give 2- (methylamino) ethyl N, N-diethyl carbamate hydrochloride (230 mg, compound BH-3) as a colorless oil.

Step 4: Preparation of 2- [chlorocarbonyl (methyl) amino] ethyl N, N-diethyl carbamate (intermediate BH)

Intermediate BH uses 2- (methylamino) ethyl N, N-diethylcarbamate hydrochloride (274 mg, compound BH-3) in place of ethyl 2- (methylamino) acetate hydrochloride with Intermediate AP. Prepared in the same manner. Crude 2- [chlorocarbonyl (methyl) amino] ethyl N, N-diethyl carbamate (250 mg, intermediate BH) was obtained and used in the next step without further purification.

Intermediate BI
2- [Chlorocarbonyl (Methyl) Amino] Ethyl Ethyl Carbonate

Step 1: Preparation of tert-butyl N- (2-hydroxyethyl) -N-methyl-carbamate (Compound BI-1)

_{Boc 2} O (3.49 g, 15.98 mmol) was added to a solution of 2- (methylamino) ethanol (1 g, 13.31 mmol) in DCM (10 mL) at 25 ° C. The reaction mixture was stirred at 25 ° C. for 16 hours and then concentrated to give a crude product. This was purified by column chromatography to give tert-butyl N- (2-hydroxyethyl) -N-methyl-carbamate (1.6 g, compound BI-1) as a colorless oil.

Step 2: Preparation of 2- [tert-butoxycarbonyl (methyl) amino] ethyl methyl carbonate (Compound BI-2)

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 to the solution at −10 ° C. The mixture was stirred at −10 ° C. for 1 hour. The reaction mixture was filtered and the filtrate was washed with 5% citric acid and brine. The organic layer was dried and concentrated to give 2- [tert-butoxycarbonyl (methyl) amino] ethyl methyl carbonate (1.22 g, compound BI-2) as a colorless oil.

Step 3: Preparation of ethyl 2- (methylamino) ethyl carbonate (Compound BI-3)

2- [tert-Butoxycarbonyl (methyl) amino] ethyl methyl carbonate (1.22 g, 4.94 mmol, compound BI-2) was added to HCl (10 mL, 40 mmol) in EA and the mixture was added to 0 ° C. at 0 ° C. The mixture was stirred for 5.5 hours and at 25 ° C. for an additional 15.5 hours. The reaction mixture was concentrated to give ethyl 2- (methylamino) ethyl carbonate (1.06 g, compound BI-3).

Step 4: Preparation of 2- [chlorocarbonyl (methyl) amino] ethyl ethyl carbonate (intermediate BI)

Intermediate BI was prepared similar to Intermediate AP using ethyl 2- (methylamino) ethyl carbonate hydrochloride (150 mg, Intermediate BI-3) instead of ethyl 2- (methylamino) acetate hydrochloride. Was done. A crude 2- [chlorocarbonyl (methyl) amino] ethyl ethyl carbonate (145 mg, intermediate BI) was obtained, which was used in the next step without further purification.

Preparation Example Example 1
6-Amino-9-Benzyl-N-Methyl-8-oxo-N-propyl-2- (propylsulfonimideyl) Purine-7-Carboxamide

Method A:
Step 1: Preparation of 4-amino-3-benzyl-2-oxo-1H-imidazol-5-carbonitrile (Compound 1a)

Benzyl isocyanate (13.2 g, 98.5 mmol) and TEA (10) to a solution of aminomalononitrile p-toluenesulfonate (25 g, 98.5 mmol, TCI, catalog number: A1119-25G) in dry DMF (100 mL). .2 g, 79.0 mmol) was added at RT. After stirring at RT for 24 hours, the reaction was concentrated in vacuo and the residue was separated into EtOAc (500 mL) and water (250 mL). The separated organic layer was washed twice with brine (50 mL) and extracted twice with sodium hydroxide solution (50 mL, 1N). The mixed sodium hydroxide solution layer was neutralized with 10 wt% sodium hydrogensulfate solution and extracted with EtOAc. The separated organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue is ground in 2-isopropoxypropane and then the suspension is filtered to yellow 4-amino-3-benzyl-2-oxo-1H-imidazol-5-carbonitrile (15 g, compound 1a). Obtained as a solid. The product was used in the next step without further purification. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 215.

Step 2: Preparation of 6-amino-9-benzyl-2-sulfanyl-7H-purine-8-one (Compound 1b)

Benzoyl isothiocyanate (28.6 g) to a solution of 4-amino-3-benzyl-2-oxo-1H-imidazol-5-carbonitrile (15.0 g, 70.0 mmol, compound 1a) in THF (700 mL). , 175.1 mmol, TCI, catalog number: A11596-100G) was added dropwise. After stirring at RT for 12 hours, the reaction mixture was concentrated in vacuo. The residue was ground in diethyl ether (100 mL) and the resulting precipitate was collected by filtration.

Sodium hydroxide (70 mL, 2N) was added to the solution of the resulting precipitate in THF (700 mL). The mixture was refluxed for 50 hours and then acidified to pH = 3 with 10 wt% aqueous sodium hydrogensulfate solution. The resulting precipitate was collected by filtration to give the crude 6-amino-9-benzyl-2-sulfanyl-7H-purine-8-one (8.1 g, compound 1b) as a yellow solid. The product was used in the next step without further purification. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 274.

Step 3: Preparation of 6-amino-9-benzyl-2- (2-propylsulfanyl) -7H-purine-8-one (Compound 1c)

Potassium carbonate (2.76 g, 20.0 mmol) to a solution of 6-amino-9-benzyl-2-sulfanyl-7H-purine-8-one (5.46 g, 20.0 mmol, compound 1b) in DMF. Was added. 1-Bromopropane (2.44 g, 20.0 mmol, TCI, Catalog No .: B0638-500G) was then slowly added to the previous solution in DMF (5.0 mL). After stirring at RT for 12 hours, the reaction mixture was poured into water (200 mL), then acidified with 10 wt% aqueous sodium hydrogensulfate solution and extracted twice with EtOAc (100 mL). The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude product. By purifying this on silica gel by flash chromatography, 6-amino-9-benzyl-2- (2-propylsulfanyl) -7H-purine-8-one (4.8 g, compound 1c) was whitened. Obtained as a solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 316.

Step 4: Preparation of 6-amino-9-benzyl-2-propylsulfinyl-7H-purine-8-one (Compound 1d)

Compound 6-amino-9-benzyl-2- (2-propylsulfanyl) -7H-purine-8-one (2.7 g, 8.7 mmol) in DCM / MeOH (500 mL, V / V = 1: 1), To the suspension of compound 1c) was added 3-chloroperbenzoic acid (2.15 g, 8.7 mmol, purity 70%, Aldrich, catalog number: 273031-100G). After stirring the reaction mixture for 2 hours, the volume of the reaction mixture was reduced to about 50 mL in vacuo. The resulting precipitate was collected by filtration, washed with methanol, dried and 6-amino-9-benzyl-2-propylsulfinyl-7H-purine-8-one (1.0 g, compound 1d). ) Was obtained as a white solid. The product was used in the next step without further purification. MS obsd. ESI ⁺ [(m ⁺ H) ⁺ ]: 332.

Step 5: Preparation of 6-amino-9-benzyl-2- (propylsulfoneimideyl) -7H-purine-8-one (Compound 1e)

6-Amino-9-benzyl-2-propylsulfinyl-7H-purine-8-one in Eaton's reagent (40 mL, phosphorus pentoxide, 7.5 wt% in methanesulfonic acid, Aldrich, catalog number: 380814-100 ML). Sodium azide (360 mg, 5.5 mmol) was added to the solution (1.52 g, 4.6 mmol, compound 1d) at 50 ° C. After stirring at this temperature for 30 minutes, the reaction mixture was cooled to RT and poured into saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted twice with n-BuOH (100 mL) and the organic phase was concentrated in vacuo. The residue was subjected to preparative HPLC purification to give 6-amino-9-benzyl-2- (propylsulfoneimideyl) -7H-purine-8-one (1.2 g, compound 1e) as a white solid. It was. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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 = 7.53Hz, 2H), 1.55-1.74 (m, 2H), 0.92 (T, J = .53Hz, 3H). MS obsd. (ESI ⁺ ) [(M ⁺ H) ⁺ ]: 347.

Separation of compound 1e by chiral HPLC gave compound 1e-A (slow elution, 500 mg) and compound 1e-B (fast elution, 490 mg) as white solids. (Separation conditions: Methanol 5% -40% (0.05% DEA) / CO _{2 on a} CharalPak AS-3 column)

Compound 1e-A: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 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 = 7.4Hz, 3H).
Compound 1e-B: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 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 = 7.4Hz, 3H).

Step 6: Preparation of 6-amino-9-benzyl-N-methyl-8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide (Example 1)

In NMP (5 mL), 6-amino-9-benzyl-2- (propylsulfonimideyl) -7H-purine-8-one (300 mg, compound 1e), pyridine (329 mg, 4.2 mmol) and DIPEA (538 mg, To a solution of 4.2 mmol), N-methyl-N-propyl-carbamoyl chloride (564 mg, 4.2 mmol, intermediate AA) was added at RT. The mixture was stirred at RT for 10 hours. The reaction mixture was concentrated and the residue was concentrated by preparative HPLC to 6-amino-9-benzyl-N-methyl-8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide ( 108 mg, Example 1) was obtained as a white solid. ^{1 1} H 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 446.

Example 1-A (slow elution, slow elution, as a white solid) by separation of the compound of Example 1 by chiral HPLC using isopropanol 5% -40% (0.05% DEA) / CO _{2 on a CharalPak AD-3 column.} 50 mg) and Example 1-B (fast elution, 40 mg) were obtained.

Example 1-A: ¹ H 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 446.
Example 1-B: ¹ H 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 446.

Method B: An alternative method for preparing 6-amino-9-benzyl-2- (propylsulfoneimideyl) -7H-purine-8-one (Compound 1e).

Step 1: Preparation of N-benzyl-6-chloro-5-nitro-2-propylsulfanyl-pyrimidine-4-amine (Compound 1f)

In THF (1.5 L), 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), THF ( (200 mL) of phenylmethaneamine (60.0 g, 559.5 mmol) was added slowly at −78 ° C. After the addition, the mixture was warmed to 25 ° C. and stirred at this temperature for 16 hours. The resulting mixture was diluted with EA (1 L) and washed 3 times with water (400 mL) and with brine (500 mL). The separated organic phase was _{dried over Na 2} SO ₄ , filtered and concentrated in vacuo to give N-benzyl-6-chloro-5-nitro-2-propylsulfanyl-pyrimidine-4-amine (180. 0 g, compound 1f) was obtained as a yellow solid and used in the next step without further purification. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 339.1.

Step 2: Preparation of N4-benzyl-6-chloro-2-propylsulfanyl-pyrimidine-4,5-diamine (1 g of compound)

To a solution of N-benzyl-6-chloro-5-nitro-2-propylsulfanyl-pyrimidine-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 25 ° C. After the addition, the mixture was stirred at 25 ° C. for 16 hours. The reaction was filtered and the filtrate was basified with saturated _{aqueous NaHCO 3} solution (800 mL), extracted 3 times with EA (400 mL) _{, dried over Na 2} SO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography to give N4-benzyl-6-chloro-2-propylsulfanyl-pyrimidine-4,5-diamine (125 g, compound 1 g) as a brown solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 309.1.

Step 3: Preparation of 9-benzyl-6-chloro-2-propylsulfanyl-7H-purine-8-one (Compound 1h)

N-Benzyl-6-chloro-2- (propylsulfanyl) pyrimidine-4,5-diamine (72.0 g, 233.1 mmol, compound 1 g) and CDI (75.2 g, 233.1 mmol) in THF (800 mL). The solution was stirred at 80 ° C. for 16 hours. The resulting mixture was diluted with EA (400 mL) and washed twice with water (200 mL) and with brine (200 mL). The separated organic layer was _{dried over Na 2} SO ₄ and concentrated in vacuo. The residue was washed with MTBE (200 mL) to give 9-benzyl-6-chloro-2-propylsulfanyl-7H-purine-8-one (58.0 g, compound 1h) as a white solid, which was obtained. It was used in the next step without further purification. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 335.1.

Step 4: Preparation of 9-benzyl-6-[(4-methoxyphenyl) methylamino] -2-propylsulfanyl-7H-purine-8-one (Compound 1i)

Solution of 9-benzyl-6-chloro-2-propylsulfanyl-7H-purine-8-one (58.0 g, compound 1h) and PMBNH ₂ (54.7 g, 398.42 mmol) in n-BuOH (600 mL). Was stirred at 120 ° C. for 20 hours. By concentrating the reaction and washing the residue with MTBE (400 mL), 9-benzyl-6-[(4-methoxyphenyl) methylamino] -2-propylsulfanyl-7H-purine-8-one (75 g). , Compound 1i) was obtained as a white solid and used in the next step without further purification. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 436.2.

Step 5: Preparation of 6-amino-9-benzyl-2-propylsulfanyl-7H-purine-8-one (Compound 1c)

9-Benzyl-6-[(4-Methoxyphenyl) methylamino] -2-propylsulfanyl-7H-purine-8-one (87.0 g, compound 1i) in TFA (200 mL) at 80 ° C. for 16 hours. Stirred. The resulting reaction mixture was concentrated and basified with saturated _{aqueous NaHCO 3} solution (600 mL). The resulting precipitate was collected by filtration and washed with (PE / DCM = 2: 1, 400 mL) to 6-amino-9-benzyl-2-propylsulfanyl-7H-purine-8-. On (38.0 g, compound 1c) was obtained as a white solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 316.1.

Step 6: Preparation of 6-amino-9-benzyl-2-propylsulfinyl-7H-purine-8-one (Compound 1d)

6-Amino-9-benzyl-2-propylsulfanyl-7H-purine-8-one (35.) in THF (200 mL) relative to a solution of m-CPBA (22.98 g, 113.2 mmol) in THF (50 mL). A suspension of 0 g, compound 1c) was added dropwise at 0 ° C. After the addition, the reaction mixture was stirred at 25 ° C. for 0.5 hours. The mixture was filtered and washed with MeCN (400 mL), MTBE (500 mL) to whiten 6-amino-9-benzyl-2-propylsulfinyl-7H-purine-8-one (35.1 g, compound 1d). Obtained as a solid of, which was used in the next step without further purification. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 332.1.

Step 7: Preparation of 6-amino-9-benzyl-2- (propylsulfoneimideyl) -7H-purine-8-one (Compound 1e)

In a solution of 6-amino-9-benzyl-2-propylsulfinyl-7H-purine-8-one (34.0 g, compound 1d) in Eaton's reagent (170.0 mL, 7.5 wt% in methanesulfonic acid). In contrast, NaN ₃ (15.34 g, 253.97 mmol) was added slowly at 60 ° C. The mixture was then stirred at 60 ° C. for 30 minutes. The resulting reaction mixture was cooled to 25 ° C. and ice-cooled NH ₃ ^. H ₂ O was poured (500mL, 1mol / L), the extracted 4 times with n-BuOH (100mL), and concentrated in vacuo. The residue was purified by preparative HPLC to give 6-amino-9-benzyl-2- (propylsulfoneimideyl) -7H-purine-8-one (10 g, compound 1e). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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 = 7.53Hz, 2H), 1.55-1.74 (m, 2H), 0.92 (T, J = 7.53Hz, 3H). MS obsd. (ESI ⁺ ) [(M ⁺ H) ⁺ ]: 347.

Example 2
6-Amino-9-Benzyl-N- (2-Methoxyethyl) -N-Methyl-8-oxo-2- (Propylsulfonimideyl) Purine-7-Carboxamide

The title compound uses N- (2-methoxyethyl) -N-methyl-carbamoyl chloride (intermediate AB) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA) in Example 1. , Method A, step 6 was prepared in the same manner. 6-Amino-9-benzyl-N- (2-methoxyethyl) -N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide (120 mg, Example 2) as a white solid Obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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 = 4Hz, 1H), 3.62 (br.dd, J = 4, 12Hz, 2H), 3.28-3.42 ( m, 6H), 3.12 (d, J = 12Hz, 3H), 3.05 (s, 1H), 1.58-1.72 (m, 2H), 0.93 (t, J = 8Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 462.

Example 2-A (fast elution, fast elution, by separation of the compound of Example 2 by chiral HPLC using 5% -40% (0.05% DEA) / CO _{2 of methanol on a CharalPak OJ-3 column as a white solid.} 33 mg) and Example 2-B (slow elution, 46 mg) were obtained.

Example 2-A: ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 = 4Hz, 1H), 3.62 (br.dd, J = 4, 12Hz, 2H), 3. 28-3.42 (m, 6H), 3.12 (d, J = 12Hz, 3H), 3.05 (s, 1H), 1.58-1.72 (m, 2H), 0.93 ( t, J = 8Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 462.
Example 2-B: ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 = 4Hz, 1H), 3.62 (br.dd, J = 4,12Hz, 2H), 3. 28-3.42 (m, 6H), 3.12 (d, J = 12Hz, 3H), 3.05 (s, 1H), 1.58-1.72 (m, 2H), 0.93 ( t, J = 8Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 462.

Example 3
6-Amino-9-Benzyl-N-Ethyl-8-oxo-N-propyl-2- (Propylsulfonimideyl) Purine-7-Carboxamide

The title compound uses N-ethyl-N-propyl-carbamoyl chloride (intermediate AC) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA), Example 1, Method A, Step. It was prepared in the same manner as in 6. 6-Amino-9-benzyl-N-ethyl-8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide (51 mg, Example 3) was obtained as a white solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.27-7.39 (m, 5H), 6.85 (br. S., 2H), 4.99 (s, 2H), 4. 20 (br.d, J = 8.0Hz, 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 = 8Hz, 1H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 474.

Example 4
6-Amino-9-Benzyl-7- [4- (1-piperidyl) piperidine-1-carbonyl] -2- (propylsulfonimideyl) purine-8-one

The title compound uses (1,4'-bipiperidine) -1'-carbonyl chloride instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA), Example 1, Method A. , Prepared in the same manner as in Step 6. 6-Amino-9-benzyl-7- [4- (1-piperidyl) piperidine-1-carbonyl] -2- (propylsulfonimideyl) purine-8-one (55 mg, Example 4) as a white powder Obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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 = 12.5Hz, 1H), 3.43-3.15 (m, 3H), 2.96 (t, J = 12.3Hz,) 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 = 7.4Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 541.2.

Example 5
6-Amino-9-Benzyl-N-Ethyl-N- (2-Methoxyethyl) -8-oxo-2- (Propylsulfonimideyl) Purine-7-Carboxamide

The title compound uses N-ethyl-N- (2-methoxyethyl) carbamoyl chloride (intermediate AD) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA), Example 1, It was prepared in the same manner as in Method A and Step 6. 6-Amino-9-benzyl-N-ethyl-N- (2-methoxyethyl) -8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide (34 mg, Example 5) as a white powder Obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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 = 8.1Hz, 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 = 7.5Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 476.3.

Example 6
6-Amino-9-Benzyl-N-Butyl-N-Ethyl-8-oxo-2- (propylsulfoneimideyl) Purine-7-Carboxamide

The title compound uses N-butyl-N-ethyl-carbamoyl chloride (intermediate AE) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA), Example 1, Method A, Step. It was prepared in the same manner as in 6. 6-Amino-9-benzyl-N-butyl-N-ethyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide (51 mg, Example 6) was obtained as a white solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.27-7.39 (m, 5H), 6.85 (br. S., 2H), 4.99 (s, 2H), 4. 20 (br.d, J = 8.0Hz, 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 = 8Hz, 1H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 474.

Example 7
6-Amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide

The title compound uses N-ethyl-N- (2-methoxyethyl) carbamoyl chloride (intermediate AF) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA), Example 1, 1. It was prepared in the same manner as in Method A and Step 6. 6-Amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide (35 mg, Example 7) as a white powder Obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.40-7.28 (m, 5H), 6.89 (br.s., 1H), 6.75 (br.s., 1H) , 5.00 (d, J = 5.5Hz, 2H), 4.24-4.16 (m, 1H), 3.77 (br.s., 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 490.5.

Example 8
6-Amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide

The title compound uses bis (2-methoxyethyl) carbamic acid chloride (intermediate AG) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA), Example 1, Method A, Step. It was prepared in the same manner as in 6. 6-Amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide (35 mg, Example 8) was obtained as a white powder. Was done. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.40-7.28 (m, 5H), 6.83 (br.s., 2H), 4.99 (s, 2H), 3. 71 (br.s., 3H), 3.52-3.27 (m, 11H), 3.09 (s, 3H), 1.73-1.59 (m, 2H), 0.93 (t) , J = 7.5Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 506.

Example 9
6-Amino-7- (azetidine-1-carbonyl) -9-benzyl-2- (propylsulfoneimideyl) purine-8-one

The title compound used azetidine-1-carbonyl chloride (intermediate AH) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA), as in Example 1, Method A, Step 6. Prepared. 6-Amino-7- (azetidine-1-carbonyl) -9-benzyl-2- (propylsulfonimideyl) purine-8-one (120 mg, Example 9) was obtained as a white powder. ^{1 1} HNMR (400 MHz, DMSO-d ₆ ) 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 = 7.40Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 430.

Example 10
6-Amino-9-Benzyl-N-Isopropyl-N-Methyl-8-oxo-2- (Propylsulfonimideyl) Purine-7-Carboxamide

The title compound uses N-isopropyl-N-methyl-carbamoyl chloride (intermediate AI) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA), Example 1, Method A, Step. It was prepared in the same manner as in 6. 6-Amino-9-benzyl-N-isopropyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide (97 mg, Example 10) was obtained as a white solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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 = 8Hz, 6H), 0.93 (t, J = 8Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 446.

Example 11
6-Amino-9-Benzyl-7- (4-Methylpiperazin-1-carbonyl) -2- (Propylsulfonimideyl) Purine-8-one

The title compound was prepared in the same manner as in Example 1, Method A, Step 6 using 4-methylpiperazin-1-carbonyl chloride instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA). It was. 6-Amino-9-benzyl-7- (4-methylpiperazin-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one (59.5 mg, Example 11) was obtained as a yellow solid. It was. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 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 = 7.2Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 473.

Example 12
6-Amino-9-Benzyl-N- (3-Methoxypropyl) -N-Methyl-8-oxo-2- (Propylsulfonimideyl) Purine-7-Carboxamide

The title compound uses N- (3-methoxypropyl) -N-methyl-carbamoyl chloride instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA), Example 1, Method A, Step. 6 was prepared in the same manner. 6-Amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide (92.2 mg, Example 12) is white Obtained as a solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 476.3.

Example 13
6-Amino-9-benzyl-N-isobutyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide

The title compound uses N-isobutyl-N-methyl-carbamoyl chloride (intermediate AL) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA), Example 1, Method A, Step. It was prepared in the same manner as in 6. 6-Amino-9-benzyl-N-isobutyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide (64 mg, Example 13) was obtained as a white solid. ^{1 1} H 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 460.

Example 14
Ethyl 2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] acetate

The title compound uses ethyl 2-((chlorocarbonyl) (methyl) amino) acetate (intermediate AP) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA) in Example 1, It was prepared in the same manner as in Method A and Step 6. Ethyl 2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] acetate (38 mg, Example 14) as a bright yellow powder Obtained. ^{1 1} H NMR (400 MHz, 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 = 7.2Hz) , 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 = 7.0Hz, 2H), 1.12 (t, J = 7.0Hz, 1H), 0.93 (t, J = 7.4Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 490.

Example 15
Ethyl 3-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate

The title compound uses ethyl 3-((chlorocarbonyl) (methyl) amino) propanoate instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA), Example 1, Method A, Step 6. Was prepared in the same manner as. Ethyl 3-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate (35 mg, Example 15) was obtained as a white powder. Was done. ^{1 1} H NMR (400 MHz, 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 = 7.1Hz, 1H), 3.99 (d, J = 7.0Hz, 1H), 3.67 (br.s., 2H), 3 .40-3.29 (m, 2H), 3.08 (s, 2H), 2.99 (s, 1H), 2.71 (t, J = 6.4Hz, 2H), 1.74-1 .56 (m, 2H), 1.27-1.05 (m, 3H), 0.93 (t, J = 7.5Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 504.

Example 16
tert-Butyl 3-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate

The title compound uses tert-butyl 3- [chlorocarbonyl (methyl) amino] propanoate (intermediate AR) in place of N-methyl-N-propyl-carbamoyl chloride (intermediate AA), Example 1, It was prepared in the same manner as in Method A and Step 6. tert-Butyl 3-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate (60 mg, Example 16) is a white powder Obtained as. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.41-7.27 (m, 5H), 6.93 (br.s., 2H), 4.99 (s, 2H), 4. 15 (s, 1H), 3.64 (br.s., 2H), 3.51-3.33 (m, 2H), 3.08 (s, 2H), 2.98 (s, 1H), 2.62 (t, J = 6.9Hz, 2H), 1.71-1.57 (m, 2H), 1.41 (s, 6H), 1.34 (s, 3H), 0.93 ( t, J = 7.4Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 532.

Example 17
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate

Examples of the title compound use ethyl (2S) -2- [chlorocarbonyl (methyl) amino] propanoate (intermediate AS) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA). 1. Prepared in the same manner as in Method A and Step 6. Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate (34.1 mg, Example 17) Was obtained as a yellow solid. ^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 7.22-7.49 (m, 5H), 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 = 7.16Hz, 3H), 1.09-1.29 (m, 3H) ), 0.94 (t, J = 7.44Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 504.2.

Example 18
tert-Butyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate

The title compound is tert-butyl (2S) -2- [chlorocarbonyl (methyl) amino] -4-methyl-pentanoate (intermediate AT) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA). Then, it was prepared in the same manner as in Example 1, Method A, and Step 6. tert-Butyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate (22 mg) , Example 18) was obtained as a white solid. ^{1 1} H NMR (400 MHz, 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 574.3.

Example 19
Isopropyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate

The title compound uses isopropyl (2S) -2- [chlorocarbonyl (methyl) amino] -4-methyl-pentanoate (intermediate AU) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA). Then, it was prepared in the same manner as in Example 1, Method A, and Step 6. Isopropyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate (43 mg, performed) Example 19) was obtained as a white powder. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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. S., 1H), 1.77-1.56 (m, 4H), 1.25-1.16 (m, 6H), 0.99-0.83 (m, 9H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 560.3.

Example 20
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-methyl-butanoate

The title compound uses ethyl (2S) -2- [chlorocarbonyl (methyl) amino] -3-methyl-butanoate (intermediate AV) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA). Then, it was prepared in the same manner as in Example 1, Method A, and Step 6. Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-methyl-butanoate (51.5 mg) , Example 20) was obtained as a white powder. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.23-7.51 (m, 5H), 6.76 (br.s., 2H), 5.01 (br.s., 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.s., 1H), 1.65 (br.s., 2H), 1.13-1.29 (m, 3H), 0.88-1.10 (m, 9H) .. MS obsd. (ESI ⁺ ) [M + H ⁺ ]: 532.2.

Example 21
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate

The title compound uses ethyl (2S) -2- [chlorocarbonyl (methyl) amino] -4-methyl-pentanoate (intermediate AW) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA). Then, it was prepared in the same manner as in Example 1, Method A, and Step 6. Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate (17.3 mg) , Example 21) was obtained as a white powder. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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.s., 3H), 1.93 (br.s., 1H) ), 1.54-1.78 (m, 4H), 1.22 (t, J = 7.09Hz, 3H), 0.77-1.01 (m, 9H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 546.3.

Example 22
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate

The title compound uses ethyl (2S) -2- [chlorocarbonyl (methyl) amino] -3-phenyl-propanoate (intermediate AX) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA). Then, it was prepared in the same manner as in Example 1, Method A, and Step 6. Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate (30 mg, performed) Example 22) was obtained as a white powder. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 580.

Example 23
Isopropyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanol

The title compound uses isopropyl (2S) -2- [chlorocarbonyl (methyl) amino] -3-phenyl-propanoate (intermediate AY) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA). Then, it was prepared in the same manner as in Example 1, Method A, and Step 6. Isopropyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate (22 mg, performed) Example 23) was obtained as a white powder. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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 = 7.4Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 594.

Example 24
tert-Butyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate

The title compound is tert-butyl (2S) -2- [chlorocarbonyl (methyl) amino] -3-phenyl-propanoate (intermediate AZ) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA). Was prepared in the same manner as in Example 1, Method A, and Step 6. tert-Butyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate (34 mg) , Example 24) was obtained as a white powder. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 608.3.

Example 25
N- [2- [Acetyl (Methyl) Amino] Ethyl] -6-Amino-9-Benzyl-N-Methyl-8-oxo-2- (propylsulfonimideyl) Purine-7-Carboxamide

The title compound uses N- [2- [acetyl (methyl) amino] ethyl] -N-methyl-carbamoyl chloride (intermediate BA) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA). Then, it was prepared in the same manner as in Example 1, Method A, and Step 6. N- [2- [Acetyl (methyl) Amino] Ethyl] -6-Amino-9-Benzyl-N-Methyl-8-oxo-2- (propylsulfonimideyl) Purine-7-Carboxamide (26.1 mg, performed) Example 25) was obtained as a white powder. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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 = 5.5Hz, 2H), 3.49-3.34 (m, 2H), 3.14 (s, 1H), 3 .12-3.02 (m, 4H), 2.86 (d, J = 7.5Hz, 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 503.2.

Example 26
Methyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate

The title compound is methyl N- [2- [chlorocarbonyl (methyl) amino] ethyl] -N-methyl-carbamate (intermediate BB) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA). It was prepared in the same manner as in Example 1, Method A, Step 6. Methyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate (65 mg, Example 26) was obtained as a yellow solid. ^{1 1} H 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 = 7.40Hz, 3H), 1.87 (dd, J = 14.12, 6.96Hz, 2H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 519.2.

Example 27
tert-butyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate

The title compound is tert-butyl N- [2- [chlorocarbonyl (methyl) amino] ethyl] -N-methyl-carbamate (intermediate BC) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA). ) Was prepared in the same manner as in Example 1, Method A, and Step 6. tert-butyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate ( 32 mg, Example 27) was obtained as a white powder. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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.s., 2H), 3.48-3.34 (m, 2H), 3.10 (s, 2H), 3.07 (S, 1H), 2.86 (d, J = 12.8Hz, 2H), 2.74 (d, J = 9.5Hz, 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 = 7.4Hz) , 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 562.

Example 28
Ethyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate

The title compound is ethyl N- [2- [chlorocarbonyl (methyl) amino] ethyl] -N-methyl-carbamate (intermediate BD) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA). It was prepared in the same manner as in Example 1, Method A, Step 6. Ethyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate (87 mg, Example 28) was obtained as a yellow solid. ^{1 1} H NMR (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. S., 2H), 2.73 (s, 1H), 1. 76-1.99 (m, 2H), 1.22-1.31 (m, 3H), 1.05 (s, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 533.2.

Example 29
2-[[6-Amino-9-Benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N-butyl-N-methyl-carbamate

The title compound uses 2- [chlorocarbonyl (methyl) amino] ethyl N-butyl-N-methyl-carbamate (intermediate BE) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA). The preparation was carried out in the same manner as in Example 1, Method A, and Step 6. 2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N-butyl-N-methyl-carbamate (19 mg, compound 29) ) Was obtained as a yellow solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.25-7.48 (m, 5H), 6.96 (br. S., 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.s., 2H), 1.05-1.47 (m, 6H), 0.93 (t, J = 7.40Hz, 3H), 0 .70-0.87 (m, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 561.2.

Example 30
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl pyrrolidine-1-carboxylate

The title compound was carried out using 2- [chlorocarbonyl (methyl) amino] ethylpyrrolidine-1-carboxylate (intermediate BF) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA). It was prepared in the same manner as in Example 1, Method A, and Step 6. 2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl pyrrolidine-1-carboxylate (10.0 mg, Example 30) ) Was obtained as a yellow solid. ^{1 1} H 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 545.2.

Example 31
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N-methyl-N-propyl-carbamate

The title compound uses 2- [chlorocarbonyl (methyl) amino] ethyl N-methyl-N-propyl-carbamate (intermediate BG) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA). The preparation was carried out in the same manner as in Example 1, Method A, and Step 6. 2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N-methyl-N-propyl-carbamate (3.7 mg, Example 31) was obtained as a yellow solid. ^{1 1} H NMR (400 MHz, CD ₃ OD) 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 547.2.

Example 32
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N, N-diethylcarbamate

The title compound was carried out using 2- [chlorocarbonyl (methyl) amino] ethyl N, N-diethylcarbamate (intermediate BH) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA). It was prepared in the same manner as in Example 1, Method A, and Step 6. 2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N, N-diethylcarbamate (21.7 mg, Example 32) ) Was obtained as a yellow solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 547.2.

Example 33
2-[[6-amino-9-benzyl-8-oxo-2- (propyl sulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl ethyl carbonate

The title compound uses 2- [chlorocarbonyl (methyl) amino] ethyl ethyl carbonate (intermediate BI) instead of N-methyl-N-propyl-carbamoyl chloride (intermediate AA) in Example 1, It was prepared in the same manner as in Method A and Step 6. 2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl ethyl carbonate (46 mg, Example 33) is a yellow solid Obtained as. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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 = 5.08Hz, 2H), 4.08-4. 27 (m, 3H), 4.37 (br.s., 1H), 5.00 (s, 2H), 6.76-7.11 (m, 2H), 7.22-7.45 (m) , 5H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 520.

Example 34-A and Example 34-B
6-Amino-N-Butyl-9- [(4-Chlorophenyl) Methyl] -N-Methyl-8-oxo-2- [S (S) -propylsulfonimideyl] Purine-7-Carboxamide and 6-Amino- N-butyl-9-[(4-chlorophenyl) methyl] -N-methyl-8-oxo-2- [S (S) -propylsulfonimideyl] purine-7-carboxamide

Step 1: Preparation of 4-amino-3-[(4-chlorophenyl) methyl] -2-oxo-1H-imidazol-5-carbonitrile (Compound 34a)

Compound 34a was prepared in the same manner as in Example 1, Method A, Step 1 using 4-chlorobenzylisocyanate instead of benzylisocyanate. 4-Amino-3-[(4-chlorophenyl) methyl] -2-oxo-1H-imidazol-5-carbonitrile (8.0 g, compound 34a) was obtained as a yellow solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 249.

Step 2: Preparation of 6-amino-9-[(4-chlorophenyl) methyl] -2-sulfanyl-7H-purine-8-one (Compound 34b)

Compound 34b replaces 4-amino-3-phenylmethyl-2-oxo-1H-imidazol-5-carbonitrile (Compound 1a) with 4-amino-3-[(4-chlorophenyl) methyl] -2-oxo. It was prepared in the same manner as in Example 1, Method A, Step 2 using -1H-imidazol-5-carbonitrile (Compound 34a). 6-Amino-9-[(4-chlorophenyl) methyl] -2-sulfanyl-7H-purine-8-one (6.4 g, compound 34b) was obtained as a yellow solid without further purification. Used in the next step. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 308.

Step 3: Preparation of 6-amino-9-[(4-chlorophenyl) methyl] -2-propylsulfanyl-7H-purine-8-one (Compound 34c)

Compound 34c is 6-amino-9-[(4-chlorophenyl) methyl] -2-sulfanyl- instead of 6-amino-9-phenylmethyl-2-sulfanyl-7H-purine-8-one (Compound 1b). It was prepared in the same manner as in Example 1, Method A, Step 3 using 7H-purine-8-one (Compound 34b). 6-Amino-9-[(4-chlorophenyl) methyl] -2-propylsulfanyl-7H-purine-8-one (800 mg, compound 34c) was obtained as a white solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 350.

Step 4: Preparation of 6-amino-9-[(4-chlorophenyl) methyl] -2-propylsulfinyl-7H-purine-8-one (Compound 34d)

Compound 34d substitutes 6-amino-9-benzyl-2-propylsulfanyl-7H-purine-8-one (Compound 1c) for 6-amino-9-[(4-chlorophenyl) methyl] -2-propylsulfanyl. It was prepared in the same manner as in Example 1, Method A, Step 4 using -7H-purine-8-one (Compound 34c). 6-Amino-9-[(4-chlorophenyl) methyl] -2-propylsulfinyl-7H-purine-8-one (150 mg, compound 34d) was obtained as a white solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 366.

Step 5: 6-amino-9-[(4-chlorophenyl) methyl] -2- (propylsulfonimideyl) -7H-purine-8-one (Compound 34e), 6-amino-9-[(4-chlorophenyl) ) Methyl] -2- [S (S) -propylsulfonimideyl) -7H-purine-8-one and 6-amino-9-[(4-chlorophenyl) methyl] -2- [S (S) -propyl Preparation of Sulfonimideyl) -7H-Prince-8-one (Compound 34e-A and Compound 34e-B)

Compound 34e is 6-amino-9-[(4-chlorophenyl) methyl]-instead of 6-amino-9-benzyl-2- (2-propylsulfinyl) -7H-purine-8-one (Compound 1d). 2-propylsulfinyl-7H-purine-8-one (Compound 34d) was prepared in the same manner as in Example 1, Method A, Step 5. 6-Amino-9-[(4-chlorophenyl) methyl] -2- (propylsulfonimideyl) -7H-purine-8-one (250 mg, compound 34e) was obtained as a white solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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) = 8Hz, 3H). MS obsd. (ESI ⁺ ) [(M ⁺ H) ⁺ ]: 381.

Compound 34e-A (fast elution, 110 mg) as a white solid by separation of compound 34e by chiral HPLC using methanol 5% -40% (0.05% DEA) / CO _{2 on a CharalPak OJ-3 column.} And compound 34e-B (slow elution, 100 mg) was obtained.

Compound 34e-A: ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 = 7.4Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 381.
Compound 34e-B: ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 = 7.5Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 381.

Step 6: 6-Amino-N-Butyl-9-[(4-chlorophenyl) Methyl] -N-Methyl-8-oxo-2- [S (S) -propylsulfonimideyl] Purine-7-Carboxamide and 6 -Amino-N-Butyl-9- [(4-chlorophenyl) methyl] -N-methyl-8-oxo-2- [S (S) -propylsulfonimideyl] purine-7-carboxamide (Example 34-A) And Example 34-B)

Examples 34-A are 6-amino-9-benzyl-2- (propylsulfonimideyl) -7H-purine-8-one (Compound 1e) and N-methyl-N-propyl-carbamoyl chloride (intermediate AA). ), Compound 34e-A and N-butyl-N-methyl-carbamoyl chloride were used in the same manner as in Example 1, Method A, and Step 6.

Examples 34-A (160 mg): ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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), 1.151.37 (m, 2H), 0.89-0.94 (m, 5H), 0.76 (t, J = 8Hz, 1H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 494.

Example 34-B (167 mg) was prepared in the same manner as in Example 34-A, using compound 34e-B instead of compound 34e-A.

Example 34-B: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.36-7.45 (m, 4H), 6.91 (br.s., 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), 1.151.37 (m, 2H), 0.89-0.94 (m, 5H), 0.76 (t, J = 7.4Hz, 1H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 494.

Example 35
6-Amino-9-[(4-chlorophenyl) Methyl] -N-Ethyl-N-Methyl-8-oxo-2- (propylsulfonimideyl) Purine-7-Carboxamide

The title compound replaces 6-amino-9-benzyl-2- (propylsulfonimideyl) -7H-purine-8-one (Compound 1e) and N-methyl-N-propyl-carbamoyl chloride (intermediate AA). 6-Amino-9-[(4-chlorophenyl) methyl] -2- (propylsulfonimideyl) -7H-purine-8-one (Compound 34e) and N-ethyl-N-methyl-carbamoyl chloride were used. The preparation was carried out in the same manner as in Example 1, Method A, and Step 6. 6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide (60 mg, Example 35) is white Obtained as a solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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 = 8.0Hz, 3H), 0.92 (t, J = 8.0Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 466.

Example 36-A and Example 36-B
6-Amino-N-Methyl-8-oxo-N-propyl-2 [S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide and 6-amino-N-methyl- 8-oxo-N-propyl-2 [S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide

Step 1: Preparation of 6-chloro-5-nitro-2-propylsulfanyl-N- (p-tolylmethyl) pyrimidine-4-amine (Compound 36a)

Compound 36a was prepared in the same manner as in Example 1, Method B, Step 1 using p-tolylmethylamine instead of phenylmethaneamine. 6-Chloro-5-nitro-2-propylsulfanyl-N- (p-tolylmethyl) pyrimidin-4-amine (3.9 g, compound 36a) was obtained as a white solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 353.

Step 2: Preparation of 6-chloro-2-propylsulfanyl-N4- (p-tolylmethyl) pyrimidine-4,5-diamine (Compound 36B)

Compound 36b replaces N-benzyl-6-chloro-5-nitro-2-propylsulfanyl-pyrimidine-4-amine (Compound 1f) with 6-chloro-5-nitro-2-propylsulfanyl-N- (p). -Tolylmethyl) Pyrimidine-4-amine (Compound 36a) was prepared in the same manner as in Example 1, Method B, Step 2. 6-Chloro-2-propylsulfanyl-N4- (p-tolylmethyl) pyrimidine-4,5-diamine (2.2 g, compound 36b) was obtained as a white solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 323.

Step 3: Preparation of 6-chloro-2-propylsulfanyl-9- (p-tolylmethyl) -7H-purine-8-one (Compound 36C)

Compound 36c is a 6-chloro-2-propylsulfanyl-N4- (p-tolylmethyl) pyrimidine-instead of N-benzyl-6-chloro-2- (propylsulfanyl) pyrimidine-4,5-diamine (Compound 1g). It was prepared in the same manner as in Example 1, Method B, Step 3 using 4,5-diamine (Compound 36b). 6-Chloro-2-propylsulfanyl-9- (p-tolylmethyl) -7H-purine-8-one (2.2 g, compound 36c) was obtained as a white solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 349.

Step 4: Preparation of 6-[(4-Methoxyphenyl) methylamino] -2-propylsulfanyl-9- (p-tolylmethyl) -7H-purine-8-one (Compound 36D)

Compound 36d is 6-chloro-2-propylsulfanyl-9- (p-tolylmethyl) -7H- instead of 9-benzyl-6-chloro-2-propylsulfanyl-7H-purine-8-one (Compound 1h). Purin-8-one (Compound 36c) was used and prepared in the same manner as in Example 1, Method B, Step 4. 6-[(4-Methoxyphenyl) methylamino] -2-propylsulfanyl-9- (p-tolylmethyl) -7H-purine-8-one (2.0 g, compound 36d) was obtained as a white solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 450.

Step 5: Preparation of 6-amino-2-propylsulfanyl-9- (p-tolylmethyl) -7H-purine-8-one (Compound 36E)

Compound 36e replaces 6-amino-9-benzyl-2-propylsulfanyl-7H-purine-8-one (Compound 1i) with 6-[(4-methoxyphenyl) methylamino] -2-propylsulfanyl-9. -(P-Tolylmethyl) -7H-purine-8-one (Compound 36d) was prepared in the same manner as in Example 1, Method B, Step 5. 6-Amino-2-propylsulfanyl-9- (p-tolylmethyl) -7H-purine-8-one (1.0 g, compound 36e) was obtained as a white solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 330.

Step 6: Preparation of 6-amino-2-propylsulfinyl-9- (p-tolylmethyl) -7H-purine-8-one (Compound 36F)

Compound 36f replaces 6-amino-9-benzyl-2- (2-propylsulfanyl) -7H-purine-8-one (Compound 1c) with 6-amino-2-propylsulfanyl-9- (p-tolylmethyl). ) -7H-Prince-8-one (Compound 36e) was prepared in the same manner as in Example 1, Method B, Step 6. 6-Amino-2-propylsulfinyl-9- (p-tolylmethyl) -7H-purine-8-one (220 mg, compound 36f) was obtained as a white solid.
MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 345.

Step 7: Preparation of 6-amino-2- (propylsulfonimideyl) -9- (p-tolylmethyl) -7H-purine-8-one (Compound 36G)

36 g of compound was 6-amino-2-propylsulfinyl-9- (p-tolylmethyl) -7H- instead of 6-amino-9-benzyl-2-propylsulfinyl-7H-purine-8-one (Compound 1d). It was prepared in the same manner as in Example 1, Method B, Step 7 using purine-8-one (Compound 36f). 6-Amino-2- (propylsulfoneimideyl) -9- (p-tolylmethyl) -7H-purine-8-one (127 mg, compound 36 g) was obtained as a white solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.67 (br.s., 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8) .0Hz, 2H), 6.98 (br.s., 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 = 8.0Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 361.

Separation of compound 36 g by chiral HPLC using 30% isopropanol (0.05% DEA) / CO ₂ on a CharalPak AD-3 column resulted in compound 36 g-A (fast elution, 50 mg) and compound 36 g-B (slow elution). , 49 mg) was obtained as a white solid.

Compound 36 g-A: ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ ppm: 10.51 (s, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0Hz, 2H), 7.00 (s, 2H), 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 = 7.40Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 361.
Compound 36 g-B: ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ ppm: 10.54 (s, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0Hz, 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 = 7.40Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 361.

Step 8: 6-amino-N-methyl-8-oxo-N-propyl-2 [S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide 6-amino-N- Preparation of Methyl-8-oxo-N-propyl-2 [S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide (Examples 36-A and 36-B)

Example 36-A uses compound 36 g-A instead of 6-amino-9-benzyl-2- (propyl sulfonimideyl) -7H-purine-8-one (Compound 1e), Example 1 , Method A, step 6 was prepared in the same manner. Example 36-A (108 mg) was obtained as a white solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 460.

Example 36-B uses compound 36 g-B instead of 6-amino-9-benzyl-2- (propyl sulfonimideyl) -7H-purine-8-one (Compound 1e), Example 1 , Method A, step 6 was prepared in the same manner. Examples 36-B (125 mg): ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.27 (d, J = 8 Hz, 2 H), 7.14 (d, J = 8 Hz, 2 H), 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 460.

Example 37-A and Example 37-B
6-Amino-2- [S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) -7- (pyrrolidin-1-carbonyl) purine-8-one and 6-amino-2- [S ( R) -propylsulfoneimideyl] -9- (p-tolylmethyl) -7- (pyrrolidin-1-carbonyl) purine-8-one

Examples 37-A are 6-amino-9-benzyl-2- (propylsulfonimideyl) -7H-purine-8-one (Compound 1e) and N-methyl-N-propyl-carbamoyl chloride (intermediate AA). ), Compound 36 g-A and pyrrolidine-1-carbonyl chloride were used in the same manner as in Example 1, Method A, and Step 6.

Example 37-A (390 mg) was obtained as a white solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 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 = 7.4Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 458.2.

Example 37-B (125 mg) was prepared in the same manner as in Example 37-A, using compound 36 g-B instead of compound 36 g-A.
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 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 = 7.4Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 458.3.

Example 38-A and Example 38-B
6-Amino-N- (2-methoxyethyl) -N-Methyl-8-oxo-2-[S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide and 6- Amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide

Examples 38-A are 6-amino-9-benzyl-2- (propylsulfonimideyl) -7H-purine-8-one (Compound 1e) and N-methyl-N-propyl-carbamoyl chloride (intermediate AA). ), Compound 36 g-A and N- (2-methoxyethyl) -N-methyl-carbamoyl chloride (intermediate AB) were used in the same manner as in Example 1, Method A, Step 6.

Example 38-A (57.8 mg) was obtained as a white solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 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 = 7.4Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 476.3.
Example 38-B (46.6 mg) was prepared in the same manner as in Example 38-A, using compound 36 g-B instead of compound 36 g-A.
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 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 = 7.4Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 476.3.

Example 39
6-Amino-N-Ethyl-N-Methyl-8-oxo-2- (propylsulfoneimideyl) -9- (p-tolylmethyl) purine-7-carboxamide

The title compound replaces N-methyl-N-propyl-carbamoyl chloride (intermediate AA) and 6-amino-9-benzyl-2- (propylsulfonimideyl) -7H-purine-8-one (compound 1e). With N-ethyl-N-methyl-carbamoyl chloride and 6-amino-2- (propylsulfonimideyl) -9- (p-tolylmethyl) -7H-purine-8-one (compound 36 g). It was prepared in the same manner as in Example 1, Method A, and Step 6. 6-Amino-N-Ethyl-N-Methyl-8-oxo-2- (propylsulfonimideyl) -9- (p-tolylmethyl) purine-7-carboxamide (141.8 mg, Example 39) is bright yellow. Obtained as a solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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 = 7.4Hz, 3H) .. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 446.1.

Example 40
6-Amino-N-Butyl-N-Methyl-8-oxo-2- (propylsulfoneimideyl) -9- (p-tolylmethyl) purine-7-carboxamide

The title compound replaces 6-amino-9-benzyl-2- (propylsulfonimideyl) -7H-purine-8-one (Compound 1e) and N-methyl-N-propyl-carbamoyl chloride (intermediate AA). Performed using 6-amino-2- (propyl sulfonimideyl) -9- (p-tolylmethyl) -7H-purine-8-one (compound 36 g) and N-butyl-N-methyl-carbamoyl chloride. It was prepared in the same manner as in Example 1, Method A, and Step 6. 6-Amino-N-Butyl-N-Methyl-8-oxo-2- (propylsulfonimideyl) -9- (p-tolylmethyl) purine-7-carboxamide (32 mg, Example 40) is obtained as a white solid. Was done. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 474.3

Examples 41-A and 41-B
6-Amino-9-[(4-chlorophenyl) Methyl] -2- [S (R) -Ethyl Sulfonimideyl] -N-Methyl-8-oxo-N-propyl-Prin-7-Carboxamide (Example 41) -A) and 6-amino-9-[(4-chlorophenyl) methyl] -2- [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide (Example 41-B)

Step 1: Preparation of 6-amino-9-[(4-chlorophenyl) methyl] -2-ethylsulfanyl-7H-purine-8-one (Compound 41a)

Compound 41a contains iodoethane and 6-amino-9-[(4-chlorophenyl) methyl] in place of bromopropane and 6-amino-9-phenylmethyl-2-sulfanyl-7H-purine-8-one (Compound 1b). -2-Sulfanyl-7H-purine-8-one (Compound 34b) was used and prepared in the same manner as in Example 1, Method A, Step 3. 6-Amino-9-[(4-chlorophenyl) methyl] -2-ethylsulfanyl-7H-purine-8-one (2.5 g, compound 41a) was obtained as a white solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 336.

Step 2: Preparation of 6-amino-9- (4-chlorobenzyl) -2-ethylsulfinyl-7H-purine-8-one (Compound 41b)

Compound 41b is 6-amino-9-[(4-chlorophenyl) methyl] -2-ethylsulfanyl instead of 6-amino-9-benzyl-2-propylsulfanyl-7H-purine-8-one (Compound 1c). It was prepared in the same manner as in Example 1, Method A, Step 4 using -7H-purine-8-one (Compound 41a). 6-Amino-9- (4-chlorobenzyl) -2-ethylsulfinyl-7H-purine-8-one (1.94 g, compound 41b) was obtained as a white solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 352.

Step 3: Preparation of 6-amino-9-[(4-chlorophenyl) methyl] -2- (ethylsulfoneimideyl) -7H-purine-8-one (Compound 41c)

Compound 41c is 6-amino-9- (4-chlorobenzyl) -2- instead of 6-amino-9-benzyl-2- (2-methylsulfinyl) -7H-purine-8-one (Compound 1d). Ethylsulfinyl-7H-purine-8-one (Compound 41b) was prepared in the same manner as in Example 1, Method A, Step 5. 6-Amino-9-[(4-chlorophenyl) methyl] -2- (ethylsulfoneimideyl) -7H-purine-8-one (217 mg, Example 41c) was obtained as a white solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 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 = 7.4Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 367.0.

化合物４１ｃ−Ａ：^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ 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＝７．４Ｈｚ，３Ｈ）．ＭＳ ｏｂｓｄ．（ＥＳＩ^＋）［（Ｍ＋Ｈ）^＋］：３６７．０． Compound 41c-A (fast elution, 31.8 mg) and compound by separation of compound 41c by chiral HPLC using methanol 5% -40% (0.05% DEA) / CO _{2 on a CharalPak IC-3 column.} 41c-B (slow elution, 10 mg) was obtained as a white solid.

Compound 41c-A: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 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 = 7.4Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 367.0.

化合物４１ｃ−Ｂ：^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ 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＝７．４Ｈｚ，３Ｈ）．ＭＳ ｏｂｓｄ．（ＥＳＩ^＋）［（Ｍ＋Ｈ）^＋］：３６７．０．

Compound 41c-B: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 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 = 7.4Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 367.0.

Step 4: 6-Amino-9-[(4-chlorophenyl) methyl] -2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide ( Examples 41-A) and 6-amino-9-[(4-chlorophenyl) methyl] -2- [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine- 7-Carboxamide (Example 41-B)

Example 41-A uses Compound 41c-B instead of 6-amino-9-benzyl-2- (propylsulfonimideyl) -7H-purine-8-one (Compound 1e), Example 1 , Method A, step 6 was prepared in the same manner. 6-Amino-9-[(4-chlorophenyl) methyl] -2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide (Example 41) -A, 78 mg) was obtained as a white solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 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 = 7.28Hz, 3H), 0.95-0.66 (m, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 466.1.

Example 41-B (125 mg) uses compound 41c-A instead of 6-amino-9-benzyl-2- (propylsulfoneimideyl) -7H-purine-8-one (compound 1e). It was prepared in the same manner as in Example 1, Method A, and Step 6. 6-Amino-9-[(4-chlorophenyl) methyl] -2- [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide (Example 41) −B, 38 mg) was obtained as a white solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 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). (MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 466.2.

The stereochemistry of Example 41-B was determined by single crystal X-ray diffraction shown in FIG.

Example 42-A and Example 42-B
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide (Example 42- A) and 6-amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide ( Example 42-B)

Examples 42-A are 6-amino-9-benzyl-2- (propylsulfonimideyl) -7H-purine-8-one (Compound 1e) and N-methyl-N-propyl-carbamoyl chloride (intermediate AA). ), Compound 41c-A and N-ethyl-N-methyl-carbamoyl chloride were used in the same manner as in Example 1, Method A, and Step 6. 6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide (Example 42- A, 40 mg) was obtained as a white solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 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) ). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 452.2.

Examples 42-B are 6-amino-9-benzyl-2- (propylsulfonimideyl) -7H-purine-8-one (Compound 1e) and N-methyl-N-propyl-carbamoyl chloride (intermediate AA). ), Compound 41c-B and N-ethyl-N-methyl-carbamoyl chloride were used in the same manner as in Example 1, Method A, and Step 6. 6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide (Example 42) −B, 38 mg) was obtained as a white solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 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) ). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 452.2.

The stereochemistry of Example 42-A was determined by single crystal X-ray diffraction shown in FIG.

Example 43-A and Example 43-B
6-Amino-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide (Example 43-A) and 6-Amino-2- [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide (Example 43-B)

Step 1: Preparation of 4-amino-2-oxo-3- (p-tolylmethyl) -1H-imidazol-5-carbonitrile (Compound 43a)

Compound 43a was prepared in the same manner as in Example 1, Method A, Step 1 using 4-methylbenzylisocyanate instead of benzylisocyanate. 4-Amino-2-oxo-3- (p-tolylmethyl) -1H-imidazol-5-carbonitrile (26.6 g, compound 43a) was obtained as a gray solid and the next step without further purification. Was used directly on. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 229.2.

Step 2: Preparation of 6-amino-9- (p-tolylmethyl) -2-sulfanyl-7H-purine-8-one (Compound 43b)

Compound 43b replaces 4-amino-3-benzyl-2-oxo-1H-imidazol-5-carbonitrile (Compound 1a) with 4-amino-2-oxo-3- (p-tolylmethyl) -1H-imidazole. It was prepared in the same manner as in Example 1, Method A, Step 2 using -5-carbonitrile (Compound 43a). 6-Amino-9- (p-tolylmethyl) -2-sulfanyl-7H-purine-8-one (20.0 g, compound 43b) was obtained as a yellow solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 288.

Step 3: Preparation of 6-amino-2-ethylsulfanyl-9- (p-tolylmethyl) -7H-purine-8-one (Compound 43c)

Compound 43c is 6-amino-9- (p-tolylmethyl) -2-sulfanyl-7H instead of 6-amino-9-benzyl-2-sulfanyl-7H-purine-8-one (Compound 1b) and bromopropane. -Prince-8-one (Compound 43b) and iodoethane were prepared in the same manner as in Example 1, Method A, Step 3. 6-Amino-2-ethylsulfanyl-9- (p-tolylmethyl) -7H-purine-8-one (13 g, compound 43c) was obtained as a yellow solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 316.

Step 4: Preparation of 6-amino-2-ethylsulfinyl-9- (p-tolylmethyl) -7H-purine-8-one (Compound 43d)

Compound 43d is 6-amino-2-ethylsulfanyl-9- (p-tolylmethyl) -7H- instead of 6-amino-9-benzyl-2-methylsulfanyl-7H-purine-8-one (Compound 1c). Purin-8-one (Compound 43c) was used and prepared in the same manner as in Example 1, Method A, Step 4. 6-Amino-2-ethylsulfinyl-9- (p-tolylmethyl) -7H-purine-8-one 6 (3.5 g, compound 43d) was obtained as a yellow solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 332.

Step 5: Preparation of 6-amino-2- (ethylsulfoneimideyl) -9- (p-tolylmethyl) -7H-purine-8-one (Compound 43e)

Compound 43e replaces 6-amino-9-benzyl-2-methylsulfinyl-7H-purine-8-one (Compound 1d) with 6-amino-2-ethylsulfinyl-9- (p-tolylmethyl) -7H-. It was prepared in the same manner as in Example 1, Method A, Step 5 using purine-8-one (Compound 43d). 6-Amino-2- (ethylsulfoneimideyl) -9- (p-tolylmethyl) -7H-purine-8-one (530 mg, compound 43e) was obtained as a yellow solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.53 (s, 1H), 7.24 (d, J = 8.03 Hz, 2H), 7.13 (d, J = 8.03 Hz, 2H), 6.94 (br.s., 2H), 4.91 (s, 2H), 4.03 (s, 1H), 3.36-3.41 (m, 2H), 2.26 ( s, 3H), 1.18 (t, J = 7.28Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 347.

Compound 43e-A (fast elution, 56.8 mg) and compound by separation of compound 43e by chiral HPLC using methanol 5% -40% (0.05% DEA) / CO _{2 on a CharalPak AD-3 column.} 43 e-B (slow elution, 56.7 mg) was obtained as a white solid.

Compound 43e-A: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.52 (br.s., 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.13 ( d, J = 7.9Hz, 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 = 7.3Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 347.

Compound 43e-B: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.56 (br.s., 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.13 ( d, J = 8.0Hz, 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 = 7.3Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 347.

Step 6: 6-Amino-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide (Example 43- A) and 6-amino-2- [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide (Example 43- Preparation of B)

Example 43-A uses Compound 43e-A instead of 6-amino-9-benzyl-2- (propylsulfonimideyl) -7H-purine-8-one (Compound 1e), Example 1 , Method A, step 6 was prepared in the same manner. 6-Amino-2- [S (R) -Ethylsulfonimideyl] -N-Methyl-8-oxo-N-propyl-9- (p-Tolylmethyl) Purine-7-Carboxamide (Examples 43-A, 58) .1 mg, fast elution, 5% to 40% isopropanol (0.05% DEA) / CO ₂ ) on a CharalPak AD-3 column was obtained as a white solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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 = 7.2Hz, 3H), 0.97-0.65 (m) , 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 446.

Example 43-B uses compound 43e-B instead of 6-amino-9-benzyl-2- (propylsulfonimideyl) -7H-purine-8-one (Compound 1e), Example 1 , Method A, step 6 was prepared in the same manner. 6-Amino-2- [S (S) -Ethyl Sulfonimideyl] -N-Methyl-8-oxo-N-propyl-9- (p-tolylmethyl) Purine-7-Carboxamide (Examples 43-B, 40) .1 mg, slow elution, 5% to 40% isopropanol (0.05% DEA) / CO ₂ ) on a CharalPak AD-3 column was obtained as a white solid: ¹ H NMR (400 MHz, DMSO-d _6). ) Δ ppm: 7.28 (d, J = 7.5Hz, 2H), 7.15 (d, J = 7.5Hz, 2H), 6.89 (br.s., 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 = 7.2Hz, 3H), 0.95-0.71 (m, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 446.3.

The stereochemistry of Example 43-B was determined by single crystal X-ray diffraction shown in FIG.

Example 44-A and Example 44-B
6-Amino-N-Ethyl-2 [S (S) -Ethyl Sulfonimideyl] -N-Methyl-8-oxo-9- (p-Trillmethyl) Purine-7-Carboxamide (Example 44-A) and 6 -Amino-N-ethyl-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide (Example 44-B)

Examples 44-A are 6-amino-9-benzyl-2- (propylsulfonimideyl) -7H-purine-8-one (Compound 1e) and N-methyl-N-propyl-carbamoyl chloride (intermediate AA). ), Compound 43e-B and N-ethyl-N-methyl-carbamoyl chloride were used in the same manner as in Example 1, Method A, and Step 6. 6-Amino-N-Ethyl-2 [S (S) -Ethylsulfonimideyl] -N-Methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide (Examples 44-A, 73. 1 mg) was obtained as a white solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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.s., 1H), 3.48-3.39 (m, 4H), 3.06-3.00 (m, 3H), 2.27 (s, 3H), 1.29-1.04 (m, 6H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 432.

Examples 44-B are 6-amino-9-benzyl-2- (propylsulfonimideyl) -7H-purine-8-one (Compound 1e) and N-methyl-N-propyl-carbamoyl chloride (intermediate AA). ), Compound 43e-A and N-ethyl-N-methyl-carbamoyl chloride were used in the same manner as in Example 1, Method A, and Step 6. 6-Amino-N-Ethyl-2- [S (R) -Ethyl Sulfonimideyl] -N-Methyl-8-oxo-9- (p-tolylmethyl) Purine-7-Carboxamide (Examples 44-B, 46) .7 mg) was obtained as a white solid: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.28 (d, J = 7.9 Hz, 2 H), 7.15 (d, J = 7). .9Hz, 2H), 6.90 (br.s., 2H), 4.95 (s, 2H), 4.19 (br.s., 1H), 3.50-3.39 (m, 4H) ), 3.10-2.96 (m, 3H), 2.27 (s, 3H), 1.27-1.10 (m, 6H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 432.

Example 45-A and Example 45-B
6-Amino-2- [S (R) ethylsulfonimideyl] -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide and 6-amino -2- [S (S) ethylsulfonimideyl] -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide

Step 1: Preparation of 4-amino-3-[(4-fluorophenyl) methyl] -2-oxo-1H-imidazol-5-carbonitrile (Compound 45a)

Compound 45a was prepared in the same manner as in Example 1, Method A, Step 1 using 4-fluorobenzyl isocyanate instead of benzyl isocyanate. 4-Amino-3-[(4-fluorophenyl) methyl] -2-oxo-1H-imidazol-5-carbonitrile (48 g, compound 45a) was obtained as a bright yellow solid, without further purification. Was used directly in the process of. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 233.

Step 2: Preparation of 6-amino-9-[(4-fluorophenyl) methyl] -2-sulfanyl-7H-purine-8-one (Compound 45b)

Compound 45b substitutes 4-amino-3-phenylmethyl-2-oxo-1H-imidazol-5-carbonitrile (Compound 1a) for 4-amino-3-[(4-fluorophenyl) methyl] -2-. It was prepared in the same manner as in Example 1, Method A, Step 2 using Oxo-1H-imidazol-5-carbonitrile (Compound 45a). 6-Amino-9-[(4-fluorophenyl) methyl] -2-sulfanyl-7H-purine-8-one (32.0 g, compound 45b) was obtained as a yellow solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 292.

Step 3: Preparation of 6-amino-2-ethylsulfanyl-9-[(4-fluorophenyl) methyl] -7H-purine-8-one (Compound 45c)

Compound 45c is 6-amino-9-[(4-fluorophenyl) methyl] -2 instead of 6-amino-9-benzyl-2-sulfanyl-7H-purine-8-one (Compound 1b) and bromopropane. -Sulfanyl-7H-purine-8-one (Compound 45b) and iodoethane were prepared in the same manner as in Example 1, Method A, Step 3. 6-Amino-2-ethylsulfanyl-9-[(4-fluorophenyl) methyl] -7H-purine-8-one (5.6 g, compound 45c) was obtained as a yellow solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 320.

Step 5: Preparation of 6-amino-2-ethylsulfinyl-9-[(4-fluorophenyl) methyl] -7H-purine-8-one (Compound 45d)

Compound 45d is 6-amino-2-ethylsulfanyl-9-[(4-fluorophenyl) methyl) instead of 6-amino-9-benzyl-2-propylsulfanyl-7H-purine-8-one (Compound 1c). ] -7H-Prince-8-one (Compound 45c) was prepared in the same manner as in Example 1, Method A, Step 4. 6-Amino-2-ethylsulfinyl-9-[(4-fluorophenyl) methyl] -7H-purine-8-one (4.8 g, compound 45d) was obtained as a yellow solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 332.

Step 6: Preparation of 6-amino-2- (ethylsulfoneimideyl) -9-[(4-fluorophenyl) methyl] -7H-purine-8-one (Compound 45e)

Compound 45e is composed of 6-amino-2-ethylsulfinyl-9-[(4-fluorophenyl) methyl) instead of 6-amino-9-benzyl-2-propylsulfinyl-7H-purine-8-one (Compound 1d). ] -7H-Prince-8-one (Compound 45d) was prepared in the same manner as in Example 1, Method A, Step 5. 6-Amino-2- (ethylsulfonimideyl) -9-[(4-fluorophenyl) methyl] -7H-purine-8-one (2.9 g, compound 45e) was obtained as a yellow solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.57 (br.s., 1H), 7.40 (dd, J = 8.5, 5.5 Hz, 2H), 7.16 (t) , J = 8.9Hz, 2H), 6.97 (br.s., 2H), 4.94 (s, 2H), 4.07 (s, 1H), 3.43-3.36 (m, 2H), 1.17 (t, J = 7.4Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 351.

Compound 45e-A (fast elution, 85.4 mg) and compound by separation of compound 45e by chiral HPLC using methanol 5% -40% (0.05% DEA) / CO _{2 on a CharalPak AD-3 column.} 45 e-B (slow elution, 36.4 mg) was obtained as a white solid.

Compound 45e-A: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.53 (br.s., 1H), 7.41 (dd, J = 8.5, 5.5 Hz, 2H), 7.17 (t, J = 8.9Hz, 2H), 6.98 (br.s., 2H), 4.95 (s, 2H), 4.07 (s, 1H), 3.45-3 .36 (m, 2H), 1.17 (t, J = 7.3Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 351.
Compound 45e-B: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.53 (br.s., 1H), 7.41 (dd, J = 8.5, 5.5 Hz, 2H), 7.17 (t, J = 8.9Hz, 2H), 6.98 (br.s., 2H), 4.95 (s, 2H), 4.07 (s, 1H), 3.44-3 .37 (m, 2H) 1.17 (t, J = 7.3Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 351.

Step 7: 6-Amino-2- (ethylsulfonimideyl) -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide (Example 45) , 6-Amino-2- [S (R) ethylsulfonimideyl] -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide and 6- Amino-2- [S (S) ethylsulfonimideyl] -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide (Example 45-A) And Preparation of Example 45-B)

In Example 45, 6-amino-2- (ethylsulfoneimideyl) -9 instead of 6-amino-9-benzyl-2- (propylsulfonimideyl) -7H-purine-8-one (Compound 1e) -[(4-Fluorophenyl) methyl] -7H-purine-8-one (Compound 45e) was prepared in the same manner as in Example 1, Method A, Step 6. 6-Amino-2- (ethylsulfonimideyl) -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide (162.4 mg, Example 45) ) Was obtained as a white solid.

Example 45-A (fast elution, 85.3 mg) by separation of the compound of Example 45 by chiral HPLC using methanol 5% -40% (0.05% DEA) / CO _{2 on a CharalPak AD-3 column.} And Example 45-B (slow elution, 52 mg) was obtained as a white solid. Example 45-A: ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.53-7.38 (m, 2H), 7.18 (t, J = 8.9 Hz, 2H), 6 .90 (br.s., 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 450.

Examples 45-B: ¹ H NMR (400 MHz, DMSO-d ₆ ) 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 450.

Example 46-A and Example 46-B
6-Amino-N-Ethyl-2- (Ethylsulfonimideyl) -9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Prin-7-Carboxamide (Example 46), 6- Amino-N-ethyl-2- [S (S)-(ethylsulfonimideyl)]-9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-purine-7-carboxamide and 6- Amino-N-ethyl-2- [S (R)-(ethylsulfonimideyl)]-9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-purine-7-carboxamide (Example) 46-A and Example 46-B)

Example 46 is of 6-amino-9-benzyl-2- (propylsulfonimideyl) -7H-purine-8-one (Compound 1e) and N-methyl-N-propyl-carbamoyl chloride (intermediate AA). Instead, use 6-amino-2- (ethylsulfonimideyl) -9-[(4-fluorophenyl) methyl] -7H-purine-8-one (Compound 45e) and N-ethyl-N-methyl carbamoyl chloride. Then, it was prepared in the same manner as in Example 1, Method A, and Step 6. 6-Amino-N-ethyl-2- (ethylsulfonimideyl) -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-purine-7-carboxamide (51 mg, Example 46) Obtained as a white solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 436.

Example 46-A (fast elution, 72 mg) and implementation by separation of the compounds of Example 46 by chiral HPLC using methanol 5% -40% (0.05% DEA) / CO _{2 on a CharalPak AD-3 column.} Example 46-B (slow elution, 45 mg) was obtained as a white solid.

Examples 46-A: ¹ H NMR (400 MHz, DMSO-d ₆ ) 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 436.
Examples 46-B: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.46-7.43 (m, 2H), 7.20-7.14 (m, 2H), 6.92 ( br.s., 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 436.

Example 47-A and Example 47-B
6-Amino-9-[(4-Bromophenyl) Methyl] -2- (Ethylsulfonimideyl) -N-Methyl-8-oxo-N-propyl-Prin-7-Carboxamide (Example 47), 6- Amino-2- [S (R) -ethylsulfonimideyl] -9-[(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide and 6-amino- 2- [S (S) -ethylsulfonimideyl] -9-[(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide

Step 1: Preparation of 4-amino-3-[(4-bromophenyl) methyl] -2-oxo-1H-imidazol-5-carbonitrile (Compound 47a)

Compound 47a was prepared in the same manner as in Example 1, Method A, Step 1 using 4-bromobenzylisocyanate instead of benzylisocyanate. 4-Amino-3-[(4-bromophenyl) methyl] -2-oxo-1H-imidazol-5-carbonitrile (500 mg, compound 47a) was obtained as a yellow solid, which was not further purified to the next. Used directly in the process. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.94 (s, 1H), 7.55-7.53 (d, J = 8.0 Hz, 2H), 7.20-7.18 ( d, J = 8.0Hz, 2H), 6.52 (br.s., 2H), 4.74 (s, 2H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 293.

Step 2: Preparation of 6-amino-9-[(4-bromophenyl) methyl] -2-sulfanyl-7H-purine-8-one (Compound 47b)

Compound 47b replaces 4-amino-3-phenylmethyl-2-oxo-1H-imidazol-5-carbonitrile (Compound 1a) with 4-amino-3-[(4-bromophenyl) methyl] -2-. It was prepared in the same manner as in Example 1, Method A, Step 2 using Oxo-1H-imidazol-5-carbonitrile (Compound 47a). 6-Amino-9-[(4-bromophenyl) methyl] -2-sulfanyl-7H-purine-8-one (300 mg, compound 47b) was obtained as a yellow solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 352.

Step 3: Preparation of 6-amino-2-ethylsulfanyl-9-[(4-bromophenyl) methyl] -7H-purine-8-one (Compound 47c)

Compound 47c is 6-amino-9-[(4-bromophenyl) methyl] -2 instead of 6-amino-9-benzyl-2-sulfanyl-7H-purine-8-one (Compound 1b) and bromopropane. -Sulfanyl-7H-purine-8-one (Compound 45b) and iodoethane were prepared in the same manner as in Example 1, Method A, Step 3. 6-Amino-2-ethylsulfanyl-9-[(4-bromophenyl) methyl] -7H-purine-8-one (5.6 g, compound 47c) was obtained as a yellow solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 380.

Step 4: Preparation of 6-amino-9-[(4-bromophenyl) methyl] -2-ethylsulfinyl-7h-purine-8-one (Compound 47d)

Compound 47d is 6-amino-9-[(4-bromophenyl) methyl] instead of 6-amino-9-benzyl-2- (2-propylsulfanyl) -7H-purine-8-one (Compound 1c). It was prepared in the same manner as in Example 1, Method B, Step 6 using -2-ethylsulfanyl-7H-purine-8-one (Compound 47c). 6-Amino-9-[(4-bromophenyl) methyl] -2-ethylsulfinyl-7H-purine-8-one (3.2 g, compound 47d) was obtained as a white solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 396.

Step 5: Preparation of 6-amino-9-[(4-bromophenyl) methyl] -2- (ethylsulfoneimideyl) -7h-purine-8-one (Compound 47e)

Compound 47e is 6-amino-9-[(4-bromophenyl) methyl] -2-ethyl instead of 6-amino-9-benzyl-2-propylsulfinyl-7H-purine-8-one (Compound 1d). Sulfinyl-7H-purine-8-one (Compound 47d) was prepared in the same manner as in Example 1, Method B, Step 7. 6-Amino-9-[(4-bromophenyl) methyl] -2- (ethylsulfoneimideyl) -7H-purine-8-one (4.0 g, compound 47e) was obtained as a white solid. MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 411.

Compound 47e-A and Compound 47e-B
Compound 47e-A (fast elution, 112 mg) and compound 47e- by separation of compound 47e by chiral HPLC using methanol 5% -40% (0.05% DEA) / CO _{2 on a CharalPak AD-3 column.} B (slow elution, 99 mg) was obtained as a white solid.

Compound 47e-A: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.58 (br.s., 1H), 7.52-7.54 (d, J = 8.0, 2H), 7.31-7.29 (t, J = 8.0Hz, 2H), 6.54 (br.s., 2H), 4.93 (s, 2H), 4.05 (s, 1H), 3 .42-3.31 (m, 2H), 1.15 (t, J = 7.3Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 411.

Compound 47e-B: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.58 (br.s., 1H), 7.54-7.52 (d, J = 8.0, 2H), 7.31-7.29 (t, J = 8.0Hz, 2H), 6.98 (br.s., 2H), 4.93 (s, 2H), 4.06 (s, 1H), 3 .40-3.37 (m, 2H), 1.15 (t, J = 7.3Hz, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 411.

Step 6: 6-Amino-9-[(4-bromophenyl) methyl] -2- (ethylsulfonimideyl) -N-methyl-8-oxo-N-propyl-purine-7-carboxamide (Example 47) , 6-Amino-9-[(4-bromophenyl) methyl] -2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide and 6 −Amino-9-[(4-bromophenyl) methyl] -2- [S (S) -ethylsulfoneimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide (Example 47) Preparation of −A and Example 47-B)

In Example 47, 6-amino-9-[(4-bromophenyl) methyl instead of 6-amino-9-benzyl-2- (propylsulfonimideyl) -7H-purine-8-one (Compound 1e)). ] -2- (Ethylsulfonimideyl) -7H-purine-8-one (Compound 47e) was prepared in the same manner as in Example 1, Method A, Step 6. 6-Amino-9-[(4-bromophenyl) methyl] -2- (ethylsulfonimideyl) -N-methyl-8-oxo-N-propyl-purine-7-carboxamide (570 mg, Example 47) Obtained as a white solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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 = 8.0Hz, 3H), 0.93-0.75 (m, 3H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 510.

Example 47-A (fast elution, 260 mg) and implementation by separation of the compounds of Example 47 by chiral HPLC using methanol 5% -40% (0.05% DEA) / CO _{2 on a CharalPak AD-3 column.} Example 47-B (slow elution, 266 mg) was obtained as a white solid.

Examples 47-A: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.56-7.54 (d, J = 8.0 Hz, 2H), 7.36-7.33 (d, J) = 8.0Hz, 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 510.
Examples 47-B: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.54-7.53 (d, J = 8.0 Hz, 2H), 7.36-7.33 (d, J) = 8.0Hz, 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 510.

Examples 48-A and 48-B
6-Amino-9-[(4-Bromophenyl) Methyl] -N-Ethyl-2- (Ethylsulfonimideyl) -N-Methyl-8-oxo-Prin-7-Carboxamide (Example 48), 6- Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (S)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide and 6- Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (R)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide (Example) 48-A and Example 48-B)

Example 48 is of 6-amino-9-benzyl-2- (propylsulfonimideyl) -7H-purine-8-one (Compound 1e) and N-methyl-N-propyl-carbamoyl chloride (intermediate AA). Instead, 6-amino-9-[(4-bromophenyl) methyl] -2- (ethylsulfonimideyl) -7H-purine-8-one (Compound 47e) and N-ethyl-N-methyl-carbamoyl chloride. It was prepared in the same manner as in Example 1, Method A, Step 6. 6-Amino-9-[(4-bromophenyl) methyl] -2- (ethylsulfonimideyl) -N-methyl-8-oxo-N-propyl-purine-7-carboxamide (469 mg, Example 48) Obtained as a white solid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) 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.s., 2H), 4.97 (s, 2H), 3.53-3.46 (m, 4H), 3.05-3.01 (m, 3H), 1 .22-1.16 (m, 6H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 496.

Example 48-A (fast elution, 198 mg) as a white solid by separating the compound of Example 48 by chiral HPLC with 5% -40% (0.05% DEA) / CO _{2 of methanol on a CharalPak AD-3 column.} And Example 48-B (slow elution, 202 mg) was obtained.

Examples 48-A: ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.56-7.54 (d, J = 8.0 Hz, 2H), 7.36-7.34 (d, J) = 8.0Hz, 2H), 6.92 (br.s., 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). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 496.
Examples 48-B: ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.56-7.54 (d, J = 8.0 Hz, 2H), 7.36-7.34 (d, J) = 8.0Hz, 2H), 6.92 (br.s., 2H), 4.97 (s, 2H), 4.24 (br.s., 1H), 3.58-3.41 (m) , 4H), 3.05-3.01 (m, 3H), 1.26-1.01 (m, 6H). MS obsd. (ESI ⁺ ) [(M + H) ⁺ ]: 496.

Example 49
Activation of Compounds and Examples in HEK293-hTLR-7 Assay HEK293-Blue-hTLR-7 Cell Assay:
Stable HEK293-Blue-hTLR-7 cell lines were purchased from InvivoGen (Cat. #: Hkb-htlr7, San Diego, California, USA). These cells were designed to study the stimulation of human TLR7 by monitoring the activation of NF-κB. A SEAP (secretory embryonic alkaline phosphatase) reporter gene was placed under the control of the IFN-β minimal promoter fused to five NF-κB and AP-1-binding sites. SEAP was introduced by activating NF-κB and AP-1 via stimulation of HEK-Blue hTLR7 cells with TLR7 ligand. Therefore, reporter expression was regulated by the NF-κB promoter upon 20 hours of stimulation with human TLR7. Cell culture supernatant SEAP reporter activity turned ^{purple or blue in the presence of QUANTI-Blue TM} kit (Cat. #: Rep-qb1, Invivogen, San Diego, Ca, USA) at a wavelength of 640 nm and alkaline phosphatase. Determined using varying detection media.

HEK293-Blue-hTLR7 cells, 4.5 g / L glucose, 50 U / mL penicillin, 50 mg / mL streptomycin, 100 mg / mL Normocin, 2 mM L-glutamine, 10% (V / V) heat inactivation In Dalveco's Modified Eagle's Medium (DMEM) containing fetal bovine serum, it was incubated in 96-well plates at a density of 250,000-450,000 cells / mL in a volume of 180 μL for 24 hours. HEK293-Blue-hTLR-7 cells were then incubated with serially diluted 20 μL of test compound in the presence of 1% final DMSO and incubated in a CO ₂ incubator for 20 hours at 37 ° C. 20 μL of supernatant from each well was then incubated with 180 μL of Quanti blue substrate solution at 37 ° C. for 2 hours and a spectrophotometer was used to read absorption at 620-655 nm. Signal transduction pathways in which TLR7 activation results in downstream NF-κB activation are widely accepted, and therefore similar reporter assays have been widely used to evaluate TLR7 agonists (Tsuneyasu Kaisho and Takashi Tanaka, Trends in). Immunology, Volume 29, Assay 7, July 2008, Page 329. Sci; Hiroaki Hemmi et al, Nature Immunology 3, 196-200 (2002).

The compounds and examples of the invention were tested for their TLR7 agonist activity described herein in the HEK293-hTLR-7 assay. The results are shown in Table 1. Example of prodrugs, found to have an _{EC 50} of from about 2.1μM to about 1000 [mu] M, the compounds of the active form is found to have an _{EC 50} of less than 0.2 [mu] M. The calculated EC _{50 (prodrug)} / EC _{50 (active form)} ratio was in the range of 32 to about 7600.

Table 1. Activities of Examples and Compounds of the Invention in the HEK293-hTLR-7 Assay

Example 50
Metabolism of Prodrugs of Compounds of Formula (I) Tests were conducted to evaluate the metabolic conversion of prodrugs, compounds of formula (I), to their corresponding active forms. When provided as a prodrug, the compound of formula (I) can be metabolized in the body to the active compound or other compound of the invention. Human liver microsomes are often used to assess the degree of metabolic conversion of prodrugs in the animal or human body.

material:
The NADPH cofactor system, including β-nicotinamide adenine dinucleotide phosphate (NADP), isocitric acid and isocitrate dehydrogenase, is described in Sigma-Aldrich Co., Ltd. Purchased from (St. Louis, MO, USA). Human liver microsomes (Cat No. 452117, Lot No. 38290) were obtained from Corning (Woburn, MA, USA). Mouse liver microsomes (Cat No. M1000, Lot No. 1310028) were obtained from Xenotech.

Dilution of compound Standard solution and other solutions The compound was dissolved in DMSO to prepare a 10 mM storage solution. A 10 μL storage solution was diluted with acetonitrile (990 μL) to give a 100 μM diluted standard solution.

Incubation Microsomes were pre-incubated with test compounds in 100 mM potassium phosphate buffer (pH 7.4) for 10 minutes at 37 ° C. The reaction was initiated by adding a NADPH regeneration system to a final incubation volume of 200 μL and shaking in a water bath at 37 ° C. The incubation mixture consisted of liver microsomes (0.5 mg microsome protein / mL), substrate (1.0 μM), and NADP (1 mM), isocitrate dehydrogenase (1 unit / mL), isocitric acid (6 mM).

Preparation of Samples for Analysis At 30 minutes, the reaction was quenched by the addition of 600 μL of cold acetonitrile, including 100 ng / mL tolbutamide and 100 ng / mL labetalol as internal standards. The sample was centrifuged at 4000 rpm for 20 minutes and the resulting supernatant was subjected to LC-MS / MS analysis.

Samples for the calibration curve were prepared as follows. 100 μL / well liver microsomes and 98 μL / well NADPH regeneration system solution are dispensed into 96-well plates. First add 600 μL of quench solution, then add 2 μL of standard curve and QC diluted standard solution.

Bioanalytical compounds were quantified on an API 4000 LC-MC / MC instrument in ESI-Positive MRM mode.

Testing was performed in the presence of human liver microsomes, Prodrug (1 μM), 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, 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, The metabolic conversion to compound 47e-A and compound 47e-B was evaluated. Table 2 summarizes the results.

Table 2: Metabolic conversion of prodrugs in human liver microsomes

Example 51
In vivo combination efficacy of the prodrug form of the compounds of the invention (Compound 41-A) with sorafenib in a highly aggressive model of hepatocellular carcinoma (tumor-free mice)
In iAST mice, IFU adenovirus (Ad-CMV-iCre vector in vivo applications, Vector Biolabs) of 5x10 ⁸ expressing Cre recombinase, a hepatocyte-specific albumin promoter, loxP-flanked stop cassette, and SV40 large Tumor development of mice was initiated by intravenous injection into transgenic mice expressing the T-antigen (Runge A, at al., Cancer Res. 74 (2014) 4157-69). Cre recombinase excises transduced intracellular arrest cassettes, causing transient viral hepatitis, resulting in polynodular tumorigenesis within 8 weeks. Female mice were subjected to vehicle (7.5% Gelatine / 0.22% NaCl for sorafenib; or 2% Klucel® hydroxypropyl cellulose LF (Ashland), 0.5% D for 41-A. -Α- Tocopherol Polyethylene Glycol 1000 Succinate (TPGS, Sigma), 0.09% Methylparaben (Sigma), 0.01% Propylparaben (Sigma)), or 90 mg / kg in sorafenib (Nexavar®, Bayer HealthCare) Or by oral tube feeding once a week with compound 41-A (10 mg / kg). Treatment with vehicle or sorafenib was initiated at week 7.5 with adenovirus administration 3 days prior to administration of compound 41-A. Animals were sacrificed 12 days after the start of treatment to determine the weight of the entire liver and tumor. N = 10 per group was analyzed using one-way ANOVA and GraphPad Prism software version 6 with Tukey's correction shown as individual points on average ± SEM. Although sorafenib was extremely effective in monotherapy, in combination with the active form of the compounds of the invention (Compound 41-A), it is also superficial in the liver in such a highly aggressive model of hepatocellular carcinoma. Examination gave 2/10 tumor-free mice. The results are shown in the table below and FIGS. 1A and 1B.

Synergistic effect of compound 41-A and sorafenib on tumor loading (tumor-free mice)

Example 52
Treatment with the prodrug form of the compound of the present invention (Compound 41-A) treated tumors derived from iAST mice that induce PD-L1 expression in hepatocellular carcinoma tumor cells as shown in FIG. .. Animals were sacrificed 12 days after the start of treatment and tumors were analyzed by flow cytometry. Tumors were resected for flow cytometry and single cell suspensions were obtained by mechanical treatment and enzymatic digestion (DNase 0.01%, Collagenase IV 1 mg / ml). The staining procedure was started with Fc receptor block using 2.4G2 antibody clone (1: 200 dilution, BD Bioscience) and leukocyte infiltration was analyzed using the following antibody (clone): CD45-FITC (30-FITC). F11, BioLegend) and CD11b-BUV737 (M1 / 70, BD Bioscience). Samples were taken using an LSR Fortessa machine (BD Bioscience) and analyzed by FlowJo version 10 (Treestar). Data showing n = 5 per group analyzed by Tukey's correction, shown as individual points on average ± SEM, using unidirectional ANOVA and GraphPad Prism software version 6. Absolute immune cell infiltration in iAST tumors was not altered by any of the described treatments (FIG. 2A), but significant changes were observed throughout the tumor's lymphatic and bone marrow composition (FIGS. 2C and D). Here, these changes were apparently caused by sorafenib, which had previously been shown to act on immune cells (Martin del Campo, et al, J Immunol. 195 (2015) 1995-2005). It was. However, treatment with 41-A induced PD-L1 expression on tumors in monotherapy and in combination with sorafenib (FIG. 2B).

Example 53
The combination of 41-A, sorafenib and anti-PD-1 in vivo increased median survival.
Polynodular tumors were induced in iAST mice as described with respect to FIG. 1 (see Example 51). Female recombinant mice were subjected to vehicle (7.5% Gelatine / 0.22% NaCl for sorafenib; or 2% Klucel® hydroxypropyl cellulose LF (registered trademark) in water for 41-A) at 7.5 weeks. Ashland), 0.5% D-α-tocopherol polyethylene glycol 1000 succinate (TPGS, Sigma), 0.09% methylparaben (Sigma), 0.01% propylparaben (Sigma)), or 90 mg / kg (Nexavar) in sorafenib. It was treated daily with virus infusion using (registered trademark), BayerHealthCare), or with compound 41-A (10 mg / kg) once weekly by oral tube feeding. Treatment with vehicle or sorafenib was started at week 7.5 by administration of adenovirus and 3 days prior to administration of compound 41-A. Anti-mouse PD-1 antibody (clone RPM1-14, BioXCell) was intraperitoneally administered at 250 μg / mouse every 3 days. The total treatment period was 2 weeks (and 3 days + 2 weeks for sorafenib), and the survival of iAST mice was monitored. Mice were sacrificed when there were signs of distress such as> 20% weight gain, fur wrinkles, and / or unstable posture. The Kaplan-Meier curve was analyzed by the Pairwise Log-Rank test (see table). In the survival setting, neither sorafenib nor 41-A was effective in monotherapy. Anti-PD-1 monotherapy even significantly reduced survival compared to VEH control. Median survival of iAST mice was significantly enhanced in the sorafenib and anti-PD-1 antibody combination group. However, the triple combination of 41-A with sorafenib and anti-PD-1 resulted in a maximum and significant prolongation of median survival of 71 days (VEH) to 104 days in this highly aggressive HCC model. (41-A + PD-1 + sorafenib). The results are shown in FIG. 3 and the table below.

Table: Pairwise Log-Rank Test test (multiple test levels = 0.00179)

Example 54
To treatment female C57BL / 6N mice with prodrug forms of the compounds of the present invention in Hep55.1c mouse model of transplanted hepatocellular carcinoma (Compound 41-A) (Jackson Laboratories) , 5x10 5 amino Hep55.1c Tumor cell lines were injected intrahepatic with Matrigel (Matrigel basement membrane matrix, Corning Cat # 354234) in a total volume of 20 μl (10 μl cell suspension + 10 μl Matrigel). Tumor volume was monitored weekly using μCT (TomoScop Synergy Twin, CT Imaging GmbH) with a single intravenous dose of contrast medium Exiron 6000 (Viscovert). Image data was reconstructed with TomoScop software and analyzed using Osirix software. When the tumor ^{reaches 80 mm 3} , mice are subjected to oral tube feeding via 10 mg / kg of 41-A compound or vehicle (2% Klucel® in water, Hydroxypropyl Cellulose LF (Ashland), 0.5). Weekly treatment with% D-α-tocopherol polyethylene glycol 1000 succinate (TPGS, Sigma), 0.09% methylparaben (Sigma), 0.01% propylparaben (Sigma)). A single dose of anti-CD40 antibody (4 mg / kg; clone FGK.45, BioXCell) was given for comparison with another agonist immunostimulant. The data shown are mean ± SEM of a minimum of n = 9 animals per group.

Weekly administration of Compound 41-A resulted in inhibition of tumor growth in Hep55.1c tumor-bearing mice compared to vehicle treatment. As previously published, single-dose anti-CD40 antibodies can eradicate tumors in subcutaneous MC38 tumors, and anti-CD40 antibodies have been shown to have inflammatory effects in the liver (Hove's S, et al, J Exp Med, DOI: 10.1084 / jam. 20171440; Publiced Antibody 7, 2018). However, no favorable therapeutic effect of anti-CD40 antibody was observed in Hep55.1c tumor-carrying mice. The results are shown in FIG. 5A.

Example 55
Compound 42-A (6-amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfoneimideyl] -N alone and in combination with anti-PD-1 The in vivo efficacy of −methyl-8-oxo-purine-7-carboxamide) results in a life-prolonging effect in the Hep55.1c mouse model of hepatocellular carcinoma.
For female C57BL / 6N mice (Jackson Laboratories), 5x105 Hep55.1c tumor cell lines were combined with Matrigel (Matrigel basement membrane matrix, Corning Cat # 354234) in a total volume of 20 μl (10 μl cell suspension + 10 μl). It was injected intrahepatic with Matrigel). Scout animals were sacrificed to determine when treatment began with a tumor volume of approximately 80 mm3. Mice were charged with compound 42-A 10 mg / kg or vehicle (2% Klucel® hydroxypropyl cellulose LF (Ashland) in water, 0.5% D-α-tocopherol polyethylene glycol 1000 succinate) via oral tube feeding. (TPGS, Sigma), 0.09% methylparaben (Sigma), 0.01% propylparaben (Sigma)), or 250 μg of anti-PD-1 antibody (clone RPM1-14, BioXCell) intraperitoneally administered, or compound 42. Treated with a combination of −A + anti-PD-1. 42-A was administered weekly (3 times in total) and anti-PD-1 antibody treatment was started on the same day. Antibody treatment was continued every 3 to 4 days for a total of 6 doses. Monotherapy with 42-A resulted in smaller tumor volume compared to VEH control and PD-1 monotherapy. The combined treatment of 42-A and anti-PD-1 also reduced tumor volume, and 3 of 9 mice were tumor-free. The results are shown in FIG. 5B and the table below.

Combined effect of compound 42-A and anti-PD-1 on tumor loading (tumor-free mice)

Example 56
Combination of the prodrug form of the compound of the present invention (Compound 41-A) with the anti-PD-1 antibody Hep55.1c mouse model of hepatocellular carcinoma 5x10 ⁵ Hep55. 1c tumor cell lines were injected intrahepatic with Matrigel (Matrigel basement membrane matrix, Corning Cat # 354234) in a total volume of 20 μl (10 μl cell suspension + 10 μl Matrigel). After 3 weeks, the animals were sacrificed and the tumor was resected from the liver. The resected tumor ^{was cut into 3} pieces of 1x1 mm and transplanted into the liver of female C57BL / 6N mice. Scout animals were sacrificed to determine when treatment began with a tumor volume of ^{approximately 80 mm 3.} Mice were presented with 41-1 or vehicle (in water, 2% Klucel® hydroxypropyl cellulose LF (Ashland)), 0.5% D-α-tocopherol polyethylene glycol 1000 succinate (TPGS,) via oral tube feeding. Sigma), 0.09% methylparaben (Sigma), 0.01% propylparaben (Sigma)), or 250 μg of anti-PD-1 antibody (clone RPM1-14, BioXCell) intraperitoneally or 41-1 + anti-PD Treated with a combination of -1. 41-A was administered weekly and anti-PD-1 antibody treatment was initiated the day after 41-A treatment and continued for a total of 8 doses every 3-4 days. Treatment with both agents was discontinued after the final dose of anti-PD-1. Monotherapy with 41-A resulted in extended life in mice compared to vehicle control (1/10) (5/10). The combined treatment of 41-A and anti-PD-1 resulted in a more significant mouse survival promotion, with 8/10 surviving 94 days after transplantation of the tumor fragment.

Example 57
Treatment with the active form of the compound of the present invention (Compound 41c-B) does not induce hyperproliferation of tumor cells in cell lines originating from hepatocellular carcinoma and cholangiocarcinoma. Hepatocellular carcinoma and cholangiocarcinoma (EGI1 and OZ) )-Derived cell lines were maintained and tested in the following media: Huh7 and EGI1 in DMEM 4.5 g / L glucose (Gibco, Cat # 31966-021), 10% FCS (GIBCO, Cat # 10500-064 Lot). 07G3690K), 2 mM L-glutamine (Thermo Fisher, Cat # 25030081), 1 mM sodium pyruvate (GIBCO Cat # 11360-039). Hep3B and HepG2 were cultured in Eagles MEM + Earl solution (PAN, Cat # P04-08510), 10% FCS, 2 mM L-glutamine, 0.1 mM NEAA (PAN Cat # P08-32100) and 1 mM sodium pyruvate. JHH1, JHH5, JHH6 and OZ were cultured in Williams'E (PAN Cat # P04-29050), 10% FCS and 2 mM L-glutamine. JHH2 was cultured using Williams'E, 10% FCS and 2 mM L-glutamine. HLE was cultured in DMEM 4.5 g / L glucose, 10% FCS and 2 mM L-glutamine. HLF was cultured in DMEM 4.5 g / L glucose, 5% FCS, 0.1 mM NEAA and 2 mM L-glutamine. JHH4 was cultured in Eagles MEM + Earl solution, 10% FCS and 2 mM L-glutamine. SkHep1 was cultured in Eagles MEM + Earl solution, 10% FCS, 2 mM L-glutamine, 0.1 mM NEAA and 1 mM sodium pyruvate. SNU449 was cultured using RPMI 1640 (PAN Cat # P04-18047) 10% FCS and 2 mM L-glutamine. Cells were seeded in each medium overnight at a density of 5,000 cells per well of 96-well clear flat-bottomed black polystyrene TC-treated microplate l (Corning, Cat # 3904). The next day, 41c-B logarithmically diluted starting from 27 μM was added and incubated for 72, 120 and 148 hours, respectively. Tumor cell numbers were determined using the Perkin Elmer Operetta Imaging System and Harmony Software by counting nuclei stained in complete medium for 20 minutes with the Hoechst 33342 dye (2 μg / ml, Sigma Cat # B2661). .. The data shown is the mean + SD of 3 wells based on the analysis of 9 images per well compared to DMSO control.

None of the cell lines tested showed a significant increase in proliferation at the time indicated when directly treated with 41c-B. The results are shown in FIG. 6A.

Example 58
Treatment using the active form of the compound of the present invention (Compound 41c-A) does not induce hyperproliferation of tumor cells in cell lines originating from hepatocellular carcinoma and cholangiocarcinoma. Hepatocellular carcinoma and cholangiocarcinoma (EGI1). Cell lines of origin were maintained and tested in the following media: Huh7 and EGI1 were DMEM 4.5 g / L glucose (Gibco, Cat # 31966-021), 10% FCS (GIBCO, Cat # 10500-064 Lot 07G3690K). , 2 mM L-glutamine (Thermo Fisher, Cat # 25030081), 1 mM sodium pyruvate (GIBCO Cat # 11360-039). Hep3B and HepG2 were cultured in Eagles MEM + Earl solution (PAN, Cat # P04-08510), 10% FCS, 2 mM L-glutamine, 0.1 mM NEAA (PAN Cat # P08-32100) and 1 mM sodium pyruvate. JHH2 was cultured in Williams'E, 10% FCS and 2 mM L-glutamine. HLF was cultured in DMEM 4.5 g / L glucose, 5% FCS, 0.1 mM NEAA and 2 mM L-glutamine. SkHep1 was cultured in Eagles MEM + Earl solution, 10% FCS, 2 mM L-glutamine, 0.1 mM NEAA and 1 mM sodium pyruvate. Cells were seeded in each medium overnight at a density of 5,000 cells per well of 96-well clear flat-bottomed black polystyrene TC-treated microplate l (Corning, Cat # 3904). The next day, 41c-A logarithmically diluted starting from 27 μM was added and incubated for 72 hours each. Tumor cell numbers were determined using the Perkin Elmer Operetta Imaging System and Harmony Software by counting nuclei stained in complete medium for 20 minutes with the Hoechst 33342 dye (2 μg / ml, Sigma Cat # B2661). .. The data shown is the mean + SD of 3 wells based on the analysis of 9 images per well compared to DMSO control.

None of the cell lines tested showed a significant increase in proliferation 72 hours later when treated directly with 41c-A. The results are shown in FIG. 6B.

Example 59
Treatment of tumor cells with the active form of the compound of the invention (Compound 41c-B) in the presence of peripheral blood inhibits tumor cell growth.
Heparinized whole blood of three different donors was diluted 1: 1 in RPMI medium (PAN Cat. # P04-18047) + 10% FCS (GIBCO Cat # 10500-064, lot 07G3690K) at 37 ° C. and 5 Incubated in% CO ₂ for 24 hours with 2.7 μM compound 41c-B. The supernatant was collected and centrifuged at 600 xg for 8 minutes to remove remaining leukocytes, platelets and erythrocytes. The supernatant was then stored at −80 ° C. until use and gently thawed at room temperature prior to addition to the cell line. Cell lines Huh7, JHH2, HLE, HLF, JHH4, Hep3B, HepG2, JHH1, EGI1, JHH5, JHH6, OZ, SkHep1, SNU449 in 100 μl of each medium (described in Example 57), 96-well transparent flat bottom. Black polystyrene TC-treated microplates (Corning, Cat # 3904) were seeded overnight at a density of 5,000 cells per well. The next day, 100 μl of whole blood supernatant was added to the cell line. As a control, a supernatant of whole blood without the addition of 41c-B compound (“whole blood without addition”) or raw RPMI medium + FCS (“medium CTRL”) was added. The cell line was incubated for 72 hours. Tumor cell numbers were determined using PerkinElmer Operata Imaging System and Harmony Software by counting nuclei stained in complete medium for 20 minutes using Hoechst 33342 (2 μg / ml, Sigma Cat # B2661). Survival was assessed by additional detection of Iodyne (PI, 1 μg / ml, Sigma Cat # P4864). The data shown is the average of 3 wells + SD based on the analysis of 9 images per well.

The results are shown in FIGS. 7A and 7B. In some cell lines (SNU449, JHH2 and SkHep), the addition of unstimulated whole blood supernatant induced growth above media control levels, while other reactions were growth reduction (OZ, JHH1). , HepG2, JHH4, JHH6, JHH5 and EGI1). However, treatment with whole blood-derived supernatants incubated with 41c-B reduced cell numbers in all cases tested compared to their respective "whole blood without addition" controls. The decrease in cell number was mainly due to the arrest of proliferation, and only the cell lines JHH2, JHH4, JHH6, Hep3B and EGI1 were determined by advanced PI positivity, leading to cell death (data not shown).

Example 60
Factors released into peripheral blood upon treatment with the active form of the compounds of the invention (Compound 41c-A) are heparinized whole blood of two different donors that inhibit growth in tumor cell lines in RPMI medium (RPMI medium. Dilute 1: 1 in PAN Cat. # P04-18047) + 10% FCS (GIBCO Cat # 10500-064, lot 07G3690K) and incubate with 2.7 μM compound 41c-A at 37 ° C. and 5% CO2 for 24 hours. did. The supernatant was collected and centrifuged at 600 xg for 8 minutes to remove remaining leukocytes, platelets and erythrocytes. The supernatant was then stored at −80 ° C. until use and gently thawed at room temperature prior to addition to the cell line. 1 of 96-well clear flat-bottomed black polystyrene TC-treated microplates (Corning, Cat # 3904) in 100 μl of each medium (shown in FIG. 6) with cell lines Huh7, JHH2, HLF, Hep3B, HepG2, EGI1 and SkHep1. Seeded overnight at a density of 5,000 cells per well. The next day, 100 μl of whole blood supernatant was added to the cell line. As a control, a supernatant of whole blood without the addition of 41c-A compound (“whole blood without addition”) or raw RPMI medium + FCS (“medium CTRL”) was added. The cell line was incubated for 72 hours. Tumor cell numbers were determined using PerkinElmer Operata Imaging System and Harmony Software by counting nuclei stained in complete medium for 20 minutes using Hoechst 33342 (2 μg / ml, Sigma Cat # B2661). Survival was assessed by additional detection of Iodyne (PI, 1 μg / ml, Sigma Cat # P4864). The data shown is the average of 3 wells + SD based on the analysis of 9 images per well.

Treatment with whole blood-derived supernatants incubated with -41c-A, the results of which are shown in FIG. 7C, reduced cell numbers in all cases tested compared to each "whole blood without addition" control. Or stabilized. Only in Hep3B, the supernatant of donor # 5 increased the proliferation of this cell line, but the supernatant from donor # 4 had no effect on tumor cell proliferation.

Example 61
Single-dose PK test in male Wister-Han rats A single-dose PK was performed in male Wister-Han rats to evaluate the pharmacokinetics of the test compounds. Two groups of animals were dosed via tube feeding (POE) for each compound. Blood samples (approximately 20 μL) were collected intravenously or via another site in groups 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 7 hours and 24 hours after administration. The blood sample was placed in a tube containing an EDTA-K2 anticoagulant and centrifuged at 5000 rpm for 6 minutes at 4 ° C. to separate plasma from the sample. After centrifugation, the resulting plasma was transferred to a clean tube for bioanalysis of both prodrug and active forms on LC / MS / MS. In the group treated with the prodrug, the concentration of the prodrug in the plasma sample was below the detection limit. The “test compounds” in Table 8 were used as internal standards for testing metabolites (active forms) of “dose compounds” in vivo. Pharmacokinetic parameters were calculated using the WinNonlin® Professional 6.2 non-compartment module. The peak concentration (C _max ) was recorded directly from the experimental observations. Areas under the plasma concentration-time curve (AUC _0-t ) were calculated using the primary trapezoidal rule up to the final detectable concentration.

C _max and AUC _0-last are two critical PK parameters for the in vivo efficacy of the test compound. _{The higher the C max} and AUC _0-last of the compound, the better the in vivo efficacy will be. The results of the PK parameters following oral administration of the active form and competing compounds are shown in Table 7. The PK parameters for prodrugs are shown in Table 8.

Following oral administration of the prodrug, the active form was observed in plasma and therefore tested. The exemplary prodrugs of the invention (Examples 41-B, 42-A, 42-B, 43-A, 45-A and 45-B) are surprisingly reference compounds (GS9620, S-2). _{And S-3) and the much improved C max} (5-175 fold increase) compared to the compounds referred to in the present invention in all active forms (Compounds 41c-A, 41c-B and 43e-A). ) And AUC _0-last (2.5-56 times increase). This result clearly demonstrated the unexpected superiority of the prodrug over the active form in PK parameters and the resulting improvement in efficacy in vivo.

Table 7.5 Mean plasma concentration and PK parameters of active form after oral administration of 7.5 mg / kg

Table 8.5 PK parameters of prodrug after oral administration of 8.5 mg / kg

Example 62
Study of LYSA solubility The LYSA study is used to determine the water solubility of the test compound. Two samples were prepared from a 10 mM DMSO storage solution. After evaporation of DMSO using a centrifugal vacuum evaporator, the compound was dissolved in 0.05 M phosphate buffer (pH 6.5), stirred for 1 hour and shaken for 2 hours. After overnight, the solution was filtered using a microtiter filter plate. The filtrate and 1/10 dilution thereof were then analyzed by HPLC-UV. In addition, a four-point calibration curve was prepared from a 10 mM storage solution and used to determine the solubility of the compound. Results are shown at μg / mL. If the percentage of sample measured in solution after evaporation divided by the calculated maximum sample volume was greater than 80%, the solubility was reported to be greater than this value.

The results of LYSA are shown in Table 9. It was apparent that when converted to various prodrugs, the solubility of the active form was surprisingly improved by 10 to 200 fold.

Table 9. Solubility data for specific compounds

Example 63
Portal Study The purpose of this study was to understand whether the prodrug remains unchanged when absorbed through the intestine into the portal circulation and to demonstrate the major sites of conversion.

Surgical procedures for portal circulation (PVC) and carotid cannulation (CAC) Surgery was performed under pentobarbital / isoflurane anesthesia. Briefly, the abdominal area was disinfected with betadine and 70% isopropyl alcohol, followed by a small midline abdominal incision. The cecum was withdrawn, the mesenteric vein was identified and isolated into a vein of approximately 5 mm. A loose ligature was placed proximally and the distal end of the vein was ligated. A small incision was made in the isolated vein and a PU catheter (enough to insert the catheter) was inserted into the liver for the appropriate length. The catheter was secured in place by tying a loose ligature around the cannulated vein. The cecum was returned to the abdominal cavity. A hole was made in the right abdominal wall and the end of the catheter was allowed to pass freely. The catheter was secured to the abdominal wall with sutures. The abdominal muscle incision was closed with suture. A small incision was made in the scapula area to exit the catheter. A catheter was passed under the skin and exposed through a scapular incision. A fixed suture was placed in the scapular region. Catheter patency was checked and then exposed from the subcutaneous space to the dorsal neck region. After gently wiping the area, the abdominal cavity was sutured. The left carotid artery was then cannulated by inserting a PE50 catheter. Both exposed catheters were tightly tied to the dorsal neck area and fixed. Animals were then restored in their cages and used for testing at least 3 days after surgery. All catheters were washed once daily with heparin saline to maintain patency.

Oral PK test in PVC / CAC double-cannula-treated rats Animals were fasted overnight (n = 3) and administered vial oral tube feeding (10 mg / kg, 10 mL / kg). Blood samples (60 μL) were simultaneously collected from portal and carotid catheters at 0.083, 0.25, 0.5, 1, 2, 4, 7, and 24 hours. All blood samples are transferred to an Eppen tube containing ₂ μL K 2 EDTA (0.5 M) as an anti-coagulant and placed on moist ice. Within 30 minutes of collection, the blood sample is then processed for plasma by centrifugation at about 4 ° C., 3000 g. Plasma samples are stored in polypropylene tubes, snap frozen on dry ice and kept at −70 ± 10 ° C. until LC / MS / MS analysis.

In portal-cannula-treated rats, oral administration of the prodrug (10 mg / kg) was followed by detection of the pharmacokinetic parameters of the prodrug and active form (mean ± Sd, n = 3) in the portal and carotid artery samples. And analyzed. The test results of Examples 1-B, 41-A, 41-B, 42-A and 43-A are summarized below.

Table 10: Examples 41-A and corresponding active forms in portal and carotid samples following oral administration of Example 41-A (10 mg / kg) in portal-cannula-treated rats. Pharmacokinetic parameters of compound 41c-B

Table 11. Example 43-A and the corresponding active form of compound 43e- in portal and carotid artery samples following oral administration of Example 43-A (10 mg / kg) in portal-cannula-treated rats. Pharmacokinetic parameters of A

Table 12. Following oral administration of Example 1-B (10 mg / kg) in portal-cannula-treated rats, Example 1-B and the corresponding active form of Compound 1e-A in the portal and systemic samples. Pharmacokinetic parameters

Table 13. Following oral administration of Example 42-A (10 mg / kg) in portal-cannula-treated rats, Example 42-A and its corresponding active form, Compound 41c-, in portal and carotid artery samples. Pharmacokinetic parameters of A

Table 14. Following oral administration of Example 41-B (10 mg / kg) in portal-cannula-treated rats, Example 41-B and its corresponding active form, Compound 41c-, in portal and carotid artery samples. Pharmacokinetic parameters of A

Based on the above results, since the _AUC active _{/ AUC total} of sampling from the carotid artery was higher compared to the _AUC active _{/ AUC total} of sampling from the portal vein, the major site of conversion of prodrug intestine I concluded that it was the liver, not the liver.

Claims (38)

Formula (I) for use in the treatment or prevention of liver cancer

[During the ceremony,
R ¹ is C _1-6 alkyl;
R ² is benzyl, which is unsubstituted or substituted with one, two, or three substituents independently selected from _{halogens and C 1-6 alkyls;}
R ³ is -NR ⁴ R ⁵ , where R ⁴ is C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl;
R ⁵ is (C _1-6 alkyl) ₂ NCOCOC _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxycarbonyl (C _1-6 alkyl) amino C _1-6 alkyl, C _1-6 Alkoxycarbonyl (Phenyl) C _1-6 Alkyl, C _1-6 Alkoxycarbonyl C _1-6 Alkyl, C _1-6 Alkoxycarbonyloxy C _1-6 Alkyl, C _1-6 Alkyl, C _1-6 Alkyl Is it a carbonyl (C _1-6 alkyl) amino C _1-6 alkyl or pyrrolidinyl carbamoyloxy C _1-6 alkyl; or R ⁴ and R ⁵ form heterocyclyls with the nitrogen they bind to]
Compound, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof;
However,
6-Amino-9-Benzyl-2- (propylsulfonimideyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-9-benzyl-7- (piperidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (Morpholine-4-carbonyl) -2- (Propylsulfonimideyl) Purine-8-one;
6-Amino-9-benzyl-7- (3,3-dimethylpyrrolidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
Ethyl 1- [6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] pyrrolidine-2-carboxylate;
6-Amino-7- (2-azaspiro [3.3] heptane-2-carbonyl) -9-benzyl-2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (2-oxa-6-azaspiro [3.3] heptane-6-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (3,3-difluoropyrrolidine-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-Benzyl-7- (3-Fluoro-3-methyl-pyrrolidin-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
And these enantiomers or diastereomers are excluded,
Compound. R ¹ is C _1-6 alkyl;
R ² is benzyl, said benzyl being unsubstituted or substituted with halogen or C _1-6 alkyl;
R ³ is azetidinyl;
Piperazinyl substituted with C _{1-6 alkyl;}
Piperidinyl substituted with piperidinyl;
Pyrrolidinyl; or −NR ⁴ R ⁵ , where R ⁴ is C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl;
R ⁵ is (C _1-6 alkyl) ₂ NCOCOC _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxycarbonyl (C _1-6 alkyl) amino C _1-6 alkyl, C _1-6 Alkoxycarbonyl (Phenyl) C _1-6 Alkyl, C _1-6 Alkoxycarbonyl C _1-6 Alkyl, C _1-6 Alkoxycarbonyloxy C _1-6 Alkyl, C _1-6 Alkyl, C _1-6 Alkyl Carbonyl (C _1-6 Alkoxy) Amino C _1-6 Alkoxy or Pyrrolidinyl Carbamoyloxy C _1-6 Alkoxy,
The compound for use according to claim 1. R ¹ is ethyl or propyl;
R ² is benzyl, bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl;
R ³ is azetidinyl;
4-Methylpiperazinyl;
Piperidinyl Piperidinil;
Pyrrolidinyl; or -NR ⁴ R ⁵ , where R ⁴ is methyl, ethyl, propyl or methoxyethyl;
R ⁵ is acetyl (methyl) aminoethyl, butyl, butyl (methyl) carbamoyloxy ethyl, diethylcarbamoyloxy ethyl, ethoxycarbonyl (methyl) aminoethyl, ethoxycarbonylethyl, ethoxycarbonyl isobutyl, ethoxycarbonyl isopentyl, ethoxycarbonylmethyl , Ethoxycarbonyloxyethyl, ethoxycarbonyl (phenyl) ethyl, ethyl, isobutyl, isopropoxycarbonyl isopentyl, isopropoxycarbonyl (phenyl) ethyl, isopropyl, methoxycarbonyl (methyl) aminoethyl, methoxyethyl, methoxypropyl, propyl, propyl (Methyl) carbamoyloxyethyl, pyrrolidinyl carbamoyloxyethyl, tert-butoxycarbonyl (methyl) aminoethyl, tert-butoxycarbonylethyl, tert-butoxycarbonyl isopentyl or tert-butoxycarbonyl (phenyl) ethyl.
The compound for use according to claim 1 or 2. R ³ is azetidinyl, 4-methylpiperazinyl, piperidinyl piperidinyl, 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, Propylcarbonylisopentyl (methyl) amino, ethoxycarbonylmethyl (methyl) amino, ethoxycarbonyloxyethyl (methyl) amino, ethoxycarbonyl (phenyl) ethyl (methyl) amino, ethyl (methyl) amino, isobutyl (methyl) amino, iso Propoxycarbonyl Isopentyl (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, pyrrolidinyl carbamoyloxyethyl (methyl) amino , Tert-Butoxycarbonyl (methyl) aminoethyl (methyl) amino, tert-butoxycarbonylethyl (methyl) amino, tert-butoxycarbonyl isopentyl (methyl) amino or tert-butoxycarbonyl (phenyl) ethyl (methyl) amino. ,
The compound for use according to claim 3. The compound for use according to any one of claims 1 to 4, wherein R ^{1 is ethyl.} The compound for use according to claim 1 or 2, wherein R ² is a benzyl substituted with a halogen or C _{1-6 alkyl.} R ² is, bromobenzyl, chlorobenzyl, fluoro benzyl or methylbenzyl, compounds for use according to any one of claims 2 6. R ² is bromo benzyl, chlorobenzyl or fluorobenzyl, the compounds for use according to claim 7. The compound for use according to claim 1 or 2, wherein R ³ is -NR ⁴ R ⁵ , where R ⁴ is C _1-6 alkyl and R ⁵ is C _{1-6 alkyl.} The compound for use according to claim 9, wherein R ³ is propyl (methyl) amino or ethyl (methyl) amino. R ¹ is C _1-6 alkyl;
R ² is benzyl and said benzyl is substituted with _{halogen or C 1-6 alkyl;}
R ³ is -NR ⁴ R ⁵ , where R ⁴ is C _1-6 alkyl and R ⁵ is C _1-6 alkyl.
The compound for use according to any one of claims 1, 2, 6 and 9. R ¹ is ethyl;
R ² is methyl benzyl, bromobenzyl, chlorobenzyl or fluorobenzyl;
R ³ is propyl (methyl) amino or ethyl (methyl) amino,
The compound for use according to claim 11. A compound for use in the treatment or prevention of liver cancer:
6-Amino-9-Benzyl-N-Methyl-8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N- (2-methoxyethyl) -N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N-Ethyl-8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-Benzyl-7- [4- (1-piperidyl) piperidine-1-carbonyl] -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-benzyl-N-Ethyl-N- (2-Methoxyethyl) -8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N-Butyl-N-Ethyl-8-oxo-2- (propylsulfoneimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-7- (azetidine-1-carbonyl) -9-benzyl-2- (propylsulfoneimideyl) purine-8-one;
6-Amino-9-benzyl-N-isopropyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-7- (4-methylpiperazin-1-carbonyl) -2- (propylsulfonimideyl) purine-8-one;
6-Amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-9-benzyl-N-isobutyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
Ethyl 2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] acetate;
Ethyl 3-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate;
tert-Butyl 3-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] propanoate;
tert-Butyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate;
Isopropyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-methyl-butanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -4-methyl-pentanoate;
Ethyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate;
Isopropyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanol;
tert-Butyl (2S) -2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] -3-phenyl-propanoate;
N- [2- [Acetyl (Methyl) Amino] Ethyl] -6-Amino-9-Benzyl-N-Methyl-8-oxo-2- (propylsulfonimideyl) Purine-7-Carboxamide;
Methyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;
tert-butyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;
Ethyl N- [2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl] -N-methyl-carbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N-butyl-N-methyl-carbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl pyrrolidine-1-carboxylate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N-methyl-N-propyl-carbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl N, N-diethylcarbamate;
2-[[6-amino-9-benzyl-8-oxo-2- (propylsulfonimideyl) purine-7-carbonyl] -methyl-amino] ethyl ethyl carbonate;
6-Amino-N-Butyl-9-[(4-Chlorophenyl) Methyl] -N-Methyl-8-oxo-2- [S (S) -propylsulfonimideyl] Purine-7-Carboxamide;
6-Amino-N-Butyl-9-[(4-Chlorophenyl) Methyl] -N-Methyl-8-oxo-2- [S (S) -propylsulfonimideyl] Purine-7-Carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-N-methyl-8-oxo-2- (propylsulfonimideyl) purine-7-carboxamide;
6-Amino-N-Methyl-8-oxo-N-propyl-2 [S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Methyl-8-oxo-N-propyl-2 [S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- [S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-2- [S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) -7- (pyrrolidin-1-carbonyl) purine-8-one;
6-Amino-N- (2-Methoxyethyl) -N-Methyl-8-oxo-2-[S (S) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N- (2-Methoxyethyl) -N-Methyl-8-oxo-2-[S (R) -propylsulfonimideyl] -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-N-Methyl-8-oxo-2- (propylsulfoneimideyl) -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Butyl-N-Methyl-8-oxo-2- (propylsulfoneimideyl) -9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -2- [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-2- [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-2 [S (S) -Ethylsulfonimideyl] -N-Methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-N-Ethyl-2- [S (R) -Ethylsulfonimideyl] -N-Methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;
6-Amino-2- [S (S) ethylsulfonimideyl] -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-2- [S (R) Ethylsulfonimideyl] -9-[(4-fluorophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-N-Ethyl-2- (Ethylsulfonimideyl) -9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Prince-7-Carboxamide;
6-Amino-N-Ethyl-2- [S (S)-(Ethylsulfonimideyl)]-9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Purin-7-Carboxamide;
6-Amino-N-Ethyl-2- [S (R)-(Ethylsulfonimideyl)]-9-[(4-fluorophenyl) Methyl] -N-Methyl-8-oxo-Purin-7-Carboxamide;
6-Amino-9-[(4-Bromophenyl) Methyl] -2- (Ethylsulfonimideyl) -N-Methyl-8-oxo-N-propyl-Prin-7-Carboxamide;
6-Amino-2- [S (R) -ethylsulfonimideyl] -9-[(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-2- [S (S) -ethylsulfonimideyl] -9-[(4-bromophenyl) methyl] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimideyl) -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (S)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide; And 6-amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (R)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide ;
More selected compounds, or pharmaceutically acceptable salts thereof, enantiomers or diastereomers. 6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2- [S (R) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- (ethylsulfonimideyl) -N-methyl-8-oxo-purine-7-carboxamide;
6-Amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (S)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide; And 6-amino-9-[(4-bromophenyl) methyl] -N-ethyl-2- [S (R)-(ethylsulfonimideyl)]-N-methyl-8-oxo-purine-7-carboxamide The compound for use according to claim 13, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. The compound is
6-Amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide;
The compound for use according to claim 13, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof. For the use according to any one of claims 1 to 15, wherein the liver cancer is hepatocellular carcinoma, hepatoma, cholangiocarcinoma, lung blastoma, liver cancer, hepatic angiosarcoma, or metastatic liver cancer. Compounds, or pharmaceutically acceptable salts, enantiomers or diastereomers. The compound for use according to any one of embodiments 1 to 15, or a pharmaceutically acceptable salt, enantiomer or diastereomer, wherein the liver cancer is hepatocellular carcinoma. A pharmaceutical composition or medicament comprising the compound according to any one of embodiments 1 to 15 and a therapeutically inert carrier for use in the treatment or prevention of liver cancer. Use of the compound according to any one of claims 1 to 15 for the preparation of a medicament for the treatment or prevention of liver cancer. A method for treating or preventing liver cancer, which comprises administering a therapeutically effective amount of the compound according to any one of claims 1 to 15. a) Treatment or prevention of liver cancer in combination with antagonist PD1 antibody or antagonist PD-L1 antibody or b) For use in treatment of liver cancer patients in combination with antagonist PD1 antibody or antagonist PD-L1 antibody The compound according to any one of claims 1 to 15, or a pharmaceutical composition or medicine containing such a compound. The compound according to any one of claims 1 to 15, or a pharmaceutical composition or medicine containing such a compound, for use in the treatment or prevention of liver cancer.
A compound, composition or drug for which treatment is combined with an antagonist PD1 antibody or antagonist PD-L1 antibody. Use of the compound according to any one of claims 1 to 15 for the preparation of a medicament for the treatment or prevention of liver cancer.
Use in which treatment is combined with antagonist PD1 antibody or antagonist PD-L1 antibody. The compound, composition, medicament or use according to any one of claims 21 to 23, wherein the treatment is combined with an antagonist PD1 antibody. The compound, composition, medicament or use according to claim 24, wherein the antagonist PD1 antibody is nivolumab or penprolizumab. The compound is 6-amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide. , The compound, composition, pharmaceutical or use according to claim 25. The compound, composition, medicament or drug according to claim 24, wherein the agonist PD1 antibody comprises a heavy chain variable domain VH containing the amino acid sequence of SEQ ID NO: 5 and a light chain variable domain VL containing the amino acid sequence of SEQ ID NO: 6. use. The compound is 6-amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide. , The compound, composition, medicament or use according to claim 26. The compound, composition, medicament or use according to any one of claims 21 to 23, wherein the treatment is combined with an antagonist PD-L1 antibody. 29. The compound, composition, medicament or use according to claim 29, wherein the antagonist PD-L1 antibody used in the combination therapy is atezolizumab or durvalumab or avelumab (atezolizumab in one preferred embodiment). The compound is 6-amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide. , The compound, composition, medicament or use according to claim 30. The compound, composition, medicament or use according to any one of claims 21 to 31, wherein an anti-angiogenic agent is further used in the combination therapy. The combination therapy further uses an anti-angiogenic agent selected from sorafenib, regorafenib, sunitinib or bevacizumab (in one preferred embodiment the anti-angiogenic agent is sorafenib; in one preferred embodiment the anti-angiogenic agent is Bevacizumab), the compound, composition, medicament or use according to any one of claims 21 to 31. a) Treatment or prevention of liver cancer in combination with anti-angiogenic agents,
Alternatively b) the compound according to any one of claims 1 to 15, or a pharmaceutical composition comprising such a compound, for use in the treatment of liver cancer patients in combination with an anti-angiogenic agent. Or medicine. The compound according to any one of claims 1 to 15, or a pharmaceutical composition or medicine containing such a compound, for use in the treatment or prevention of liver cancer.
A compound, composition or drug for which treatment is combined with an anti-angiogenic agent. Use of the compound according to any one of claims 1 to 15 for the preparation of a medicament for the treatment or prevention of liver cancer.
Use, where treatment is combined with anti-angiogenic agents. The anti-angiogenic agent is selected from sorafenib, regorafenib, sunitinib or bevacizumab (in one preferred embodiment the anti-angiogenic agent is sorafenib; in one preferred embodiment the anti-angiogenic agent is bevacizumab), claim 34. The compound, composition, pharmaceutical or use according to any one of items to 36. The compound is 6-amino-9-[(4-chlorophenyl) methyl] -N-ethyl-2 [S (S) -ethylsulfonimideyl] -N-methyl-8-oxo-purine-7-carboxamide. , The compound, composition, medicament or use according to claim 37.

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