TW202003518A - 7-substituted sulfonimidoylpurinone compounds and derivatives for the treatment and prophylaxis of liver cancer - Google Patents

Abstract

The present invention relates to compounds of formula (I),

, wherein R¹ , R² and R³ are as described herein, and their prodrugs or pharmaceutically acceptable salt, enantiomer or diastereomer thereof, for (use in) the treatment and/or prophylaxis of liver cancer.

Description

For the treatment and prevention of liver cancer 7-Substituted sulfonylimide acyl purinone compounds and derivatives

The present invention relates to a novel sulfonylimide acyl purinone derivative having Toll-like receptor agonistic activity in vivo, which is used (for) treatment and/or prevention of liver cancer.

Liver cancer is the fifth most common form of cancer. About 750,000 cases are diagnosed each year and approximately 700,000 people die from the disease each year, making it the third most common cause of cancer death worldwide (Ferlay et al., Int. J. Cancer 127: 2893-2917 (2010)). In the United States, the incidence of early-stage liver cancer has increased, and although some progress has been made in the detection and treatment of local diseases, the five-year survival time for advanced liver cancer is still well below 10% (American-Cancer-Society. 2012 . Cancer Facts & Figures 2012. Atlanta: American Cancer Society).

Established treatments for liver cancer include surgical removal of the liver part containing the tumor (partial hepatectomy), liver transplantation, transcatheter arterial chemoembolization (TACE), in situ tumor destruction by various methods, such as Radiofrequency resection (RFA) or cryosurgery and administration of sorafenib. Treatment options for patients with advanced liver disease are limited. Therefore, effective treatment of liver cancer remains a significant unmet medical need.

， 其中R¹ 至R³ 在下文中描述，或其醫藥學上可接受之鹽、對映異構體或非對映異構體。The present invention relates to compounds of formula (I),

, Where R ¹ to R ³ are described below, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Toll-like receptor (TLR) detects a wide range of conservative pathogen-associated molecular patterns (PAMP). It plays an important role in sensing invading pathogens and subsequently triggering innate immune responses. There are 10 known members of the TLR family in humans, which is the cytoplasmic tail I with an extracellular leucine-rich domain and a conserved Duol/interleukin (IL)-1 receptor (TIR) domain Type transmembrane protein. Within this family, TLR3, TLR7, TLR8 and TLR9 are located in the endosome.

TLR7 can be activated by binding to a specific small molecule ligand (ie, TLR7 agonist) or its natural ligand (ie, single-stranded RNA, ssRNA). After ssRNA binds to TLR7, Xianxin's receptor in its dimeric form undergoes structural changes, resulting in the subsequent recruitment of adaptor proteins at its cytoplasmic domain, which includes myeloid differentiation primary response gene 88 (MyD88). After triggering the receptor signaling cascade via the MyD88 pathway, cytoplasmic transcription factors such as interferon regulatory factor 7 (IRF-7) and nuclear factor kappa B (NF-κB) are activated. These transcription factors then translocate to the nucleus and trigger the transcription of various genes such as IFN-α and other antiviral cytokine genes.

WO201772662 is about TLR7 agonist-anti-HER2 conjugate for treating HER2-positive cancer. Hotz et al., Oncoimmunology 2012, 227-228 are concerned with cancer treatment by TLR7 agonists. However, to date, no TLR7 agonists have been used systematically to treat cancer. It is known that only the local TLR7 agonist imiquimod induces immune-mediated rejection of skin cancer metastasis in patients with breast cancer (Adams S., Kozhaya L., Martiniuk F., Meng TC, Chiriboga L ., Liebes L., Hochman T., Shuman N., Axelrod D., Speyer J., et al. Clin. Cancer Res. 2012;18:6748-6757).

The present invention relates to a series of novel 6-amino-2-sulfonylimide acetyl-9-substituted-7-substituted-purin-8-one compounds with a dioxin-like receptor agonistic activity and their pre Medicine, which is used for the treatment or prevention of liver cancer (prophylaxis/prevention).

The strong and safe TLR7 agonist prodrug described herein has 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-sulfonylimide amide-9-substituted-7-substituted-purin-8-one compounds with proton-like receptor agonistic activity and their prodrugs. The present invention also provides the biological activity of these compounds to induce the release of cytokines/chemokines and increase the content of SEAP by activating the Tudor-like receptors (such as TLR7 receptors), prodrugs in the presence of human hepatocytes to The metabolic transformation of the parent compound and the therapeutic or prophylactic use of these compounds and pharmaceutical compositions containing these compounds and their prodrugs to treat or prevent liver cancer. The invention also provides compounds with excellent activity. In addition, the compound of formula (I) also shows good solubility and PK distribution.

， 其中 R¹ 為C_1-6 烷基； R² 為苄基，該苄基未經取代或經一個、兩個或三個獨立地選自鹵素及C_1-6 烷基之取代基取代； R³ 為-NR⁴ R⁵ ，其中 R⁴ 為C_1-6 烷基或C_1-6 烷氧基C_1-6 烷基； R⁵ 為(C_1-6 烷基)₂ NCOOC_1-6 烷基、C_1-6 烷氧基C_1-6 烷基、C_1-6 烷氧基羰基(C_1-6 烷基)胺基C_1-6 烷基、C_1-6 烷氧基羰基(苯基)C_1-6 烷基、C_1-6 烷氧基羰基C_1-6 烷基、C_1-6 烷氧基羰基氧基C_1-6 烷基、C_1-6 烷基、C_1-6 烷基羰基(C_1-6 烷基)胺基C_1-6 烷基或吡咯啶基胺甲醯基氧基C_1-6 烷基；或 R⁴ 及R⁵ 與其所連接之氮一起形成雜環基； 或其醫藥學上可接受之鹽、對映異構體或非對映異構體； 其用於肝癌之治療或預防； 其限制條件為不包括 6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7-(吡咯啶-1-羰基)嘌呤-8-酮； 6-胺基-9-苄基-7-(哌啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(嗎啉-4-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3,3-二甲基吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 1-[6-胺基-9-苄基-8-側氧基-2-(丙基磺醯亞胺醯基)嘌呤-7-羰基]吡咯啶-2-甲酸乙酯； 6-胺基-7-(2-氮雜螺[3.3]庚烷-2-羰基)-9-苄基-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(2-氧雜-6-氮雜螺[3.3]庚烷-6-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3,3-二氟吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3-氟-3-甲基-吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 及其對映異構體或非對映異構體。The present invention relates to novel compounds of formula (I),

, Where 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 halogen and C _1-6 alkyl; R ³ is -NR ⁴ R ⁵ , wherein R ⁴ is C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl; R ⁵ is (C _1-6 alkyl) ₂ NCOOC _1-6 Alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxycarbonyl (C _1-6 alkyl) amine 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 alkylcarbonyl (C _1-6 alkyl) amine C _1-6 alkyl or pyrrolidinyl amine methylacetoxy C _1-6 alkyl; or R ⁴ and R ⁵ to which they are attached Together, nitrogen forms a heterocyclic group; or a pharmaceutically acceptable salt, enantiomer, or diastereomer; it is used for the treatment or prevention of liver cancer; its restriction is that it does not include 6-amino- 9-benzyl-2-(propylsulfonyliminamide)-7-(pyrrolidin-1-carbonyl)purin-8-one; 6-amino-9-benzyl-7-(piperidin- 1-carbonyl)-2-(propylsulfonylimideamide)purin-8-one; 6-amino-9-benzyl-7-(morpholin-4-carbonyl)-2-(propylsulfonate Amidimide)purine-8-one; 6-amino-9-benzyl-7-(3,3-dimethylpyrrolidin-1-carbonyl)-2-(propylsulfonylimideamide) Group) purine-8-one; 1-[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide)purine-7-carbonyl]pyrrolidine-2- Ethyl formate; 6-amino-7-(2-azaspiro[3.3]heptane-2-carbonyl)-9-benzyl-2-(propylsulfonylimide)purin-8-one ; 6-amino-9-benzyl-7-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-2-(propylsulfonylamidoimido)purine-8 -Ketone; 6-amino-9-benzyl-7-(3,3-difluoropyrrolidin-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; 6- Amino-9-benzyl-7-(3-fluoro-3-methyl-pyrrolidine-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; and its enantiomers Isomers or diastereomers.

These prodrug compounds are particularly suitable for the treatment of liver cancer as they are activated in the liver (converted to their active form). It exhibits valuable anti-tumor efficacy in vivo and anti-hepatoma cells in vitro (by activating peripheral blood cells and/or factors) in liver cancer cell models (alone or in combination with anti-PD1/PD1 antibodies or anti-angiogenic agents).

The present invention also relates to the use thereof for the manufacture of a medicament for the treatment or prevention of liver cancer, and a medicament based on the compound according to the invention for the treatment or prevention of liver cancer. Therefore, the compound of formula (I) is suitable for the treatment or prevention of liver cancer, especially for the treatment or prevention of hepatocellular carcinoma, liver cancer, cholangiocarcinoma, hepatoblastoma, hepatocellular carcinoma, hepatic angiosarcoma or metastatic liver cancer.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art of the present invention. In addition, the following definitions are set forth to illustrate and define the meaning and scope of different terms used to describe the present invention.

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

The term "C _1-6 alkoxy" means a group of the 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 third butoxy. Specific "C _1-6 alkoxy" groups are methoxy, ethoxy, and isopropoxy. More specifically, C _1-6 alkoxy is ethoxy.

The terms "halogen" and "halo" are used interchangeably herein and refer to fluorine, chlorine, bromine, or iodine.

The term "heterocyclic group" means a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system having 3 to 10 ring atoms, which contains 1 to 5 ring heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. In a specific embodiment, the heterocyclic group is a monovalent saturated monocyclic system having 4 to 7 ring atoms, which contains 1, 2 or 3 ring heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Examples of monocyclic saturated heterocyclic groups are aziridinyl, oxirane, aziridine, oxirane, pyrrolidinyl, dimethylpyrrolidinyl, ethoxycarbonylpyrrolidinyl, Tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropiperanyl, tetrahydrothiopiperanyl, Piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, azepanyl, diazacycloheptyl, homopiperazinyl or oxazacycloheptyl. The monocyclic saturated heterocyclic group may be additionally substituted with one to three substituents independently selected from halogen, C _1-6 alkyl, and C _1-6 alkoxycarbonyl. Examples of substituted monocyclic saturated heterocyclic groups are 4-methylpiperazinyl, dimethylpyrrolidinyl, ethoxycarbonylpyrrolidinyl, difluoropyrrolidinyl, and fluoro(methyl)pyrrolidinyl. Examples of bicyclic saturated heterocyclic groups are azabicyclo[3.2.1]octyl, quinuclidinyl, oxazabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, oxaza Bicyclo[3.3.1]nonyl, thioazabicyclo[3.3.1]nonyl, azaspiro[3.3]heptyl and oxazaspiro[3.3]heptyl. Examples of partially unsaturated heterocyclic groups are dihydrofuranyl, imidazolinyl, dihydrooxazolyl, tetrahydropyridyl and dihydropiperanyl.

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)-, wherein "C _1-6 alkyl" is as defined above. The specific "C _1-6 alkylcarbonyl" is acetyl.

The term "enantiomer" refers to two stereoisomers of a compound, which are non-overlapping mirror images of each other.

The term "diastereomers" refers to stereoisomers that have two or more epicenters and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity.

The term "pharmaceutically acceptable salts" indicates salts that are not biological or otherwise undesirable. Pharmaceutically acceptable salts include both acid addition salts and base addition salts.

The term "pharmaceutically acceptable acid addition salts" indicates the use of inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and selected from aliphatic, cycloaliphatic, aromatic, araliphatic, hetero Organic acids of cyclic, carboxylic and sulfonic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid , Fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, o-aminobenzoic acid, benzoic acid, cinnamic acid, mandelic acid, embolic acid, phenylacetic acid, methanesulfonic acid, ethyl Sulfonic acid, p-toluenesulfonic acid and salicylic acid form their pharmaceutically acceptable salts.

The term "pharmaceutically acceptable base addition salt" refers to their pharmaceutically acceptable salts formed with organic or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as Propylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, spermine, Histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, cocoaine, purine, piperazine, Piperidine, N-ethylpiperidine and polyamine resin salts.

Compounds of general formula (I) and prodrugs containing one or several paracentric centers can exist in the form of racemates, mixtures of diastereomers or photoactive single isomers. Racemates can be separated into enantiomers according to known methods. In particular, the diastereoisomeric salts that can be separated by crystallization are reacted from racemic mixtures by reaction with photoactive acids such as D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid form.

The term "prodrug" refers to a form or derivative of a compound that is metabolized into the pharmacologically active form of the compound in vivo by the individual after administration, for example, by a biological fluid or enzyme in order to produce the desired pharmacological effect. Prodrugs are described in, for example, "The Organic Chemistry of Drug Design and Drug Action" by Richard B. Silverman, Academic Press, San Diego, 2004, Chapter 8 Prodrugs and Drug Delivery Systems, Section 497- On page 558.

"Medicinal active metabolite" means a medicinal active product produced by in vivo metabolism of a specified compound or its salt. After entering the body, most drugs are used as substrates for chemical reactions that can change their physical properties and biological effects. These metabolic shifts, which generally affect the polarity of the compounds of the present invention, change the way drugs are distributed in the body and excreted by the body. However, in some cases, drug metabolism is required for therapeutic effects.

The term "therapeutically effective amount" indicates an amount of the compound or molecule of the present invention that achieves the following effects when administered to an individual: (i) treatment or prevention of a specific disease, condition or disorder, (ii) reduction, improvement or elimination of a specific disease, condition Or one or more symptoms of a disorder, or (iii) prevent or delay the onset of one or more symptoms of a specific disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, the condition of the disease being treated, the severity of the disease being treated, the age and relative health of the individual, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.

The term "pharmaceutical composition" indicates a mixture or solution to be administered to a mammal, such as a human in need thereof, containing a therapeutically effective amount of an effective pharmaceutical ingredient together with a pharmaceutically acceptable excipient.

， 其中 R¹ 為C_1-6 烷基； R² 為苄基，該苄基未經取代或經一個、兩個或三個獨立地選自鹵素及C_1-6 烷基之取代基取代； R³ 為-NR⁴ R⁵ ，其中 R⁴ 為C_1-6 烷基或C_1-6 烷氧基C_1-6 烷基； R⁵ 為(C_1-6 烷基)₂ NCOOC_1-6 烷基、C_1-6 烷氧基C_1-6 烷基、C_1-6 烷氧基羰基(C_1-6 烷基)胺基C_1-6 烷基、C_1-6 烷氧基羰基(苯基)C_1-6 烷基、C_1-6 烷氧基羰基C_1-6 烷基、C_1-6 烷氧基羰基氧基C_1-6 烷基、C_1-6 烷基、C_1-6 烷基羰基(C_1-6 烷基)胺基C_1-6 烷基或吡咯啶基胺甲醯基氧基C_1-6 烷基；或 R⁴ 及R⁵ 與其所連接之氮一起形成雜環基； 或其醫藥學上可接受之鹽、對映異構體或非對映異構體； 其用於肝癌之治療或預防； 其限制條件為不包括 6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7-(吡咯啶-1-羰基)嘌呤-8-酮； 6-胺基-9-苄基-7-(哌啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(嗎啉-4-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3,3-二甲基吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 1-[6-胺基-9-苄基-8-側氧基-2-(丙基磺醯亞胺醯基)嘌呤-7-羰基]吡咯啶-2-甲酸乙酯； 6-胺基-7-(2-氮雜螺[3.3]庚烷-2-羰基)-9-苄基-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(2-氧雜-6-氮雜螺[3.3]庚烷-6-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3,3-二氟吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3-氟-3-甲基-吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 及其對映異構體或非對映異構體。 本發明之另一實施例為(ii)式(I)化合物，其中 R¹ 為C_1-6 烷基； R² 為苄基，該苄基未經取代或經鹵素或C_1-6 烷基取代； R³ 為氮雜環丁基； 經C_1-6 烷基取代之哌嗪基； 經哌啶基取代之哌啶基； 吡咯啶基；或 -NR⁴ R⁵ ，其中 R⁴ 為C_1-6 烷基或C_1-6 烷氧基C_1-6 烷基； R⁵ 為(C_1-6 烷基)₂ NCOOC_1-6 烷基、C_1-6 烷氧基C_1-6 烷基、C_1-6 烷氧基羰基(C_1-6 烷基)胺基C_1-6 烷基、C_1-6 烷氧基羰基(苯基)C_1-6 烷基、C_1-6 烷氧基羰基C_1-6 烷基、C_1-6 烷氧基羰基氧基C_1-6 烷基、C_1-6 烷基、C_1-6 烷基羰基(C_1-6 烷基)胺基C_1-6 烷基或吡咯啶基胺甲醯基氧基C_1-6 烷基； 或其醫藥學上可接受之鹽、對映異構體或非對映異構體，其用於肝癌之治療或預防。 TLR7 Agonist And prodrugs The present invention relates to a compound of formula (I),

, among them R¹ For C_1-6 alkyl; R² Is benzyl, which is unsubstituted or independently selected from halogen and C by one, two or three_1-6 Substitution of alkyl groups; R³ -NR⁴ R⁵ ,among them R⁴ For C_1-6 Alkyl or C_1-6 Alkoxy C_1-6 alkyl; R⁵ Is (C_1-6 alkyl)₂ NCOOC_1-6 Alkyl, C_1-6 Alkoxy C_1-6 Alkyl, C_1-6 Alkoxycarbonyl (C_1-6 Alkyl)amine 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 Alkylcarbonyl (C_1-6 Alkyl)amine C_1-6 Alkyl or pyrrolidinylamine methoxycarbonyl C_1-6 Alkyl; or R⁴ And R⁵ Together with the nitrogen to which it is attached form a heterocyclic group; Or its pharmaceutically acceptable salts, enantiomers or diastereomers; It is used for the treatment or prevention of liver cancer; The restrictions are not included 6-amino-9-benzyl-2-(propylsulfonylimide)-7-(pyrrolidin-1-carbonyl)purin-8-one; 6-amino-9-benzyl-7-(piperidin-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; 6-amino-9-benzyl-7-(morpholine-4-carbonyl)-2-(propylsulfonylimide)purin-8-one; 6-amino-9-benzyl-7-(3,3-dimethylpyrrolidin-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; 1-[6-Amino-9-benzyl-8-oxo-2-(propylsulfonylimide)purine-7-carbonyl]pyrrolidine-2-carboxylic acid ethyl ester; 6-amino-7-(2-azaspiro[3.3]heptane-2-carbonyl)-9-benzyl-2-(propylsulfonylimide acetyl)purin-8-one; 6-Amino-9-benzyl-7-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-2-(propylsulfonylimideamide)purine-8- ketone; 6-amino-9-benzyl-7-(3,3-difluoropyrrolidine-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; 6-amino-9-benzyl-7-(3-fluoro-3-methyl-pyrrolidine-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; And its enantiomers or diastereomers. Another embodiment of the present invention is (ii) a compound of formula (I), wherein R¹ For C_1-6 alkyl; R² Is benzyl, the benzyl is unsubstituted or halogen or C_1-6 Alkyl substitution R³ Is azetidinyl; By C_1-6 Alkyl substituted piperazinyl; Piperidinyl substituted with piperidinyl; Pyrrolidinyl; or -NR⁴ R⁵ ,among them R⁴ For C_1-6 Alkyl or C_1-6 Alkoxy C_1-6 alkyl; R⁵ Is (C_1-6 alkyl)₂ NCOOC_1-6 Alkyl, C_1-6 Alkoxy C_1-6 Alkyl, C_1-6 Alkoxycarbonyl (C_1-6 Alkyl)amine 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 Alkylcarbonyl (C_1-6 Alkyl)amine C_1-6 Alkyl or pyrrolidinylamine methoxycarbonyl C_1-6 alkyl; Or a pharmaceutically acceptable salt, enantiomer or diastereomer, which is used for the treatment or prevention of liver cancer.

Another embodiment of the present invention is (iii) a compound of formula (I), wherein R ¹ is ethyl or propyl; R ² is benzyl, bromobenzyl, chlorobenzyl, fluorobenzyl, or methylbenzyl; R ³ is azetidinyl; 4-methylpiperazinyl; piperidinylpiperidinyl; pyrrolidinyl; or -NR ⁴ R ⁵ , where R ⁴ is methyl, ethyl, propyl or methoxy Ethyl; R ⁵ is acetyl(methyl)aminoethyl, butyl, butyl(methyl)amine, methyloxyethyl, diethylamine, methyloxyethyl, ethoxy Carbonylcarbonyl(methyl)aminoethyl, ethoxycarbonylethyl, ethoxycarbonylisobutyl, ethoxycarbonylisopentyl, ethoxycarbonylmethyl, ethoxycarbonyloxyethyl, Ethoxycarbonyl (phenyl) ethyl, ethyl, isobutyl, isopropoxycarbonyl isopentyl, isopropoxycarbonyl (phenyl) ethyl, isopropyl, methoxycarbonyl (methyl )Aminoethyl, methoxyethyl, methoxypropyl, propyl, propyl (methyl)amine, methyloxyethyl, pyrrolidinylamine, methyloxyethyl, third Butoxycarbonyl (methyl)aminoethyl, third butoxycarbonyl ethyl, third butoxycarbonyl isopentyl or third butoxycarbonyl (phenyl) ethyl; or its pharmaceutical Acceptable salts, enantiomers or diastereomers are used for the treatment or prevention of liver cancer.

Another embodiment of the present invention is (iii-1) a compound of formula (I), wherein R ¹ is ethyl or propyl; R ² is benzyl, chlorobenzyl, fluorobenzyl, or methylbenzyl; R ³ is Azetidinyl; 4-methylpiperazinyl; piperidinylpiperidinyl; pyrrolidinyl; or -NR ⁴ R ⁵ , where R ⁴ is methyl, ethyl, propyl or methoxyethyl ; R ⁵ is acetyl(methyl)aminoethyl, butyl, butyl(methyl)aminomethyloxyethyl, diethylaminomethyloxyethyl, ethoxycarbonyl (Methyl)aminoethyl, ethoxycarbonylethyl, ethoxycarbonylisobutyl, ethoxycarbonylisopentyl, ethoxycarbonylmethyl, ethoxycarbonyloxyethyl, ethoxy Carbonylcarbonyl(phenyl)ethyl, ethyl, isobutyl, isopropoxycarbonylisopentyl, isopropoxycarbonyl(phenyl)ethyl, isopropyl, methoxycarbonyl(methyl)amine Ethyl, methoxyethyl, methoxypropyl, propyl, propyl(methyl)amine, methyloxyethyl, pyrrolidinylamine, methyloxyethyl, third butoxy Carbonylcarbonyl (methyl)aminoethyl, third butoxycarbonyl ethyl, third butoxycarbonyl isopentyl or third butoxycarbonyl (phenyl) ethyl; or pharmaceutically acceptable The salt, enantiomer or diastereomer is used for the treatment or prevention of liver cancer.

Another embodiment of the present invention is (iv) a compound of formula (I), wherein R ³ is azetidinyl, 4-methylpiperazinyl, piperidinylpiperidinyl, pyrrolidinyl, acetyl Methyl)aminoethyl(methyl)amino, bis(methoxyethyl)amino, butyl(ethyl)amino, butyl(methyl)amino, butyl(methyl)carbonyl Oxyethyl(methyl)amino, diethylcarbonyloxyethyl(methyl)amino, ethoxycarbonyl(methyl)aminoethyl(methyl)amino, ethoxycarbonylethyl (Methyl)amino, ethoxycarbonyl isobutyl (methyl)amino, ethoxycarbonyl isopentyl (methyl)amino, ethoxycarbonylmethyl (methyl)amino, ethyl Oxycarbonyloxyethyl(methyl)amino, ethoxycarbonyl(phenyl)ethyl(methyl)amino, ethyl(methyl)amino, isobutyl(methyl)amino, Isopropyloxycarbonyl isoamyl (methyl) amine, isopropyloxycarbonyl (phenyl) ethyl (methyl) amine, isopropyl (methyl) amine, methoxycarbonyl (methyl )Aminoethyl(methyl)amino, methoxyethyl(ethyl)amino, methoxyethyl(methyl)amino, methoxyethyl(propyl)amino, methoxy Propyl(methyl)amino, propyl(ethyl)amino, propyl(methyl)amino, propyl(methyl)carbonyloxyethyl(methyl)amino, pyrrolidinylcarbonyl Oxyethyl (methyl) amino, third butoxycarbonyl (methyl) amino ethyl (methyl) amino, third butoxycarbonyl ethyl (methyl) amino, third butyl Oxycarbonyl isoamyl (methyl) amine or third butoxycarbonyl (phenyl) ethyl (methyl) amine; or its pharmaceutically acceptable salts, enantiomers or diastereomers Enantiomer, which is used for the treatment or prevention of liver cancer.

Another embodiment of the present invention is (v) a compound of formula (I), wherein R ¹ is ethyl, which is used for the treatment or prevention of liver cancer.

Another embodiment of the present invention is (vi) a compound of formula (I), wherein R ² is benzyl substituted with halogen or C _1-6 alkyl, which is used for the treatment or prevention of liver cancer.

Another embodiment of the present invention is (vii) a compound of formula (I), wherein R ² is bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl, which is used for the treatment or prevention of liver cancer.

Another embodiment of the present invention is a (vii-1) compound of formula (I), wherein R ² is chlorobenzyl, fluorobenzyl or methylbenzyl, which is used for the treatment or prevention of liver cancer.

Another embodiment of the present invention is (viii) a compound of formula (I), wherein R ² is bromobenzyl, chlorobenzyl or fluorobenzyl, which is used for the treatment or prevention of liver cancer.

Another embodiment of the present invention is (viii-1) a compound of formula (I), wherein R ² is chlorobenzyl or fluorobenzyl, which is used for the treatment or prevention of liver cancer.

Another embodiment of the present invention is (ix) a compound of formula (I), wherein R ³ is -NR ⁴ R ⁵ , wherein R ⁴ is C _1-6 alkyl, and R ⁵ is C _1-6 alkyl, which is used For the treatment or prevention of liver cancer.

Another embodiment of the present invention is (x) a compound of formula (I), wherein R ³ is a propyl (methyl) amino group or an ethyl (methyl) amino group, which is used for the treatment or prevention of liver cancer.

Another embodiment of the present invention is (xi) a compound of formula (I), wherein R ¹ is C _1-6 alkyl; R ² is benzyl, the benzyl is substituted with halogen or C _1-6 alkyl; R ³ Is -NR ⁴ R ⁵ , wherein R ⁴ is C _1-6 alkyl, R ⁵ is C _1-6 alkyl; or a pharmaceutically acceptable salt, enantiomer or diastereomer , Which is used for the treatment or prevention of liver cancer.

Another embodiment of the present invention is (xii) a compound of formula (I), wherein R ¹ is ethyl; R ² is methylbenzyl, bromobenzyl, chlorobenzyl, or fluorobenzyl; R ³ is propyl (methyl Group) amine group or ethyl (methyl) amine group; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, which is used for the treatment or prevention of liver cancer.

Another embodiment of the present invention is (xii-1) a compound of formula (I), wherein R ¹ is ethyl; R ² is methylbenzyl, chlorobenzyl, or fluorobenzyl; R ³ is propyl (methyl) Amino group or ethyl (methyl) amine group; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, which is used for the treatment or prevention of liver cancer.

Another embodiment of the present invention is that (xiii) is the following specific compound of formula (I): 6-amino-9-benzyl-N-methyl-8-oxo-N-propyl-2-( Propylsulfonylimide) purine-7-methylamide; 6-amino-9-benzyl-N-(2-methoxyethyl)-N-methyl-8-oxo- 2-(propylsulfonylimideamide)purine-7-carboxamide; 6-amino-9-benzyl- N -ethyl-8-pentoxy- N -propyl-2-(propylene Sulfamoylimidamide)purine-7-carboxamide; 6-amino-9-benzyl-7-[4-(1-piperidinyl)piperidine-1-carbonyl]-2-(propylene Sulfonylimide) purin-8-one; 6-amino-9-benzyl- N -ethyl- N-( 2-methoxyethyl)-8-oxo-2-( Propylsulfonylimide)purine-7-methylamide; 6-amino-9-benzyl- N -butyl- N -ethyl-8-oxo-2-(propylsulfonyl Iminyl)purine-7-methylamide; 6-amino-9-benzyl- N- (2-methoxyethyl)-8- pendant- N -propyl-2-(propylene Sulfonylimide) purine-7-carboxamide; 6-amino-9-benzyl- N,N -bis(2-methoxyethyl)-8-oxo-2-( Propylsulfonylimide)purine-7-methylamide; 6-amino-7-(azetidine-1-carbonyl)-9-benzyl-2-(propylsulfonylimide Acetyl) purin-8-one; 6-amino-9-benzyl- N -isopropyl- N -methyl-8-oxo-2-(propylsulfonylimide acetyl)purine- 7-formamide; 6-amino-9-benzyl-7-(4-methylpiperazine-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; 6 -Amino-9-benzyl- N- (3-methoxypropyl) -N- methyl-8-oxo-2-(propylsulfonylimidoamide)purine-7-formamide Amine; 6-amino-9-benzyl- N -isobutyl- N -methyl-8-oxo-2-(propylsulfonylimide)purine-7-methylamide; 2 -[[6-Amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino] ethyl acetate; 3- [[6-Amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino] ethyl propionate; 3- [[6-Amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino] propionic acid third butyl ester; (2 S )-2-[[6-Amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino] Ethyl propionate; (2S)-2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonylimide)purine-7-carbonyl]-methyl -Amino]-4-methyl-valeric acid third Butyl ester; (2S)-2-[[6-Amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amine Group]-4-methyl-isopropyl valerate; (2S)-2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonylimide) Purine-7-carbonyl]-methyl-amino]-3-methyl-butyric acid ethyl ester; (2S)-2-[[6-amino-9-benzyl-8-oxo-2- (Propylsulfonylimide) Purine-7-carbonyl]-methyl-amino]-4-methyl-valeric acid ethyl ester; (2S)-2-[[6-amino-9-benzyl Yl-8-oxo-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]-3-phenyl-propionic acid ethyl ester; (2S)-2- [[6-Amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]-3-phenyl-propyl Isopropyl acid ester; (2S)-2-[[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide)purine-7-carbonyl]-methyl -Amino]-3-phenyl-propionic acid tert-butyl ester; N- [2-[acetoyl(methyl)amino]ethyl]-6-amino-9-benzyl- N -methyl Yl-8-oxo-2-(propylsulfonylimideamide)purine-7-carboxamide; N- [2-[[6-amino-9-benzyl-8-oxo -2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]ethyl] -N -methyl-carbamic acid methyl ester; N- [2-[[6- Amino-9-benzyl-8-oxo-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]ethyl] -N -methyl-amino Third butyl formate; N- [2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7-carbonyl]-methyl -Amino]ethyl] -N -methyl-carbamic acid ethyl ester; N -butyl- N -methyl-carbamic acid 2-[[6-amino-9-benzyl-8-side oxygen Yl-2-(propylsulfonyliminyl)purine-7-carbonyl]-methyl-amino]ethyl; pyrrolidine-1-carboxylic acid 2-[[6-amino-9-benzyl- 8-Penoxy-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]ethyl; N- methyl- N -propyl-aminocarboxylic acid 2-[ [6-Amino-9-benzyl-8-oxo-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]ethyl ester; N,N- di Ethylaminocarboxylic acid 2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino] Ethyl ester; Carbonic acid 2-[[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide acetyl)purine-7-carbonyl]-methyl-amino]ethyl Ethyl ester; 6-amino-N-butyl-9-[(4-chlorophenyl ) Methyl]-N-methyl-8-oxo-2-[S(R)-propylsulfonylimido]purine-7-methylamide; 6-amino-N-butyl -9-[(4-chlorophenyl)methyl]-N-methyl-8-oxo-2-[S(S)-propylsulfonylimide acetyl]purine-7-methylamide ; 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl- N- methyl-8- pendant-2-(propylsulfonylimide)purine- 7-methylamide; 6-amino- N -methyl-8-pentoxy- N -propyl-2[S( S )-propylsulfonylimideamide]-9-(p-tolyl Methyl)purine-7-methylamide; 6-amino- N -methyl-8-oxo- N -propyl-2[S( R )-propylsulfonylimideamide]-9 -(P-tolylmethyl)purine-7-carboxamide; 6-amino-2-[S (S) -propylsulfonylimide]-9-(p-tolylmethyl)-7 -(Pyrrolidin-1-carbonyl)purin-8-one; 6-amino-2-[S( R )-propylsulfonylimido]-9-(p-tolylmethyl)-7- (Pyrrolidin-1-carbonyl)purin-8-one; 6-amino- N- (2-methoxyethyl) -N- methyl-8-oxo-2-[S( S )- Propylsulfonylimide]-9-(p-tolylmethyl)purine-7-formamide; 6-amino- N- (2-methoxyethyl) -N -methyl-8 -Penoxy-2-[S( R )-propylsulfonylimide]-9-(p-tolylmethyl)purine-7-formamide; 6-amino- N -ethyl- N- methyl-8-oxo-2-(propylsulfonylimide)-9-(p-tolylmethyl)purine-7-carboxamide; 6-amino- N -butyl -N -methyl-8- pendant-2-(propylsulfonylimide)-9-(p-tolylmethyl)purine-7-carboxamide; 6-amino-9-[ (4-chlorophenyl)methyl]-2-[S( R )-ethylsulfonylimide]- N -methyl-8-oxo- N -propyl-purine-7-methyl Acetamide; 6-amino-9-[(4-chlorophenyl)methyl]-2-[S( S )-ethylsulfonylimide] -N -methyl-8-pentoxy -N -propyl-purine-7-methylamide; 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl-2[S( S )-ethylsulfonylamide Aminyl] -N -methyl-8-oxo-purine-7-carboxamide; 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl-2- [S( R )-ethylsulfonylimide]- N -methyl-8-oxo-purine-7-methylamide; 6-amino-2-[S( S )-ethyl Sulfonylimide] -N -methyl-8-oxo- N -propyl-9-(p-tolylmethyl)purine-7-methylamide ; 6-amino-2-[S( R )-ethylsulfonylimide] -N -methyl-8-oxo- N -propyl-9-(p-tolylmethyl)purine -7-formamide; 6-amino- N -ethyl-2[S(S)-ethylsulfonylimide] -N -methyl-8-oxo-9-(p-toluene Methyl))purine-7-carboxamide; 6-amino- N -ethyl-2-[S( R )-ethylsulfonylimide] -N -methyl-8-oxo -9-(p-tolylmethyl)purine-7-formamide; 6-amino-2-[S( S )ethylsulfonylimide]-9-[(4-fluorophenyl) Methyl] -N -methyl-8-oxo- N -propyl-purine-7-carboxamide; 6-amino-2-[S( R ) ethylsulfonylimide] 9-[(4-fluorophenyl)methyl] -N -methyl-8-oxo- N -propyl-purine-7-carboxamide; 6-amino- N -ethyl-2- (Ethylsulfonylimideamide)-9-[(4-fluorophenyl)methyl] -N -methyl-8-oxo-purine-7-methylamide; 6-amino- N -Ethyl-2-[S( S )-(ethylsulfonylimide)]-9-[(4-fluorophenyl)methyl]- N -methyl-8-oxo-purine -7-formamide; 6-amino- N -ethyl-2-[S( R )-(ethylsulfonylimide)]-9-[(4-fluorophenyl)methyl] -N -methyl-8-oxo-purine-7-carboxamide; 6-amino-9-[(4-bromophenyl)methyl]-2-(ethylsulfonylimide amide )- N- methyl-8-oxo- N -propyl-purine-7-carboxamide; 6-amino-2-[S( R )-ethylsulfonylimide]-9 -[(4-Bromophenyl)methyl] -N -methyl-8-oxo- N -propyl-purine-7-carboxamide; 6-amino-2-[S( S )- Ethylsulfonylimide]-9-[(4-bromophenyl)methyl] -N -methyl-8-oxo- N -propyl-purine-7-methylamide; 6- Amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-(ethylsulfonylimide) -N -methyl-8-oxo-purine-7- Formamide; 6-amino-9-[(4-bromophenyl)methyl]- N -ethyl-2-[S( S )-(ethylsulfonylimide)]- N- Methyl-8-oxo-purine-7-carboxamide; and 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-[S( R )- (Ethylsulfonylimide)]- N -methyl-8-oxo-purine-7-formamide; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof Isomers, which are used in the treatment or prevention of liver cancer.

Another embodiment of the present invention is that (xiv) is the following more specific compound of formula (I): 6-amino-9-benzyl-N-methyl-8-oxo-N-propyl-2- (Propylsulfonylimide) Purine-7-methylamide; 6-amino-9-[(4-chlorophenyl)methyl]-2-[S( R )-ethylsulfonylamide Aminyl] -N -methyl-8-oxo- N -propyl-purine-7-carboxamide; 6-amino-9-[(4-chlorophenyl)methyl]-2- [S( S )-ethylsulfonylimide]- N -methyl-8-oxo- N -propyl-purine-7-methylamide; 6-amino-9-[(4 -Chlorophenyl)methyl] -N -ethyl-2[S( S )-ethylsulfonylimide] -N -methyl-8-oxo-purine-7-methylamide; 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl-2-[S( R )-ethylsulfonylimide] -N -methyl-8-side Oxy-purine-7-carboxamide; 6-amino-2-[S( S )-ethylsulfonylimide] -N -methyl-8-oxo- N -propyl- 9-(p-tolylmethyl)purine-7-carboxamide; 6-amino-2-[S( R )-ethylsulfonylimide]- N -methyl-8-oxo -N -propyl-9-(p-tolylmethyl)purine-7-methylamide; 6-amino- N -ethyl-2[S(S)-ethylsulfonylimideamide]- N -methyl-8-oxo-9-(p-tolylmethyl)purine-7-carboxamide; 6-amino- N -ethyl-2-[S( R )-ethylsulfonamide Iminyl] -N -methyl-8-oxo-9-(p-tolylmethyl)purine-7-methylamide; 6-amino-2-(ethylsulfonyliminamide) )-9-[(4-fluorophenyl)methyl]-N-methyl-8-oxo-N-propyl-purine-7-carboxamide; 6-amino-2-[S( S ) Ethylsulfonylimide]-9-[(4-fluorophenyl)methyl] -N -methyl-8-oxo- N -propyl-purine-7-methylamide; 6-Amino-2-[S( R )ethylsulfonylimide]-9-[(4-fluorophenyl)methyl]- N -methyl-8-oxo- N -propyl -Purine-7-methylamide; 6-amino- N -ethyl-2-(ethylsulfonylimideamide)-9-[(4-fluorophenyl)methyl] -N -methyl Yl-8-oxo-purine-7-methylamide; 6-amino- N -ethyl-2-[S( S )-(ethylsulfonylimideamide)]-9-[( 4-fluorophenyl)methyl] -N -methyl-8-oxo-purine-7-carboxamide; 6-amino- N -ethyl-2-[S( R )-(ethyl Sulfonylimide)]-9-[(4-fluorophenyl)methyl] -N -methyl-8-oxo-purine Purine-7-methylamide; 6-amino-9-[(4-bromophenyl)methyl]-2-(ethylsulfonylimidoamide) -N -methyl-8-oxo -N -propyl-purine-7-methylamide; 6-amino-2-[S( R )-ethylsulfonylimideamide]-9-[(4-bromophenyl)methyl] -N -methyl-8-oxo- N -propyl-purine-7-carboxamide; 6-amino-2-[S( S )-ethylsulfonylimide]-9- [(4-Bromophenyl)methyl] -N -methyl-8-oxo- N -propyl-purine-7-carboxamide; 6-amino-9-[(4-bromophenyl )Methyl] -N -ethyl-2-(ethylsulfonylimide) -N- methyl-8-oxo-purine-7-methylamide; 6-amino-9-[ (4-Bromophenyl)methyl] -N -ethyl-2-[S( S )-(ethylsulfonylimide)]- N -methyl-8-oxo-purine-7 -Methamide; and 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-[S( R )-(ethylsulfonylimide)]- N -methyl-8-oxo-purine-7-carboxamide; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, which is used for the treatment or prevention of liver cancer .

Another embodiment of the present invention is that (xv) is the following more specific compound of formula (I): 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl-2[S( S )-ethylsulfonylimide]- N -methyl-8-oxo-purine-7-formamide; 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl-2-[S( R )-ethylsulfonylimide acetyl]- N -methyl-8-oxo-purine-7-methylamide; 6-amino-9- [(4-Bromophenyl)methyl] -N -ethyl-2-(ethylsulfonylimide) -N- methyl-8-oxo-purine-7-methylamide; 6 -Amino-9-[(4-bromophenyl)methyl]- N -ethyl-2-[S( S )-(ethylsulfonylimide)]- N -methyl-8- Pendant-purine-7-carboxamide; and 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-[S( R )-(ethylsulfonamide Iminamide)]- N -methyl-8-oxo-purine-7-carboxamide; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, which Used for the treatment or prevention of liver cancer.

。In some embodiments, the compounds of the present invention are tested and compared with the following reference compounds. As the most successful biopharmaceutical company dedicated to the discovery and development of TLR7 agonists to treat liver diseases, Gilead has the most advanced TLR7 agonist pipeline and cutting-edge compounds, such as GS-9620, which has entered Phase II research. In this application, Gilead compound GS-9620 disclosed in US20100143301, compound S-2 and compound S-3 disclosed in JP1999193282 are selected as reference compounds in Example 49:

.

The synthesis of the compounds of the present invention can be prepared by any conventional means. Suitable methods for synthesizing these compounds and their starting materials are provided in the following schemes and examples. Unless otherwise specified, all substituents, especially R ¹ to R ¹⁴ , are as defined above. In addition and unless expressly stated otherwise, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to those skilled in organic chemistry.

藉由異氰酸酯VII 與胺基丙二腈對甲苯磺酸酯之環化來製備式VI 化合物。隨後藉由在無機鹼(諸如NaOH或KOH)存在下使式VI 化合物與苯甲醯基異硫氰酸酯反應來合成雙環V。在鹼(諸如K₂ CO₃ 、NaH或Cs₂ CO₃ )存在下用烷基鹵使雙環V 烷基化，得到式IV 化合物。藉由用氧化劑(諸如間氯過氧苯甲酸、脲-過氧化氫加合物及HIO₄ )氧化式IV 化合物來製備式III 化合物。藉由用亞胺化試劑(諸如在酸中之疊氮化鈉，該酸為例如伊通氏(Eaton's)試劑或PPA)亞胺化式III 化合物，獲得式II 化合物。藉由在混合鹼(諸如吡啶與三乙胺、吡啶與DIPEA、DMAP與三乙胺或DMAP與DIPEA)存在下使式II 化合物與氯化胺甲醯反應，獲得式I 化合物。 Process 1

The compound of formula VI is prepared by cyclization of isocyanate VII and aminomalononitrile p-toluenesulfonate. The bicyclic V is then synthesized by reacting the compound of formula VI with benzoyl isothiocyanate in the presence of an inorganic base such as NaOH or KOH. Alkylation of the bicyclic 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 . By (chloroperbenzoic acid, such as inter-urea - hydrogen peroxide adduct and HIO ₄₎ oxidizing the compound of formula IV to compound of formula III. The compound of formula II is obtained by imidizing the compound of formula III with an imidization reagent, such as sodium azide in an acid, such as Eaton's reagent or PPA. The compound of formula I is obtained by reacting the compound of formula II with amine chloride chloride in the presence of a mixed base such as pyridine and triethylamine, pyridine and DIPEA, DMAP and triethylamine or DMAP and DIPEA.

Process 2

Compounds of formula II can also be prepared as in Scheme 2.

The compound of formula X is prepared by reacting the compound of formula XI with R ² NH ₂ . Reduction of compound X with a reducing agent (such as AcOH containing zinc or iron powder) gives the compound of formula IX . Cyclization of compounds of formula IX with cyclization reagents such as phosgene, carbonyldiimidazole, diethyl carbonate, and triphosgene gives compounds of formula VIII . By treatment with a compound of formula PMBNH ₂ VIII, IVa compound of formula. The compound of formula III is prepared by deprotecting the compound of formula IVa with an acid (such as CF ₃ COOH), followed by oxidation with an oxidizing agent (such as m-chloroperoxybenzoic acid, urea-hydrogen peroxide adduct, and HIO ₄ ). By imidizing the compound of formula III with an imidization reagent (such as an acid containing sodium azide, for example, Yton's reagent or PPA), the compound of formula II is obtained.

， 在混合鹼存在下與氯化胺甲醯之反應； 其中R¹ 及R² 如上文所定義。A method for preparing the compound of formula (I) is also described, which comprises the following reaction: compound of formula (II)

, Reaction with ammonium chloride chloride in the presence of a mixed base; where R ¹ and R ² are as defined above.

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

The compound of formula (I) for the treatment or prevention of liver cancer is also an object of the present invention when manufactured according to the above method.

Pharmaceutical composition and administration Another embodiment provides a pharmaceutical composition or medicament for the treatment or prevention of liver cancer, which contains the compound of the present invention and a therapeutically inert carrier, diluent or excipient, and uses the present invention Compounds to prepare such compositions and pharmaceutical methods. In one example, the compound of formula (I) can be formulated by: at ambient temperature, at an appropriate pH, and at the desired purity, with a physiologically acceptable carrier, that is, The dose and concentration in the dosage form are mixed with a carrier that is non-toxic to the recipient. The pH of the formulation depends mainly on the specific application and the concentration of the compound, but it is preferably in any numerical range between about 3 and about 8. In one example, the compound of formula (I) is formulated to pH 5 in acetate buffer. In another embodiment, the compound of formula (I) is sterile. The compounds can be stored, for example, in the form of solid or amorphous compositions, in the form of lyophilized formulations or aqueous solutions.

The composition is formulated, administered and administered in a manner consistent with good medical practice. Factors considered in this context include the specific condition being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the condition, the site of drug delivery, the method of administration, the time of administration, and others known to medical practitioners factor. The "effective amount" of the compound to be administered will be determined by such considerations and is to activate the TLR7 receptor and make it possible to produce (but not limited to) INF-α that can be used for, but not limited to, the treatment or prevention of patients with hepatitis B and/or C virus infection The minimum amount necessary for other cytokines.

In one example, each dosage of the pharmaceutically effective amount of the compound of the invention administered parenterally will be in the range of about 0.1 to 50 mg/kg or about 0.1 to 30 mg/kg per day based on the patient's body weight, The typical initial range of compounds used is 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosage forms such as lozenges and capsules preferably contain from about 20 to about 1000 mg of the compound of the present invention.

The compounds of the invention can be administered by any suitable means, including oral, superficial (including buccal and sublingual), transrectal, transvaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, Intrathecal and epidural and intranasal, and if local treatment is needed, then intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

The compound of the present invention can be administered in any convenient administration form, such as lozenges, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, and the like. Such compositions may contain conventional components in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, bulking agents, and other active agents.

A typical formulation is prepared by mixing the compound of the invention with a carrier or excipient. Suitable carriers and excipients are well known in those skilled in the art and described in detail in, for example, Ansel, Howard C., et al., Ansel 's Pharmaceutical Dosage Forms and Drug Delivery Systems Philadelphia:. Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light shielding agents, slip agents, processing aids, colorants, Sweeteners, fragrances, flavoring agents, diluents, and other known additives that make drugs (that is, compounds of the present invention or pharmaceutical compositions thereof) delicately present or help to manufacture pharmaceutical products (that is, drugs).

Examples of suitable oral dosage forms are those containing about 20 to 1000 mg of the compound of the present invention mixed with about 30 to 90 mg of anhydrous lactose, about 5 to 40 mg of croscarmellose sodium, and about 5 to 30 mg of polyvinylpyrrolidine Lozenges of ketone (PVP) K30 and about 1 to 10 mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with the solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate and compressed into a tablet form using conventional equipment. Aerosol formulations can be prepared by dissolving, for example, 20 to 1000 mg of the compound of the present invention in a suitable buffer solution (e.g. phosphate buffer) and adding a tonicity adjusting agent (e.g. salt such as sodium chloride) if necessary Instance. The solution can be filtered, for example, using a 0.2 micron filter to remove impurities and contaminants.

Therefore, the examples include pharmaceutical compositions comprising the compound of formula (I) or a pharmaceutically acceptable salt or enantiomer or diastereomer thereof.

In another embodiment, including the compound of formula (I) or a pharmaceutically acceptable salt or enantiomer or diastereomer and a pharmaceutically acceptable carrier or excipient Pharmaceutical composition.

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

Indications and treatment The present invention provides methods for treating or preventing liver cancer in patients in need. In some embodiments, the liver cancer is hepatocellular carcinoma, liver tumor, cholangiocarcinoma, hepatoblastoma, hepatocarcinoma, hepatic angiosarcoma, 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 usually characterized by unregulated cell growth/proliferation. Examples of liver cancer include, but are not limited to, hepatocellular carcinoma, liver tumor, hepatoblastoma, cholangiocarcinoma, hepatoblastoma, liver cancer, sarcoma, lymphoma, and hepatic angiosarcoma. In various embodiments, liver cancer (e.g., HCC) may be intermediate, advanced, 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) may comprise a single tumor, multiple tumors, or poorly defined tumors with an invasive growth pattern (into the portal vein or hepatic vein). Liver cancer (e.g., HCC) may include fibrous lamellar, pseudo-gland (adenoids), polymorphism (giant cells), or clear cell patterns. Liver cancer (eg, HCC) may contain a fully differentiated form, and tumor cells resemble hepatocytes, forming trabecular bone, spinal cord, and nests, and/or contain bile pigment in the cytoplasm. Liver cancer (eg, HCC) may include a poorly differentiated form, and malignant epithelial cells are non-cohesive, polymorphic, degenerative, and/or huge. In some embodiments, liver cancer (eg, HCC) is associated with hepatitis B, hepatitis C, cirrhosis, or type 2 diabetes. The terms "cell proliferative disorder" and "proliferative disorder" refer to disorders related to a certain degree of abnormal cell proliferation. In one embodiment, the cell proliferative disorder is cancer.

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

， 其中 R¹ 為C_1-6 烷基； R² 為苄基，該苄基未經取代或經一個、兩個或三個獨立地選自鹵素及C_1-6 烷基之取代基取代； R³ 為-NR⁴ R⁵ ，其中 R⁴ 為C_1-6 烷基或C_1-6 烷氧基C_1-6 烷基； R⁵ 為(C_1-6 烷基)₂ NCOOC_1-6 烷基、C_1-6 烷氧基C_1-6 烷基、C_1-6 烷氧基羰基(C_1-6 烷基)胺基C_1-6 烷基、C_1-6 烷氧基羰基(苯基)C_1-6 烷基、C_1-6 烷氧基羰基C_1-6 烷基、C_1-6 烷氧基羰基氧基C_1-6 烷基、C_1-6 烷基、C_1-6 烷基羰基(C_1-6 烷基)胺基C_1-6 烷基或吡咯啶基胺甲醯基氧基C_1-6 烷基；或 R⁴ 及R⁵ 與其所連接之氮一起形成雜環基； 或其醫藥學上可接受之鹽、對映異構體或非對映異構體； 其用於肝癌之治療或預防； 其限制條件為不包括 6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7-(吡咯啶-1-羰基)嘌呤-8-酮； 6-胺基-9-苄基-7-(哌啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(嗎啉-4-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3,3-二甲基吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 1-[6-胺基-9-苄基-8-側氧基-2-(丙基磺醯亞胺醯基)嘌呤-7-羰基]吡咯啶-2-甲酸乙酯； 6-胺基-7-(2-氮雜螺[3.3]庚烷-2-羰基)-9-苄基-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(2-氧雜-6-氮雜螺[3.3]庚烷-6-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3,3-二氟吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3-氟-3-甲基-吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 及其對映異構體或非對映異構體， 且其中式I之前藥化合物在人類肝中轉化成式II之活性藥物

， 其中R¹ 及R² 如上文所定義。In a preferred embodiment of the invention, the compounds described herein are particularly suitable as prodrugs that are converted into active drugs mainly in the liver. One of the embodiments of the present invention is a prodrug compound described herein for treating liver cancer, wherein the compound is a prodrug of formula (I),

, Where 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 halogen and C _1-6 alkyl; R ³ is -NR ⁴ R ⁵ , wherein R ⁴ is C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl; R ⁵ is (C _1-6 alkyl) ₂ NCOOC _1-6 Alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxycarbonyl (C _1-6 alkyl) amine 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 alkylcarbonyl (C _1-6 alkyl) amine C _1-6 alkyl or pyrrolidinyl amine methylacetoxy C _1-6 alkyl; or R ⁴ and R ⁵ to which they are attached Nitrogen together forms a heterocyclic group; or a pharmaceutically acceptable salt, enantiomer or diastereomer; it is used for the treatment or prevention of liver cancer; its restriction is that it does not include 6-amino 9-benzyl-2-(propylsulfonyliminamide)-7-(pyrrolidin-1-carbonyl)purin-8-one; 6-amino-9-benzyl-7-(piperidin- 1-carbonyl)-2-(propylsulfonylimideamide)purin-8-one; 6-amino-9-benzyl-7-(morpholin-4-carbonyl)-2-(propylsulfonate Amidimide)purine-8-one; 6-amino-9-benzyl-7-(3,3-dimethylpyrrolidin-1-carbonyl)-2-(propylsulfonylimideamide) Group) purine-8-one; 1-[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide)purine-7-carbonyl]pyrrolidine-2- Ethyl formate; 6-amino-7-(2-azaspiro[3.3]heptane-2-carbonyl)-9-benzyl-2-(propylsulfonylimide)purin-8-one ; 6-amino-9-benzyl-7-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-2-(propylsulfonylamidoimido)purine-8 -Ketone; 6-amino-9-benzyl-7-(3,3-difluoropyrrolidin-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; 6- Amino-9-benzyl-7-(3-fluoro-3-methyl-pyrrolidine-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; and its enantiomers Isomers or diastereomers, and the prodrug compound of formula I is converted into the active drug of formula II in human liver

, Where R ¹ and R ² are as defined above.

An exemplary conversion rate using human liver microsomes is shown in Example 50. Also Example 61 demonstrates the first site where the liver is converted into its active form as a prodrug.

A preferred embodiment of the present invention are the (prodrug) compounds described herein, wherein these compounds are susceptible to liver enzymes CYP2C9 and CYP2C19 and converted into their active forms. A preferred embodiment of the present invention are the (prodrug) compounds described herein, wherein these compounds display ≥10 nmol/min/mg protein in human hepatocytes and ≤2 nmol/min/mg protein in human intestinal epithelial cells Conversion rate to active compound (as measured using human hepatocytes and human intestinal epithelial cells in appropriate tests).

Combination therapy One aspect of the present invention is a patient with liver cancer treated by a combined treatment/combination treatment with a compound of formula I and anti-PD-L1/PD1 axis therapy.

Unexpectedly, we found that the combination therapy of the compound of formula I and anti-PD-L1/PD1 axis therapy is highly effective for liver tumors.

， 其中 R¹ 為C_1-6 烷基； R² 為苄基，該苄基未經取代或經一個、兩個或三個獨立地選自鹵素及C_1-6 烷基之取代基取代； R³ 為-NR⁴ R⁵ ，其中 R⁴ 為C_1-6 烷基或C_1-6 烷氧基C_1-6 烷基； R⁵ 為(C_1-6 烷基)₂ NCOOC_1-6 烷基、C_1-6 烷氧基C_1-6 烷基、C_1-6 烷氧基羰基(C_1-6 烷基)胺基C_1-6 烷基、C_1-6 烷氧基羰基(苯基)C_1-6 烷基、C_1-6 烷氧基羰基C_1-6 烷基、C_1-6 烷氧基羰基氧基C_1-6 烷基、C_1-6 烷基、C_1-6 烷基羰基(C_1-6 烷基)胺基C_1-6 烷基或吡咯啶基胺甲醯基氧基C_1-6 烷基；或 R⁴ 及R⁵ 與其所連接之氮一起形成雜環基； 或其醫藥學上可接受之鹽、對映異構體或非對映異構體； 其限制條件為不包括 6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7-(吡咯啶-1-羰基)嘌呤-8-酮； 6-胺基-9-苄基-7-(哌啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(嗎啉-4-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3,3-二甲基吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 1-[6-胺基-9-苄基-8-側氧基-2-(丙基磺醯亞胺醯基)嘌呤-7-羰基]吡咯啶-2-甲酸乙酯； 6-胺基-7-(2-氮雜螺[3.3]庚烷-2-羰基)-9-苄基-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(2-氧雜-6-氮雜螺[3.3]庚烷-6-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3,3-二氟吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3-氟-3-甲基-吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 及其對映異構體或非對映異構體， 其用於 a)與拮抗性PD1或拮抗性PD-L1抗體組合治療肝癌， 或 b)與拮抗性PD1或拮抗性PD-L1抗體組合治療患有肝癌之患者。Therefore, one aspect of the present invention is a compound of formula (I) (or a medicament or pharmaceutical composition containing such a compound),

, Where 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 halogen and C _1-6 alkyl; R ³ is -NR ⁴ R ⁵ , wherein R ⁴ is C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl; R ⁵ is (C _1-6 alkyl) ₂ NCOOC _1-6 Alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxycarbonyl (C _1-6 alkyl) amine 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 alkylcarbonyl (C _1-6 alkyl) amine C _1-6 alkyl or pyrrolidinyl amine methylacetoxy C _1-6 alkyl; or R ⁴ and R ⁵ to which they are attached Nitrogen forms a heterocyclic group together; or a pharmaceutically acceptable salt, enantiomer or diastereomer; its limitation is that it does not include 6-amino-9-benzyl-2-(propylene Sulfasulfonimide amide)-7-(pyrrolidin-1-carbonyl)purin-8-one; 6-amino-9-benzyl-7-(piperidin-1-carbonyl)-2-(propylene Sulfonylimide)purine-8-one; 6-amino-9-benzyl-7-(morpholine-4-carbonyl)-2-(propylsulfonylimide acetyl)purine-8 -Ketone; 6-amino-9-benzyl-7-(3,3-dimethylpyrrolidin-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; 1 -[6-Amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide)purine-7-carbonyl]pyrrolidine-2-carboxylic acid ethyl ester; 6-amino- 7-(2-azaspiro[3.3]heptane-2-carbonyl)-9-benzyl-2-(propylsulfonylimide)purin-8-one; 6-amino-9-benzyl Yl-7-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-2-(propylsulfonylimide)purin-8-one; 6-amino-9 -Benzyl-7-(3,3-difluoropyrrolidine-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; 6-amino-9-benzyl-7 -(3-fluoro-3-methyl-pyrrolidine-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; and its enantiomers or diastereomers It is used for a) combination of antagonistic PD1 or antagonistic PD-L1 antibody to treat liver cancer, or b) combination of antagonistic PD1 or antagonistic PD-L1 antibody to treat patients with liver cancer.

， 其中 R¹ 為C_1-6 烷基； R² 為苄基，該苄基未經取代或經一個、兩個或三個獨立地選自鹵素及C_1-6 烷基之取代基取代； R³ 為-NR⁴ R⁵ ，其中 R⁴ 為C_1-6 烷基或C_1-6 烷氧基C_1-6 烷基； R⁵ 為(C_1-6 烷基)₂ NCOOC_1-6 烷基、C_1-6 烷氧基C_1-6 烷基、C_1-6 烷氧基羰基(C_1-6 烷基)胺基C_1-6 烷基、C_1-6 烷氧基羰基(苯基)C_1-6 烷基、C_1-6 烷氧基羰基C_1-6 烷基、C_1-6 烷氧基羰基氧基C_1-6 烷基、C_1-6 烷基、C_1-6 烷基羰基(C_1-6 烷基)胺基C_1-6 烷基或吡咯啶基胺甲醯基氧基C_1-6 烷基；或 R⁴ 及R⁵ 與其所連接之氮一起形成雜環基； 或其醫藥學上可接受之鹽、對映異構體或非對映異構體； 其限制條件為不包括 6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7-(吡咯啶-1-羰基)嘌呤-8-酮； 6-胺基-9-苄基-7-(哌啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(嗎啉-4-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3,3-二甲基吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 1-[6-胺基-9-苄基-8-側氧基-2-(丙基磺醯亞胺醯基)嘌呤-7-羰基]吡咯啶-2-甲酸乙酯； 6-胺基-7-(2-氮雜螺[3.3]庚烷-2-羰基)-9-苄基-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(2-氧雜-6-氮雜螺[3.3]庚烷-6-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3,3-二氟吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3-氟-3-甲基-吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 及其對映異構體或非對映異構體， 其用於肝癌之治療或預防 其中拮抗性PD1或拮抗性PD-L1抗體經共投與(其中治療係與拮抗性PD1或拮抗性PD-L1抗體組合)。An embodiment of the present invention is a compound of formula (I) (or a medicament or pharmaceutical composition containing such a compound),

, Where 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 halogen and C _1-6 alkyl; R ³ is -NR ⁴ R ⁵ , wherein R ⁴ is C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl; R ⁵ is (C _1-6 alkyl) ₂ NCOOC _1-6 Alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxycarbonyl (C _1-6 alkyl) amine 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 alkylcarbonyl (C _1-6 alkyl) amine C _1-6 alkyl or pyrrolidinyl amine methylacetoxy C _1-6 alkyl; or R ⁴ and R ⁵ to which they are attached Nitrogen forms a heterocyclic group together; or a pharmaceutically acceptable salt, enantiomer or diastereomer; its limitation is that it does not include 6-amino-9-benzyl-2-(propylene Sulfonyl iminamide)-7-(pyrrolidin-1-carbonyl)purin-8-one; 6-amino-9-benzyl-7-(piperidin-1-carbonyl)-2-(propylene Sulfonylimide) purine-8-one; 6-amino-9-benzyl-7-(morpholine-4-carbonyl)-2-(propylsulfonylimide acetyl)purine-8 -Ketone; 6-amino-9-benzyl-7-(3,3-dimethylpyrrolidin-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; 1 -[6-Amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide)purine-7-carbonyl]pyrrolidine-2-carboxylic acid ethyl ester; 6-amino- 7-(2-azaspiro[3.3]heptane-2-carbonyl)-9-benzyl-2-(propylsulfonylimide)purin-8-one; 6-amino-9-benzyl Yl-7-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-2-(propylsulfonylimide)purin-8-one; 6-amino-9 -Benzyl-7-(3,3-difluoropyrrolidine-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; 6-amino-9-benzyl-7 -(3-fluoro-3-methyl-pyrrolidine-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; and its enantiomers or diastereomers It is used in the treatment or prevention of liver cancer in which antagonistic PD1 or antagonistic PD-L1 antibody is co-administered (wherein the treatment is combined with antagonistic PD1 or antagonistic PD-L1 antibody).

， 其中 R¹ 為C_1-6 烷基； R² 為苄基，該苄基未經取代或經一個、兩個或三個獨立地選自鹵素及C_1-6 烷基之取代基取代； R³ 為-NR⁴ R⁵ ，其中 R⁴ 為C_1-6 烷基或C_1-6 烷氧基C_1-6 烷基； R⁵ 為(C_1-6 烷基)₂ NCOOC_1-6 烷基、C_1-6 烷氧基C_1-6 烷基、C_1-6 烷氧基羰基(C_1-6 烷基)胺基C_1-6 烷基、C_1-6 烷氧基羰基(苯基)C_1-6 烷基、C_1-6 烷氧基羰基C_1-6 烷基、C_1-6 烷氧基羰基氧基C_1-6 烷基、C_1-6 烷基、C_1-6 烷基羰基(C_1-6 烷基)胺基C_1-6 烷基或吡咯啶基胺甲醯基氧基C_1-6 烷基；或 R⁴ 及R⁵ 與其所連接之氮一起形成雜環基； 或其醫藥學上可接受之鹽、對映異構體或非對映異構體； 其限制條件為不包括 6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7-(吡咯啶-1-羰基)嘌呤-8-酮； 6-胺基-9-苄基-7-(哌啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(嗎啉-4-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3,3-二甲基吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 1-[6-胺基-9-苄基-8-側氧基-2-(丙基磺醯亞胺醯基)嘌呤-7-羰基]吡咯啶-2-甲酸乙酯； 6-胺基-7-(2-氮雜螺[3.3]庚烷-2-羰基)-9-苄基-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(2-氧雜-6-氮雜螺[3.3]庚烷-6-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3,3-二氟吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3-氟-3-甲基-吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 及其對映異構體或非對映異構體， 其用於製備供肝癌之治療或預防用之藥劑 其中拮抗性PD1或拮抗性PD-L1抗體經共投與(其中治療係與拮抗性PD1或拮抗性PD-L1抗體組合)。An embodiment of the present invention is the use of a compound of formula (I),

, Where 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 halogen and C _1-6 alkyl; R ³ is -NR ⁴ R ⁵ , wherein R ⁴ is C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl; R ⁵ is (C _1-6 alkyl) ₂ NCOOC _1-6 Alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxycarbonyl (C _1-6 alkyl) amine 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 alkylcarbonyl (C _1-6 alkyl) amine C _1-6 alkyl or pyrrolidinyl amine methylacetoxy C _1-6 alkyl; or R ⁴ and R ⁵ to which they are attached Nitrogen forms a heterocyclic group together; or a pharmaceutically acceptable salt, enantiomer or diastereomer; its limitation is that it does not include 6-amino-9-benzyl-2-(propylene Sulfonyl iminamide)-7-(pyrrolidin-1-carbonyl)purin-8-one; 6-amino-9-benzyl-7-(piperidin-1-carbonyl)-2-(propylene Sulfonylimide) purine-8-one; 6-amino-9-benzyl-7-(morpholine-4-carbonyl)-2-(propylsulfonylimide acetyl)purine-8 -Ketone; 6-amino-9-benzyl-7-(3,3-dimethylpyrrolidin-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; 1 -[6-Amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide)purine-7-carbonyl]pyrrolidine-2-carboxylic acid ethyl ester; 6-amino- 7-(2-azaspiro[3.3]heptane-2-carbonyl)-9-benzyl-2-(propylsulfonylimide)purin-8-one; 6-amino-9-benzyl Yl-7-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-2-(propylsulfonylimide)purin-8-one; 6-amino-9 -Benzyl-7-(3,3-difluoropyrrolidine-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; 6-amino-9-benzyl-7 -(3-fluoro-3-methyl-pyrrolidine-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; and its enantiomers or diastereomers It is used for the preparation of a medicament for the treatment or prevention of liver cancer in which the antagonistic PD1 or antagonistic PD-L1 antibody is co-administered (wherein the treatment is combined with the antagonistic PD1 or antagonistic PD-L1 antibody).

In another embodiment of the present invention, the specific compound of formula (I) used in combination therapy with antagonistic PD1 or antagonistic PD-L1 antibody is selected from the group consisting of 6-amino-9-benzyl-N-methyl Yl-8-oxo-N-propyl-2-(propylsulfonylimide acetyl)purine-7-methylamide; 6-amino-9-benzyl-N-(2-methoxy Ethyl)-N-methyl-8-oxo-2-(propylsulfonylimide)purine-7-methylamide; 6-amino-9-benzyl- N -ethyl -8-Penoxy- N -propyl-2-(propylsulfonylimide)purine-7-formamide; 6-amino-9-benzyl-7-[4-(1- Piperidinyl)piperidin-1-carbonyl]-2-(propylsulfonylimide)purin-8-one; 6-amino-9-benzyl- N -ethyl- N-( 2- Methoxyethyl)-8- pendant-2-(propylsulfonylimide) purine-7-formamide; 6-amino-9-benzyl- N -butyl- N- Ethyl-8-oxo-2-(propylsulfonylimide acetyl) purine-7-methylamide; 6-amino-9-benzyl- N- (2-methoxyethyl) -8-Penoxy- N -propyl-2-(propylsulfonylimide) purine-7-formamide; 6-amino-9-benzyl- N,N -bis(2- Methoxyethyl)-8- pendant-2-(propylsulfonylimide)purine-7-formamide; 6-amino-7-(azetidine-1-carbonyl )-9-benzyl-2-(propylsulfonylimide)purin-8-one; 6-amino-9-benzyl- N -isopropyl- N -methyl-8-side oxygen Yl-2-(propylsulfonylimide) purine-7-carboxamide; 6-amino-9-benzyl-7-(4-methylpiperazine-1-carbonyl)-2-( Propylsulfonylimide) purin-8-one; 6-amino-9-benzyl- N- (3-methoxypropyl) -N -methyl-8-oxo-2- (Propylsulfonylimide) purine-7-carboxamide; 6-amino-9-benzyl- N -isobutyl- N -methyl-8-oxo-2-(propyl Sulfonylimide)purine-7-formamide; 2-[[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide acetyl)purine-7 -Carbonyl]-methyl-amino] ethyl acetate; 3-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide acetyl)purine-7- Carbonyl]-methyl-amino] ethyl propionate; 3-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7- Carbonyl]-methyl-amino] propionic acid tert-butyl ester; (2S)-2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide) Yl)purine-7-carbonyl]-methyl-amino] ethyl propionate; (2S)-2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonate (Imidimide) purine-7 -Carbonyl]-methyl-amino]-4-methyl-valeric acid third butyl ester; (2S)-2-[[6-amino-9-benzyl-8-oxo-2-( Propylsulfonylimide)purine-7-carbonyl]-methyl-amino]-4-methyl-valeric acid isopropyl ester; (2S)-2-[[6-amino-9-benzyl Yl-8-oxo-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]-3-methyl-butyric acid ethyl ester; (2S)-2- [[6-Amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]-4-methyl-pentyl Ethyl acid ester; (2S)-2-[[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide)purine-7-carbonyl]-methyl- Amino]-3-phenyl-propionic acid ethyl ester; (2S)-2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide) Purine-7-carbonyl]-methyl-amino]-3-phenyl-propionic acid isopropyl ester; (2S)-2-[[6-amino-9-benzyl-8-pentoxy-2 -(Propylsulfonylimide)purine-7-carbonyl]-methyl-amino]-3-phenyl-propionic acid tert-butyl ester; N- [2-[ethyl acetyl (methyl) Amino]ethyl]-6-amino-9-benzyl- N -methyl-8-oxo-2-(propylsulfonylimide)purine-7-methylamide; N- [2-[[6-Amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]ethyl]- N -methyl-carbamic acid methyl ester; N- [2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide acetyl)purine-7- Carbonyl]-methyl-amino]ethyl] -N -methyl-aminocarbamic acid third butyl ester; N- [2-[[6-amino-9-benzyl-8-pentoxy-2 -(Propylsulfonylimide)purine-7-carbonyl]-methyl-amino]ethyl] -N -methyl-ethyl carbamate; N -butyl- N -methyl-amine Carboxylic acid 2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimido)purine-7-carbonyl]-methyl-amino]ethyl ester; Pyrrolidine-1-carboxylic acid 2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino ] Ethyl; N- methyl- N -propyl-carbamic acid 2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide acetyl)purine -7-carbonyl]-methyl-amino]ethyl; N,N -diethylaminocarboxylic acid 2-[[6-amino-9-benzyl-8-oxo-2-(propyl Sulfonylimide)purine-7-carbonyl]-methyl-amino]ethyl; 2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonate of carbonic acid Amidimide)purine-7-carbonyl]-methyl-amino]ethyl ethyl ; 6-amino-N-butyl-9-[(4-chlorophenyl)methyl]-N-methyl-8-oxo-2-[S(R)-propylsulfonylimide Acetyl]purine-7-carboxamide; 6-amino-N-butyl-9-[(4-chlorophenyl)methyl]-N-methyl-8-oxo-2-[S (S)-propylsulfonylimide]purine-7-formamide; 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl- N -methyl- 8-Penoxy-2-(propylsulfonylimide) purine-7-formamide; 6-amino- N -methyl-8-pentoxy- N -propyl-2[S (S)-propylsulfonylimide]-9-(p-tolylmethyl)purine-7-formamide; 6-amino- N -methyl-8-oxo- N -propyl Yl-2[S(R)-propylsulfonylimide acetyl]-9-(p-tolylmethyl)purine-7-methanamide; 6-amino-2-[S (S) -propylene Sulfasulfonylimide]-9-(p-tolylmethyl)-7-(pyrrolidin-1-carbonyl)purin-8-one; 6-amino-2-[S( R )-propyl Sulfonylimide]-9-(p-tolylmethyl)-7-(pyrrolidin-1-carbonyl)purin-8-one; 6-amino- N- (2-methoxyethyl) -N- methyl-8-oxo-2-[S(S)-propylsulfonylimide]-9-(p-tolylmethyl)purine-7-methylamide; 6-amine yl - N - (2- methoxyethyl) - N- methyl-8-oxo -2- [S (R) - (PEI) acyl sulfonamide propyl] -9- (p-tolyl A Group) purine-7-methylamide; 6-amino- N -ethyl- N- methyl-8- pendant-2-(propylsulfonylimide)-9-(p-tolyl Methyl)purine-7-methylamide; 6-amino- N -butyl- N -methyl-8- pendant-2-(propylsulfonylimideamide)-9-(p-toluene Methyl)purine-7-methylamide; 6-amino-9-[(4-chlorophenyl)methyl]-2-[S( R )-ethylsulfonylimideamide]- N -Methyl-8-oxo- N -propyl-purine-7-carboxamide; 6-amino-9-[(4-chlorophenyl)methyl]-2-[S( S )- Ethylsulfonylimide] -N -methyl-8-pentoxy- N -propyl-purine-7-methylamide; 6-amino-9-[(4-chlorophenyl)methyl Group] -N -ethyl-2[S( S )-ethylsulfonylimide] -N -methyl-8-oxo-purine-7-methylamide; 6-amino-9 -[(4-chlorophenyl)methyl] -N -ethyl-2-[S( R )-ethylsulfonylimide] -N -methyl-8-oxo-purine-7 -Methamide; 6-amino-2-[S( S )-ethylsulfonylimide] -N -methyl-8-oxo- N -propyl-9-( P-tolylmethyl)purine-7-methylamide; 6-amino-2-[S( R )-ethylsulfonylimidoamide]- N -methyl-8-oxo- N- Propyl-9-(p-tolylmethyl)purine-7-carboxamide; 6-amino- N -ethyl-2[S(S)-ethylsulfonylimide] -N -methyl Yl-8-pentoxy-9-(p-tolylmethyl)purine-7-carboxamide; 6-amino- N -ethyl-2-[S( R )-ethylsulfonylimide amide Group] -N -methyl-8-oxo-9-(p-tolylmethyl)purine-7-formamide; 6-amino-2-[S( S )ethylsulfonylimideamide Group]-9-[(4-fluorophenyl)methyl] -N -methyl-8-pentoxy- N -propyl-purine-7-carboxamide; 6-amino-2-[S ( R )ethylsulfonylimide amide]-9-[(4-fluorophenyl)methyl]- N -methyl-8-oxo- N -propyl-purine-7-methylamide ; 6-amino- N -ethyl-2-(ethylsulfonylimide)-9-[(4-fluorophenyl)methyl] -N -methyl-8-oxo-purine -7-formamide; 6-amino- N -ethyl-2-[S( S )-(ethylsulfonylimide)]-9-[(4-fluorophenyl)methyl] -N -methyl-8- pendant-purine-7-carboxamide; 6-amino- N -ethyl-2-[S( R )-(ethylsulfonylimide amide)]- 9-[(4-fluorophenyl)methyl] -N -methyl-8-oxo-purine-7-carboxamide; 6-amino-9-[(4-bromophenyl)methyl ]-2-(Ethylsulfonylimideamide) -N- methyl-8-oxo- N -propyl-purine-7-methylamide; 6-amino-2-[S( R )-Ethylsulfonylimide]-9-[(4-bromophenyl)methyl] -N -methyl-8-oxo- N -propyl-purine-7-methylamide; 6-amino-2-[S( S )-ethylsulfonylimide]-9-[(4-bromophenyl)methyl]- N -methyl-8-oxo- N- Propyl-purine-7-carboxamide; 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-(ethylsulfonylimide) -N- Methyl-8-oxo-purine-7-carboxamide; 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-[S( S )-( Ethylsulfonylimide)]- N -methyl-8-oxo-purine-7-methylamide; and 6-amino-9-[(4-bromophenyl)methyl]- N -ethyl-2-[S( R )-(ethylsulfonylimide)]- N -methyl-8-oxo-purine-7-methylamide; or its pharmacologically acceptable Accepted salts, enantiomers or diastereomers.

In another embodiment of the invention, the specific compound of formula (I) used in combination therapy with antagonistic PD1 or antagonistic PD-L1 antibody is selected from the following: 6-amino-9-[(4-chlorobenzene Yl)methyl] -N -ethyl-2[S( S )-ethylsulfonylimide]]- N -methyl-8-oxo-purine-7-methylamide; 6-amine Yl-9-[(4-chlorophenyl)methyl] -N -ethyl-2-[S( R )-ethylsulfonylimide] -N -methyl-8-oxo- Purine-7-methylamide; 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-(ethylsulfonylimideamide) -N -methyl- 8-oxo-purine-7-carboxamide; 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-[S( S )-(ethylsulfonate (Imidimide)]- N -methyl-8-oxo-purine-7-carboxamide; and 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl Yl-2-[S( R )-(ethylsulfonylimide)]- N -methyl-8-oxo-purine-7-methylamide; or a pharmaceutically acceptable salt thereof , Enantiomers or diastereomers.

In another embodiment of the present invention, the specific compound of formula (I) used in combination therapy with antagonistic PD1 or antagonistic PD-L1 antibody is: 6-amino-9-[(4-chlorobenzene Group) Methyl] -N -ethyl-2[S( S )-ethylsulfonylimide]]- N -methyl-8-oxo-purine-7-methylamide.

In one embodiment, the compound of formula I and the antagonistic PD1 or antagonistic PD-L1 antibody are co-administered (or combined therapy or combined therapy or combined therapy). In one embodiment, the compound of formula I and antagonist PD1 or antagonist PD-L1 antibody are co-administered sequentially (or in combination therapy or in combination therapy or combination therapy).

The term "co-administration/co-administering", "combination therapy", "combination therapy" or "combination therapy" means as described herein, for example to be formulated independently Administration/application form (or in a single formulation/application form) to administer the compound of formula I as described herein and the antagonistic PD1 or PD-L1 antibody. Co-administration can be simultaneous or sequential in either order, where there is a period of time when two (or all) active agents exert their biological activities simultaneously. (E.g. via intravenous (i.v.) continuous infusion) simultaneous or sequential co-administration. In one embodiment, co-administered simultaneously. In one embodiment, co-administered sequentially. (E.g. via intravenous (i.v.) continuous infusion) simultaneous or sequential co-administration.

It goes without saying that the antibody is administered to the patient in a "therapeutically effective amount" (or simply "effective amount"), which is the tissue, system, animal that will cause researchers, veterinarians, medical doctors or other clinicians to explore Or the amount of each compound or combination of human biological or medical response.

The amount of co-administration and the timing of co-administration will depend on the type of patient being treated (race, gender, age, weight, etc.) and the severity of the disease or condition being treated. The compounds of Formula I and the antibodies are co-administered to the patient once or within a series of treatments (eg, on the same day or after that day) as appropriate.

PD-1/PD-L1/PD-L2 pathway: The important negative costimulatory signal that regulates T cell activation consists of the planned death-1 receptor (PD-1) (CD279) and its ligand-binding partner PD-L1 (B7-H1, CD274; SEQ ID NO: 13 ) And PD-L2 (B7-DC, CD273). The negative regulatory effect of PD-1 is shown by PD-1 knockout (Pdcd1-/-), which tends to autoimmune. Nishimura et al., Immunity 11: 141-51 (1999); Nishimura et al., Science 291: 319-22 (2001). PD-1 is associated with CD28 and CTLA-4, but lacks a homodimeric membrane adjacent to cysteine. The cytoplasmic domain of PD-1 contains an immunoreceptor tyrosine-based inhibition motif (ITIM, V/IxYxxL/V). PD-1 only binds to PD-L1 and PD-L2. Freeman et al., J. Exp. Med. 192: 1-9 (2000); Dong et al., Nature Med. 5: 1365-1369 (1999); Latchman et al., Nature Immunol. 2: 261-268 (2001) ; Tseng et al., J. Exp. Med. 193: 839-846 (2001).

PD-1 can be expressed on T cells, B cells, natural killer T cells, activated mononuclear cells and dendritic cells (DC). PD-1 is expressed by activated but not stimulated human CD4+ and CD8+ T cells, B cells, and bone marrow cells. This is in contrast to the more restricted CD28 and CTLA-4 performance. Nishimura et al., Int. Immunol. 8: 773-80 (1996); Boettler et al., J. Virol. 80: 3532-40 (2006). There are at least 4 PD-1 variants colonized from activated human T cells, including the lack of (i) exon 2, (ii) exon 3, (iii) exons 2 and 3 or (iv ) Transcripts of exons 2 to 4. Nielsen et al., Cell. Immunol. 235: 109-16 (2005). With the exception of PD-1 deltaex3, all variants in resting peripheral blood mononuclear cells (PBMC) are equivalent to full-length PD -1 Similar level of performance. After activation of human T cells with anti-CD3 and anti-CD28, the expression of all variants was significantly induced. The PD-1 deltaex3 variant lacks a transmembrane domain and is similar to soluble CTLA-4, which plays an important role in autoimmunity. Ueda et al., Nature 423: 506-11 (2003). This variant is enriched in the synovial fluid and serum of patients with rheumatoid arthritis. Wan et al., J. Immunol. 177: 8844-50 (2006).

The two PD-1 ligands differ in their expression patterns. PD-L1 is constitutively expressed on mouse T cells 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, cornea, lung, vascular epithelium, liver non-parenchymal cells, mesenchymal stem cells, pancreatic islets, placental fusion cell trophoblasts, keratinocytes, etc.) [Keir, etc. Human, Annu. Rev. Immunol. 26: 677-704 (2008)], and is upregulated on various cell types after activation. Both type I and type II interferon IFN upregulate PD-L1. Eppihimer et al., Microcirculation 9: 133-45 (2002); Schreiner et al., J. Neuroimmunol. 155: 172-82 (2004). When MyD88, TRAF6 and MEK were inhibited, PD-L1 expression in cell lines decreased. 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). Phosphatase and tensin homolog (PTEN), which is a type of cellular phospholipase that regulates phospholipid inositol 3-kinase (phosphatidylinositol 3-kinase; PI3K) and Akt signaling, is missing or inhibited to increase Post-transcriptional PD-L1 performance in cancer. Parsa et al., Nat. Med. 13: 84-88 (2007).

PD-L2 performance is more restricted than PD-L1. PD-L2 is induced on DCs, macrophages, and bone marrow-derived mast cells. PD-L2 is also expressed on about half to two-thirds of resting peritoneal B1 cells, but not on conventional B2 B cells. Zhong et al., Eur. J. Immunol. 37: 2405-10 (2007). PD-L2+ B1 cells bind choline phospholipids and may be important for innate immune responses against bacterial antigens. Induction of PD-L2 by IFN-γ is partially dependent on NF-κB. Liang et al., Eur. J. Immunol. 33: 2706-16 (2003). PD-L2 can also be induced on monocytes and macrophages by M-CF, IL-4 and IFN-γ. Yamazaki et al., J. Immunol. 169: 5538-45 (2002); Loke et al., PNAS 100: 5336-41 (2003).

PD-1 signaling typically has a greater role in the production of interleukins than in cell proliferation, with significant effects on the production of IFN-γ, TNF-α, and IL-2. PD-1 mediated inhibitory signaling also depends on the strength of TCR signaling, which provides greater inhibition under lower levels of TCR stimulation. This reduction can be by co-stimulation via CD28 [Freeman et al., J. Exp. Med. 192: 1027-34 (2000)] or co-stimulation in the presence of IL-2 [Carter et al., Eur. J. Immunol. 32: 634-43 (2002)] overcome.

There is already evidence that the signaling through PD-L1 and PD-L2 can be bidirectional. That is, in addition to regulating TCR or BCR signaling, signaling can also be transported back to cells expressing PD-L1 and PD-L2. Although treatment of dendritic cells with natural human anti-PD-L2 antibodies isolated from patients with Waldenstrom's macroglobulinemia has not been found to upregulate MHC II or B7 costimulatory molecules, this Cell-like cells do produce larger amounts of proinflammatory interleukins, especially TNF-α and IL-6, and stimulate T cell proliferation. Nguyen et al., J. Exp. Med. 196: 1393-98 (2002). Treatment of mice with this antibody also (1) enhances resistance to transplanted b16 melanoma and rapidly induces tumor-specific CTL. Radhakrishnan et al., J. Immunol. 170: 1830-38 (2003); Radhakrishnan et al., Cancer Res. 64: 4965-72 (2004); Heckman et al., Eur. J. Immunol. 37: 1827-35 (2007) ); (2) Block the development of respiratory inflammatory diseases in a mouse model of allergic asthma. Radhakrishnan et al., J. Immunol. 173: 1360-65 (2004); Radhakrishnan et al., J. Allergy Clin. Immunol. 116: 668-74 (2005).

Other evidence of reverse signaling to dendritic cells ("DC") is derived from bone marrow cultivated by soluble PD-1 (PD-1 EC domain fused with Ig constant region-"s-PD-1") DC research is produced. Kuipers et al., Eur. J. Immunol. 36: 2472-82 (2006). This sPD-1 inhibits DC activation and enhances IL-10 production in a reversible manner by administration of anti-PD-1.

In addition, several studies have shown a PD-1 independent receptor for PD-L1 or PD-L2. B7.1 has been identified as a binding partner for PD-L1. Butte et al., Immunity 27: 111-22 (2007). Chemical cross-linking studies indicate that PD-L1 and B7.1 can interact via their IgV-like domains. B7.1: PD-L1 interaction can induce inhibitory signals into T cells. PD-L1 transmits the inhibitory signal through the connection of B7.1 on CD4+ T cells or B7.1 through the connection of PD-L1 on CD4+ T cells. T cells lacking CD28 and CTLA-4 showed reduced proliferation and cytokine production when stimulated with anti-CD3 plus B7.1 coated beads. In T cells lacking all receptors for B7.1 (ie, CD28, CTLA-4, and PD-L1), T cell proliferation and cytokine production are no longer coated with anti-CD3 plus B7.1 Bead suppression. This indicates that in the absence of CD28 and CTLA-4, B7.1 specifically acts via PD-L1 on T cells. Similarly, T cells lacking PD-1, when stimulated in the presence of anti-CD3 plus PD-L1 coated beads, showed reduced proliferation and cytokine production, thus confirming that PD-L1 ligation is associated with B7 on T cells .1 Inhibition. When T cells lack all known receptors for PD-L1 (ie, without PD-1 and B7.1), T cell proliferation is no longer reduced by anti-CD3 plus PD-L1 coated beads. Therefore, PD-L1 can exert its inhibitory effect on T cells via B7.1 or PD-1.

The direct interaction between B7.1 and PD-L1 indicates that the current understanding of costimulation is incomplete and underestimates the importance of the performance of these molecules on T cells. Studies on PD-L1-/-T cells have shown that PD-L1 on T cells can downregulate T cell cytokines production. Latchman et al., Proc. Natl. Acad. Sci. USA 101: 10691-96 (2004). Since PD-L1 and B7.1 are both expressed on T cells, B cells, DCs and macrophages, there may be a directional interaction between B7.1 and PD-L1 on these cell types. In addition, PD-L1 on non-hematopoietic cells can interact with B7.1 and PD-1 on T cells, which raises the question of whether PD-L1 is involved in its regulation. One possible explanation for the inhibitory effect of the B7.1:PD-L1 interaction is that the T-cell PD-L1 may trap or isolate APC B7.1 from its interaction with CD28.

Therefore, the antagonism of signaling through PD-L1 (including blocking the interaction of PD-L1 with PD-1, B7.1, or both), thereby preventing PD-L1 from sending negative costimulatory signals to T cells and other Antigen presenting cells may enhance immunity and tumor immunity in response to infection (eg, acute and chronic).

An exemplary PD-L1 antagonist is the anti-PD-L1 antibody atezolizumab. The other antagonistic PD-L1 antibodies are durvalumab (durvalumab) and avilumab (avelumab).

In another embodiment, it can be resisted by antagonists such as the antagonistic PD1 antibody peclizumab or nivolumab or an anti-PD1 antibody comprising the variable heavy and light chain domains of PD1-0103-0312 The PD-1 antibody blocks anti-PD-L1/PD1 interaction.

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 "antagonistic anti-PD-L1" ”Refers to a KD value of 1.0 × 10 ^-8 mol/l or lower. In one embodiment, it specifically binds to human PD with a binding affinity of 1.0 × 10 ^-9 mol/l or lower. Antibody to L1 antigen. The binding affinity was determined using standard binding analysis, such as surface plasmon resonance technology (BIAcore®, GE-Healthcare Uppsala, Sweden). Thus, as used herein, the "human antibodies that bind to the PD-L1" refers to 1.0 × 10 ^-8 mol / l or less (in one embodiment 1.0 × 10 ^-8 mol / l embodiment ^- 1.0 × 10 - ¹³ mol/l) KD in one embodiment at 1.0 × 10 ^-9 mol/l or lower (in one embodiment 1.0 × 10 ^-9 mol/l-1.0 × 10 ^-13 mol/l) The binding affinity of KD is an antibody that specifically binds to human PD-L1 antigen.

The term "human PD1" refers to human protein PD1 (SEQ ID NO: 14, typically PD-1 signaling). As used herein, "binding to human PD1" or "specifically binding to human PD1" or "binding to human PD1" or "anti-PD1 antibody" or "antagonistic PD1" means 1.0×10 ^-8 mol The KD value of /l or lower, in one embodiment, the binding affinity of the KD value of 1.0×10 ^-9 mol/l or lower specifically binds to the antibody of human PD1 antigen. The binding affinity was determined using standard binding analysis, such as surface plasmon resonance technology (BIAcore®, GE-Healthcare Uppsala, Sweden). Thus, as used herein, "human antibodies that bind to the PD1" refers to KD 1.0 × 10 ^-8 mol / l or less (in one embodiment 1.0 × 10 ^-8 mol / l embodiment ^- 1.0 × 10 - ¹³ mol/l), in one embodiment KD 1.0×10 ^-9 mol/l or lower (in one embodiment 1.0×10 ^-9 mol/l-1.0×10 ^-13 mol/l) binding affinity An antibody that specifically binds to human PD1 antigen.

As used herein, "variable domain" (the variable domain of the light chain (VL), the variable domain of the heavy chain (VH)) means each of the light chain and the heavy chain pair, which directly involves binding the antibody to the antigen . The domains of variable human light and heavy chains have the same general structure and each domain contains four framework (FR) regions whose sequence is widely conserved, with three "hypervariable regions" (or Complementarity determining region (CDR) connection. The framework region adopts a β-sheet configuration and the CDR can form a loop connecting the β-sheet structure. The CDR3 regions of the antibody heavy and light chains play a particularly important role in the binding specificity/affinity of the antibodies according to the invention and therefore provide another object of the invention.

The term "constant region" as used in this application means the sum of the domains of antibodies other than the variable region. The constant region is not directly involved in binding antigen, but exhibits various effector functions. Depending on the amino acid sequence of the constant region of its heavy chain, antibodies are divided into the following categories: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into subcategories, such as IgG1, IgG2, IgG3 And IgG4, IgA1 and IgA2. 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).

The term "constant region derived from human origin" or "human constant region" as used in this application means the constant heavy chain region and/or constant light chain κ or λ of human antibodies of subclass IgG1, IgG2, IgG3 or IgG4 Area. Such constant regions are well known in current advanced technology and are described, for example, by Kabat, EA, et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991) (See also, for example, Johnson, G., and Wu, TT, Nucleic Acids Res. 28 (2000) 214-218; Kabat, EA, et al., Proc. Natl. Acad. Sci. USA 72 (1975) 2785-2788 ). In applications for numbering of positions and mutations, according to the EU numbering system of Kabat, EA, et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991) (EU Index) is used and referred to as "EU Index number according to Kabat".

In one embodiment, the antagonist anti-PD1 antibody that binds to human PD1 for the combination therapy described herein is nivolumab or peclizumab and is characterized by including the following VH and VL sequence: Table:

In a preferred embodiment of the present invention, as described herein for the combination therapy of the compound of Formula I selected from: 6-amino-9 - [(4-chlorophenyl) methyl] - N - Ethyl-2[S( S )-ethylsulfonylimide] -N -methyl-8-oxo-purine-7-methylamide; 6-amino-9-[(4- Chlorophenyl)methyl] -N -ethyl-2-[S( R )-ethylsulfonylimide]]- N -methyl-8-oxo-purine-7-methylamide; 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-(ethylsulfonylimide) -N -methyl-8-oxo-purine- 7-formamide; 6-amino-9-[(4-bromophenyl)methyl]- N -ethyl-2-[S( S )-(ethylsulfonylimide amide)]- N -methyl-8-oxo-purine-7-carboxamide; or 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-[S( R )-(Ethylsulfonylimide)]- N -methyl-8-oxo-purine-7-methylamide; or its pharmaceutically acceptable salts, enantiomers or non- Enantiomer; (in a preferred embodiment, 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl-2[S( S )-ethylsulfonamide [Imidic group] -N -methyl-8- pendant-purine-7-formamide); and the antagonistic PD1 antibody used in combination therapy is nivolumab or peclizumab.

In one embodiment, the antagonist anti-PD1 antibody that binds to human PD1 for the combination therapy described herein is a mono- or multispecific antagonist PD1 antibody and includes the following heavy chain variable domains as described herein VH and light chain variable domain VL sequences: Table:

Preferably, this anti-PD1 antibody based on the heavy chain variable domain VH and light chain variable domain VL sequences of PD1-0103-0312 comprises the heavy chain constant region of IgG1 subtype (eg, SEQ ID NO: 16 or SEQ ID NO: 17, and eventually also other mutations, see bispecific examples below) and human kappa light chain constant region (eg, SEQ ID NO: 15).

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 and i) the bispecific antibody comprises human Constant heavy chain region of IgG1 subclass, which includes mutations L234A, L235A, and P329G (according to the EU Index number of Kabat); and where ii) in the constant heavy chain region, S354C and T366W mutations are contained in one CH3 domain and Y349C , T366S, L368A, and Y407V mutations are included in another CH3 domain (according to Kabat's EU Index numbering).

In another preferred embodiment of the present invention, the compound of formula I used in the combination therapy described herein is selected from the following: 6-amino-9-[(4-chlorophenyl)methyl] -N -Ethyl-2[S( S )-ethylsulfonylimide]- N -methyl-8-oxo-purine-7-methylamide; 6-amino-9-[(4 -Chlorophenyl)methyl] -N -ethyl-2-[S( R )-ethylsulfonylimide] -N -methyl-8-oxo-purine-7-methylamide ; 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-(ethylsulfonylimide) -N -methyl-8-oxo-purine -7-methylamide; 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-[S(S)-(ethylsulfonylimideamide)] -N -methyl-8-oxo-purine-7-carboxamide; or 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-[S( R )-(ethylsulfonylimideamide)]- N -methyl-8-oxo-purine-7-methylamide; or a pharmaceutically acceptable salt, enantiomer or Diastereomer; (in a preferred embodiment, 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl-2[S( S )-ethylsulfonate (Imidimide) -N -methyl-8-oxo-purine-7-formamide); and the antagonistic PD1 antibody used in combination therapy contains the amino acid sequence of SEQ ID NO: 5 The chain variable domain VH and the light chain variable domain VL having the amino acid sequence SEQ ID NO: 6.

In one embodiment, the antibody that binds to human PD-L1 for the combination therapy described herein is attuzumab or devarizumab or avilimumab and is characterized by comprising as described herein The following VH and VL sequences are described: Table:

In another preferred embodiment of the present invention, the compound of formula I used in the combination therapy described herein is selected from the following: 6-amino-9-[(4-chlorophenyl)methyl] -N -Ethyl-2[S( S )-ethylsulfonylimide]- N -methyl-8-oxo-purine-7-methylamide; 6-amino-9-[(4 -Chlorophenyl)methyl] -N -ethyl-2-[S( R )-ethylsulfonylimide]]- N -methyl-8-oxo-purine-7-methylamide ; 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-(ethylsulfonylimide) -N -methyl-8-oxo-purine -7-formamide; 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-[S(S)-(ethylsulfonylimideamide)] -N -methyl-8-oxo-purine-7-carboxamide; or 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-[S( R )-(ethylsulfonylimideamide)]- N -methyl-8-oxo-purine-7-methylamide; or a pharmaceutically acceptable salt, enantiomer or Diastereomer; (in a preferred embodiment, 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl-2[S( S )-ethylsulfonate (Imidimide) -N -methyl-8-oxo-purine-7-formamide); and the antagonist PD-L1 antibody used in combination therapy is atezumab or devaruzumab Anti- or Avilizumab (atrizumab in a preferred embodiment).

Another aspect of the invention is that patients with liver cancer are treated by a combination of a compound of formula I and an anti-angiogenic agent as described above. The anti-angiogenic agent can be co-administered with the compound of formula I alone or in combination with the combined therapy of the compound of formula I and anti-PD-L1/PD1 axis therapy. Anti-angiogenic agents as used herein include (but are not limited to) small molecule tyrosine kinase inhibitors (TKI) that competitively bind to the intracellular receptor domains of VEGF, PDGF and other angiogenic growth factors, For example, sorafenib (4-{4-[3-(4-chloro-3-trifluoromethylphenyl)ureido]phenoxy}pyridine-2-carbonmethyl amide (carbonsäuremethylamid); Nexavar ^TM ), regorafenib (4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]aminomethylamino}amino)-3-fluorophenoxy] -N-methylpyridine-2-carboxamide-Hydrat; Stivarga ^TM ) and sunitinib (N-[2-(diethylamino)ethyl]-5-]([Z)-( 5-fluoro-1,2-dihydro-2-oxo-3H-indole-3-benzylidene)-methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide ; Sutent ^™ ), but also includes anti-VEGF or anti-VEGF receptor antibodies, such as, for example, bevacizumab (Avastin ^™ ).

In a preferred embodiment of the present invention, the compound of formula I used in combination therapy with the anti-angiogenic agents described herein is selected from the group consisting of 6-amino-9-benzyl-N-methyl- 8-Penoxy-N-propyl-2-(propylsulfonylimide acetyl) purine-7-methylamide; 6-amino-9-benzyl-N-(2-methoxyethyl Group)-N-methyl-8-oxo-2-(propylsulfonylimide)purine-7-methylamide; 6-amino-9-benzyl- N -ethyl-8 -Penoxy- N -propyl-2-(propylsulfonylimide)purine-7-formamide; 6-amino-9-benzyl-7-[4-(1-piperidine Group) Piperidine-1-carbonyl]-2-(propylsulfonylimide)purin-8-one; 6-amino-9-benzyl- N -ethyl- N-( 2-methoxy Ethyl)-8- pendant-2-(propylsulfonylimide)purine-7-carboxamide; 6-amino-9-benzyl- N -butyl- N -ethyl -8-Penoxy-2-(propylsulfonylimide) purine-7-formamide; 6-amino-9-benzyl- N- (2-methoxyethyl)-8 -Penoxy- N -propyl-2-(propylsulfonylimide)purine-7-formamide; 6-amino-9-benzyl- N,N -bis(2-methoxy Ethyl)-8- pendant-2-(propylsulfonylimide) purine-7-carboxamide; 6-amino-7-(azetidine-1-carbonyl)- 9-benzyl-2-(propylsulfonylimide) purin-8-one; 6-amino-9-benzyl- N -isopropyl- N -methyl-8-oxo- 2-(propylsulfonylimideamide)purine-7-carboxamide; 6-amino-9-benzyl-7-(4-methylpiperazine-1-carbonyl)-2-(propyl Sulfonylimide) purin-8-one; 6-amino-9-benzyl- N- (3-methoxypropyl) -N -methyl-8-oxo-2-(propylene Sulfamoylimidamide)purine-7-methylamide; 6-amino-9-benzyl- N -isobutyl- N -methyl-8-oxo-2-(propylsulfonamide Iminyl)purine-7-carboxamide; 2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonyliminyl)purine-7-carbonyl ]-Methyl-amino] ethyl acetate; 3-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonylimide)purine-7-carbonyl] -Methyl-amino] ethyl propionate; 3-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7-carbonyl] -Methyl-amino] third butyl propionate; (2S)-2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide) Purine-7-carbonyl]-methyl-amino] propionic acid ethyl ester; (2S)-2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonyl sulfa Aminyl)purine-7-carbonyl]- Methyl-amino]-4-methyl-valeric acid third butyl ester; (2S)-2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonamide Imidyl)purine-7-carbonyl]-methyl-amino]-4-methyl-valeric acid isopropyl ester; (2S)-2-[[6-amino-9-benzyl-8- Pendant-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]-3-methyl-butyric acid ethyl ester; (2S)-2-[[6- Amino-9-benzyl-8-oxo-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]-4-methyl-valeric acid ethyl ester; (2S)-2-[[6-Amino-9-benzyl-8- pendant-2-(propylsulfonylimido)purine-7-carbonyl]-methyl-amino]- 3-Phenyl-propionic acid ethyl ester; (2S)-2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide acetyl)purine-7- Carbonyl]-methyl-amino]-3-phenyl-isopropyl propionate; (2S)-2-[[6-amino-9-benzyl-8-oxo-2-(propyl Sulfonylimide)purine-7-carbonyl]-methyl-amino]-3-phenyl-propionic acid tert-butyl ester; N- [2-[ethylamino(methyl)amino]ethyl Group]-6-amino-9-benzyl- N -methyl-8-pentoxy-2-(propylsulfonylimide)purine-7-carboxamide; N- [2-[ [6-Amino-9-benzyl-8-oxo-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]ethyl] -N -methyl -Methyl carbamate; N- [2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonylimide)purine-7-carbonyl]-methyl -Amino]ethyl] -N -methyl-carbamic acid third butyl ester; N- [2-[[6-amino-9-benzyl-8-oxo-2-(propyl Sulfonylimide)purine-7-carbonyl]-methyl-amino]ethyl] -N -methyl-ethyl carbamate; N -butyl- N -methyl-carbamic acid 2- [[6-Amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino] ethyl ester; pyrrolidine-1 -2-[[6-Amino-9-benzyl-8-oxo-2-(propylsulfonylimidoacetyl)purine-7-carbonyl]-methyl-amino]ethyl ester of formic acid; N- methyl- N -propyl-carbamic acid 2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonylimide acetyl)purine-7-carbonyl ]-Methyl-amino]ethyl ester; N,N -diethylaminocarboxylic acid 2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonimide Acetyl)purine-7-carbonyl]-methyl-amino]ethyl; 2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonyliminoamide) carbonate Group) purine-7-carbonyl]-methyl-amino]ethyl ethyl; 6-amine -N-Butyl-9-[(4-chlorophenyl)methyl]-N-methyl-8-oxo-2-[S(R)-propylsulfonylimide acetyl]purine -7-carboxamide; 6-amino-N-butyl-9-[(4-chlorophenyl)methyl]-N-methyl-8-oxo-2-[S(S)- Propylsulfonylimide]purine-7-carboxamide; 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl- N -methyl-8-side oxygen Yl-2-(propylsulfonylimide)purine-7-formamide; 6-amino- N -methyl-8-pentoxy- N -propyl-2[S(S)- Propylsulfonylimide]-9-(p-tolylmethyl)purine-7-formamide; 6-amino- N -methyl-8-oxo- N -propyl-2[ S(R)-propylsulfonylimide]-9-(p-tolylmethyl)purine-7-formamide; 6-amino-2-[S (S) -propylsulfonylamide Aminyl]-9-(p-tolylmethyl)-7-(pyrrolidin-1-carbonyl)purin-8-one; 6-amino-2-[S( R )-propylsulfonimide Acyl]-9-(p-tolylmethyl)-7-(pyrrolidin-1-carbonyl)purin-8-one; 6-amino- N- (2-methoxyethyl) -N- methyl 8-Penoxy-2-[S(S)-propylsulfonylimide]-9-(p-tolylmethyl)purine-7-carboxamide; 6-amino- N- (2-Methoxyethyl) -N- methyl-8-oxo-2-[S( R )-propylsulfonylimide acetyl]-9-(p-tolylmethyl)purine- 7-Methylamide; 6-Amino- N -ethyl- N- methyl-8-oxo-2-(propylsulfonylimideamide)-9-(p-tolylmethyl)purine -7-formamide; 6-amino- N -butyl- N -methyl-8-pentoxy-2-(propylsulfonylimide amide)-9-(p-tolylmethyl) Purine-7-methylamide; 6-amino-9-[(4-chlorophenyl)methyl]-2-[S( R )-ethylsulfonylimideamide]- N -methyl- 8-Penoxy- N -propyl-purine-7-carboxamide; 6-amino-9-[(4-chlorophenyl)methyl]-2-[S( S )-ethylsulfonamide Imino]]- N -methyl-8- pendant- N -propyl-purine-7-formamide; 6-amino-9-[(4-chlorophenyl)methyl] -N -Ethyl-2[S( S )-ethylsulfonylimide]- N -methyl-8-oxo-purine-7-methylamide; 6-amino-9-[(4 -Chlorophenyl)methyl] -N -ethyl-2-[S( R )-ethylsulfonylimide] -N -methyl-8-oxo-purine-7-methylamide ; 6-amino-2-[S( S )-ethylsulfonylimide] -N -methyl-8-oxo- N -propyl-9-(p-tolylmethyl Group) purine-7-carboxamide; 6-amino-2-[S( R )-ethylsulfonylimide] -N -methyl-8-oxo- N -propyl-9 -(P-tolylmethyl)purine-7-methylamide; 6-amino- N -ethyl-2[S(S)-ethylsulfonylimide] -N -methyl-8- Pendant-9-(p-tolylmethyl)purine-7-carboxamide; 6-amino- N -ethyl-2-[S( R )-ethylsulfonylimide] -N -Methyl-8-oxo-9-(p-tolylmethyl)purine-7-carboxamide; 6-amino-2-[S( S )ethylsulfonylimideamide]-9 -[(4-fluorophenyl)methyl] -N -methyl-8-oxo- N -propyl-purine-7-carboxamide; 6-amino-2-[S( R ) ethyl Sulfasulfonimide amide]-9-[(4-fluorophenyl)methyl] -N -methyl-8- pendant- N -propyl-purine-7-methylamide; 6-amine -N -ethyl-2-(ethylsulfonylimide)-9-[(4-fluorophenyl)methyl] -N -methyl-8-oxo-purine-7-methyl Acylamine; 6-amino- N -ethyl-2-[S( S )-(ethylsulfonylimide)]-9-[(4-fluorophenyl)methyl] -N -methyl Yl-8-oxo-purine-7-carboxamide; 6-amino- N -ethyl-2-[S( R )-(ethylsulfonylimide)]-9-[( 4-fluorophenyl)methyl] -N -methyl-8-oxo-purine-7-carboxamide; 6-amino-9-[(4-bromophenyl)methyl]-2- (Ethylsulfonylimide) -N- methyl-8-oxo- N -propyl-purine-7-methylamide; 6-amino-2-[S( R )-ethyl Sulfonylimide]-9-[(4-bromophenyl)methyl] -N -methyl-8-oxo- N -propyl-purine-7-methanamide; 6-amino -2-[S( S )-ethylsulfonylimide]-9-[(4-bromophenyl)methyl]- N -methyl-8-oxo- N -propyl-purine -7-formamide; 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-(ethylsulfonylimide) -N -methyl-8 -Penoxy-purine-7-carboxamide; 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-[S( S )-(ethylsulfonamide Iminamide)]- N -methyl-8-oxo-purine-7-carboxamide; and 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl -2-[S( R )-(ethylsulfonylimide)]- N -methyl-8-oxo-purine-7-methylamide; or a pharmaceutically acceptable salt thereof, Enantiomers or diastereomers; and the anti-angiogenic agents used in combination therapy are sorafenib, regofenib, and sunid Tenib or bevacizumab (preferably sorafenib or bevacizumab).

In a preferred embodiment of the present invention, the compound of formula I used in combination therapy with the anti-angiogenic agents described herein is selected from the following: 6-amino-9-[(4-chlorophenyl) Methyl] -N -ethyl-2[S( S )-ethylsulfonylimide] -N -methyl-8-oxo-purine-7-carboxamide; 6-amino- 9-[(4-chlorophenyl)methyl] -N -ethyl-2-[S( R )-ethylsulfonylimide] -N -methyl-8-oxo-purine- 7-formamide; 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-(ethylsulfonylimide) -N -methyl-8- Pendant-purine-7-carboxamide; 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-[S( S )-(ethylsulfonamide Amide)]- N -methyl-8-oxo-purine-7-methylamide; or 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl- 2-[S( R )-(ethylsulfonylimide)]- N -methyl-8-oxo-purine-7-methylamide; or its pharmaceutically acceptable salt, right Enantiomer or diastereomer; (in a preferred embodiment, 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl-2[S(S )-Ethylsulfonylimide] -N -methyl-8-oxo-purine-7-formamide); and the anti-angiogenic agents used in combination therapy are sorafenib and rego Finib, sunitinib or bevacizumab (preferably sorafenib or bevacizumab).

In a preferred embodiment of the present invention, the compound of formula I used in combination therapy with the antagonistic PD1 or antagonistic PD-L1 antibody and anti-angiogenic agent described herein is selected from the group consisting of: 6-amino- 9-benzyl-N-methyl-8-oxo-N-propyl-2-(propylsulfonylimide acetyl) purine-7-methylamide; 6-amino-9-benzyl -N-(2-methoxyethyl)-N-methyl-8- pendant-2-(propylsulfonylimide acetyl) purine-7-methyl amide; 6-amino-9 -Benzyl- N -ethyl-8-oxo- N -propyl-2-(propylsulfonylimide)purine-7-methylamide; 6-amino-9-benzyl- 7-[4-(1-piperidinyl)piperidin-1-carbonyl]-2-(propylsulfonylimidoacetinyl)purin-8-one; 6-amino-9-benzyl- N- Ethyl- N-( 2-methoxyethyl)-8- pendant-2-(propylsulfonylimide)purine-7-carboxamide; 6-amino-9-benzyl -N -butyl- N -ethyl-8- pendant-2-(propylsulfonylimide) purine-7-methylamide; 6-amino-9-benzyl- N- ( 2-methoxyethyl)-8- pendant- N -propyl-2-(propylsulfonylimide)purine-7-methylamide; 6-amino-9-benzyl- N,N -bis(2-methoxyethyl)-8- pendant-2-(propylsulfonylimide)purine-7-methylamide; 6-amino-7-(nitrogen Heterocyclobutane-1-carbonyl)-9-benzyl-2-(propylsulfonylimide)purin-8-one; 6-amino-9-benzyl- N -isopropyl- N -Methyl-8-oxo-2-(propylsulfonylimideamide)purine-7-formamide; 6-amino-9-benzyl-7-(4-methylpiperazine- 1-carbonyl)-2-(propylsulfonylimide)purin-8-one; 6-amino-9-benzyl- N- (3-methoxypropyl) -N -methyl- 8-Penoxy-2-(propylsulfonylimide) purine-7-formamide; 6-amino-9-benzyl- N -isobutyl- N -methyl-8-side Oxy-2-(propylsulfonylimide)purine-7-formamide; 2-[[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonyl Iminyl)purine-7-carbonyl]-methyl-amino] ethyl acetate; 3-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonamide Aminyl)purine-7-carbonyl]-methyl-amino] ethyl propionate; 3-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonyl sulfide Aminyl)purine-7-carbonyl]-methyl-amino]propionic acid tert-butyl ester; (2S)-2-[[6-amino-9-benzyl-8-oxo-2- (Propylsulfonylimide) Purine-7-carbonyl]-methyl-amino] ethyl propionate; (2S)-2-[[6-amino-9-benzyl-8-side oxygen Yl-2-(propylene Sulfamoylimidamide)purine-7-carbonyl]-methyl-amino]-4-methyl-valeric acid third butyl ester; (2S)-2-[[6-amino-9-benzyl Yl-8-oxo-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]-4-methyl-pentanoic acid isopropyl ester; (2S)-2 -[[6-Amino-9-benzyl-8-oxo-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]-3-methyl- Ethyl butyrate; (2S)-2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimido)purine-7-carbonyl]-methyl -Amino]-4-methyl-valeric acid ethyl ester; (2S)-2-[[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide amide ) Purine-7-carbonyl]-methyl-amino]-3-phenyl-propionic acid ethyl ester; (2S)-2-[[6-amino-9-benzyl-8-pentoxy-2 -(Propylsulfonylimide)purine-7-carbonyl]-methyl-amino]-3-phenyl-isopropyl propionate; (2S)-2-[[6-amino-9 -Benzyl-8-oxo-2-(propylsulfonylimide acetyl)purine-7-carbonyl]-methyl-amino]-3-phenyl-propionic acid third butyl ester; N- [2-[Ethyl(methyl)amino]ethyl]-6-amino-9-benzyl- N -methyl-8-oxo-2-(propylsulfonylimideamide) ) Purine-7-carboxamide; N- [2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7-carbonyl] -Methyl-amino]ethyl] -N -methyl-methyl carbamate; N- [2-[[6-amino-9-benzyl-8-oxo-2-(propyl Sulfonylimide)purine-7-carbonyl]-methyl-amino]ethyl] -N -methyl-aminocarbamic acid third butyl ester; N- [2-[[6-amino-9 -Benzyl-8-oxo-2-(propylsulfonylimide acetyl)purine-7-carbonyl]-methyl-amino]ethyl] -N -methyl-carbamic acid ethyl ester; N -Butyl- N -methyl-carbamic acid 2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide acetyl)purine-7-carbonyl ]-Methyl-amino] ethyl ester; pyrrolidine-1-carboxylic acid 2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine -7-carbonyl]-methyl-amino] ethyl; N- methyl- N -propyl-carbamic acid 2-[[6-amino-9-benzyl-8-oxo-2- (Propylsulfonylimide) purine-7-carbonyl]-methyl-amino]ethyl; N,N -diethylaminocarboxylic acid 2-[[6-amino-9-benzyl- 8-Penoxy-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]ethyl; 2-[[6-amino-9-benzyl-8 carbonate -Penoxy-2-(propylsulfonylimide)purine-7-carbonyl ]-Methyl-amino]ethyl ethyl; 6-amino-N-butyl-9-[(4-chlorophenyl)methyl]-N-methyl-8-oxo-2- [S(R)-propylsulfonylimide acetyl] purine-7-methylamide; 6-amino-N-butyl-9-[(4-chlorophenyl)methyl]-N-methyl 8-Penoxy-2-[S(S)-propylsulfonylimide]purine-7-methylamide; 6-amino-9-[(4-chlorophenyl)methyl ] -N -ethyl- N- methyl-8-oxo-2-(propylsulfonylimide)purine-7-methylamide; 6-amino- N -methyl-8- Pendant- N -propyl-2[S( S )-propylsulfonylimide]-9-(p-tolylmethyl)purine-7-methylamide; 6-amino- N- Methyl-8-oxo- N -propyl-2[S( R )-propylsulfonylimide]-9-(p-tolylmethyl)purine-7-methylamide; 6- Amino-2-[S (S) -propylsulfonyliminyl]-9-(p-tolylmethyl)-7-(pyrrolidin-1-carbonyl)purin-8-one; 6-amine Yl-2-[S( R )-propylsulfonylimide acetyl]-9-(p-tolylmethyl)-7-(pyrrolidin-1-carbonyl)purin-8-one; 6-amino -N -(2-methoxyethyl)- N- methyl-8-oxo-2-[S(S)-propylsulfonyliminyl]-9-(p-tolylmethyl ) Purine-7-methylamide; 6-amino- N- (2-methoxyethyl) -N- methyl-8-oxo-2-[S( R )-propylsulfonamide Aminyl]-9-(p-tolylmethyl)purine-7-carboxamide; 6-amino- N -ethyl- N -methyl-8-oxo-2-(propylsulfonamide Iminyl)-9-(p-tolylmethyl)purine-7-carboxamide; 6-amino- N -butyl- N -methyl-8-oxo-2-(propylsulfonate Acetamidoamide)-9-(p-tolylmethyl)purine-7-formamide; 6-amino-9-[(4-chlorophenyl)methyl]-2-[S( R ) -Ethylsulfonylimide] -N -methyl-8-pentoxy- N -propyl-purine-7-methylamide; 6-amino-9-[(4-chlorophenyl) Methyl]-2-[S( S )-ethylsulfonylimide]- N -methyl-8-oxo- N -propyl-purine-7-methylamide; 6-amino -9-[(4-chlorophenyl)methyl] -N -ethyl-2[S( S )-ethylsulfonylimide] -N -methyl-8-oxo-purine- 7-formamide; 6-amino-9-[(4-chlorophenyl)methyl]- N -ethyl-2-[S( R )-ethylsulfonylimide]- N- Methyl-8-oxo-purine-7-formamide; 6-amino-2-[S( S )-ethylsulfonylimide] -N -methyl- 8-Penoxy- N -propyl-9-(p-tolylmethyl)purine-7-carboxamide; 6-amino-2-[S( R )-ethylsulfonylimide] -N -methyl-8-oxo- N -propyl-9-(p-tolylmethyl)purine-7-carboxamide; 6-amino- N -ethyl-2[S(S) -Ethylsulfonylimide] -N -methyl-8-pentoxy-9-(p-tolylmethyl)purine-7-methylamide; 6-amino- N -ethyl-2 -[S( R )-ethylsulfonylimide]- N -methyl-8-oxo-9-(p-tolylmethyl)purine-7-methylamide; 6-amino- 2-[S( S )ethylsulfonylimide]-9-[(4-fluorophenyl)methyl]- N -methyl-8-oxo- N -propyl-purine-7 -Methamide; 6-amino-2-[S( R )ethylsulfonylimide]-9-[(4-fluorophenyl)methyl] -N -methyl-8-side oxygen -N -propyl-purine-7-methylamide; 6-amino- N -ethyl-2-(ethylsulfonylimideamide)-9-[(4-fluorophenyl)methyl ]- N -Methyl-8-oxo-purine-7-carboxamide; 6-amino- N -ethyl-2-[S( S )-(ethylsulfonylimide amide)] -9-[(4-fluorophenyl)methyl] -N -methyl-8-oxo-purine-7-carboxamide; 6-amino- N -ethyl-2-[S( R )-(Ethylsulfonylimide)]-9-[(4-fluorophenyl)methyl] -N -methyl-8-oxo-purine-7-methylamide; 6-amine Yl-9-[(4-bromophenyl)methyl]-2-(ethylsulfonylimide) -N- methyl-8-oxo- N -propyl-purine-7-methyl Acylamine; 6-amino-2-[S( R )-ethylsulfonylimide acetyl]-9-[(4-bromophenyl)methyl]- N -methyl-8-oxo -N -propyl-purine-7-carboxamide; 6-amino-2-[S( S )-ethylsulfonylimide]-9-[(4-bromophenyl)methyl] -N -methyl-8-oxo- N -propyl-purine-7-carboxamide; 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2 -(Ethylsulfonylimide) -N- methyl-8-oxo-purine-7-formamide; 6-amino-9-[(4-bromophenyl)methyl]- N -ethyl-2-[S( S )-(ethylsulfonylimide)]- N -methyl-8-oxo-purine-7-methylamide; and 6-amino- 9-[(4-Bromophenyl)methyl] -N -ethyl-2-[S( R )-(ethylsulfonylimide)]- N -methyl-8-oxo- Purine-7-carboxamide; or a pharmaceutically acceptable salt, enantiomer or diastereomer; and i) antagonistic The PD1 antibody is nivolumab or peclizumab or the heavy chain variable domain VH including SEQ ID NO: 5 and the light chain variable domain VL of SEQ ID NO: 6; ii) antagonistic PD-L1 The antibody is attuzumab or devarizumab or avilumumab (atrizumab in a preferred embodiment) and the anti-angiogenic agent used in combination therapy is sorafenib, Regofenib, sunitinib or bevacizumab (preferably sorafenib or bevacizumab).

In a preferred embodiment of the present invention, the compound of Formula I used in combination therapy with the antagonistic PD1 or antagonistic PD-L1 antibody and anti-angiogenic agent described herein is selected from the group consisting of: 6-amino- 9-[(4-chlorophenyl)methyl] -N -ethyl-2[S( S )-ethylsulfonylimide] -N -methyl-8-oxo-purine-7 -Formamide; 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl-2-[S( R )-ethylsulfonylimide] -N -methyl Yl-8-oxo-purine-7-carboxamide; 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-(ethylsulfonylimide amide Group)- N- methyl-8-oxo-purine-7-carboxamide; 6-amino-9-[(4-bromophenyl)methyl]- N -ethyl-2-[S ( S )-(ethylsulfonylimideamide)]- N -methyl-8-oxo-purine-7-carboxamide; or 6-amino-9-[(4-bromophenyl )Methyl]- N -ethyl-2-[S( R )-(ethylsulfonylimide)]- N -methyl-8-oxo-purine-7-methylamide; or A pharmaceutically acceptable salt, enantiomer or diastereomer; (in a preferred embodiment, 6-amino-9-[(4-chlorophenyl)methyl]- N -ethyl-2[S( S )-ethylsulfonylimide] -N -methyl-8-oxo-purine-7-formamide); and i) the antagonistic PD1 antibody is Nivolumab or peclizumab or the heavy chain variable domain VH comprising SEQ ID NO: 5 and the light chain variable domain VL of SEQ ID NO: 6; ii) the antagonistic PD-L1 antibody is Terizumab or devarizumab or avilumumab (atezuzumab in a preferred embodiment) and the anti-angiogenic agents used in combination therapy are sorafenib, regorafenib Ninety, sunitinib or bevacizumab (preferably sorafenib or bevacizumab). In the following, specific embodiments of the present invention are included :

， 其中 R¹ 為C_1-6 烷基； R² 為苄基，該苄基未經取代或經一個、兩個或三個獨立地選自鹵素及C_1-6 烷基之取代基取代； R³ 為-NR⁴ R⁵ ，其中 R⁴ 為C_1-6 烷基或C_1-6 烷氧基C_1-6 烷基； R⁵ 為(C_1-6 烷基)₂ NCOOC_1-6 烷基、C_1-6 烷氧基C_1-6 烷基、C_1-6 烷氧基羰基(C_1-6 烷基)胺基C_1-6 烷基、C_1-6 烷氧基羰基(苯基)C_1-6 烷基、C_1-6 烷氧基羰基C_1-6 烷基、C_1-6 烷氧基羰基氧基C_1-6 烷基、C_1-6 烷基、C_1-6 烷基羰基(C_1-6 烷基)胺基C_1-6 烷基或吡咯啶基胺甲醯基氧基C_1-6 烷基；或 R⁴ 及R⁵ 與其所連接之氮一起形成雜環基； 或其醫藥學上可接受之鹽、對映異構體或非對映異構體；(或其醫藥組合物或藥劑)； 其用於肝癌之治療或預防； 其限制條件為不包括 6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7-(吡咯啶-1-羰基)嘌呤-8-酮； 6-胺基-9-苄基-7-(哌啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(嗎啉-4-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3,3-二甲基吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 1-[6-胺基-9-苄基-8-側氧基-2-(丙基磺醯亞胺醯基)嘌呤-7-羰基]吡咯啶-2-甲酸乙酯； 6-胺基-7-(2-氮雜螺[3.3]庚烷-2-羰基)-9-苄基-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(2-氧雜-6-氮雜螺[3.3]庚烷-6-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3,3-二氟吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 6-胺基-9-苄基-7-(3-氟-3-甲基-吡咯啶-1-羰基)-2-(丙基磺醯亞胺醯基)嘌呤-8-酮； 及其對映異構體或非對映異構體。1. A compound of formula (I),

, Where 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 halogen and C _1-6 alkyl; R ³ is -NR ⁴ R ⁵ , wherein R ⁴ is C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl; R ⁵ is (C _1-6 alkyl) ₂ NCOOC _1-6 Alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxycarbonyl (C _1-6 alkyl) amine 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 alkylcarbonyl (C _1-6 alkyl) amine C _1-6 alkyl or pyrrolidinyl amine methylacetoxy C _1-6 alkyl; or R ⁴ and R ⁵ to which they are attached Together, nitrogen forms a heterocyclic group; or a pharmaceutically acceptable salt, enantiomer, or diastereomer; (or a pharmaceutical composition or agent thereof); it is used for the treatment or prevention of liver cancer; The restriction is that it does not include 6-amino-9-benzyl-2-(propylsulfonylimide)-7-(pyrrolidin-1-carbonyl)purin-8-one; 6-amino-9 -Benzyl-7-(piperidine-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; 6-amino-9-benzyl-7-(morpholin-4 -Carbonyl)-2-(propylsulfonylimide)purin-8-one; 6-amino-9-benzyl-7-(3,3-dimethylpyrrolidin-1-carbonyl)- 2-(propylsulfonylimide)purine-8-one; 1-[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide) purine -7-carbonyl]pyrrolidine-2-carboxylic acid ethyl ester; 6-amino-7-(2-azaspiro[3.3]heptane-2-carbonyl)-9-benzyl-2-(propylsulfonamide Imino) purin-8-one; 6-amino-9-benzyl-7-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-2-(propyl Sulfonylimide)purine-8-one; 6-amino-9-benzyl-7-(3,3-difluoropyrrolidine-1-carbonyl)-2-(propylsulfonylimide amide Group) purin-8-one; 6-amino-9-benzyl-7-(3-fluoro-3-methyl-pyrrolidine-1-carbonyl)-2-(propylsulfonylimide) Purine-8-one; and its enantiomers or diastereomers.

2. The compound for use as in embodiment 1, wherein R ¹ is C _1-6 alkyl; R ² is benzyl, the benzyl is 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 NCOOC _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _{1 -6} alkoxycarbonyl (C _1-6 alkyl) amine 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 alkylcarbonyl (C _1-6 alkyl) amine C _{1 -6} alkyl or pyrrolidinylamine methoxycarbonyl C _1-6 alkyl.

3. The compound for use as in Example 1 or 2, wherein R ¹ is ethyl or propyl; R ² is benzyl, bromobenzyl, chlorobenzyl, fluorobenzyl, or methylbenzyl; R ³ is nitrogen Heterocyclobutyl; 4-methylpiperazinyl; piperidinylpiperidinyl; pyrrolidinyl; or -NR ⁴ R ⁵ , where R ⁴ is methyl, ethyl, propyl or methoxyethyl; R ⁵ is acetyl(methyl)aminoethyl, butyl, butyl(methyl)amine, methyloxyethyl, diethylamine, methyloxyethyl, ethoxycarbonyl ( (Methyl)aminoethyl, ethoxycarbonylethyl, ethoxycarbonylisobutyl, ethoxycarbonylisopentyl, ethoxycarbonylmethyl, ethoxycarbonyloxyethyl, ethoxy Carbonyl (phenyl) ethyl, ethyl, isobutyl, isopropoxycarbonyl isopentyl, isopropoxycarbonyl (phenyl) ethyl, isopropyl, methoxycarbonyl (methyl) amine Ethyl, methoxyethyl, methoxypropyl, propyl, propyl (methyl)amine, methyloxyethyl, pyrrolidinylamine, methyloxyethyl, third butoxy Carbonyl (methyl) aminoethyl, third butoxycarbonyl ethyl, third butoxycarbonyl isopentyl or third butoxycarbonyl (phenyl) ethyl.

4. The compound for use as in Example 3, wherein R ³ is azetidinyl, 4-methylpiperazinyl, piperidinylpiperidinyl, pyrrolidinyl, acetyl(methyl)amino Ethyl(methyl)amino, bis(methoxyethyl)amino, butyl(ethyl)amino, butyl(methyl)amino, butyl(methyl)aminomethyloxy Ethyl (methyl)amino, diethylamine, methyloxyethyl (methyl)amino, ethoxycarbonyl (methyl)aminoethyl (methyl)amino, ethoxycarbonyl Ethyl (methyl) amino group, ethoxycarbonyl isobutyl (methyl) amino group, ethoxycarbonyl isopentyl (methyl) amino group, ethoxycarbonyl methyl (methyl) amino group, Ethoxycarbonyloxyethyl (methyl)amino, ethoxycarbonyl (phenyl)ethyl (methyl)amino, ethyl (methyl)amino, isobutyl (methyl)amino , Isopropoxycarbonyl isoamyl (methyl) amine, isopropoxycarbonyl (phenyl) ethyl (methyl) amine, isopropyl (methyl) amine, methoxycarbonyl (methyl )Aminoethyl(methyl)amino, methoxyethyl(ethyl)amino, methoxyethyl(methyl)amino, methoxyethyl(propyl)amino, methoxy Propyl propyl (methyl) amine, propyl (ethyl) amine, propyl (methyl) amine, propyl (methyl) amine, methyloxyethyl (methyl) amine, pyrrole Pyridylamine Methyloxyethyl (methyl)amino, third butoxycarbonyl (methyl)aminoethyl (methyl)amino, third butoxycarbonylethyl (methyl) Amino group, third butoxycarbonyl isopentyl (methyl) amino group or third butoxycarbonyl (phenyl) ethyl (methyl) amino group.

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

6. The compound for use as in embodiment 1 or 2, wherein R ² is benzyl substituted with halogen or C _1-6 alkyl.

7. The compound for use according to any one of embodiments 2 to 6, wherein R ² is bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl.

8. The compound for use as in Example 7, wherein R ² is bromobenzyl, chlorobenzyl or fluorobenzyl.

9. The compound for use as in embodiment 1 or 2, wherein R ³ is NR ⁴ R ⁵ , wherein R ⁴ is C _1-6 alkyl, and R ⁵ is C _1-6 alkyl.

10. The compound for use as in Example 9, wherein R ³ is propyl(methyl)amino or ethyl(methyl)amino.

11. The compound for use as in any one of embodiments 1, 2, 6 and 9, wherein R ¹ is C _1-6 alkyl; R ² is benzyl, the benzyl is halogen or C _1-6 alkyl R ³ is -NR ⁴ R ⁵ , wherein R ⁴ is C _1-6 alkyl, and R ⁵ is C _1-6 alkyl.

12. The compound for use as in Example 11, wherein R ¹ is ethyl; R ² is methylbenzyl, bromobenzyl, chlorobenzyl or fluorobenzyl; R ³ is propyl(methyl)amine or Ethyl (methyl) amine group.

13. A compound for the treatment or prevention of liver cancer, which is selected from the group consisting of: 6-amino-9-benzyl-N-methyl-8-oxo-N-propyl-2-(propylsulfonamide Iminyl)purine-7-methylamide; 6-amino-9-benzyl-N-(2-methoxyethyl)-N-methyl-8-oxo-2-(propylene Sulfamoyliminoacetamide)purine-7-methylamide; 6-amino-9-benzyl-N-ethyl-8-oxo-N-propyl-2-(propylsulfonamide Aminyl)purine-7-methylamide; 6-amino-9-benzyl-7-[4-(1-piperidinyl)piperidin-1-carbonyl]-2-(propylsulfonamide Amino) purin-8-one; 6-amino-9-benzyl- N -ethyl- N-( 2-methoxyethyl)-8-pentoxy-2-(propylsulfonyl Iminyl)purine-7-methylamide; 6-amino-9-benzyl- N -butyl- N -ethyl-8-oxo-2-(propylsulfonylimideamide) ) Purine-7-carboxamide; 6-amino-9-benzyl- N- (2-methoxyethyl)-8-pentoxy- N -propyl-2-(propylsulfonamide Aminyl)purine-7-methylamide; 6-amino-9-benzyl- N,N -bis(2-methoxyethyl)-8-pentoxy-2-(propylsulfonamide Iminyl)purine-7-carboxamide; 6-amino-7-(azetidine-1-carbonyl)-9-benzyl-2-(propylsulfonyliminamide)purine -8-keto; 6-amino-9-benzyl- N -isopropyl- N -methyl-8-pentoxy-2-(propylsulfonylimide acetyl) purine-7-methyl amide Amine; 6-amino-9-benzyl-7-(4-methylpiperazine-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; 6-amino- 9-benzyl- N- (3-methoxypropyl) -N- methyl-8-pentoxy-2-(propylsulfonylimide acetyl) purine-7-methyl amide; 6- Amino-9-benzyl- N -isobutyl- N -methyl-8-pentoxy-2-(propylsulfonylimide acetyl) purine-7-methylamide; 2-[[6 -Amino-9-benzyl-8-oxo-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]ethyl acetate; 3-[[6- Amino-9-benzyl-8-oxo-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]propionic acid ethyl ester; 3-[[6- Amino-9-benzyl-8-oxo-2-(propylsulfonyliminyl)purine-7-carbonyl]-methyl-amino]propionic acid tert-butyl ester; (2S)- 2-[[6-Amino-9-benzyl-8-oxo-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]propionic acid ethyl ester; (2S)-2-[[6-Amino-9-benzyl-8- pendant-2-(propylsulfonylimido)purine-7-carbonyl]-methyl-amino]- 3-Butyl 4-methyl-valerate; (2S)-2-[ [6-Amino-9-benzyl-8-oxo-2-(propylsulfonylimido)purine-7-carbonyl]-methyl-amino]-4-methyl-pentanoic acid Isopropyl ester; (2S)-2-[[6-Amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7-carbonyl]-methyl- Amino]-3-methyl-butyric acid ethyl ester; (2S)-2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide) Purine-7-carbonyl]-methyl-amino]-4-methyl-valeric acid ethyl ester; (2S)-2-[[6-amino-9-benzyl-8-oxo-2- (Propylsulfonylimide) purine-7-carbonyl]-methyl-amino]-3-phenyl-propionic acid ethyl ester; (2S)-2-[[6-amino-9-benzyl Yl-8-oxo-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]-3-phenyl-isopropyl propionate; (2S)-2 -[[6-Amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]-3-phenyl- Third butyl propionate; N- [2-[acetyl(methyl)amino]ethyl]-6-amino-9-benzyl-N-methyl-8-oxo-2- (Propylsulfonylimide)purine-7-formamide; N- [2-[[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide Acetyl)purine-7-carbonyl]-methyl-amino]ethyl] -N -methyl-carbamic acid methyl ester; N- [2-[[6-amino-9-benzyl-8- Pendant-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]ethyl] -N -methyl-carbamic acid third butyl ester; N- [2 -[[6-Amino-9-benzyl-8-oxo-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]ethyl]- N- Ethyl methyl-carbamate; N -butyl- N -methyl-carbamic acid 2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonamide Aminyl)purine-7-carbonyl]-methyl-amino]ethyl; pyrrolidine-1-carboxylic acid 2-[[6-amino-9-benzyl-8-oxo-2-(propylene Sulfamoylimidamide)purine-7-carbonyl]-methyl-amino]ethyl; N- methyl- N -propyl-carbamic acid 2-[[6-amino-9-benzyl -8-Penoxy-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]ethyl; N,N -diethylaminocarboxylic acid 2-[[6 -Amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]ethyl ester; carbonic acid 2-[[6- Amino-9-benzyl-8-oxo-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]ethyl ethyl; 6-amino-N -Butyl-9-[(4-chlorophenyl)methyl]-N-methyl-8-side oxygen Yl-2-[S(R)-propylsulfonylimide acetyl]purine-7-methylamide; 6-amino-N-butyl-9-[(4-chlorophenyl)methyl] -N-methyl-8-oxo-2-[S(S)-propylsulfonylimide]purine-7-methylamide; 6-amino-9-[(4-chlorobenzene Yl)methyl] -N -ethyl- N- methyl-8-oxo-2-(propylsulfonylimide acetyl)purine-7-methylamide; 6-amino- N -methyl Yl-8-oxo- N -propyl-2[S(S)-propylsulfonylimide]-9-(p-tolylmethyl)purine-7-methylamide; 6-amine -N -Methyl-8-oxo- N -propyl-2[S(R)-propylsulfonylimide]-9-(p-tolylmethyl)purine-7-formyl Amine; 6-amino-2-[S (S) -propylsulfonylimido]-9-(p-tolylmethyl)-7-(pyrrolidin-1-carbonyl)purin-8-one ; 6-amino-2-[S( R )-propylsulfonylimide acetyl]-9-(p-tolylmethyl)-7-(pyrrolidin-1-carbonyl)purin-8-one; 6-Amino- N- (2-methoxyethyl) -N- methyl-8-pentoxy-2-[S(S)-propylsulfonylimide]-9-(pair Tolylmethyl)purine-7-carboxamide; 6-amino- N- (2-methoxyethyl) -N- methyl-8-oxo-2-[S( R )-propylene Sulfonylimide]-9-(p-tolylmethyl)purine-7-formamide; 6-amino- N -ethyl- N -methyl-8-oxo-2-( Propylsulfonyliminamide)-9-(p-tolylmethyl)purine-7-formamide; 6-amino- N -butyl- N -methyl-8-oxo-2- (Propylsulfonylimideamide)-9-(p-tolylmethyl)purine-7-formamide; 6-amino-9-[(4-chlorophenyl)methyl]-2-[ S( R )-ethylsulfonylimide]- N -methyl-8-oxo- N -propyl-purine-7-methylamide; 6-amino-9-[(4- Chlorophenyl)methyl]-2-[S( S )-ethylsulfonylimide] -N -methyl-8-oxo- N -propyl-purine-7-methylamide; 6-Amino-9-[(4-chlorophenyl)methyl] -N -ethyl-2[S( S )-ethylsulfonylimide] -N -methyl-8-side oxygen -Purine-7-methylamide; 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl-2-[S( R )-ethylsulfonylimideamide ]- N -methyl-8-oxo-purine-7-carboxamide; 6-amino-2-[S( S )-ethylsulfonylimide]- N -methyl-8 -Penoxy- N -propyl-9-(p-tolylmethyl)purine-7-carboxamide; 6-amino-2-[S( R )-ethylsulfonate Amidimide] -N -methyl-8-oxo- N -propyl-9-(p-tolylmethyl)purine-7-methylamide; 6-amino- N -ethyl- 2[S(S)-ethylsulfonylimide] -N -methyl-8-oxo-9-(p-tolylmethyl)purine-7-methylamide; 6-amino- N -ethyl-2-[S( R )-ethylsulfonylimide]- N -methyl-8-oxo-9-(p-tolylmethyl)purine-7-methylamide ; 6-amino-2-[S( S ) ethylsulfonylimide]-9-[(4-fluorophenyl)methyl] -N -methyl-8-oxo- N- Propyl-purine-7-formamide; 6-amino-2-[S( R )ethylsulfonylimide]-9-[(4-fluorophenyl)methyl] -N -methyl Yl-8-oxo- N -propyl-purine-7-carboxamide; 6-amino- N -ethyl-2-(ethylsulfonylimide)-9-[(4- Fluorophenyl)methyl] -N -methyl-8-oxo-purine-7-carboxamide; 6-amino- N -ethyl-2-[S( S )-(ethylsulfonamide Iminamide)]-9-[(4-fluorophenyl)methyl] -N -methyl-8-oxo-purine-7-methylamide; 6-amino- N -ethyl- 2-[S( R )-(ethylsulfonylimide)]-9-[(4-fluorophenyl)methyl]- N -methyl-8-oxo-purine-7-methyl Acylamine; 6-amino-9-[(4-bromophenyl)methyl]-2-(ethylsulfonylimide) -N -methyl-8-oxo- N -propyl -Purine-7-carboxamide; 6-amino-2-[S( R )-ethylsulfonylimide]-9-[(4-bromophenyl)methyl]- N -methyl -8-Penoxy- N -propyl-purine-7-carboxamide; 6-amino-2-[S( S )-ethylsulfonylimide]-9-[(4-bromo Phenyl)methyl] -N -methyl-8-oxo- N -propyl-purine-7-carboxamide; 6-amino-9-[(4-bromophenyl)methyl]- N -ethyl-2-(ethylsulfonylimide) -N- methyl-8-oxo-purine-7-formamide; 6-amino-9-[(4-bromobenzene Yl)methyl] -N -ethyl-2-[S( S )-(ethylsulfonylimide)]- N -methyl-8-oxo-purine-7-methylamide; And 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-[S( R )-(ethylsulfonylimide)]- N -methyl- 8-Penoxy-purine-7-carboxamide; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

14. The compound of embodiment 13, which is selected from: 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl-2[S( S )-ethylsulfonylimide Acyl] -N -methyl-8-oxo-purine-7-carboxamide; 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl-2-[ S( R )-ethylsulfonylimide]- N -methyl-8-oxo-purine-7-methylamide; 6-amino-9-[(4-bromophenyl)methyl Group] -N -ethyl-2-(ethylsulfonylimide) -N- methyl-8-oxo-purine-7-methylamide; 6-amino-9-[(4 -Bromophenyl)methyl] -N -ethyl-2-[S( S )-(ethylsulfonylimide)]- N -methyl-8-oxo-purine-7-methyl Amide; and 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-[S( R )-(ethylsulfonylimide amide)]- N- Methyl-8-oxo-purine-7-carboxamide; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

14. The compound for use as in embodiment 13, wherein the compound is 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl-2[S( S )-ethyl Sulfonylimide] -N -methyl-8-oxo-purine-7-methylamide.

16. The compound or pharmaceutically acceptable salt, enantiomer or diastereomer as in any one of embodiments 1 to 15, wherein the liver cancer is hepatocellular carcinoma, liver cancer, cholangiocarcinoma, liver Blastoma, hepatocellular carcinoma, hepatic angiosarcoma or metastatic liver cancer.

17. The compound or pharmaceutically acceptable salt, enantiomer or diastereomer of any one of embodiments 1 to 15, 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, which is used for the treatment or prevention of liver cancer.

19. The 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, the method comprising administering a therapeutically effective amount of a compound according to any one of Examples 1 to 15.

21. A compound as claimed in any one of embodiments 1 to 15, or a pharmaceutical composition or medicament comprising such a compound, for use in a) Combination with antagonistic PD1 antibody or antagonistic PD-L1 antibody to treat or prevent liver cancer, or b) Treatment of patients with liver cancer in combination with antagonistic PD1 antibody or antagonistic PD-L1 antibody.

22. A compound according to any one of embodiments 1 to 15, or a pharmaceutical composition or medicament comprising such a compound, It is used for the treatment or prevention of liver cancer The treatment is combined with antagonistic PD1 antibody or antagonistic PD-L1 antibody.

23. Use of a compound as in any one of embodiments 1 to 15; It is used to prepare a medicament for the treatment or prevention of liver cancer The treatment is combined with antagonistic PD1 antibody or antagonistic PD-L1 antibody.

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

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

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

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

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

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

30. The compound, composition, medicament or use as in Example 29, Wherein the antagonist PD-L1 antibody used in the combination therapy is atezumab or devarizumab or avilimumab (atrizumab in a preferred embodiment).

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

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

33. The compound, composition, medicament or use according to any one of embodiments 21 to 31, wherein the additional anti-angiogenic agent is selected from sorafenib, regofenib, sunitinib or bevacizumab (In a preferred embodiment, the anti-angiogenic agent is sorafenib; in a preferred embodiment, the anti-angiogenic agent is bevacizumab) for use in the combination therapy.

34. A compound as claimed in any one of embodiments 1 to 15, or a pharmaceutical composition or medicament comprising such a compound, for use in a) Combined with anti-angiogenic agents to treat or prevent liver cancer, or b) Treatment of patients with liver cancer in combination with anti-angiogenic agents.

35. A compound according to any one of embodiments 1 to 15, or a pharmaceutical composition or medicament comprising such a compound, It is used for the treatment or prevention of liver cancer Wherein the treatment is combined with anti-angiogenic agents.

36. The use of a compound as in any one of embodiments 1 to 15; It is used to prepare a medicament for the treatment or prevention of liver cancer Wherein the treatment is combined with anti-angiogenic agents.

37. The compound, composition, medicament, or use of any one of embodiments 34 to 36, wherein the anti-angiogenic agent is selected from sorafenib, regofenib, sunitinib, or bevacizumab ( In a preferred embodiment, the anti-angiogenic agent is sorafenib; in a preferred embodiment, the anti-angiogenic agent is bevacizumab).

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

39. The invention is as described above.

Description of amino acid sequence SEQ ID NO: 1 heavy chain variable domain of anti-PD1 antibody nivolumab SEQ ID NO: 2 anti-PD1 antibody light chain variable domain of nivolumab SEQ ID NO: 3 anti PD1 antibody heavy chain variable domain of peclizumab SEQ ID NO: 4 anti-PD1 antibody light chain variable domain of peclizumab SEQ ID NO: 5 heavy chain of anti-PD1 antibody PD1-0103-0312 Variable domain 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 Atezumab SEQ ID NO: 8 Light chain variable domain of anti-PD-L1 antibody Atezumab SEQ ID NO: 9 Heavy chain variable domain of anti-PD-L1 antibody Devaruzumab SEQ ID NO: 10 Anti-PD-L1 antibody German Varuzumab light chain variable domain SEQ ID NO: 11 anti-PD-L1 antibody avilumumab heavy chain variable domain SEQ ID NO: 12 anti-PD-L1 antibody avilumumab light Chain variable domain SEQ ID NO: 13 Exemplary human PD-L1 SEQ ID NO: 14 Exemplary human PD1 SEQ ID NO: 15 Human κ 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 on L234A, L235A, P329G

Examples The present invention will be more fully understood with reference to the following examples. However, it should not be interpreted as limiting the scope of the invention.

abbreviation aq. water-based BSA:N,O- Bis(trimethylsilyl)acetamide CDI:N,N ' -Carbonyldiimidazole DIEPA:N,N- Diethylpropylamine DBU: 1,8-diazabicycloundec-7-ene DPPA: Diphenylphosphoryl azide EC₅₀ : The molar concentration of the agonist that produces a 50% maximum possible response to the agonist. EDC:N 1-((ethylimino)methylene)-N 3,N 3-dimethylpropane-1,3-diamine EtOAc or EA: ethyl acetate HATU: (3-oxyhexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine) hr(s): hour HPLC: high performance liquid chromatography HOBt:N- Hydroxybenzotriazole MS (ESI): Mass spectrometry (electrospray ionization) m-CPBA: 3-chloroperbenzoic acid MTEB: methyl tertiary butyl ether NMP:N- Methylpyrrolidone obsd: observed value PE: Petroleum ether PMB: p-methoxybenzyl PPA: polyphosphoric acid QOD every other day QW once a week RT or rt: room temperature sat. TFA: trifluoroacetic acid TEA: Triethylamine V/V volume ratio

General experimental conditions Intermediate products 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. Silicone brand and pore size: i) KP-SIL 60 Å, particle size: 40-60 µm; ii) CAS registration number: Silica Gel: 63231-67-4, particle size: 47-60 micron silicone; iii) purchased from Qingdao ZCX of Haiyang Chemical Co., Ltd, hole: 200-300 or 300-400.

Using preparative HPLC on reverse phase columns, use X Bridge ^TM Perp C ₁₈ (5 µm, OBD ^TM 30×100 mm) columns or SunFire ^TM Perp C ₁₈ (5 µm, OBD ^TM 30×100 mm) tubes The column purifies the intermediate product and the final compound.

LC/MS spectrum was obtained using Waters UPLC-SQD Mass. Standard LC/MS conditions are as follows (operation time 3 minutes): Acidic conditions: A: H ₂ O containing 0.1% formic acid and 1% acetonitrile; B: Acetonitrile containing 0.1% formic acid; Alkaline conditions: A: containing 0.05% NH _3. H ₂ O of H ₂ O; B: acetonitrile.

Mass spectra (MS): usually only ions indicating the mass of the parent nucleus are reported, and unless otherwise stated, the mass ions quoted are positive mass ions (M+H) ⁺ .

The NMR spectrum was obtained using Bruker Avance 400 MHz.

All reactions involving air-sensitive reagents are carried out under an argon atmosphere. Unless otherwise indicated, the reagents were used as is from commercial suppliers without further purification.

Preparative examples Preparation of intermediate products

Intermediate AA N- methyl chloride - N- propyl - carbamoyl XI

To a mixture of N -methylpropane-1-amine (5 g, 68.4 mmol) and sodium bicarbonate (11.5 g, 137 mmol) in DCM (70 mL) was added dropwise bis(tricarbonate) at 0°C. Chloromethyl ester) (8.11 g, 27.3 mmol) in DCM (30 mL). The mixture was stirred at room temperature for 2 hours and filtered. The filtrate was concentrated under vacuum. The obtained chlorinated N-methyl-N-propyl-aminoformamide (7.2 g, intermediate product AA ) was used in the next step without further purification.

Intermediate AB chloride N- (2- methoxyethyl) - N- methyl - carbamoyl XI

The intermediate product AB is prepared similarly to the intermediate product AA by using 2-methoxy- N -methyl-ethylamine instead of N -methylpropane-1-amine. N- (2-methoxyethyl)-N-methyl-aminoformamide chloride (8 g, intermediate product AB ) was obtained and used in the next step without further purification.

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

The intermediate product AC is prepared similarly to the intermediate product AA by using N -ethylpropan-1-amine instead of N -methylpropane-1-amine. N -ethyl- N -propyl-aminoformamide chloride (12.6 g, intermediate product AC ) was obtained as a yellow oil and used in the next step without further purification.

Intermediate product AD chloride N- ethyl - N- (2 -methoxyethyl )

The intermediate product AD is prepared similarly to the intermediate product AA by using N -ethyl-2-methoxyethylamine instead of N -methylpropane-1-amine. Crude N -ethyl- N- (2-methoxyethyl)aminecarboxamide (2.5 g, intermediate product AD ) was obtained as a pale yellow oil and used in the next step without further purification.

Intermediate product AE chloride N - butyl - N - ethyl - amine

Similar to intermediate product AA, intermediate product AE was prepared by using N -ethylbutan-1-amine (5 g) instead of N -methylpropane-1-amine. Crude N -butyl- N -ethyl-aminecarboxamide (6.3 g, intermediate product AE ) was obtained as a pale yellow oil and used in the next step without further purification.

Intermediate AF chloride N- (2- methoxyethyl) - N- propyl - carbamoyl XI

Similar to intermediate product AA , intermediate product AF was prepared by using N- (2-methoxyethyl)propane-1-amine (2 g, 17.1 mmol) instead of N -methylpropane-1-amine. The crude N- (2-methoxyethyl) -N -propyl-aminecarboxamide (2.5 g, intermediate product AF ) was obtained as a light yellow oil and used in the next step without further purification.

Intermediate G chloride N,N- bis (2 -methoxyethyl ) amine formamide

Similar to intermediate product AA , intermediate product AG was prepared by using bis(2-methoxyethyl)amine (2 g, 15 mmol) instead of N -methylpropane-1-amine. Crude N,N-bis(2-methoxyethyl)aminecarboxamide (2.6 g, intermediate product AG ) was obtained as a pale yellow oil and used in the next step without further purification.

Intermediate product AH azetidine- 1- carbonyl

Similar to the intermediate product AA by using azetidine hydrochloride (10.7 g, 107 mmol) and sodium bicarbonate (3 equivalents) instead of N -methylpropane-1-amine and sodium bicarbonate (2 equivalents) To prepare intermediate product AH . The crude azetidine-1-carbonyl (1.5 g, intermediate product AH ) was obtained as a light yellow oil and used in the next step without further purification.

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

Similar to intermediate product AA , intermediate product AI was prepared by using N -methylpropane-2-amine (5 g, 19.4 mmol) instead of N -methylpropane-1-amine. The crude N -isopropyl- N -methyl-aminecarboxamide (8.6 g, intermediate product AI ) was obtained as a yellow oil and used in the next step without further purification.

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

Similar to the intermediate product AA, the intermediate product AL was prepared by using N -2-dimethylpropane-1-amine (4.8 g) instead of N -methylpropane-1-amine. Crude N -isobutyl- N -methyl-aminecarboxamide (8.1 g, intermediate product AL ) was obtained as a pale yellow oil and used in the next step without further purification.

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

To a solution of triphosgene (728 mg, 2.45 mmol) in DCM (5 mL) at 0°C was added dropwise 2-(methylamino) ethyl acetate hydrochloride (1.3 g, 8.46 mmol) and pyridine ( 1 mL) in DCM (5 mL). The reaction mixture turned orange and a yellow precipitate appeared, then it was allowed to warm to room temperature. After stirring for 1 hour, an aqueous HCl solution (0.1 N, 25 mL) was added to the reaction mixture, and the organic layer was separated, washed twice with 0.1 N HCl (10 mL), washed with brine (10 mL), and washed with Na ₂ SO ₄ Dry and concentrate under vacuum to give crude ethyl 2-[chlorocarbonyl(methyl)amino]acetate (2.0 g, intermediate product AP ) as a light yellow oil and use in the next step without further purification.

Intermediate product AR 3-[ chlorocarbonyl ( methyl ) amino ] propionate tert - butyl ester

在-45℃下向丙烯酸第三丁酯(3 g)於DMF (40 mL)中之溶液中添加甲胺鹽酸鹽(4.74 g，70 mmol)及DBU (21.4 g，140 mmol)。隨後使反應溫度升溫至-10℃。在相同溫度下攪拌反應混合物2.5小時。添加Et₂ O (200 mL)且將所得混合物用鹽水(50 mL)洗滌四次。經分離的有機層經Na₂ SO₄ 乾燥且在真空下濃縮，得到呈淡黃色油狀之3-(甲胺基)丙酸第三丁酯(3.5 g，化合物 AR-1 )。 Step 1 : Preparation of tert- butyl 3-( methylamino ) propionate ( Compound AR-1)

To a solution of tert-butyl acrylate (3 g) in DMF (40 mL) was added methylamine hydrochloride (4.74 g, 70 mmol) and DBU (21.4 g, 140 mmol) at -45°C. The reaction temperature was subsequently increased 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 four times with brine (50 mL). The separated organic layer was dried over Na ₂ SO ₄ and concentrated under vacuum to give tert-butyl 3-(methylamino)propionate (3.5 g, compound AR-1 ) as a pale yellow oil.

類似於中間產物 AP 藉由使用3-(甲胺基)丙酸第三丁酯(3.4 g，化合物 AR-1 )而非2-(甲胺基)乙酸乙酯鹽酸鹽來製備中間產物 AR 。獲得粗製3-[氯羰基(甲基)胺基]丙酸第三丁酯(3.5 g，中間產物 AR )且不經進一步純化即用於下一步驟。 Step 2 : Preparation of 3-[ chlorocarbonyl ( methyl ) amino ] propionic acid tert - butyl ester ( intermediate product AR)

Similar to intermediate product AP , intermediate product AR was prepared by using tertiary butyl 3-(methylamino)propionate (3.4 g, compound AR-1 ) instead of 2-(methylamino)ethyl acetate hydrochloride . Crude 3-[chlorocarbonyl(methyl)amino]propionic acid third butyl ester (3.5 g, intermediate product AR ) was obtained and used in the next step without further purification.

Intermediate product AS (2S)-2-[ chlorocarbonyl ( methyl ) amino ] ethyl propionate

在0℃下在0.5小時內向(2S)-2-(甲胺基)丙酸(1 g, 9.70 mmol)於EtOH (10 mL)中之溶液中逐滴添加SOCl₂ (1.50 g, 12.61 mmol)。在25℃將反應混合物攪拌15.5小時，隨後用EA (20 mL)稀釋，用H₂ O (5 mL)及鹽水(5 mL)洗滌。有機層經Na₂ SO₄ 乾燥且在真空下濃縮。獲得呈黃色油狀之(2S)-2-(甲胺基)丙酸乙酯鹽酸鹽(1.8 g，化合物 AS -1 )且不經進一步純化即用於下一步驟。 Step 1 : Preparation of (2S)-2-( methylamino ) ethyl propionate hydrochloride ( Compound AS -1)

To a solution of (2S)-2-(methylamino)propionic acid (1 g, 9.70 mmol) in EtOH (10 mL) was added SOCl ₂ (1.50 g, 12.61 mmol) dropwise at 0°C within 0.5 hours . The reaction mixture was stirred at 25° C. for 15.5 hours, then diluted with EA (20 mL), washed with H ₂ O (5 mL) and brine (5 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under vacuum. (2S)-2-(Methylamino) propionic acid ethyl ester hydrochloride (1.8 g, compound AS -1 ) was obtained as a yellow oil and used in the next step without further purification.

藉由10 wt% NaHCO₃ 水溶液將(2S)-2-(甲胺基)丙酸乙酯鹽酸鹽(1.8 g，化合物 AS-1 )於EA (10 mL)中之溶液調節至pH = 8。將反應混合物在室溫下攪拌0.5小時。有機層用鹽水(5 mL)洗滌，經Na₂ SO₄ 乾燥且在真空下濃縮。獲得呈黃色油狀之(2S)-2-(甲胺基)丙酸乙酯(620 mg，化合物 AS-2 )且不經進一步純化即用於下一步驟。 Step 2 : Preparation of (2S)-2-( methylamino ) ethyl propionate ( Compound AS-2)

A solution of (2S)-2-(methylamino) propionic acid ethyl ester hydrochloride (1.8 g, compound AS-1 ) in EA (10 mL) was adjusted to pH = 8 with 10 wt% NaHCO ₃ aqueous solution . The reaction mixture was stirred at room temperature for 0.5 hour. The organic layer was washed with brine (5 mL), dried over Na ₂ SO ₄ and concentrated under vacuum. Ethyl (2S)-2-(methylamino)propanoate (620 mg, compound AS-2 ) was obtained as a yellow oil and used in the next step without further purification.

類似於中間產物 AP 藉由使用(2S)-2-(甲胺基)丙酸乙酯(260 mg，化合物 AS -2 )而非2-(甲胺基)乙酸乙酯鹽酸鹽來製備中間產物 AS 。獲得呈黃色油狀之粗製(2S)-2-[氯羰基(甲基)胺基]丙酸乙酯(200 mg，中間產物 AS )且不經進一步純化即用於下一步驟。 Step 3 : Preparation of (2S)-2-[ chlorocarbonyl ( methyl ) amino ] ethyl propionate ( intermediate product AS )

AP by the use of similar intermediate (2S) -2- (methylamino) propanoate (260 mg, Compound AS -2) instead of 2- (methylamino) acetate hydrochloride was prepared intermediate Product AS . Crude ethyl (2S)-2-[chlorocarbonyl(methyl)amino]propionate (200 mg, intermediate product AS ) was obtained as a yellow oil and used in the next step without further purification.

Intermediate product AT (2S)-2-[ chlorocarbonyl ( methyl ) amino ]-4 -methyl - pentanoic acid tert - butyl ester

在-78℃下將2-甲基丙烯(25 g，446 mmol)鼓泡至DCM (50 mL)中。隨後在0℃下將2-甲基丙烯溶液中添加至(S)-4-甲基-2-(甲胺基)戊酸鹽酸鹽(500 mg，2.75 mmol)及H₂ SO₄ (3.68 g，2 mL，37.5 mmol)於二噁烷(20 mL)中之溶液中。將反應混合物在室溫下於密封管內攪拌18小時。將反應溶液倒入至冰冷的KOH水溶液(8.4 g於水(30 mL)中)中且將所得混合物用DCM (50 mL)萃取兩次。經合併之有機層用鹽水(30 mL)洗滌兩次，經Na₂ SO₄ 乾燥且在真空下濃縮，得到呈淡黃色油狀之粗產物(2S)-4-甲基-2-(甲胺基)戊酸第三丁酯(化合物 AT-1 )。 Step 1: (2S) -4- methyl-2- (methylamino) pentanoic acid tert-butyl ester (Compound AT-1) Preparation of

2-Methylpropene (25 g, 446 mmol) was bubbled into DCM (50 mL) at -78 °C. The 2-methacrylic acid solution was then added to (S)-4-methyl-2-(methylamino) valerate hydrochloride (500 mg, 2.75 mmol) and H ₂ SO ₄ (3.68 g, 2 mL, 37.5 mmol) in a solution of dioxane (20 mL). The reaction mixture was stirred in a sealed tube at room temperature for 18 hours. The reaction solution was poured into an ice-cold aqueous KOH solution (8.4 g in water (30 mL)) and the resulting mixture was extracted twice with DCM (50 mL). The combined organic layer was washed twice with brine (30 mL), dried over Na ₂ SO ₄ and concentrated under vacuum to give the crude product (2S)-4-methyl-2-(methylamine as a pale yellow oil Radical) tert-butyl valerate ( compound AT-1 ).

類似於中間產物 AP 藉由使用(2S)-4-甲基-2-(甲胺基)戊酸第三丁酯(300 mg，化合物 AT-1 )而非2-(甲胺基)乙酸乙酯鹽酸鹽來製備中間產物 AT 。獲得呈淡黃色油狀之粗製(2S)-2-[氯羰基(甲基)胺基]-4-甲基-戊酸第三丁酯(350 mg，中間產物 AT )且不經進一步純化即用於下一步驟。 Step 2: (2S) -2- -4- methyl [chloro carbonyl (methyl) amino] - pentanoic acid tert-butyl ester (Intermediate AT) Preparation of

Similar to the intermediate product AP by using (2S)-4-methyl-2-(methylamino)pentanoic acid tert-butyl ester (300 mg, compound AT-1 ) instead of 2-(methylamino)ethyl acetate Ester hydrochloride to prepare the intermediate product AT . The crude (2S)-2-[chlorocarbonyl(methyl)amino]-4-methyl-pentanoic acid third butyl ester (350 mg, intermediate product AT ) was obtained as a pale yellow oil without further purification Used in the next step.

Intermediate AU (2S)-2-[ chlorocarbonyl ( methyl ) amino ]-4 -methyl - pentanoic acid isopropyl ester

在室溫下向(S)-4-甲基-2-(甲胺基)戊酸鹽酸鹽(0.5 g)於i- PrOH (7.8 g，10 mL)中之溶液中逐滴添加亞硫醯氯(655 mg，402 µL)。將所得混合物攪拌且回流持續16小時且隨後在真空下濃縮。將殘餘物用NaHCO₃ (30 mL)飽和水溶液鹼化且用DCM (50 mL)萃取。有機層用鹽水洗滌，經Na₂ SO₄ 乾燥且在真空下濃縮。將殘餘物用HCl/EtOAc (10 mL，1 mmol/mL)成鹽且濃縮，得到呈白色固體之(2S)-4-甲基-2-(甲胺基)戊酸異丙酯鹽酸鹽(510 mg，化合物 AU-1 )。 Step 1 : Preparation of (2S)-4 -methyl -2-( methylamino ) valeric acid isopropyl ester hydrochloride ( Compound AU-1)

To a solution of (S)-4-methyl-2-(methylamino)valerate hydrochloride (0.5 g) in i- PrOH (7.8 g, 10 mL) was added dropwise sulfite at room temperature Acyl chloride (655 mg, 402 µL). The resulting mixture was stirred and refluxed for 16 hours and then concentrated under vacuum. The residue was basified with saturated aqueous NaHCO ₃ (30 mL) and extracted with DCM (50 mL). The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was salted with HCl/EtOAc (10 mL, 1 mmol/mL) and concentrated to give (2S)-4-methyl-2-(methylamino)pentanoic acid isopropyl ester hydrochloride as a white solid (510 mg, compound AU-1 ).

類似於中間產物 AP 藉由使用(2S)-4-甲基-2-(甲胺基)戊酸異丙酯鹽酸鹽(500 mg，化合物 AU-1 )而非2-(甲胺基)乙酸乙酯鹽酸鹽來製備中間產物 AU 。獲得呈淡黃色油狀之粗製(2S )-2-[氯羰基(甲基)胺基]-4-甲基-戊酸異丙酯(650 mg，中間產物 AU )且不經進一步純化即用於下一步驟。 Step 2 : Preparation of (2 S )-2-[ chlorocarbonyl ( methyl ) amino ]-4 -methyl - valeric acid isopropyl ester ( intermediate product AU)

Similar to the intermediate product AP by using (2S)-4-methyl-2-(methylamino)valeric acid isopropyl ester hydrochloride (500 mg, compound AU-1 ) instead of 2-(methylamino) Ethyl acetate hydrochloride to prepare intermediate product AU . The crude (2 S )-2-[chlorocarbonyl(methyl)amino]-4-methyl-pentanoic acid isopropyl ester (650 mg, intermediate product AU ) was obtained as a pale yellow oil without further purification Used in the next step.

Intermediate product AV (2 S )-2-[ chlorocarbonyl ( methyl ) amino ]-3 -methyl - butyric acid ethyl ester

在室溫下向(2S )-3-甲基-2-(甲胺基)丁酸(1.0 g，7.6 mmol)於EtOH (10 mL)中之溶液中逐滴添加亞硫醯氯(2.45 g，21 mmol)。將所得混合物攪拌且回流持續16小時且隨後在真空下濃縮。將殘餘物用NaHCO₃ (30 mL)飽和水溶液鹼化且用DCM (50 mL)萃取兩次。經合併有機層用鹽水洗滌，經Na₂ SO₄ 乾燥且在真空下濃縮。將殘餘物溶解於HCl/EtOAc (10 mL，1 M)中且濃縮，得到呈白色固體之(2S )-3-甲基-2-(甲胺基)丁酸乙酯鹽酸鹽(1.9 g，化合物 AV-1 )。 Step 1 : Preparation of (2S)-3 -methyl -2-( methylamino ) butyric acid ethyl ester hydrochloride ( Compound AV-1)

To a solution of (2 S )-3-methyl-2-(methylamino)butanoic acid (1.0 g, 7.6 mmol) in EtOH (10 mL) was added dropwise sulfenyl chloride (2.45) at room temperature g, 21 mmol). The resulting mixture was stirred and refluxed for 16 hours and then concentrated under vacuum. The residue was basified with saturated aqueous NaHCO ₃ (30 mL) and extracted twice with DCM (50 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was dissolved in HCl/EtOAc (10 mL, 1 M) and concentrated to give (2 S )-3-methyl-2-(methylamino)butyric acid ethyl ester hydrochloride (1.9 g, compound AV-1 ).

類似於中間產物 AP 藉由使用(2S)-3-甲基-2-(甲胺基)丁酸乙酯鹽酸鹽(500 mg，化合物 AV-1 )而非2-(甲胺基)乙酸乙酯鹽酸鹽來製備中間產物 AV 。獲得呈淡黃色油狀之粗製(2S )-2-[氯羰基(甲基)胺基]-3-甲基-丁酸乙酯(600 mg，中間產物 AV )且不經進一步純化即用於下一步驟。Step 2: Preparation of (2 S )-2-[chlorocarbonyl(methyl)amino]-3-methyl-butyric acid ethyl ester ( intermediate product AV )

Similar to the intermediate product AP by using (2S)-3-methyl-2-(methylamino)butyric acid ethyl ester hydrochloride (500 mg, compound AV-1 ) instead of 2-(methylamino)acetic acid Ethyl ester hydrochloride to prepare intermediate product AV . The crude (2 S )-2-[chlorocarbonyl(methyl)amino]-3-methyl-butyric acid ethyl ester (600 mg, intermediate product AV ) was obtained as a light yellow oil and used without further purification To the next step.

Intermediate product AW (2 S )-2-[ chlorocarbonyl ( methyl ) amino ]-4 -methyl - pentanoic acid ethyl ester

在室溫下向(2S )-4-甲基-2-(甲胺基)戊酸(1 g，6.9 mmol)於EtOH (10 mL)中之溶液中逐滴添加亞硫醯氯(1.07 g，8.3 mmol)。將所得混合物在回流下攪拌持續16小時且隨後真空濃縮。將殘餘物用NaHCO₃ (30 mL)飽和水溶液鹼化且用DCM (50 mL)萃取。有機層用鹽水洗滌，經Na₂ SO₄ 乾燥且在真空下濃縮。將殘餘物用HCl/EtOAc (10 mL，1 mmol/mL)成鹽且濃縮，得到呈白色固體之(2S)-4-甲基-2-(甲胺基)戊酸乙酯鹽酸鹽(1.8 mg，化合物 AW-1 )。 Step 1 : Preparation of (2S)-4 -methyl -2-( methylamino ) valeric acid ethyl ester hydrochloride ( Compound AW-1)

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

類似於中間產物 AP 藉由使用(2S)-4-甲基-2-(甲胺基)戊酸乙酯鹽酸鹽(610 mg，AW-1 )而非2-(甲胺基)乙酸乙酯鹽酸鹽來製備中間產物 AW 。獲得呈淡黃色油狀之粗製(2S)-2-[氯羰基(甲基)胺基]-4-甲基-戊酸乙酯(280 mg，中間產物 AW )且不經進一步純化即用於下一步驟。 Step 2 : Preparation of (2S)-2-[ chlorocarbonyl ( methyl ) amino ]-4 -methyl - valeric acid ethyl ester ( intermediate product AW)

Similar to the intermediate product AP by using (2S)-4-methyl-2-(methylamino)valeric acid ethyl ester hydrochloride (610 mg, AW-1 ) instead of 2-(methylamino)ethyl acetate Ester hydrochloride to prepare intermediate product AW . The crude (2S)-2-[chlorocarbonyl(methyl)amino]-4-methyl-pentanoic acid ethyl ester (280 mg, intermediate product AW ) was obtained as a pale yellow oil and used without further purification The next step.

類似於中間產物 AP 藉由使用(S)-2-(甲胺基)-3-苯基丙酸乙酯並非2-(甲胺基)乙酸乙酯鹽酸鹽來製備中間產物 AX 。獲得呈淡黃色油狀之粗製(2S)-2-[氯羰基(甲基)胺基]-3-苯基-丙酸乙酯(200 mg，中間產物 AX )且不經進一步純化即用於下一步驟。 Intermediate AX (2S)-2-[ chlorocarbonyl ( methyl ) amino ]-3 -phenyl - propionic acid ethyl ester

The intermediate product AX is prepared similarly to the intermediate product AP by using (S)-2-(methylamino)-3-phenylpropionic acid ethyl ester instead of 2-(methylamino) ethyl acetate hydrochloride. The crude (2S)-2-[chlorocarbonyl(methyl)amino]-3-phenyl-propionic acid ethyl ester (200 mg, intermediate AX ) was obtained as a pale yellow oil and used without further purification The next step.

Intermediate AY (2 S )-2-[ chlorocarbonyl ( methyl ) amino ]-3 -phenyl - isopropyl propionate

Similar to the intermediate product AP by using (2S)-2-(methylamino)-3-phenyl-propionic acid isopropyl ester (190 mg) instead of 2-(methylamino) ethyl acetate hydrochloride Preparation of intermediate product AY . The crude (2S)-2-[chlorocarbonyl(methyl)amino]-3-phenyl-propionic acid isopropyl ester (220 mg, intermediate product AY ) was obtained as a light brown oil and used without further purification To the next step.

Intermediate AZ (S)-2-(( chlorocarbonyl )( methyl ) amino )-3 -phenyl propionate tert - butyl ester

在-78℃下將2-甲基丙烯(25 g，446 mmol)鼓泡至DCM (50 mL)中。隨後在0℃下將2-甲基丙烯溶液添加至(S )-2-(甲胺基)-3-苯基丙酸(500 mg)及H₂ SO₄ (3.68 g，2 mL)於二噁烷(20 mL)中之溶液中。將反應混合物在室溫下於密封管內攪拌18小時。 將反應混合物倒入至冰冷的KOH水溶液(8.4 g於水(30mL)中)中且將所得混合物用DCM (50 mL)萃取兩次。有機層用鹽水(30 mL)洗滌2次，經Na₂ SO₄ 乾燥且在真空下濃縮，得到呈淡黃色油狀之(2S)-2-(甲胺基)-3-苯基-丙酸第三丁酯(710 mg，化合物 AZ-1 )。 Step 1 : Preparation of (2S)-2-( methylamino )-3 -phenyl - propionic acid tert- butyl ester ( Compound AZ-1)

2-Methylpropene (25 g, 446 mmol) was bubbled into DCM (50 mL) at -78 °C. Then add 2-methacrylic acid solution to ( S )-2-(methylamino)-3-phenylpropionic acid (500 mg) and H ₂ SO ₄ (3.68 g, 2 mL) at 2 In a solution in oxane (20 mL). The reaction mixture was stirred in a sealed tube at room temperature for 18 hours. The reaction mixture was poured into ice-cold aqueous KOH (8.4 g in water (30 mL)) 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 and concentrated under vacuum to give (2S)-2-(methylamino)-3-phenyl-propionic acid as a light yellow oil Third butyl ester (710 mg, compound AZ-1 ).

類似於中間產物 AP 藉由使用(2S)-2-(甲胺基)-3-苯基-丙酸第三丁酯(化合物 AZ -1 )而非2-(甲胺基)乙酸乙酯鹽酸鹽來製備中間產物 AZ 。獲得呈淡黃色油狀之粗製(2S )-2-[氯羰基(甲基)胺基]-3-苯基-丙酸第三丁酯(360 mg，中間產物 AZ )且不經進一步純化即用於下一步驟。 Step 2 : Preparation of (S)-2-(( chlorocarbonyl )( methyl ) amino )-3 -phenylpropionic acid tert - butyl ester ( intermediate product AZ)

Similar to the intermediate product AP by using (2S)-2-(methylamino)-3-phenyl-propionic acid tert-butyl ester ( Compound AZ -1 ) instead of 2-(methylamino) ethyl acetate Acid salt to prepare intermediate product AZ . Crude (2 S )-2-[chlorocarbonyl(methyl)amino]-3-phenyl-propionic acid tert-butyl ester (360 mg, intermediate product AZ ) was obtained as a pale yellow oil without further purification It is used in the next step.

Intermediate BA chloride N- [2- [acetyl (methyl) amino] ethyl] - N - methyl - carbamoyl XI

在0℃下向甲基(2-(甲胺基)乙基)胺基甲酸第三丁酯(1.13 g，6 mmol)於吡啶(10 mL)中之溶液中逐滴添加乙酸酐(3.06 g，30 mmol)。隨後將溶液在室溫下攪拌0.5小時。真空移除溶劑且將殘餘物分配於EtOAc (50 mL)與NaHCO₃ 飽和水溶液(25 mL)之間。將有機層分離，用鹽水(20 mL)洗滌，經Na₂ SO₄ 乾燥且在真空下濃縮，得到呈黃色油狀之N -[2-[乙醯基(甲基)胺基]乙基]-N -甲基-胺基甲酸第三丁酯(1.28 g，化合物 BA-1 )。 Carbamic acid tert-butyl ester (Compound BA-1) Preparation of - N- [2- [acetyl (methyl) amino] ethyl] -N- methyl-: Step 1

To a solution of methyl(2-(methylamino)ethyl)carbamic acid tert-butyl ester (1.13 g, 6 mmol) in pyridine (10 mL) was added acetic anhydride (3.06 g) dropwise at 0°C , 30 mmol). The solution was then stirred at room temperature for 0.5 hour. The solvent was removed in vacuo and the residue was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO ₃ (25 mL). The organic layer was separated, washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated under vacuum to give N- [2-[ethylamino(methyl)amino]ethyl] as a yellow oil -N -methyl-carbamic acid tert-butyl ester (1.28 g, compound BA-1 ).

在室溫下將N -[2-[乙醯基(甲基)胺基]乙基]-N-甲基-胺基甲酸第三丁酯(1.1 g，化合物 BA-1 )於HCl/EtOAc(10 mL，含1N HCl之EtOAc)中之混合物攪拌2小時，隨後將混合物過濾。將收集之固體用EtOAc (5 mL)洗滌三次且在真空下乾燥，得到呈白色固體之粗製N -甲基-N -(2-(甲胺基)乙基)乙醯胺鹽酸鹽(460 mg，化合物 BA-2 )。 Step 2: N - Preparation of (2- (methylamino) ethyl) as acetamide hydrochloride (Compound BA-2) of - methyl - N

N- [2-[Acetyl(methyl)amino]ethyl]-N-methyl-aminocarboxylic acid tert-butyl ester (1.1 g, compound BA-1 ) was added to HCl/EtOAc at room temperature The mixture (10 mL, 1N HCl in EtOAc) was stirred for 2 hours, and then the mixture was filtered. The collected solid was washed three times with EtOAc (5 mL) and dried under vacuum to give crude N -methyl- N- (2-(methylamino)ethyl)acetamide hydrochloride (460) as a white solid mg, compound BA-2 ).

類似於中間產物 AP 藉由使用N -甲基-N -(2-(甲胺基)乙基)乙醯胺鹽酸鹽(200 mg，化合物 BA-2 )而非2-(甲胺基)乙酸乙酯鹽酸鹽來製備中間產物 BA 。獲得粗製氯化N -[2-[乙醯基(甲基)胺基]乙基]-N -甲基-胺甲醯(300 mg，中間產物 BA )且不經進一步純化即用於下一步驟。 Methyl acyl amine (Intermediate BA) - A chlorinated N - [2- [acetyl (methyl) amino] ethyl] - N - methyl: Step 3

Similar to the intermediate product AP by using N -methyl- N- (2-(methylamino)ethyl)acetamide hydrochloride (200 mg, compound BA-2 ) instead of 2-(methylamino) Ethyl acetate hydrochloride to prepare intermediate product BA . Crude N- [2-[ethylamino(methyl)amino]ethyl] -N -methyl-aminecarboxamide (300 mg, intermediate product BA ) was obtained and used in the next step without further purification step.

Intermediate BB N- [2-[ chlorocarbonyl ( methyl ) amino ] ethyl ] -N - methyl - carbamic acid methyl ester

在-70℃下在1小時內向N,N'- 二甲基乙烷-1,2-二胺(10 g)於THF (40 mL)中之溶液中逐滴添加氯甲酸甲酯(1.92 g)。將混合物在25℃下攪拌15小時且隨後過濾且用水及鹽水洗滌。將有機層乾燥且濃縮，得到黃色殘餘物，將殘餘物藉由管柱層析純化，得到呈無色油狀之N -甲基-N -[2-(甲胺基)乙基]胺基甲酸甲酯(2 g，化合物 BB-1 )。 Step 1: N - methyl - N - [2- (methylamino) ethyl] amino carboxylate (Compound BB-1) Preparation of

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

類似於中間產物 AP 藉由使用N -甲基-N -[2-(甲胺基)乙基]胺基甲酸甲酯(2.0 g，化合物 BB-1 )而非2-(甲胺基)乙酸乙酯鹽酸鹽來製備中間產物 BB 。獲得粗製N -[2-[氯羰基(甲基)胺基]乙基]-N -甲基-胺基甲酸甲酯(2.2 g，中間產物 BB )且不經進一步純化即用於下一步驟。 Step 2: N - [[chloro carbonyl (methyl) amino] ethyl 2] - Preparation of amino acid methyl ester (Intermediate BB) of - N - methyl

Similar to the intermediate product AP by using N -methyl- N- [2-(methylamino)ethyl]methylcarbamate (2.0 g, compound BB-1 ) instead of 2-(methylamino)acetic acid Ethyl ester hydrochloride to prepare intermediate product BB . Crude N- [2-[chlorocarbonyl(methyl)amino]ethyl] -N -methyl-carbamic acid methyl ester (2.2 g, intermediate product BB ) was obtained and used in the next step without further purification .

Intermediate BC N- [2-[ chlorocarbonyl ( methyl ) amino ] ethyl ] -N - methyl -carbamic acid tert - butyl ester

在0℃下歷經1小時向N ,N '-二甲基乙烷-1,2-二胺(40.4 g)於DCM (300 mL)中之溶液中逐滴添加Boc₂ O (10 g, 10.6 mL, 45.8 mmol)於DCM (100 mL)中之溶液。在室溫下攪拌反應混合物18小時。有機層用NaHCO₃ 飽和水溶液(50 mL)、鹽水(50 mL)洗滌，經Na₂ SO₄ 乾燥且在真空下濃縮。藉由管柱層析純化殘餘物，得到呈黃色油狀之N -甲基-N -[2-(甲胺基)乙基]胺基甲酸第三丁酯(6.8 g，化合物 BC-1 )。¹ H NMR (400MHz, CDCl₃ )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 1: N - methyl - N - [2- (methylamino) ethyl] carbamic acid tert-butyl ester (Compound BC-1) Preparation of

To a solution of N , N' -dimethylethane-1,2-diamine (40.4 g) in DCM (300 mL) was added dropwise Boc ₂ O (10 g, 10.6) at 0°C over 1 hour mL, 45.8 mmol) in DCM (100 mL). The reaction mixture was stirred at room temperature for 18 hours. The organic layer was washed with saturated aqueous NaHCO ₃ (50 mL), brine (50 mL), dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by column chromatography to obtain N -methyl- N- [2-(methylamino)ethyl]aminocarboxylic acid third butyl ester (6.8 g, compound BC-1 ) as a yellow oil . ¹ H NMR (400MHz, CDCl ₃ ) δ ppm: 3.34 (br. s., 2H), 2.89 (s, 3H), 2.74 (t, J = 6.7 Hz, 2H), 2.46 (s, 3H), 1.47 ( s, 9H).

類似於中間產物 AP 藉由使用N -甲基-N -[2-(甲胺基)乙基]胺基甲酸第三丁酯(1.15 g，化合物 BC-1 )而非2-(甲胺基)乙酸乙酯鹽酸鹽來製備中間產物 BC 。獲得粗製N -[2-[氯羰基(甲基)胺基]乙基]-N -甲基-胺基甲酸第三丁酯(1.3 g，中間產物 BC )且不經進一步純化即用於下一步驟。 Step 2: N - [[chlorocarbonyl-2- (methyl) amino] ethyl] - N - methyl - Preparation of carbamic acid tert-butyl ester (Intermediate BC) of

Similar to the intermediate product AP by using N -methyl- N- [2-(methylamino)ethyl]carbamic acid third butyl ester (1.15 g, compound BC-1 ) instead of 2-(methylamino ) Ethyl acetate hydrochloride to prepare intermediate product BC . Crude N- [2-[chlorocarbonyl(methyl)amino]ethyl] -N -methyl-carbamic acid tert-butyl ester (1.3 g, intermediate product BC ) was obtained and used without further purification. One step.

Intermediate BD N- [2-[ chlorocarbonyl ( methyl ) amino ] ethyl ]-N- methyl - carbamic acid ethyl ester

在-70℃下在1小時內向N,N'- 二甲基乙烷-1,2-二胺(10 g)於DCM (40 mL)中之溶液中逐滴添加氯甲酸乙酯(2.58 g)。在25℃下將反應混合物攪拌15小時且隨後過濾且用水及鹽水洗滌。將有機層乾燥且真空濃縮。藉由管柱層析純化黃色殘餘物，得到呈無色油狀之N -甲基-N -[2-(甲胺基)乙基]胺基甲酸乙酯(2 g，化合物 BD-1 )。 [(Methylamino) ethyl 2] amino carboxylate (Compound BD-1) Preparation of - N - methyl - N: Step 1

To a solution of N,N' -dimethylethane-1,2-diamine (10 g) in DCM (40 mL) was added dropwise ethyl chloroformate (2.58 g) at -70°C within 1 hour ). The reaction mixture was stirred at 25°C for 15 hours and 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 obtain ethyl N -methyl- N- [2-(methylamino)ethyl]carbamate (2 g, compound BD-1 ) as a colorless oil.

類似於中間產物 AA 藉由使用N -甲基-N -[2-(甲胺基)乙基]胺基甲酸乙酯(化合物 BD-1 )而非2-(甲胺基)乙酸乙酯鹽酸鹽來製備中間產物 BD 。獲得粗製N -[2-[氯羰基(甲基)胺基]乙基]-N -甲基-胺基甲酸乙酯(2.2 g，中間產物 BD )且不經進一步純化即用於下一步驟。 Step 2: N - [[2- chloro carbonyl (methyl) amino] ethyl] - Preparation of urethane (intermediate BD) of - N - methyl

Similar to intermediate product AA by using N -methyl- N- [2-(methylamino)ethyl]ethyl carbamate ( compound BD-1 ) instead of 2-(methylamino) ethyl acetate salt Acid salt to prepare intermediate product BD . Crude N- [2-[chlorocarbonyl(methyl)amino]ethyl] -N -methyl-carbamic acid ethyl ester (2.2 g, intermediate product BD ) was obtained and used in the next step without further purification .

Intermediate BE N - butyl - N - methyl - carbamic acid 2- [chloro carbonyl (methyl) amino] ethyl ester

在25℃下向2-(甲胺基)乙醇(10 g，133.14 mmol)於DCM (10 mL)中之溶液中添加Boc₂ O (34.87 g，159.77 mmol)。將混合物在25℃下攪拌16小時且隨後濃縮。藉由管柱層析純化殘餘物，得到呈無色油狀之N -(2-羥乙基)-N -甲基-胺基甲酸第三丁酯(20 g，化合物 BE-1 )。 Step 1: N - (2- hydroxyethyl) - N - methyl - carbamic acid tert-butyl ester (Compound BE-1) Preparation of

To a solution of 2-(methylamino)ethanol (10 g, 133.14 mmol) in DCM (10 mL) was added Boc ₂ O (34.87 g, 159.77 mmol) at 25°C. The mixture was stirred at 25°C for 16 hours and then concentrated. The residue was purified by column chromatography to obtain N- (2-hydroxyethyl) -N -methyl-carbamic acid third butyl ester (20 g, compound BE-1 ) as a colorless oil.

在-10℃下在1小時內向N -(2-羥乙基)-N -甲基-胺基甲酸第三丁酯(880 mg，化合物 BE-1 )及Et₃ N (1 g，10.08 mmol)於DCM (10 mL)中之溶液中逐滴添加氯化N -丁基-N -甲基-胺甲醯(903 mg，7.04 mmol)。在25℃下將反應混合物攪拌15小時且隨後過濾且用水及鹽水洗滌。將有機層乾燥且濃縮，得到呈無色油狀之N -丁基-N -甲基-胺基甲酸2-[第三丁氧基羰基(甲基)胺基]乙酯(2 g，化合物 BE-2 )。 Step 2: N - 2- Preparation of [butoxycarbonyl (methyl) amino third butoxy] ethyl ester (Compound BE-2) The amino acid - butyl - N - methyl

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

向N -丁基-N -甲基-胺基甲酸2-[第三丁氧基羰基(甲基)胺基]乙酯(1 g,化合物 BE-2 )之溶液中添加HCl/EA (40 mL, 1M)。將反應混合物在0℃下攪拌0.5小時且升溫至25℃且額外攪拌15.5小時。將反應混合物濃縮，得到呈無色油狀之2-(甲胺基)乙基-N -丁基-N -甲基-胺基甲酸酯鹽酸鹽(400 mg，化合物 BE-3 )。 Step 3: N - butyl - N - methyl - carbamic acid 2- (methylamino) ethyl ester hydrochloride (Compound BE-3) Preparation of

To a solution of N -butyl- N -methyl-carbamic acid 2-[third butoxycarbonyl (methyl)amino] ethyl ester (1 g, compound BE-2 ) was added HCl/EA (40 mL, 1M). The reaction mixture was stirred at 0°C for 0.5 hours and warmed to 25°C and stirred for an additional 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.

類似於中間產物 AP 藉由使用N -丁基-N -甲基-胺基甲酸2-(甲胺基)乙酯鹽酸鹽(374 mg，化合物 BE-3 )而非2-(甲胺基)乙酸乙酯鹽酸鹽來製備中間產物 BE 。獲得粗製N -丁基-N -甲基-胺基甲酸2-[氯羰基(甲基)胺基]乙酯(330 mg，中間產物 BE )且不經進一步純化即用於下一步驟。 Step 4: N - butyl - N - methyl - carbamic acid 2- [chloro carbonyl (methyl) amino] ethyl ester was prepared (intermediate BE) of

Similar to the intermediate product AP by using N -butyl- N -methyl-carbamic acid 2-(methylamino) ethyl ester hydrochloride (374 mg, compound BE-3 ) instead of 2-(methylamino ) Ethyl acetate hydrochloride to prepare intermediate product BE . Crude N -butyl- N -methyl-carbamic acid 2-[chlorocarbonyl(methyl)amino]ethyl ester (330 mg, intermediate product BE ) was obtained and used in the next step without further purification.

Intermediate BF pyrrolidine- 1- carboxylic acid 2-[ chlorocarbonyl ( methyl ) amino ] ethyl ester

在25℃下向2-(甲胺基)乙醇(10 g, 133.14 mmol)於DCM (10 mL)中之溶液中添加Boc₂ O (34.87 g, 159.77 mmol)。在25℃下將混合物攪拌16小時。將反應混合物濃縮，得到殘餘物，藉由管柱層析將其純化，得到呈無色油狀之N -(2-羥乙基)-N -甲基-胺基甲酸第三丁酯(20 g，化合物 BF -1 )。 Step 1: N - (2- hydroxyethyl) - N - methyl - carbamic acid tert-butyl ester (Compound BF-1) Preparation of

To a solution of 2-(methylamino)ethanol (10 g, 133.14 mmol) in DCM (10 mL) was added Boc ₂ O (34.87 g, 159.77 mmol) at 25°C. The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated to obtain a residue, which was purified by column chromatography to obtain N- (2-hydroxyethyl) -N -methyl-carbamic acid third butyl ester (20 g) as a colorless oil , Compound BF -1 ).

在0℃下歷時0.5小時向N -(2-羥乙基)-N -甲基-胺基甲酸第三丁酯(300 mg，1.71 mmol，化合物 BF-1 )及Et₃ N (578 mg，5.71 mmol)於DCM (5 mL)中之溶液中逐滴添加氯化吡咯啶-1-羰基(458 mg，3.4 mmol)且隨後在25℃下攪拌15.5小時。在過濾之後，濾液用水及鹽水洗滌。將有機層乾燥並濃縮，得到呈無色油狀之吡咯啶-1-甲酸2-[第三丁氧基羰基(甲基)胺基]乙酯(335 mg，化合物 BF-2 )。 Step 2: Preparation of pyrrolidine-carboxylic acid -1-2- [Third butoxycarbonyl (methyl) amino] ethyl ester (Compound BF-2) of

N- (2-hydroxyethyl) -N -methyl-carbamic acid third butyl ester (300 mg, 1.71 mmol, compound BF-1 ) and Et ₃ N (578 mg, 5.71 mmol) in a solution in DCM (5 mL) was added dropwise pyrrolidine-1-carbonyl (458 mg, 3.4 mmol) and then 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 pyrrolidine-1-carboxylic acid 2-[third butoxycarbonyl(methyl)amino]ethyl ester (335 mg, compound BF-2 ) as a colorless oil.

將吡咯啶-1-甲酸2-[第三丁氧基羰基(甲基)胺基]乙酯(335 mg，化合物BF-2)添加至含HCl之EA(12.3 mL，1M)中，且在0℃下將混合物攪拌0.5小時且隨後在25℃下額外攪拌15.5小時。將反應混合物濃縮，得到呈無色油狀之吡咯啶-1-甲酸2-(甲胺基)乙酯鹽酸鹽(300 mg，化合物 BF-3 )。 Pyrrolidine-1-carboxylic acid 2- (methylamino) ethyl ester hydrochloride (Compound BF-3) Preparation of: Step 3

Pyrrolidine-1-carboxylic acid 2-[third butoxycarbonyl (methyl)amino] ethyl ester (335 mg, compound BF-2) was added to EA (12.3 mL, 1M) containing HCl, and at The mixture was stirred at 0°C for 0.5 hours and then at 25°C for an additional 15.5 hours. The reaction mixture was concentrated to give pyrrolidine-1-carboxylic acid 2-(methylamino)ethyl ester hydrochloride (300 mg, compound BF-3 ) as a colorless oil.

類似於中間產物 AP 藉由使用吡咯啶-1-甲酸2-(甲胺基)乙酯鹽酸鹽(299 mg，化合物 BF-3 )而非2-(甲胺基)乙酸乙酯鹽酸鹽來製備中間產物 BF 。獲得粗吡咯啶-1-甲酸2-[氯羰基(甲基)胺基]乙酯(230 mg，中間產物 BF )且不經進一步純化即用於下一步驟。 Step 4: Preparation of 2- [chloro carbonyl (methyl) amino] pyrrole-1-carboxylic acid ethyl ester (Intermediate BF) of

Similar to the intermediate product AP by using pyrrolidine-1-carboxylic acid 2-(methylamino) ethyl ester hydrochloride (299 mg, compound BF-3 ) instead of 2-(methylamino) ethyl acetate hydrochloride To prepare the intermediate product BF . Crude pyrrolidine-1-carboxylic acid 2-[chlorocarbonyl(methyl)amino]ethyl ester (230 mg, intermediate BF ) was obtained and used in the next step without further purification.

Intermediate BG N- methyl - N - propyl - carbamic acid 2- [chloro carbonyl (methyl) amino] ethyl ester

在25℃下向2-(甲胺基)乙醇(10 g，133.14 mmol)於DCM (10 mL)中之溶液中添加Boc₂ O (34.87 g，159.77 mmol)。將反應混合物在25℃下攪拌16小時，隨後濃縮得到殘餘物，藉由管柱層析將其純化，得到呈無色油狀之N -(2-羥乙基)-N -甲基-胺基甲酸第三丁酯(20 g，化合物 BG-1 )。 Step 1: N - (2- hydroxyethyl) - N - methyl - carbamic acid tert-butyl ester (Compound BG-1) Preparation of

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

在0℃下歷時0.5小時向N-(2-羥乙基)-N-甲基-胺基甲酸第三丁酯(265 mg，化合物 BG-1 )及Et₃ N (1 mL，5.71 mmol)於DCM (5 mL)中之溶液中逐滴添加氯化N -甲基-N -丙基-胺甲醯(410 mg，1.83 mmol)。將反應混合物在25℃下攪拌15.5小時且隨後過濾且濾液用水和鹽水洗滌。將有機層乾燥並濃縮，得到呈無色油狀之N -甲基-N -[2-[甲基(丙基)胺甲醯基]氧基乙基]胺基甲酸第三丁酯(380 mg，化合物 BG-2 )。 Step 2: tert-butyl - N - methyl - N - Preparation of [2- [methyl (propyl) carbamoyl acyl] oxyethyl] amine carboxylate (Compound BG-2) of

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

將N -甲基-N -[2-[甲基(丙基)胺甲醯基]氧基乙基]胺基甲酸第三丁酯(380 mg，化合物 BG-2 )添加至含HCl之EA(13.7 mL，1M)中。在0℃下將混合物攪拌0.5小時。隨後在25℃下將混合物額外攪拌15.5小時並濃縮，得到呈無色油狀之N -甲基-N -丙基-胺基甲酸2-(甲胺基)乙酯鹽酸鹽(300 mg，化合物 BG-3 )。 Methyl - - N-propyl - carbamic acid 2- (methylamino) ethyl ester hydrochloride (Compound BG-3) Preparation of N: 3 steps

Add N -methyl- N- [2-[methyl(propyl)aminemethanyl]oxyethyl]carbamic acid tert-butyl ester (380 mg, compound BG-2 ) to EA containing HCl (13.7 mL, 1M). The mixture was stirred at 0°C for 0.5 hour. The mixture was subsequently stirred at 25°C for an additional 15.5 hours and concentrated to give N -methyl- N -propyl-carbamic acid 2-(methylamino)ethyl ester hydrochloride (300 mg, compound ) as a colorless oil BG-3 ).

類似於中間產物 AP 藉由使用N -甲基-N -丙基-胺基甲酸2-(甲胺基)乙酯鹽酸鹽(330 mg，化合物 BG-3 )而非2-(甲胺基)乙酸乙酯鹽酸鹽來製備中間產物 BG 。獲得2-[氯羰基(甲基)胺基]乙基-N -甲基-N -丙基-胺基甲酸酯(300 mg，中間產物 BG )且不經進一步純化即用於下一步驟。 Step 4: N - 2- [chloro carbonyl (methyl) amino] Preparation of carbamic acid ethyl ester (Intermediate BG) of - methyl - N - propyl

Similar to the intermediate product AP by using N -methyl- N -propyl-carbamic acid 2-(methylamino) ethyl ester hydrochloride (330 mg, compound BG-3 ) instead of 2-(methylamino ) Ethyl acetate hydrochloride to prepare intermediate product BG . 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 product BH N,N -diethylaminocarboxylic acid 2-[ chlorocarbonyl ( methyl ) amino ] ethyl ester

在25℃下向2-(甲胺基)乙醇(10 g，133.14 mmol)於DCM (10 mL)中之溶液中添加Boc₂ O (34.87 g，159.77 mmol)。在25℃下將混合物攪拌16小時且隨後濃縮，藉由管柱層析純化殘餘物，得到呈無色油狀之N -(2-羥乙基)-N -甲基-胺基甲酸第三丁酯(20 g，化合物 BH-1 )。 Carbamic acid tert-butyl ester (Compound BH-1) of Preparation - N- (2- hydroxyethyl) -N- methyl-: Step 1

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

在0℃下歷時0.5小時向N -(2-羥乙基)-N -甲基-胺基甲酸第三丁酯(200 mg，1.14 mmol，化合物 BH-1 )及Et₃ N (578 mg，5.71 mmol)於DCM (5 mL)中之溶液中逐滴添加氯化N,N -二乙基胺甲醯(248 mg，1.83 mmol)且在25℃下攪拌15.5小時。在過濾之後，濾液用水及鹽水洗滌。將有機層乾燥並濃縮，得到呈無色油狀之N,N -二乙基胺基甲酸2-[第三丁氧基羰基(甲基)胺基]乙酯(313 mg，化合物 BH-2 )。 Preparation of N, N- diethylamino-carboxylate (Compound BH-2) - A 2- [Third butoxycarbonyl (methyl) amino] ethyl: Step 2

N- (2-hydroxyethyl) -N -methyl-carbamic acid tert-butyl ester (200 mg, 1.14 mmol, compound BH-1 ) and Et ₃ N (578 mg, 5.71 mmol) in a solution in DCM (5 mL) was added dropwise N,N -diethylamine formamide (248 mg, 1.83 mmol) and 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-[third butoxycarbonyl(methyl)amino]ethyl N,N -diethylcarbamate (313 mg, compound BH-2 ) as a colorless oil. .

將N,N -二乙基胺基甲酸2-[第三丁氧基羰基(甲基)胺基]乙酯(436 mg，1.77 mmol，化合物 BH-2 )添加至含HCl之EA(17 mL，1M)中。在0℃下將混合物攪拌0.5小時。隨後在25℃下將混合物額外攪拌15.5小時並濃縮，得到呈無色油狀之N,N-二乙基胺基甲酸2-(甲胺基)乙酯鹽酸鹽(230 mg，化合物 BH-3 )。 Amino acid diethyl 2- (methylamino) ethyl ester hydrochloride (Compound BH-3) Preparation of - N, N: 3 steps

Add N,N -diethylaminocarboxylic acid 2-[third butoxycarbonyl(methyl)amino]ethyl ester (436 mg, 1.77 mmol, compound BH-2 ) to EA (17 mL) containing HCl , 1M). The mixture was stirred at 0°C for 0.5 hour. The mixture was subsequently stirred at 25°C for an additional 15.5 hours and concentrated to give 2-(methylamino) ethyl N,N-diethylcarbamate hydrochloride (230 mg, compound BH-3 ) as a colorless oil ).

類似於中間產物 AP 藉由使用N,N -二乙基胺基甲酸2-(甲胺基)乙酯鹽酸鹽(274 mg，化合物 BH-3 )而非2-(甲胺基)乙酸乙酯鹽酸鹽來製備中間產物 BH 。獲得粗製N,N -二乙基胺基甲酸2-[氯羰基(甲基)胺基]乙酯(250 mg，中間產物 BH )且不經進一步純化即用於下一步驟。 Step 4: N, N - diethylamino acid 2- [chloro carbonyl (methyl) amino] ethyl ester was prepared (intermediate BH) of

Similar to the intermediate product AP by using N,N -diethylcarbamic acid 2-(methylamino)ethyl ester hydrochloride (274 mg, compound BH-3 ) instead of 2-(methylamino)acetic acid ethyl Ester hydrochloride to prepare intermediate BH . Crude N,N -diethylaminocarboxylic acid 2-[chlorocarbonyl(methyl)amino]ethyl ester (250 mg, intermediate BH ) was obtained and used in the next step without further purification.

Intermediate product BI carbonate 2-[ chlorocarbonyl ( methyl ) amino ] ethyl ethyl

在25℃下向2-(甲胺基)乙醇(1 g，13.31 mmol)於DCM (10 mL)中之溶液中添加Boc₂ O (3.49 g，15.98 mmol)。在25℃下將反應混合物攪拌16小時，隨後濃縮得到粗產物，藉由管柱層析將其純化，得到呈無色油狀之N -(2-羥乙基)-N -甲基-胺基甲酸第三丁酯(1.6 g，化合物 BI-1 )。 Step 1: N - (2- hydroxyethyl) - N - methyl - carbamic acid tert-butyl ester (Compound BI-1) Preparation of

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

在-10℃下向N- (2-羥乙基)-N-甲基-胺基甲酸第三丁酯(1 g，化合物 BI-1 )、DMAP (0.1 g)及吡啶(1.15 g，11.41 mmol)於EA (20 mL)中之溶液中逐滴添加氯甲酸甲酯(1.21 g，11.15 mmol)。將混合物在-10℃下攪拌1小時。將反應混合物過濾且將濾液用5%檸檬酸及鹽水洗滌。將有機層乾燥且濃縮，得到呈無色油狀之碳酸2-[第三丁氧基羰基(甲基)胺基]乙酯甲酯(1.22 g，化合物 BI -2 )。 Step 2: Preparation of [butoxycarbonyl (methyl) amino third butoxy] ethyl ester (Compound BI-2) of the carbonic acid 2-

N- (2-hydroxyethyl)-N-methyl-carbamic acid tert-butyl ester (1 g, compound BI-1 ), DMAP (0.1 g) and pyridine (1.15 g, 11.41 mmol) in a solution in EA (20 mL) was added methyl chloroformate (1.21 g, 11.15 mmol) dropwise. 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-[third butoxycarbonyl(methyl)amino]ethyl methyl carbonate (1.22 g, compound BI -2 ) as a colorless oil.

將碳酸2-[第三丁氧基羰基(甲基)胺基]乙酯甲酯(1.22 g，4.94 mmol，化合物 BI -2 )添加至含HCl之EA(10 mL，40 mmol)中，且在0℃下將混合物攪拌0.5小時且在25℃下額外攪拌15.5小時。將反應混合物濃縮，得到碳酸乙酯2-(甲胺基)乙酯鹽酸鹽(1.06 g，化合物 BI -3 )。 Step 3: Preparation of ethyl ester hydrochloride (Compound BI -3) of ethyl carbonate, 2- (methylamino)

2-[Third-butoxycarbonyl(methyl)amino]ethyl ethyl carbonate (1.22 g, 4.94 mmol, compound BI -2 ) was added to EA (10 mL, 40 mmol) containing HCl, and The mixture was stirred at 0°C for 0.5 hours and at 25°C for an additional 15.5 hours. The reaction mixture was concentrated to obtain ethyl carbonate 2-(methylamino)ethyl ester hydrochloride (1.06 g, compound BI -3 ).

類似於中間產物 AP 藉由使用碳酸乙酯2-(甲胺基)乙酯鹽酸鹽(150 mg，中間產物 BI -3 )而非2-(甲胺基)乙酸乙酯鹽酸鹽來製備中間產物 BI 。獲得粗製碳酸2-[氯羰基(甲基)胺基]乙基乙酯(145 mg，中間產物 BI )且不經進一步純化即用於下一步驟。 Step 4: [chloro carbonyl (methyl) amino] ethyl ethyl carbonate prepared in (Intermediate BI) of

Similar to intermediate product AP was prepared by using ethyl carbonate 2-(methylamino) ethyl ester hydrochloride (150 mg, intermediate product BI -3 ) instead of 2-(methylamino) ethyl acetate hydrochloride Intermediate product BI . Crude 2-[chlorocarbonyl(methyl)amino]ethyl ethyl carbonate (145 mg, intermediate product BI ) was obtained and used in the next step without further purification.

Preparative examples

Example 1 6- Amino -9- benzyl- N - methyl - 8 -pentoxy - N - propyl -2-( propylsulfonylimide acetyl ) purine - 7- methylamide

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

To a solution of aminomalononitrile p-toluenesulfonate (25 g, 98.5 mmol, TCI, catalog number: A1119-25G) in anhydrous THF (100 mL) was added benzyl isocyanate ( 13.2 g, 98.5 mmol) and TEA (10.2 g, 79.0 mmol). After stirring at room temperature for 24 hours, the reaction was concentrated under vacuum and the residue was partitioned between 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 combined sodium hydroxide solution layer was neutralized with 10 wt% sodium bisulfate solution and extracted with EtOAc. The separated organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was triturated in 2-isopropoxypropane and the suspension was then filtered to give 4-amino-3-benzyl-2-oxo-1H-imidazole-5-carbonitrile as a yellow solid (15 g, compound 1a ). The product was used in the next step without further purification. MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 215.

向4-胺基-3-苄基-2-側氧基-1H-咪唑-5-甲腈(15.0 g，70.0 mmol，化合物1a)於THF (700 mL)中之溶液中逐滴添加苯甲醯基異硫氰酸酯(28.6 g，175.1 mmol，TCI，目錄號：A11596-100G)。在室溫下攪拌12小時之後，真空濃縮反應混合物。在乙醚(100 mL)中濕磨殘餘物且藉由過濾收集所得沈澱物。 Step 2: Preparation of 2-sulfonic acyl -7H- purin-8-one (Compound 1b) of 6- benzyl-9-

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

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

向6-胺基-9-苄基-2-磺醯基-7H -嘌呤-8-酮(5.46 g，20.0 mmol，化合物 1b )於DMF中之溶液中添加碳酸鉀(2.76 g，20.0 mmol)。且隨後將1-溴丙烷(2.44 g，20.0 mmol，TCI，目錄號：B0638-500G)緩慢添加至先前溶液中。在室溫下攪拌12小時之後，將反應混合物倒入水(200 mL)中，隨後用10 wt%硫酸氫鈉水溶液酸化且用EtOAc (100 mL)萃取兩次。將有機層用鹽水洗滌，經Na₂ SO₄ 乾燥且真空濃縮，得到粗產物，藉由矽膠急驟層析將粗產物純化，得到呈白色固體之6-胺基-9-苄基-2-(2-丙基磺醯基)-7H -嘌呤-8-酮(4.8 g，化合物 1c )。MS觀測值 (ESI⁺ ) [(M+H)⁺ ]: 316。 Step 3: - purin-8-one (Compound 1c) of 6-amino-benzyl-2- -9- (2-propyl sulfo acyl) -7 H

Acyl -7 H -2-sulfonamide To 6-benzyl-9- yl - purin-8-one (5.46 g, 20.0 mmol, Compound 1b) was added potassium carbonate (2.76 g of a solution in DMF, 20.0 mmol ). And then 1-bromopropane (2.44 g, 20.0 mmol, TCI, catalog number: B0638-500G) was slowly added to the previous solution. After stirring at room temperature for 12 hours, the reaction mixture was poured into water (200 mL), followed by acidification with 10 wt% aqueous sodium hydrogen sulfate solution and extraction with EtOAc (100 mL) twice. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by silica gel flash chromatography to give 6-amino-9-benzyl-2-(white solid 2-propylsulfonyl)-7 H -purin-8-one (4.8 g, compound 1c ). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 316.

向化合物6-胺基-9-苄基-2-(2-丙基磺醯基)-7H -嘌呤-8-酮(2.7 g，8.7 mmol，化合物1c)於DCM/MeOH (500 mL，V/V=1:1)中之懸浮液中添加3-氯過苯甲酸(2.15 g，8.7 mmol，70%純度，Aldrich，目錄號：273031-100G)。將反應混合物攪拌2小時之後，在真空中將反應混合物之體積減小至約50 mL。藉由過濾收集所得沈澱物，用甲醇洗滌且乾燥，得到呈白色固體之6-胺基-9-苄基-2-丙基亞磺醯基-7H -嘌呤-8-酮(1.0 g，化合物 1d )。產物未經進一步純化即用於下一步驟。MS觀測值 (ESI⁺ ) [(M+H)⁺ ]: 332。 Step 4: 6-benzyl-2-propyl-9- alkylsulfinyl acyl -7 H - purin-8-one (Compound 1d) of

The compound 6-benzyl-2-9- (2-sulfo-propyl-acyl) -7 H - purin-8-one (2.7 g, 8.7 mmol, Compound 1c) in DCM / MeOH (500 mL, 3-chloroperbenzoic acid (2.15 g, 8.7 mmol, 70% purity, Aldrich, catalog number: 273031-100G) was added to the suspension in V/V=1:1). 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 and dried to afford a white solid of 6-amino-benzyl-2-propyl -9- alkylsulfinyl acyl -7 H - purin-8-one (1.0 g, Compound 1d ). The product was used in the next step without further purification. MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 332.

在50℃下，向6-胺基-9-苄基-2-丙基亞磺醯基-7H -嘌呤-8-酮(1.52 g, 4.6 mmol,化合物 1d )於伊通氏試劑(Eaton's reagent) (40 mL, 五氧化磷, 7.5 wt%於甲磺酸中, Aldrich, 目錄號: 380814-100ML)中之溶液中添加疊氮化鈉(360 mg, 5.5 mmol)。在此溫度下攪拌30分鐘之後，將反應混合物冷卻至室溫且倒入至飽和碳酸氫鈉水溶液中。反應混合物用n- BuOH (100 mL)萃取兩次，且真空濃縮有機相。提供殘餘物以藉由製備型HPLC進行純化，得到呈白色固體狀之6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7H -嘌呤-8-酮(1.2 g，化合物 1e )。¹ H NMR (400 MHz, DMSO-d₆ )δ ppm: 10.65 (br. s., 1H), 7.26-7.37 (m, 5H), 6.98 (br. s., 2H), 4.97 (s, 2H), 4.02 (s, 1H), 3.33 (t,J = 7.53 Hz, 2H), 1.55-1.74 (m, 2H), 0.92 (t,J =7.53 Hz, 3H)。 MS觀測值 (ESI⁺ ) [(M⁺ H)⁺ ]: 347。 Step 5: - purin-8-one (compound 1e) of 6-amino--9- benzyl-2- (propylsulfonyl (PEI) acyl) -7 H

At 50 ℃, of 6-benzyl-2-propyl-9- alkylsulfinyl acyl -7 H - purin-8-one (1.52 g, 4.6 mmol, Compound 1d) in YITONG's reagent (Eaton's reagent) (40 mL, phosphorus pentoxide, 7.5 wt% in methanesulfonic acid, Aldrich, catalog number: 380814-100ML) was added sodium azide (360 mg, 5.5 mmol). After stirring at this temperature for 30 minutes, the reaction mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate. The reaction mixture was extracted twice with n- BuOH (100 mL), and the organic phase was concentrated in vacuo. The residue was purified to provide by preparative HPLC, to give a white solid of 6--9- benzyl-2- (propylsulfonyl (PEI) acyl) -7 H - purin-8-one ( 1.2 g, compound 1e ). 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 = 7.53 Hz, 2H), 1.55-1.74 (m, 2H), 0.92 (t, J =7.53 Hz, 3H). MS observation (ESI ⁺ ) [(M ⁺ H) ⁺ ]: 347.

Separation of compound 1e by palm HPLC gave compound 1e-A (slow dissolution, 500 mg) and compound 1e-B (faster dissolution, 490 mg) as white solids. (Separation conditions: methanol 5%-40% (0.05% DEA)/CO ₂ on ChiralPak 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 = 7.4 Hz, 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 = 7.4 Hz, 3H).

在室溫下向6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7H -嘌呤-8-酮(300 mg，化合物 1e )、吡啶(329 mg，4.2 mmol)及DIPEA (538 mg，4.2 mmol)於NMP (5 mL)中之溶液中添加氯化N -甲基-N -丙基-胺甲醯(564 mg，4.2 mmol，中間產物 AA )。在室溫下將混合物攪拌10小時。將反應混合物濃縮且藉由製備型HPLC純化殘餘物，得到呈白色固體狀之6-胺基-9-苄基-N -甲基-8-側氧基-N -丙基-2-(丙基磺醯亞胺醯基)嘌呤-7-甲醯胺(108 mg，實例 1 )。¹ H NMR (400 MHz, DMSO-d₆ )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觀測值 (ESI⁺ ) [(M+H)⁺ ]: 446。 Step 6 : 6- Amino -9- benzyl- N - methyl -8 -pentoxy - N - propyl -2-( propylsulfonylimide acetyl ) purine -7- methylamide ( example 1) preparation of

At room temperature, of 6-benzyl-2-9- (acyl imine sulfonylurea propyl) -7 H - purin-8-one (300 mg, compound 1e), pyridine (329 mg, 4.2 mmol) and DIPEA (538 mg, 4.2 mmol) in NMP (5 mL) were added N -methyl- N -propyl-aminoformamide chloride (564 mg, 4.2 mmol, intermediate product AA ). The mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give 6-amino-9-benzyl- N -methyl-8-oxo- N -propyl-2-(propylene as a white solid Sulfasulfonimide (acetyl))purine-7-methylamide (108 mg, Example 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 446.

By isopropyl alcohol 5%-40% (0.05% DEA)/CO ₂ on ChiralPak AD-3 column by palm HPLC separation of Example 1 compound, to give Example 1-A as a white solid (compared Slow dissolution, 50 mg) and Example 1-B (faster dissolution, 40 mg). 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 observation (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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 446.

步驟 1 ： N - 苄基 -6- 氯 -5- 硝基 -2- 丙基磺醯基 - 嘧啶 -4- 胺 ( 化合物 1f) 之製備

Method B : Alternative method for preparing 6- amino -9- benzyl- 2-( propylsulfonylimide )-7 H - purin -8- one ( Compound 1e)

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

To a mixture of 4,6-dichloro-5-nitro-2-propylsulfonyrimidine (150.0 g, 559.5 mmol) and DIPEA (108.5 g, 839.2 mmol) in THF (1.5 L) at -78°C To the solution was slowly added THF (200 mL) containing phenylmethylamine (60.0 g, 559.5 mmol). 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), washed three 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-propylsulfonyl-pyrimidine-4-amine as a yellow solid (180.0 g, compound 1f ) and used in the next step without further purification. MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 339.1.

在25℃下向N-苄基-6-氯-5-硝基-2-丙基磺醯基-嘧啶-4-胺(180 g，化合物 1f )及HOAc (319 g，5.31 mol)於THF (3.0 L)中之溶液中緩慢添加Zn (174 g，2.66 mol)。在添加之後，在25℃下攪拌混合物16小時。將反應物過濾且將濾液用NaHCO₃ (800 mL)飽和水溶液鹼化，用EA (400 mL)萃取三次，經Na₂ SO₄ 乾燥且真空濃縮。藉由矽膠層析法純化殘餘物，得到呈棕色固體狀之N 4-苄基-6-氯-2-丙基磺醯基-嘧啶-4,5-二胺(125 g，化合物 1g )。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 309.1。 Step 2: N 4- benzyl-6-chloro-2-propyl sulfo acyl - pyrimidine-4,5-diamine (Compound 1g) of

N-benzyl-6-chloro-5-nitro-2-propylsulfonyl-pyrimidin-4-amine (180 g, compound 1f ) and HOAc (319 g, 5.31 mol) in THF at 25°C (3.0 L) was slowly added Zn (174 g, 2.66 mol) to the solution. 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 (800 mL), extracted three times with EA (400 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography to obtain N 4-benzyl-6-chloro-2-propylsulfonyl-pyrimidine-4,5-diamine (125 g, compound 1 g ) as a brown solid. MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 309.1.

在80℃下將N -苄基-6-氯-2-(丙基磺醯基)嘧啶-4,5-二胺(72.0 g，233.1 mmol，化合物 1g )及CDI (75.2 g，233.1 mmol)於THF (800 mL)中之溶液攪拌16小時。將所得混合物用EA (400 mL)稀釋，接著用水(200 mL)洗滌兩次且用鹽水(200 mL)洗滌。經分離有機層經Na₂ SO₄ 乾燥並真空濃縮。將殘餘物用MTBE (200 mL)洗滌，得到呈白色固體狀之9-苄基-6-氯-2-丙基磺醯基-7H-嘌呤-8-酮(58.0 g，化合物 1h )，且不經進一步純化即用於下一步驟。 MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 335.1。 Step 3: 9-benzyl-6-chloro-2-propyl sulfo acyl -7 H - purin-8-one (Compound 1h) Preparation of

At 80°C, N -benzyl-6-chloro-2-(propylsulfonyl)pyrimidine-4,5-diamine (72.0 g, 233.1 mmol, compound 1 g ) and CDI (75.2 g, 233.1 mmol) The solution in THF (800 mL) was stirred for 16 hours. The resulting mixture was diluted with EA (400 mL), then washed twice with water (200 mL) and 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 obtain 9-benzyl-6-chloro-2-propylsulfonyl-7H-purin-8-one (58.0 g, compound 1h ) as a white solid, and Used in the next step without further purification. MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 335.1.

在120℃下將9-苄基-6-氯-2-丙基磺醯基-7H -嘌呤-8-酮(58.0 g，化合物 1h )及PMBNH₂ (54.7 g，398.42 mmol)於n- BuOH (600 mL)中之溶液攪拌20小時。將反應物濃縮且將殘餘物用MTBE (400 mL)洗滌，得到呈白色固體狀之9-苄基-6-[(4-甲氧基苯基)甲胺基]-2-丙基磺醯基-7H -嘌呤-8-酮(75 g，化合物 1i )且不經進一步純化即用於下一步驟。MS觀測值 (ESI⁺ ) [(M+H)⁺ ]: 436.2。 Step 4: 9-benzyl-6 - [(4-methoxyphenyl) methylamino] -2-propyl sulfonic acyl -7 H - purin-8-one (Compound 1i) of

At 120 deg.] C 9-benzyl-6-chloro-2-propyl sulfo acyl -7 H - purin-8-one (58.0 g, compound 1h) and _{PMBNH 2 (54.7 g, 398.42 mmol} ) in n- The solution in BuOH (600 mL) was stirred for 20 hours. The reaction was concentrated and the residue was washed with MTBE (400 mL) to give 9-benzyl-6-[(4-methoxyphenyl)methylamino]-2-propylsulfonamide as a white solid yl -7 H - purin-8-one (75 g, compound 1i) was used without further purification in the next step. MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 436.2.

在80℃下將含9-苄基-6-[(4-甲氧基苯基)甲胺基]-2-丙基磺醯基-7H -嘌呤-8-酮(87.0 g，化合物 1i )之TFA (200 mL)攪拌16小時。將所得反應混合物濃縮，用飽和NaHCO₃ 水溶液(600 mL)鹼化。藉由過濾收集所得沈澱物且用(PE/DCM=2:1，400 mL)洗滌，得到呈白色固體狀之6-胺基-9-苄基-2-丙基磺醯基-7H-嘌呤-8-酮(38.0 g，化合物 1c )。MS obsd.觀測值 (ESI⁺ ) [(M+H)⁺ ]: 316.1。 Purin-8-one (Compound 1c) - A 6-amino-sulfo-2-propyl-benzyl -9- acyl -7 H: Step 5

At 80 deg.] C containing 9-benzyl-6 - [(4-methoxyphenyl) methylamino] -2-propyl sulfonic acyl -7 H - purin-8-one (87.0 g, Compound 1i ) Of TFA (200 mL) was stirred for 16 hours. The resulting reaction mixture was concentrated and basified with saturated aqueous NaHCO ₃ (600 mL). The resulting precipitate was collected by filtration and washed with (PE/DCM=2:1, 400 mL) to obtain 6-amino-9-benzyl-2-propylsulfonyl-7H-purine as a white solid -8-one (38.0 g, compound 1c ). MS obsd. Observed value (ESI ⁺ ) [(M+H) ⁺ ]: 316.1.

在0℃下向m- CPBA (22.98 g，113.2 mmol)於THF (50 mL)中之溶液中逐滴添加6-胺基-9-苄基-2-丙基磺醯基-7H-嘌呤-8-酮(35.0 g，化合物1c)於THF (200 mL)中之懸浮液。在添加之後，在25℃下將反應混合物攪拌0.5小時。過濾混合物且用MeCN (400 mL)、MTBE (500 mL)洗滌，得到呈白色固體狀之6-胺基-9-苄基-2-丙基亞磺醯基-7H -嘌呤-8-酮(35.1 g，化合物 1d )，其不經進一步純化即用於下一步驟。 MS觀測值 (ESI⁺ ) [(M+H)⁺ ]: 332.1。 Step 6: 6-benzyl-2-propyl-9- alkylsulfinyl acyl -7 H - purin-8-one (Compound 1d) of

To a solution of m- CPBA (22.98 g, 113.2 mmol) in THF (50 mL) was added 6-amino-9-benzyl-2-propylsulfonyl-7H-purine at 0°C dropwise A suspension of 8-one (35.0 g, compound 1c) in THF (200 mL). After the addition, the reaction mixture was stirred at 25°C for 0.5 hour. The mixture was filtered and washed with MeCN (400 mL), (500 mL) was washed with MTBE, to give a white solid of 6- benzyl-2-propyl-9- alkylsulfinyl acyl -7 H - purin-8-one (35.1 g, compound 1d ), which was used in the next step without further purification. MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 332.1.

在60℃下向6-胺基-9-苄基-2-丙基亞磺醯基-7H -嘌呤-8-酮(34.0 g,化合物 1d )於伊通氏試劑(170.0 mL, 7.5 wt%於甲磺酸中)中之溶液中，緩慢添加NaN₃ (15.34 g, 253.97 mmol)。隨後在60℃下將混合物攪拌30分鐘。將所得反應混合物冷卻至25℃，倒入冰冷NH₃ .H₂ O (500 mL, 1 mol/L)中，用n- BuOH (100 mL)萃取四次並真空濃縮。殘餘物藉由製備型HPLC純化，得到6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7H-嘌呤-8-酮(10 g，化合物 1e )。¹ H NMR (400 MHz, DMSO-d₆ )δ ppm: 10.65 (br. s., 1H), 7.26-7.37 (m, 5H), 6.98 (br. s., 2H), 4.97 (s, 2H), 4.02 (s, 1H), 3.33 (t,J = 7.53 Hz, 2H), 1.55-1.74 (m, 2H), 0.92 (t,J =7.53 Hz, 3H)。MS觀測值 (ESI⁺ ) [(M⁺ H)⁺ ]: 347。 Step 7: - Preparation purin-8-one (compound 1e) of 6-amino--9- benzyl-2- (propylsulfonyl (PEI) acyl) -7 H

At 60 deg.] C solution of 6-benzyl-2-propyl-9- alkylsulfinyl acyl -7 H - purin-8-one (34.0 g, Compound 1d) in YITONG's reagent (170.0 mL, 7.5 wt % In methanesulfonic acid), slowly add NaN ₃ (15.34 g, 253.97 mmol). The mixture was subsequently stirred at 60°C for 30 minutes. The resulting reaction mixture was cooled to 25°C, poured into ice-cold NH ₃ .H ₂ O (500 mL, 1 mol/L), extracted four times with n- BuOH (100 mL) and concentrated in vacuo. The residue was purified by preparative HPLC to obtain 6-amino-9-benzyl-2-(propylsulfonylimide)-7H-purin-8-one (10 g, compound 1e ). 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 = 7.53 Hz, 2H), 1.55-1.74 (m, 2H), 0.92 (t, J =7.53 Hz, 3H). MS observation (ESI ⁺ ) [(M ⁺ H) ⁺ ]: 347.

Example 2 6- amino -9- benzyl- N- (2 -methoxyethyl ) -N- methyl -8 -oxo -2-( propylsulfonylimide ) purine -7 - A Amides

Similar to Example 1 , Method A, Step 6 by using N- (2-methoxyethyl) chloride -N - methyl-aminoformamide ( intermediate product AB ) instead of N -methyl- N chloride - propyl - methyl acyl amine (intermediate AA) to prepare the title compound. 6-Amino-9-benzyl- N- (2-methoxyethyl) -N- methyl-8-oxo-2-(propylsulfonylimide amide) is obtained as a white solid ) Purine-7-carboxamide (120 mg, Example 2 ). 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 = 4 Hz, 1H), 3.62 (br. dd, J = 4, 12 Hz, 2H), 3.28-3.42 (m, 6H), 3.12 (d, J = 12 Hz, 3H ), 3.05 (s, 1H), 1.58-1.72 (m, 2H), 0.93 (t, J = 8 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 462.

Using methanol 5%-40% (0.05% DEA)/CO ₂ on a ChiralPak OJ-3 column by palm HPLC separation of the compound of Example 2 , to obtain Example 2-A as a white solid (faster dissolution, 33 mg) and Example 2-B (slower dissolution, 46 mg). 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 = 4 Hz, 1H), 3.62 (br. dd, J = 4, 12 Hz, 2H), 3.28-3.42 (m, 6H), 3.12 (d, J = 12 Hz, 3H), 3.05 (s, 1H), 1.58-1.72 (m, 2H), 0.93 (t, J = 8Hz, 3H). MS observation (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 = 4 Hz, 1H), 3.62 (br. dd, J = 4, 12 Hz, 2H), 3.28-3.42 (m, 6H), 3.12 (d, J = 12 Hz, 3H), 3.05 (s, 1H), 1.58-1.72 (m, 2H), 0.93 (t, J = 8Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 462.

Example 3 6- amino -9- benzyl- N - ethyl - 8 -pentoxy - N - propyl -2-( propylsulfonylimide acetyl ) purine -7 - methylamide

Similar to Example 1 , Method A, Step 6 by using N- ethyl- N -propyl-aminoformamide chloride ( intermediate product AC ) instead of N -methyl- N- propyl-amineformamide chloride ( Intermediate AA ) to prepare the title compound. 6-Amino-9-benzyl- N -ethyl-8-oxo- N -propyl-2-(propylsulfonylimide acetyl)purine-7-methyl amide was obtained as a white solid Amine (51 mg, Example 3 ). 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 = 8.0 Hz, 1H), 3.13-3.54 (m, 4H), 1.46-1.72 (m, 4H), 1.30-1.39 (m, 1H), 1.00-1.26 (m, 6H), 0.81-0.95 (m, 5H), 0.73 (t, J = 8 Hz, 1H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 474.

Example 4 6- Amino -9- benzyl- 7-[4-(1 -piperidinyl ) piperidin- 1- carbonyl ]-2-( propylsulfonyliminyl ) purin -8- one

Similar to Example 1 , Method A , Step 6 , by using chloride (1,4'-dipiperidine)-1'-carbonyl instead of chloride N- methyl- N -propyl-aminoformamide ( middle Product AA ) to prepare the title compound. 6-Amino-9-benzyl-7-[4-(1-piperidinyl)piperidin-1-carbonyl]-2-(propylsulfonylimide acetyl)purine was obtained as a white powder 8-one (55 mg, Example 4 ). 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 = 12.5 Hz, 1H), 3.43-3.15 (m, 3H), 2.96 (t, J = 12.3 Hz, 2H), 2.56 (m, 4H), 1.83 (m, 1H), 1.79- 1.54 (m, 4H), 1.50 (br. s., 4H), 1.45-1.33 (m, 3H), 0.93 (t, J = 7.4 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 541.2.

Example 5 6- amino -9- benzyl- N - ethyl - N- ( 2 -methoxyethyl )-8- pendant -2-( propylsulfonylimide ) purine -7 - A Amides

Similar to Example 1, Method A, Step 6, by use of ethyl chloride, N- - N - (2- methoxyethyl) carbamoyl acyl (Intermediate AD) chloride instead of N- methyl - N - propyl - methyl acyl amine (intermediate AA) to prepare the title compound. 6-Amino-9-benzyl- N -ethyl- N- (2-methoxyethyl)-8-oxo-2-(propylsulfonylimideamide) was obtained as a white powder ) Purine-7-carboxamide (34 mg, Example 5). 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 = 8.1 Hz, 1H), 3.67 (br. s., 2H), 3.63-3.51 (m, 2H), 3.50-3.34 (m, 4H), 3.29 (s, 1H), 3.11 ( s, 2H), 1.73-1.59 (m, 2H), 1.23-1.07 (m, 3H), 0.93 (t, J = 7.5 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 476.3.

Example 6 6 - Amino -9- benzyl- N - butyl - N - ethyl -8 -oxo -2-( propylsulfonylimide acetyl ) purine -7- methyl amide

Similar to Example 1 , Method A , Step 6 , by using N -butyl chloride -N -ethyl-carbamide ( intermediate product AE ) instead of N -methyl chloride - N- propyl chloride Acetyl ( intermediate AA ) to prepare the title compound. 6-Amino-9-benzyl- N -butyl- N -ethyl-8-oxo-2-(propylsulfonylimidoamide)purine-7-methylamide was obtained as a white solid Amine (51 mg, Example 6) . 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 = 8.0 Hz, 1H), 3.13-3.54 (m, 4H), 1.46-1.72 (m, 4H), 1.30-1.39 (m, 1H), 1.00-1.26 (m, 6H), 0.81-0.95 (m, 5H), 0.73 (t, J = 8 Hz, 1H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 474.

Example 7 6- amino -9- benzyl- N- (2 -methoxyethyl )-8- pendant - N - propyl -2-( propylsulfonylimide ) purine -7 - A Amides

Similar to Example 1 , Method A , Step 6 , by using N- ethyl chloride - N-(2-methoxyethyl)aminecarboxamide ( intermediate product AF ) instead of N -methyl chloride - N - propyl - methyl acyl amine (intermediate AA) to prepare the title compound. 6-Amino-9-benzyl- N- (2-methoxyethyl)-8-oxo -N- propyl-2-(propylsulfonylimide amide) was obtained as a white powder ) Purine-7-carboxamide (35 mg, Example 7 ). 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 = 5.5 Hz, 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 490.5.

Example 8 6- amino -9- benzyl- N,N - bis (2 -methoxyethyl )-8- pendant -2-( propylsulfonylimide ) purine -7- methyl Amide

Similar to Example 1 , Method A , Step 6 , by using chlorinated bis(2-methoxyethyl)carbamic acid ( intermediate product AG ) instead of N -methyl- N- propyl-amine methyl chloride Acetyl ( intermediate AA ) to prepare the title compound. Obtained as a white powder of 6-amino-9-benzyl- N,N -bis(2-methoxyethyl)-8- pendant-2-(propylsulfonylimide)purine -7-formamide (35 mg, Example 8 ). 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 = 7.5 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 506.

Example 9 6- amino -7-( azetidine- 1- carbonyl )-9- benzyl- 2-( propylsulfonylimide ) purin -8- one

Similar to Example 1 , Method A , Step 6 , by using azetidine chloride-1-carboxamide ( intermediate product AH ) instead of N- methyl- N- propyl-amine carboxamide ( intermediate) Product AA ) to prepare the title compound. 6-Amino-7-(azetidine-1-carbonyl)-9-benzyl-2-(propylsulfonylimide)purin-8-one (120 mg) was obtained as a white powder , Example 9 ). 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 = 7.40 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 430.

Example 10 6- Amino -9- benzyl- N - isopropyl- N - methyl -8 -oxo -2-( propylsulfonylimide acetyl ) purine -7- methyl amide

Similar to Example 1 , Method A , Step 6 , by using N- isopropyl- N -methyl-amine chloride ( intermediate product AI ) instead of N -methyl- N- propyl-amine chloride Formamide ( intermediate product AA ) to prepare the title compound. Obtained as a white solid 6-amino-9-benzyl- N -isopropyl- N -methyl-8-oxo-2-(propylsulfonylimide acetyl)purine-7-methyl Acetamide (97 mg, Example 10 ). 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 = 8 Hz, 6H), 0.93 (t, J = 8 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 446.

Example 11 6- amino -9- benzyl- 7-(4 -methylpiperazine- 1- carbonyl )-2-( propylsulfonylimide ) purin -8- one

Similar to Example 1 , Method A , Step 6 , by using 4-methylpiperazine-1-carboxamide chloride instead of N -methyl- N -propyl-carboxamide chloride ( intermediate product AA ) Preparation of the title compound. 6-Amino-9-benzyl-7-(4-methylpiperazine-1-carbonyl)-2-(propylsulfonyliminyl)purin-8-one (59.5) was obtained as a yellow solid mg, Example 11 ). 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 = 7.2 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 473.

Example 12 6- amino -9- benzyl- N- (3 -methoxypropyl ) -N- methyl -8- pendant -2-( propylsulfonylimide ) purine -7 - A Amides

Similar to Example 1 , Method A , Step 6 , by using N-( 3-methoxypropyl) -N- methyl-aminoformamide chloride instead of N -methyl- N -propyl chloride Carboxamide ( intermediate product AA ) to prepare the title compound. 6-amino-9-benzyl- N- (3-methoxypropyl) -N- methyl-8-oxo-2-(propylsulfonylimide amide) was obtained as a white solid ) Purine-7-carboxamide (92.2 mg, Example 12 ). 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 476.3.

Example 13 6- Amino -9- benzyl- N - isobutyl- N - methyl -8 -oxo -2-( propylsulfonylimide acetyl ) purine -7- methylamide

Similar to Example 1 , Method A , Step 6 , by using N- isobutyl- N -methyl-amine chloride ( intermediate product AL ) instead of N -methyl- N- propyl -amine chloride Formamide ( intermediate product AA ) to prepare the title compound. Obtained as a white solid 6-amino-9-benzyl- N -isobutyl- N -methyl-8-oxo-2-(propylsulfonylimide)purine-7-methyl Acetamide (64 mg, Example 13 ). 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 460.

Example 14 2-[[6- Amino -9- benzyl- 8- pendant -2-( propylsulfonylimido ) purine -7- carbonyl ] -methyl - amino ] ethyl acetate

Similar to Example 1 , Method A , Step 6 , by using 2-((chlorocarbonyl)(methyl)amino)ethyl acetate ( intermediate product AP ) instead of N -methyl- N- propyl chloride Carboxamide ( intermediate product AA ) to prepare the title compound. 2-[[6-Amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide acetyl)purine-7-carbonyl]-methyl-amine was obtained as a pale yellow powder Ethyl] ethyl acetate (38 mg, Example 14 ). ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm: 7.41-7.27 (m, 5H), 6.82 (br. s., 1H), 5.04-4.95 (m, 2H), 4.35 (br. s., 1H ), 4.28 (br. s., 1H), 4.23-4.16 (m, 2H), 4.08 (q, J = 7.2 Hz, 1H), 3.43-3.28 (m, 3H), 3.15 (s, 2H), 3.08 (s, 1H), 1.71-1.58 (m, 2H), 1.24 (t, J = 7.0 Hz, 2H), 1.12 (t, J = 7.0 Hz, 1H), 0.93 (t, J = 7.4 Hz, 3H) . MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 490.

Example 15 3-[[6- Amino -9- benzyl- 8- pendant -2-( propylsulfonylimide ) purine -7- carbonyl ] -methyl - amino ] ethyl propionate ester

Similar to Example 1 , Method A , Step 6 , by using ethyl 3-((chlorocarbonyl)(methyl)amino)propionate instead of chlorinated N -methyl- N -propyl-aminoformamide ( Intermediate AA ) to prepare the title compound. Obtained 3-[[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide acetyl)purine-7-carbonyl]-methyl-amino as a white powder ] Ethyl propionate (35 mg, Example 15 ). ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm: 7.43-7.26 (m, 5H), 6.93 (br. s., 2H), 4.99 (s, 2H), 4.16 (s, 1H), 4.08 (q , J = 7.1 Hz, 1H), 3.99 (d, J = 7.0 Hz, 1H), 3.67 (br. s., 2H), 3.40-3.29 (m, 2H), 3.08 (s, 2H), 2.99 (s , 1H), 2.71 (t, J = 6.4 Hz, 2H), 1.74-1.56 (m, 2H), 1.27-1.05 (m, 3H), 0.93 (t, J = 7.5 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 504.

Example 16 3-[[6- Amino -9- benzyl- 8- pendant -2-( propylsulfonylimido ) purine -7- carbonyl ] -methyl - amino ] propanoic acid Tributyl ester

Similar to Example 1 , Method A , Step 6 , by using 3-[chlorocarbonyl (methyl)amino] propionic acid third butyl ester ( intermediate product AR ) instead of chlorinated N -methyl- N -propyl -Aminoformamide ( intermediate product AA ) to prepare the title compound. Obtained 3-[[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide acetyl)purine-7-carbonyl]-methyl-amino as a white powder ] Third butyl propionate (60 mg, Example 16 ). 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 = 6.9 Hz, 2H), 1.71-1.57 (m, 2H ), 1.41 (s, 6H), 1.34 (s, 3H), 0.93 (t, J = 7.4 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 532.

Example 17 (2S)-2-[[6- Amino -9- benzyl- 8- pendant -2-( propylsulfonylimide acetyl ) purine -7- carbonyl ] -methyl - amino ] Ethyl propionate

Similar to Example 1 , Method A , Step 6 , by using (2 S )-2-[chlorocarbonyl(methyl)amino]propionic acid ethyl ester ( intermediate product AS ) instead of N -methyl- N chloride -Propyl-aminoformamide ( intermediate product AA ) to prepare the title compound. Obtained as a yellow solid (2 S )-2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide acetyl)purine-7-carbonyl]- Methyl-amino] ethyl propionate (34.1 mg, Example 17 ). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ ppm: 7.22-7.49 (m, 5 H), 6.78 (br. s., 2H), 4.93-5.08 (m, 2H), 4.75 (br. s. , 1H), 3.96-4.29 (m, 3H), 3.30-3.46 (m, 2H), 3.09 (s, 2H), 2.93 (br. s., 1H), 1.55-1.77 (m, 2H), 1.48 ( d, J = 7.16 Hz, 3H), 1.09-1.29 (m, 3H), 0.94 (t, J = 7.44 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 504.2.

Example 18 (2 S )-2-[[6- amino -9- benzyl- 8- pendant -2-( propylsulfonylimide acetyl ) purine -7- carbonyl ] -methyl - amine Yl ]-4 -methyl - valerate

Similar to Example 1 , Method A , Step 6 , by using (2 S )-2-[chlorocarbonyl(methyl)amino]-4-methyl-pentanoic acid third butyl ester ( intermediate product AT ) instead Chloride N -methyl- N -propyl-aminoformamide ( intermediate product AA ) to prepare the title compound. Obtain (2S)-2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonylimidoamide)purine-7-carbonyl]-methyl as a white solid -Amino]-4-methyl-valeric acid tert-butyl ester (22 mg, Example 18 ). ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm: 7.42-7.27 (m, 5H), 6.78 (br. s., 2H), 5.05-4.96 (m, 2H), 4.78 (br. s., 1H ), 4.33 (br. s., 1H), 3.51-3.37 (m, 2H), 3.01 (s, 3H), 1.75-1.54 (m, 4H), 1.44 (s, 8H), 1.33-1.11 (m, 2H), 0.99-0.82 (m, 9H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 574.3.

Example 19 (2S)-2-[[6- Amino -9- benzyl- 8- pendant -2-( propylsulfonylimide ) purine -7- carbonyl ] -methyl - amino ]-4 -Methyl - valeric acid isopropyl ester

Similar to Example 1 , Method A , Step 6 , by using (2 S )-2-[chlorocarbonyl(methyl)amino]-4-methyl-valeric acid isopropyl ester ( intermediate product AU ) instead of chlorine N -methyl- N -propyl-aminoformamide ( intermediate product AA ) was used to prepare the title compound. (2 S )-2-[[6-Amino-9-benzyl-8-oxo-2-(propylsulfonylimide acetyl)purine-7-carbonyl]- was obtained as a white powder Methyl-amino]-4-methyl-valeric acid isopropyl ester (43 mg, Example 19 ). ¹ H NMR (400MHz, 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 560.3.

Example 20 (2 S )-2-[[6- Amino -9- benzyl- 8 -pentoxy -2-( propylsulfonylimide acetyl ) purine -7- carbonyl ] -methyl - amine Yl ]-3 -methyl - butyric acid ethyl ester

Similar to Example 1 , Method A , Step 6 , by using (2 S )-2-[chlorocarbonyl(methyl)amino]-3-methyl-butyric acid ethyl ester ( intermediate product AV ) instead of chlorination N -methyl- N -propyl-aminoformamide ( intermediate product AA ) to prepare the title compound. Obtain (2S)-2-[[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide acetyl)purine-7-carbonyl]-methyl as a white powder -Amino]-3-methyl-butyric acid ethyl ester (51.5 mg, Example 20 ). 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 observation (ESI ⁺ ) [M+H ⁺ ]: 532.2.

Example 21 (2S)-2-[[6- Amino -9- benzyl- 8- pendant -2-( propylsulfonylimido ) purine -7- carbonyl ] -methyl - amino ]-4 -Methyl - valeric acid ethyl ester

Similar to Example 1 , Method A , Step 6 , by using (2S)-2-[chlorocarbonyl(methyl)amino]-4-methyl-valeric acid ethyl ester ( intermediate product AW ) instead of N chloride - methyl - N- propyl - carbamoyl acyl (intermediate AA) to prepare the title compound. (2 S )-2-[[6-Amino-9-benzyl-8-oxo-2-(propylsulfonylimide acetyl)purine-7-carbonyl]- was obtained as a white powder Methyl-amino]-4-methyl-valeric acid ethyl ester (17.3 mg, Example 21 ). 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 = 7.09 Hz, 3H ), 0.77-1.01 (m, 9H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 546.3.

Example 22 (2 S )-2-[[6- amino -9- benzyl- 8- pendant -2-( propylsulfonylimide acetyl ) purine -7- carbonyl ] -methyl - amine yl] -3-phenyl - propionic acid ethyl ester

Similar to Example 1 , Method A , Step 6 , by using (2 S )-2-[chlorocarbonyl(methyl)amino]-3-phenyl-propionic acid ethyl ester ( intermediate AX ) instead of chlorination N -methyl- N -propyl-aminoformamide ( intermediate product AA ) to prepare the title compound. (2 S )-2-[[6-Amino-9-benzyl-8-oxo-2-(propylsulfonylimide acetyl)purine-7-carbonyl]- was obtained as a white powder Methyl-amino]-3-phenyl-propionic acid ethyl ester (30 mg, Example 22 ). ¹ H NMR (400MHz, 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 580.

Example 23 (2 S )-2-[[6- amino -9- benzyl- 8- pendant -2-( propylsulfonylimide ) purine -7- carbonyl ] -methyl - amine Yl ]-3 -phenyl - isopropyl propionate

Similar to Example 1 , Method A , Step 6 , by using (2 S )-2-[chlorocarbonyl(methyl)amino]-3-phenyl-isopropyl propionate ( intermediate product AY ) instead of chlorine N -methyl- N -propyl-aminoformamide ( intermediate product AA ) was used to prepare the title compound. (2 S )-2-[[6-Amino-9-benzyl-8-oxo-2-(propylsulfonylimide acetyl)purine-7-carbonyl]- was obtained as a white powder Methyl-amino]-3-phenyl-propionic acid isopropyl ester (22 mg, Example 23 ). ¹ H NMR (400MHz, 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 = 7.4 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 594.

Example 24 (2S)-2-[[6- Amino -9- benzyl- 8 -pentoxy -2-( propylsulfonylimide acetyl ) purine -7- carbonyl ] -methyl - amino ]-3 -Phenyl - propionic acid tert-butyl ester

Similar to Example 1 , Method A , Step 6 , by using (2 S )-2-[chlorocarbonyl(methyl)amino]-3-phenyl-propionic acid tert-butyl ester ( intermediate AZ ) instead Chloride N -methyl- N -propyl-aminoformamide ( intermediate product AA ) to prepare the title compound. (2 S )-2-[[6-Amino-9-benzyl-8-oxo-2-(propylsulfonylimide acetyl)purine-7-carbonyl]- was obtained as a white powder Methyl-amino]-3-phenyl-propionic acid tert-butyl ester (34 mg, Example 24 ). ¹ H NMR (400MHz, 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 608.3.

Example 25 N- [2-[ Acetyl ( methyl ) amino ] ethyl ] -6- amino -9- benzyl- N - methyl - 8 -oxo -2-( propylsulfonamide Iminyl ) purine -7- methylamide

Similar to Example 1 , Method A , Step 6 , by using N- [2-[acetoyl(methyl)amino]ethyl] -N -methyl-aminecarboxamide ( intermediate product BA ) The non-chlorinated N -methyl- N -propyl-aminoformamide ( intermediate product AA ) was used to prepare the title compound. Obtain N- [2-[Acetyl(methyl)amino]ethyl]-6-amino-9-benzyl- N- methyl-8-oxo-2-(white powder) Propylsulfonylimide) purine-7-formamide (26.1 mg, Example 25 ). ¹ H NMR (400MHz, 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 = 5.5 Hz, 2H), 3.49-3.34 (m, 2H), 3.14 (s, 1H), 3.12-3.02 (m, 4H), 2.86 (d, J = 7.5 Hz, 2H), 2.69-2.64 (m, 1H), 2.05 (s, 1H), 1.99 (s, 1H), 1.91-1.83 (m, 1H), 1.70-1.59 (m, 2H), 0.97-0.90 (m, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 503.2.

Example 26 N- [2-[[6- Amino -9- benzyl- 8 -pentoxy -2-( propylsulfonylimide ) purine -7- carbonyl ] -methyl - amino ] Ethyl ] -N - methyl - carbamic acid methyl ester

Similar to Example 1 , Method A , Step 6 , by using N- [2-[chlorocarbonyl(methyl)amino]ethyl] -N -methyl-carbamic acid methyl ester ( intermediate product BB ) instead Chloride N -methyl- N -propyl-aminoformamide ( intermediate product AA ) to prepare the title compound. Obtain N- [2-[[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide acetyl)purine-7-carbonyl]-methyl as a yellow solid -Amino]ethyl] -N -methyl-carbamic acid methyl ester (65 mg, Example 26 ). 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 = 7.40 Hz, 3H), 1.87 (dd, J = 14.12, 6.96 Hz, 2H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 519.2.

Example 27 N- [2-[[6- Amino -9- benzyl- 8 -pentoxy -2-( propylsulfonylimido ) purine -7- carbonyl ] -methyl-amino] Ethyl] -N - methyl-carbamic acid tert-butyl ester

Similar to Example 1 , Method A , Step 6 , by using N- [2-[chlorocarbonyl(methyl)amino]ethyl] -N -methyl-carbamic acid third butyl ester ( intermediate product BC ) Instead of chlorinating N -methyl- N -propyl-aminoformamide ( intermediate product AA ) to prepare the title compound. Obtain N- [2-[[6-Amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide acetyl)purine-7-carbonyl]-methyl as a white powder -Amino]ethyl] -N -methyl-carbamic acid tert-butyl ester (32 mg, Example 27 ). ¹ H NMR (400MHz, 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 = 12.8 Hz, 2H), 2.74 (d , J = 9.5 Hz, 1H), 2.70-2.60 (m, 1H), 1.72-1.54 (m, 2H), 1.39 (s, 6H), 1.23 (s, 2H), 1.13 (s, 2H), 0.93 ( t, J = 7.4 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 562.

Example 28 N- [2-[[6- Amino -9- benzyl- 8 -pentoxy -2-( propylsulfonylimide ) purine -7- carbonyl ] -methyl - amino ] ethyl] - N - methyl - urethane

Similar to Example 1 , Method A , Step 6 , by using N- [2-[chlorocarbonyl(methyl)amino]ethyl] -N -methyl-carbamic acid ethyl ester ( intermediate product BD ) instead Chloride N -methyl- N -propyl-aminoformamide ( intermediate product AA ) to prepare the title compound. Obtain N- [2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonylimido)purine-7-carbonyl]-methyl as a yellow solid -Amino]ethyl] -N -methyl-ethyl carbamate (87 mg, Example 28 ). 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 533.2.

Example 29 N- butyl - N - methyl - amino acid 2 - [[6-benzyl-8-9- oxo-2- (propylsulfonyl (PEI) acyl) purine -7 - carbonyl] - methyl - amino] ethyl ester

Similar to Example 1 , Method A , Step 6 , by using N -butyl- N -methyl-carbamic acid 2-[chlorocarbonyl (methyl)amino] ethyl ester ( intermediate product BE ) instead of chlorination N -methyl- N -propyl-aminoformamide ( intermediate product AA ) to prepare the title compound. N -butyl- N -methyl-carbamic acid 2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonylimide amide) is obtained as a yellow solid ) Purine-7-carbonyl]-methyl-amino] ethyl ester (19 mg, compound 29 ). 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 = 7.40 Hz, 3H), 0.70-0.87 (m, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 561.2.

Pyrrolidin-l-carboxylic acid Example 30 2 - [[6-benzyl-8-9- oxo-2- (propylsulfonyl (PEI) acyl) purin-7-carbonyl] - methyl - Amino ] ethyl

Similar to Example 1 , Method A , Step 6 , by using pyrrolidine-1-carboxylic acid 2-[chlorocarbonyl(methyl)amino]ethyl ester ( intermediate product BF ) instead of chlorinated N -methyl- N- Propyl-aminoformamide ( intermediate product AA ) to prepare the title compound. Pyrrolidine-1-carboxylic acid 2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonylimide acetyl)purine-7-carbonyl] was obtained as a yellow solid -Methyl-amino] ethyl ester (10.0 mg, Example 30 ). 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 545.2.

Example 31 N- Methyl - N- propyl - amino acid 2 - [[6-benzyl-8-9- oxo-2- (propylsulfonyl (PEI) acyl) purine -7 - carbonyl] - methyl - amino] ethyl ester

Similar to Example 1 , Method A , Step 6 , by using N- methyl- N- propyl-carbamic acid 2-[chlorocarbonyl (methyl)amino] ethyl ester ( intermediate product BG ) instead of chlorination N -methyl- N -propyl-aminoformamide ( intermediate product AA ) to prepare the title compound. N- methyl- N- propyl -carbamic acid 2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonylimide amide) is obtained as a yellow solid ) Purine-7-carbonyl]-methyl-amino] ethyl ester (3.7 mg, Example 31 ). 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 547.2.

Example 32 N,N -diethylaminocarboxylic acid 2-[[6- amino -9- benzyl- 8- pendant -2-( propylsulfonylimide acetyl ) purine -7- carbonyl ] - methyl - amino] ethyl ester

Similar to Example 1 , Method A , Step 6 , by using 2-[chlorocarbonyl(methyl)amino]ethyl N,N -diethylcarbamate ( intermediate BH ) instead of N -methyl chloride -N -propyl-carbamoyl ( intermediate product AA ) to prepare the title compound. N,N -diethylaminocarboxylic acid 2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonylimide acetyl)purine- was obtained as a yellow solid 7-carbonyl]-methyl-amino] ethyl ester (21.7 mg, Example 32 ). 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 547.2.

Example 33 Carbonic acid 2-[[6- amino -9- benzyl- 8- pendant -2-( propylsulfonylimide acetyl ) purine -7- carbonyl ] -methyl - amino ] ethyl Ethyl

Similar to Example 1 , Method A , Step 6 , by using 2-[chlorocarbonyl(methyl)amino]ethyl ethyl carbonate ( intermediate product BI ) instead of chlorinated N -methyl- N -propyl- Carboxamide ( intermediate product AA ) to prepare the title compound. Obtained as a yellow solid, 2-[[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino ] Ethyl ethyl ester (46 mg, Example 33 ). 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 = 5.08 Hz, 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 observation (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( R ) -Propylsulfonylimide ] purine -7- carboxamide and 6- amino - N - butyl- 9-[(4- chlorophenyl ) methyl ] -N - methyl -8- Pendant -2-[S( S ) -propylsulfonylimide acetyl ] purine -7- methylamide

類似於實例 1 、方法 A 、步驟 1 ，藉由使用異氰酸4-氯苯甲酯而非異氰酸苯甲酯來製備化合物 34a 。獲得呈黃色固體狀之4-胺基-3-[(4-氯苯基)甲基]-2-側氧基-1H-咪唑-5-甲腈(8.0 g，化合物 34a )。MS觀測值 (ESI⁺ ) [(M+H)⁺ ]: 249。 Step 1 : Preparation of 4- amino- 3-[(4- chlorophenyl ) methyl ]-2 -oxo - 1H - imidazole -5 -carbonitrile ( Compound 34a)

Similar to Example 1 , Method A , Step 1 , compound 34a was prepared by using 4-chlorobenzyl isocyanate instead of benzyl isocyanate. 4-Amino-3-[(4-chlorophenyl)methyl]-2-oxo-1H-imidazole-5-carbonitrile (8.0 g, compound 34a ) was obtained as a yellow solid. MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 249.

類似於實例 1 、方法 A 、 步驟 2 ，藉由使用4-胺基-3-[(4-氯苯基)甲基]-2-側氧基-1H -咪唑-5-甲腈(化合物 34a )而非4-胺基-3-苯基甲基-2-側氧基-1H-咪唑-5-甲腈(化合物 1a )來製備化合物34b 。獲得呈黃色固體狀之6-胺基-9-[(4-氯苯基)甲基]-2-磺醯基-7H -嘌呤-8-酮(6.4 g，化合物 34b )且其不經進一步純化即用於下一步驟。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 308。 [(4-chlorophenyl) methyl] -2-sulfonamide acyl -7 H - - purin-8-one (Compound 34b) of 6-amino--9: Step 2

Similar to Example 1 , Method A , Step 2 , by using 4-amino-3-[(4-chlorophenyl)methyl]-2-oxo- 1H -imidazole-5-carbonitrile ( compound 34a ) instead of 4-amino-3-phenylmethyl-2-oxo-1H-imidazole-5-carbonitrile ( compound 1a ) to prepare compound 34b . Was obtained as a yellow solid of 6-amino-9 - [(4-chlorophenyl) methyl] -2-sulfonamide acyl -7 H - purin-8-one (6.4 g, compound 34b) and which was used without Further purification is used in the next step. MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 308.

類似於實例 1 、方法 A 、 步驟 3 ，藉由使用6-胺基-9-[(4-氯苯基)甲基]-2-磺醯基-7H -嘌呤-8-酮(化合物 34b )而非6-胺基-9-苯基甲基-2-磺醯基-7H -嘌呤-8-酮(化合物 1b )來製備化合物34c 。獲得呈白色固體狀之6-胺基-9-[(4-氯苯基)甲基]-2-丙基磺醯基-7H -嘌呤-8-酮(800 mg，化合物 34c )。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 350。 [(4-chlorophenyl) methyl] -2-propyl sulfonic acyl -7 H - - purin-8-one (Compound 34c) of 6-amino--9: Step 3

Similar to Example 1, Method A, Step 3, by using 6-amino-9 - [(4-chlorophenyl) methyl] -2-sulfonamide acyl -7 H - purin-8-one (Compound 34b ) instead of 6-amino-9-phenyl-2-sulfo acyl -7 H - purin-8-one (compound 1b) to prepare compound 34c. Was obtained as a white solid of 6-amino-9 - [(4-chlorophenyl) methyl] -2-propyl sulfonic acyl -7 H - purin-8-one (800 mg, compound 34c). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 350.

類似於實例 1 、方法 A 、 步驟 4 ，藉由使用6-胺基-9-[(4-氯苯基)甲基]-2-丙基磺醯基-7H -嘌呤-8-酮(化合物 34c )而非6-胺基-9-苄基-2-丙基磺醯基-7H -嘌呤-8-酮(化合物 1c )來製備化合物 34d 。獲得呈白色固體狀之6-胺基-9-[(4-氯苯基)甲基]-2-丙基亞磺醯基-7H -嘌呤-8-酮(150 mg，化合物 34d )。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 366。 [(4-chlorophenyl) methyl] -2-methylsulfoximide acyl -7 H - - purin-8-one (Compound 34d is) of 6-amino--9: Step 4

Similar to Example 1, Method A, Step 4, by using 6-amino-9 - [(4-chlorophenyl) methyl] -2-propyl sulfonic acyl -7 H - purin-8-one ( compound 34c) instead of 6-amino-sulfo-2-propyl-benzyl -9- acyl -7 H - purin-8-one (compound 1c) to prepare compound 34d. Was obtained as a white solid of 6-amino-9 - [(4-chlorophenyl) methyl] -2-methylsulfoximide acyl -7 H - purin-8-one (150 mg, compound 34d). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 366.

34e-A 及 34e-B 類似於實例 1 、方法 A 、 步驟 5 ，藉由使用6-胺基-9-[(4-氯苯基)甲基]-2-丙基亞磺醯基-7H -嘌呤-8-酮(化合物 34d )而非6-胺基-9-苄基-2-(2-丙基亞磺醯基)-7H -嘌呤-8-酮(化合物 1d )來製備化合物 34e 。獲得呈白色固體狀之6-胺基-9-[(4-氯苯基)甲基]-2-(丙基磺醯亞胺醯基)-7H -嘌呤-8-酮(250 mg，化合物 34e )。¹ H NMR (400 MHz, DMSO-d₆ )δ ppm: 10.60 (br. s, 1H), 7.32-7.42 (m, 4H), 6.98 (br. s, 2H), 4.96 (s, 2H), 4.03 (s, 1H), 3.25-3.41 (m, 2H), 1.56-1.68 (m, 2H), 0.91 (t,J = 8 Hz, 3H)。MS觀測值 (ESI⁺ ) [(M⁺ H)⁺ ]: 381。 Step 5 : 6- amino- 9-[(4- chlorophenyl ) methyl ]-2-( propylsulfonylimide )-7 H - purin -8- one ( compound 34e) , 6- Amino- 9-[(4- chlorophenyl ) methyl ] -2-[S(S) -propylsulfonylimide )-7 H -purin -8- one and 6- amino- 9 -[(4- chlorophenyl ) methyl ] -2-[S(S) -propylsulfonylimide )-7 H -purin -8- one ( compound 34e-A and compound 34e-B) the preparation

34e-A and 34e-B are similar to Example 1 , Method A , Step 5 , by using 6-amino-9-[(4-chlorophenyl)methyl]-2-propylsulfinyl-7 H - purin-8-one (compound 34d is) instead of 6-amino--9- benzyl-2- (2-methylsulfoximide acyl) -7 H - purin-8-one (compound 1d) was prepared Compound 34e . Was obtained as a white solid of 6-amino-9 - [(4-chlorophenyl) methyl] -2- (propylsulfonyl (PEI) acyl) -7 H - purin-8-one (250 mg, Compound 34e ). 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 = 8 Hz, 3H). MS observation (ESI ⁺ ) [(M ⁺ H) ⁺ ]: 381.

Using methanol 5%-40% (0.05% DEA)/CO ₂ on a ChiralPak OJ-3 column to separate compound 34e by palm HPLC, compound 34e-A was obtained as a white solid (faster dissolution, 110 mg) and compound 34e-B (slow dissolution, 100 mg). 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 = 7.4 Hz, 3H). MS observation (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 = 7.5 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 381.

類似於實例 1 、方法 A 、步驟 6 ，藉由使用化合物 34e-A 及氯化N -丁基-N -甲基-胺甲醯而非6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7H -嘌呤-8-酮(化合物 1e )及氯化N-甲基-N-丙基-胺甲醯(中間產物 AA )來製備實例 34-A 。實例 34-A ( 160 mg) ：¹ H NMR (400 MHz, DMSO-d₆ )δ ppm: 7.37-7.45 (m, 4H), 6.91 (br. s., 2H), 4.99 (s, 2H), 4.17 (s, 1H), 3.28-3.40 (m, 4H), 3.05 (s, 2H), 3.02 (s, 1H), 1.49-1.70 (m, 4H), 1.15-1.37 (m, 2H), 0.89-0.94 (m, 5H), 0.76 (t,J = 8 Hz, 1H)。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 494。 Step 6 : 6- Amino - N - butyl- 9-[(4- chlorophenyl ) methyl ] -N - methyl -8 -oxo -2-[S( R ) -propylsulfonamide Imino ]] purine -7- carboxamide and 6- amino - N - butyl- 9-[(4- chlorophenyl ) methyl ] -N - methyl -8 -oxo -2- [S( S ) -propylsulfonylimide acetyl ] purine -7- methylamide ( Example 34-A and Example 34-B)

Similar to Example 1 , Method A , Step 6 , by using compound 34e-A and chloride N -butyl- N -methyl-aminoformamide instead of 6-amino-9-benzyl-2-(propylene sulfonic imine acyl group) -7 H - purin-8-one (compound 1e) and N- methyl -N--propyl chloride - methyl acyl amine (intermediate AA) prepared by example 34-A. Example 34-A ( 160 mg ) : 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), 1.15-1.37 (m, 2H), 0.89- 0.94 (m, 5H), 0.76 (t, J = 8 Hz, 1H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 494.

Similar to Example 34-A , Example 34-B (167 mg) was prepared by 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), 1.15-1.37 (m, 2H), 0.89-0.94 (m, 5H), 0.76 (t, J = 7.4 Hz, 1H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 494.

類似於實例 1 、方法 A 、步驟 6 ，藉由使用6-胺基-9-[(4-氯苯基)甲基]-2-(丙基磺醯亞胺醯基)-7H -嘌呤-8-酮(化合物 34e )及氯化N- 乙基-N -甲基-胺甲醯而非6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7H-嘌呤-8-酮(化合物 1e )及氯化N-甲基-N-丙基-胺甲醯(中間產物 AA )來製備標題化合物。獲得呈白色固體狀之6-胺基-9-[(4-氯苯基)甲基]-N -乙基-N- 甲基-8-側氧基-2-(丙基磺醯亞胺醯基)嘌呤-7-甲醯胺(60 mg，實例 35 )。¹ H NMR (400 MHz, DMSO-d₆ )δ ppm: 7.40 (s, 4H), 6.91 (br s, 2H), 4.99 (s, 2H), 4.16 (s, 1H), 3.34-3.44 (m, 4H), 3.05 (s, 2H), 3.01 (s, 1H), 1.58-1.67 (m, 2H), 1.18 (t,J = 8.0 Hz, 3H), 0.92 (t,J = 8.0 Hz, 3H)。MS觀測值 (ESI⁺ ) [(M+H)⁺ ]: 466。 Example 35 6- amino- 9-[(4- chlorophenyl ) methyl ] -N - ethyl - N- methyl -8- pendant -2-( propylsulfonylimide ) purine -7- formamide

Similar to Example 1 , Method A , Step 6 , by using 6-amino-9-[(4-chlorophenyl)methyl]-2-(propylsulfonylimide)-7 H -purine -8-one ( compound 34e ) and N- ethyl- N -methyl-aminoformamide chloride instead of 6-amino-9-benzyl-2-(propylsulfonylimide amide)-7H -Purin-8-one ( Compound 1e ) and N-methyl-N-propyl-aminoformamide chloride ( intermediate product AA ) to prepare the title compound. 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl- N- methyl-8-oxo-2-(propylsulfonimide) was obtained as a white solid Acyl)purine-7-carboxamide (60 mg, Example 35 ). 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 = 8.0 Hz, 3H), 0.92 (t, J = 8.0 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 466.

Example 36-A and Example 36-B 6- amino - N - methyl -8 -pentoxy - N - propyl- 2[S( S ) -propylsulfonylimide acetyl ]-9-( P-tolylmethyl ) purine -7- methylamide and 6- amino - N - methyl -8 -pentoxy - N - propyl- 2[S( R ) -propylsulfonylimide amide ]-9-( p-tolylmethyl ) purine -7- carboxamide

類似於實例 1 、方法 B 、 步驟 1 ，藉由使用對甲苯基甲基胺而非苯基甲胺來製備化合物 36a 。獲得呈白色固體狀之6-氯-5-硝基-2-丙基磺醯基-N -(對甲苯基甲基)嘧啶-4-胺(3.9 g，化合物 36a )。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 353。 (Methyl-p-tolyl) pyrimidin-4-amine (Compound 36a) of Preparation - 6-Chloro-5-nitro-2-propyl sulfo acyl - N: Step 1

Similar to Example 1 , Method B , Step 1 , compound 36a was prepared by using p-tolylmethylamine instead of phenylmethylamine. 6-chloro-5-nitro-2-propylsulfonyl- N- (p-tolylmethyl)pyrimidin-4-amine (3.9 g, compound 36a ) was obtained as a white solid. MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 353.

類似於實例 1 、方法 B 、 步驟 2 ，藉由使用6-氯-5-硝基-2-丙基磺醯基-N -(對甲苯基甲基)嘧啶-4-胺(化合物 36a )而非N- 苄基-6-氯-5-硝基-2-丙基磺醯基-嘧啶-4-胺(化合物 1f )來製備化合物 36b 。獲得呈白色固體狀之6-氯-2-丙基磺醯基-N 4-(對甲苯基甲基)嘧啶-4,5-二胺(2.2 g，化合物 36b )。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 323。Step 2: Preparation of 6-chloro-2-propylsulfonyl-N4-(p-tolylmethyl)pyrimidine-4,5-diamine (Compound 36B)

Similar to Example 1 , Method B , Step 2 , by using 6-chloro-5-nitro-2-propylsulfonyl- N- (p-tolylmethyl)pyrimidine-4-amine ( Compound 36a ) Non- N- benzyl-6-chloro-5-nitro-2-propylsulfonyl-pyrimidin-4-amine ( compound 1f ) was used to prepare compound 36b . 6-chloro-2-propylsulfonyl- N 4-(p-tolylmethyl)pyrimidine-4,5-diamine (2.2 g, compound 36b ) was obtained as a white solid. MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 323.

類似於實例 1 、方法 B 、 步驟 3 ，藉由使用6-氯-2-丙基磺醯基-N 4-(對甲苯基甲基)嘧啶-4,5-二胺(化合物 36b )而非N- 苄基-6-氯-2-(丙基磺醯基)嘧啶-4,5-二胺(化合物 1g )來製備化合物 36c 。獲得呈白色固體狀之6-氯-2-丙基磺醯基-9-(對甲苯基甲基)-7H -嘌呤-8-酮(2.2 g，化合物 36c )。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 349。Step 3: Preparation of 6-chloro-2-propylsulfonyl-9-(p-tolylmethyl)-7H-purin-8-one (Compound 36C)

Similar to Example 1 , Method B , Step 3 , by using 6-chloro-2-propylsulfonyl- N 4-(p-tolylmethyl)pyrimidine-4,5-diamine ( Compound 36b ) instead N- benzyl-6-chloro-2-(propylsulfonyl)pyrimidine-4,5-diamine ( compound 1g ) was used to prepare compound 36c . Was obtained as a white solid of 6-chloro-2-propyl-9- sulfonylurea (p-ylmethyl) -7 H - purin-8-one (2.2 g, compound 36c). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 349.

類似於實例 1 、方法 B 、 步驟 4 ，藉由使用6-氯-2-丙基磺醯基-9-(對甲苯基甲基)-7H -嘌呤-8-酮(化合物 36c )而非9-苄基-6-氯-2-丙基磺醯基-7H -嘌呤-8-酮(化合物 1h )來製備化合物 36d 。獲得呈白色固體狀之6-[(4-甲氧基苯基)甲胺基]-2-丙基磺醯基-9-(對甲苯基甲基)-7H -嘌呤-8-酮(2.0 g，化合物 36d )。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 450。Step 4: 6-[(4-methoxyphenyl)methylamino]-2-propylsulfonyl-9-(p-tolylmethyl)-7H-purin-8-one (Compound 36D) preparation

Similar to Example 1, Method B, Step 4, by using 6-chloro-2-propyl-9-sulfonylurea (toluene-yl methyl) -7 H - purin-8-one (Compound 36c) instead of benzyl-6-chloro-2-propyl sulfo acyl -7 H - purin-8-one (compound 1h) to prepare compound 36d. 6-[(4-methoxyphenyl)methylamino]-2-propylsulfonyl-9-(p-tolylmethyl)-7 H -purin-8-one (white solid) was obtained 2.0 g, compound 36d ). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 450.

類似於實例 1 、方法 B 、 步驟 5 ，藉由使用6-[(4-甲氧基苯基)甲胺基]-2-丙基磺醯基-9-(對甲苯基甲基)-7H -嘌呤-8-酮(化合物 36d )而非6-胺基-9-苄基-2-丙基磺醯基-7H -嘌呤-8-酮(化合物 1i) 來製備化合物 36e 。獲得呈白色固體狀之6-胺基-2-丙基磺醯基-9-(對甲苯基甲基)-7H -嘌呤-8-酮(1.0 g，化合物 36e )。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 330。Step 5: Preparation of 6-amino-2-propylsulfonyl-9-(p-tolylmethyl)-7H-purin-8-one (Compound 36E)

Similar to Example 1 , Method B , Step 5 , by using 6-[(4-methoxyphenyl)methylamino]-2-propylsulfonyl-9-(p-tolylmethyl)-7 H - purin-8-one (compound 36d is) instead of 6-amino-sulfo-2-propyl-benzyl -9- acyl -7 H - purin-8-one (compound 1i) to prepare compound 36e. Was obtained as a white solid of 6-amino-2-propyl sulfonic acyl-9- (p-ylmethyl) -7 H - purin-8-one (1.0 g, compound 36e). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 330.

類似於實例 1 、方法 B 、 步驟 6 ，藉由使用6-胺基-2-丙基磺醯基-9-(對甲苯基甲基)-7H -嘌呤-8-酮(化合物 36e )而非6-胺基-9-苄基-2-(2-丙基磺醯基)-7H-嘌呤-8-酮(化合物 1c )來製備化合物 36f 。獲得呈白色固體狀之6-胺基-2-丙基亞磺醯基-9-(對甲苯基甲基)-7H -嘌呤-8-酮(220 mg，化合物 36f )。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 345。Step 6: Preparation of 6-amino-2-propylsulfinyl-9-(p-tolylmethyl)-7H-purin-8-one (Compound 36F)

Similar to Example 1, Method B, Step 6, by using 6-amino-2-sulfo-propyl-acyl-9- (p-ylmethyl) -7 H - purin-8-one (Compound 36e) and Non-6-amino-9-benzyl-2-(2-propylsulfonyl)-7H-purin-8-one ( compound 1c ) was used to prepare compound 36f . Was obtained as a white solid of 6-amino-2-propylthio methylsulfoximide acyl-9- (p-ylmethyl) -7 H - purin-8-one (220 mg, compound 36f). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 345.

類似於實例 1 、方法 B 、 步驟 7 ，藉由使用6-胺基-2-丙基亞磺醯基-9-(對甲苯基甲基)-7H -嘌呤-8-酮(化合物 36f )而非6-胺基-9-苄基-2-丙基亞磺醯基-7H -嘌呤-8-酮(化合物 1d )來製備化合物 36g 。獲得呈白色固體狀之6-胺基-2-(丙基磺醯亞胺醯基)-9-(對甲苯基甲基)-7H -嘌呤-8-酮(127 mg，化合物 36g )。¹ H NMR (400 MHz, DMSO-d₆ )δ ppm: 10.67 (br. s., 1H), 7.23 (d,J = 8.0 Hz, 2H), 7.13 (d,J = 8.0 Hz, 2H), 6.98 (br. 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 = 8.0 Hz, 3H)。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 361。Step 7: Preparation of 6-amino-2-(propylsulfonylimide)-9-(p-tolylmethyl)-7H-purin-8-one (Compound 36G)

Similar to Example 1, Method B, Step 7, by using 6-amino-2-propyl methylsulfoximide acyl-9- (p-ylmethyl) -7 H - purin-8-one (Compound 36f) instead of 6- benzyl-2-propyl-9- alkylsulfinyl acyl -7 H - purin-8-one (compound 1d) to prepare compound 36g. Was obtained as a white solid of 6-amino-2- (propylsulfonyl (PEI) acyl) -9- (p-ylmethyl) -7 H - purin-8-one (127 mg, Compound 36g). 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 = 8.0 Hz, 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 = 8.0 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 361.

Using 30% isopropanol (0.05% DEA)/CO ₂ on ChiralPak AD-3 column to separate compound 36g by palm HPLC, compound 36g-A was obtained as white solid (faster dissolution, 50 mg) And compound 36g-B (slow dissolution, 49 mg). Compound 36g-A : ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ ppm: 10.51 (s, 1 H), 7.22 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.00 (s, 2 H), 4.91 (s, 2H), 4.03 (s, 1H), 3.35-3.31 (m, 2H), 2.26 (s, 3H), 1.70-1.58 (m, 2H), 0.93 (t, J = 7.40 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 361. Compound 36g-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 = 8.0 Hz, 2H ), 6.97 (s, 2H), 4.91 (s, 2H), 4.04 (s, 1H), 3.34-3.30 (m, 2H), 2.26 (s, 3H), 1.72-1.57 (m, 2H), 0.93 ( t, J = 7.40 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 361.

類似於實例 1 、方法 A 、 步驟 6 ，藉由使用化合物 36g-A 而非6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7H -嘌呤-8-酮(化合物 1e )來製備實例 36 -A。獲得呈白色固體狀之實例 36-A (108 mg)。¹ H NMR (400 MHz, DMSO-d₆ )δ ppm: 7.27 (d,J = 8 Hz, 2H), 7.14 (d,J = 8 Hz, 2H), 6.87 (br. s., 2H), 4.95 (s, 2H), 4.15 (s, 1H), 3.33-3.57 (m, 4H), 3.05 (s, 2H), 3.02 (s, 1H), 2.26 (s, 3H), 1.52-1.73 (m, 4H), 0.75-0.97 (m, 6H)。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 460。 Step 8 : 6- Amino - N - methyl -8 -oxo - N - propyl- 2[S( S ) -propylsulfonylimido ]-9-( p-tolylmethyl ) Purine -7- methylamide and 6- amino - N - methyl -8 -pentoxy - N - propyl- 2[S( R ) -propylsulfonylimideamide ]-9-( pair Preparation of tolylmethyl ) purine -7- carboxamide ( Example 36-A and Example 36-B)

Similar to Example 1, Method A, Step 6, by using instead of the compound 36g-A-9- benzyl-2-6- (propylsulfonyl (PEI) acyl) -7 H - purin-8 Ketone ( Compound 1e ) to prepare Example 36- A. Example 36-A (108 mg) was obtained as a white solid. 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 460.

Similar to Example 1, Method A, Step 6, by using instead of the compound 36g-B-benzyl-2-9- 6- (propylsulfonyl (PEI) acyl) -7 H - purin-8 Ketone ( Compound 1e ) to prepare Example 36-B . Example 36-B (125 mg): 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, 5H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 460.

類似於實例 1 、方法 A 、步驟 6 ，藉由使用化合物 36g-A 及氯化吡咯啶-1-甲醯而非6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7H -嘌呤-8-酮(化合物 1e )及氯化N-甲基-N-丙基-胺甲醯(中間產物 AA )來製備實例 37-A 。 Example 37-A and Example 37-B 6- Amino -2-[S( S ) -propylsulfonylimidoamide ]-9-( p-tolylmethyl )-7-( pyrrolidin- 1- Carbonyl ) purin -8- one and 6- amino -2-[S( R ) -propylsulfonylimide acetyl ]-9-( p-tolylmethyl )-7-( pyrrolidin- 1- carbonyl ) Purine -8- one

Similar to Example 1 , Method A , Step 6 , by using compound 36g-A and pyrrolidine-1-carboxamide instead of 6-amino-9-benzyl-2-(propylsulfonylimide) Radical)-7 H -purin-8-one ( compound 1e ) and N-methyl-N-propyl-aminoformamide chloride ( intermediate product AA ) to prepare Example 37-A .

Example 37- A (390 mg) was obtained as a white solid. 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 = 7.4 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 458.2.

Similar to Example 37-A , Example 37- B (125 mg) was prepared by using compound 36g-B instead of compound 36g-A . 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 = 7.4 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 458.3.

類似於實例 1 、方法 A 、步驟 6 ，藉由使用化合物 36g-A 及氯化N-(2-甲氧基乙基)-N-甲基-胺甲醯(中間產物 AB )而非6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7H-嘌呤-8-酮(化合物 1e )及氯化N -甲基-N -丙基-胺甲醯(中間產物 AA )來製備實例 38-A 。 Example 38-A and Example 38-B 6- amino - N- (2 -methoxyethyl ) -N- methyl -8- pendant -2-[S( S ) -propylsulfonamide acyl amine] -9- (methyl p-tolyl) purin-7-amine and 6-amino-acyl - N- methyl-oxo -8- - N - (2- methoxyethyl) - 2-[S( R ) -propylsulfonylimide acetyl ]-9-( p-tolylmethyl ) purine -7- methyl amide

Similar to Example 1 , Method A , Step 6 , by using compound 36g-A and N-(2-methoxyethyl) chloride-N-methyl-aminecarboxamide ( intermediate product AB ) instead of 6 Amino-9-benzyl-2-(propylsulfonylimide)-7H-purin-8-one ( compound 1e ) and N -methyl- N -propyl-aminecarboxamide ( middle Product AA ) to prepare Example 38-A .

Example 38-A (57.8 mg) was obtained as a white solid. 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 = 7.4 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 476.3.

Example 38-B (46.6 mg) was prepared similar to Example 38-A by using compound 36g-B instead of compound 36g-A . 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 = 7.4 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 476.3.

類似於實例 1 、方法 A 、步驟 6 ，藉由使用氯化N- 乙基-N -甲基-胺甲醯及6-胺基-2-(丙基磺醯亞胺醯基)-9-(對甲苯基甲基)-7H -嘌呤-8-酮(化合物 36g )而非氯化N -甲基-N -丙基-胺甲醯(中間產物 AA )及6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7H -嘌呤-8-酮(化合物 1e )來製備標題化合物。獲得呈淡黃色固體狀之6-胺基-N -乙基-N- 甲基-8-側氧基-2-(丙基磺醯亞胺醯基)-9-(對甲苯基甲基)嘌呤-7-甲醯胺(141.8 mg，實例 39 )。¹ H NMR (400 MHz, DMSO-d₆ )δ ppm: 7.26 (d,J = 7.9 Hz, 2H), 7.15 (d,J = 7.9 Hz, 2H), 6.89 (s, 2H), 4.95 (s, 2H), 4.24 - 4.07 (m, 1H), 3.52 - 3.35 (m, 4H), 3.10 - 2.95 (m, 3H), 2.26 (s, 3H), 1.77 - 1.55 (m, 2H), 1.24 - 1.10 (m, 3H), 0.95 (t,J = 7.4 Hz, 3H)。MS觀測值 (ESI⁺ ) [(M+H)⁺ ]: 446.1。 Example 39 6- amino - N - ethyl - N- methyl -8- pendant -2-( propylsulfonylimide )-9-( p-tolylmethyl ) purine -7- methyl Amide

Similar to Example 1 , Method A , Step 6 , by using N- ethyl- N -methyl-amine chloride and 6-amino-2-(propylsulfonylimideamide)-9- (P-tolylmethyl)-7 H -purin-8-one ( compound 36g ) instead of chlorinated N -methyl- N -propyl-aminoformamide ( intermediate product AA ) and 6-amino-9- benzyl-2- (propylsulfonyl (PEI) acyl) -7 H - purin-8-one (compound 1e) The title compound was prepared. 6-Amino- N -ethyl- N- methyl-8-oxo-2-(propylsulfonylimide)-9-(p-tolylmethyl) was obtained as a light yellow solid Purine-7-carboxamide (141.8 mg, Example 39 ). 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 = 7.4 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 446.1.

類似於實例 1 、方法 A 、步驟 6 ，藉由使用6-胺基-2-(丙基磺醯亞胺醯基)-9-(對甲苯基甲基)-7H -嘌呤-8-酮(化合物 36g )及氯化N -乙基-N -甲基-胺甲醯而非6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7H -嘌呤-8-酮(化合物 1e )及氯化N -甲基-N -丙基-胺甲醯(中間產物 AA )來製備標題化合物。獲得呈白色固體狀之6-胺基-N -丁基-N -甲基-8-側氧基-2-(丙基磺醯亞胺醯基)-9-(對甲苯基甲基)嘌呤-7-甲醯胺(32 mg，實例 40) 。¹ H NMR (400 MHz, DMSO-d₆ )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觀測值 (ESI⁺ ) [(M+H)⁺ ]: 474.3 Example 40 6- amino - N - butyl - N - methyl -8- pendant -2-( propylsulfonylimide )-9-( p-tolylmethyl ) purine -7- methyl Amide

Similar to Example 1, Method A, Step 6, by using 6-amino-2- (propylsulfonyl (PEI) acyl) -9- (p-ylmethyl) -7 H - purin-8-one (compound 36g) chloride and N - ethyl - N - methyl - amine instead of methyl 6- acyl-2-benzyl-9- (acyl imine sulfonylurea propyl) -7 H - purin - The 8-one ( compound 1e ) and N -methyl- N -propyl-aminecarboxamide ( intermediate product AA ) were prepared to prepare the title compound. Obtain 6-amino- N -butyl- N -methyl-8-pentoxy-2-(propylsulfonylimidoamide)-9-(p-tolylmethyl)purine as a white solid -7-formamide (32 mg, Example 40) . 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 474.3

Example 41-A and Example 41-B 6- amino- 9-[(4- chlorophenyl ) methyl ]-2-[S( R ) -ethylsulfonylimide ]- N -methyl -8 -oxo - N - propyl - purine -7- carboxamide ( Example 41-A) and 6- amino- 9-[(4- chlorophenyl ) methyl ]-2-[S( S) -ethylsulfonylimide ]-N- methyl -8 -pentoxy -N- propyl - purine -7- methylamide ( Example 41-B)

類似於實例 1 、方法 A 、步驟 3 ，藉由使用碘乙烷及6-胺基-9-[(4-氯苯基)甲基]-2-磺醯基-7H -嘌呤-8-酮(化合物 34b )而非溴丙烷及6-胺基-9-苯基甲基-2-磺醯基-7H -嘌呤-8-酮(化合物 1b )來製備化合物 41a 。獲得呈白色固體狀之6-胺基-9-[(4-氯苯基)甲基]-2-乙基磺醯基-7H -嘌呤-8-酮(2.5 g，化合物 41a )。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 336。 Step 1: 6-amino-9 - [(4-chlorophenyl) methyl] -2-ethyl sulfonic acyl -7 H - purin-8-one (Compound 41a) Preparation of

Similar to Example 1, Method A, Step 3, by using ethyl iodide and 6-amino-9 - [(4-chlorophenyl) methyl] -2-sulfonamide acyl -7 H - purin-8 one (compound 34b) and bromopropane instead of 6-amino-9-phenyl-2-sulfo acyl -7 H - purin-8-one (compound 1b) to prepare compound 41a. Was obtained as a white solid of 6-amino-9 - [(4-chlorophenyl) methyl] -2-ethyl sulfonic acyl -7 H - purin-8-one (2.5 g, compound 41a). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 336.

類似於實例 1 、方法 A 、 步驟 4 ，藉由使用6-胺基-9-[(4-氯苯基)甲基]-2-乙基磺醯基-7H -嘌呤-8-酮(化合物 41a )而非6-胺基-9-苄基-2-丙基磺醯基-7H -嘌呤-8-酮(化合物 1c )來製備化合物 41b 。獲得呈白色固體狀之6-胺基-9-(4-氯苄基)-2-乙基亞磺醯基-7H-嘌呤-8-酮(1.94 g，化合物 41b )。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 352。 Preparation of 6-amino-9- (4-chlorobenzyl) -2-ethyl alkylsulfinyl acyl -7H- purin-8-one (Compound 41b) of: Step 2

Similar to Example 1, Method A, Step 4, by using 6-amino-9 - [(4-chlorophenyl) methyl] -2-ethyl sulfonic acyl -7 H - purin-8-one ( compound 41a) instead of 6- benzyl-2-propyl-9- sulfo acyl -7 H - purin-8-one (compound 1c) to prepare compound 41b. 6-Amino-9-(4-chlorobenzyl)-2-ethylsulfinyl-7H-purin-8-one (1.94 g, compound 41b ) was obtained as a white solid. MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 352.

類似於實例 1 、方法 A 、 步驟 5 ，藉由使用6-胺基-9-(4-氯苄基)-2-乙基亞磺醯基-7H -嘌呤-8-酮(化合物 41b )而非6-胺基-9-苄基-2-(2-丙基亞磺醯基)-7H -嘌呤-8-酮(化合物 1d )來製備化合物 41c 。獲得呈白色固體狀之6-胺基-9-[(4-氯苯基)甲基]-2-(乙基磺醯亞胺醯基)-7H -嘌呤-8-酮(217 mg，實例 41c )。¹ H NMR (400 MHz, DMSO-d₆ )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 = 7.4 Hz, 3H)。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 367.0。 Step 3: 6-amino-9 - [(4-chlorophenyl) methyl] -2- (ethyl sulfonylurea acyl imine) -7 H - purin-8-one (Compound 41c) Preparation of

Similar to Example 1, Method A, Step 5, by using 6-amino-9- (4-chlorobenzyl) -2-ethyl alkylsulfinyl acyl -7 H - purin-8-one (Compound 41b) instead of 6-amino--9- benzyl-2- (2-methylsulfoximide acyl) -7 H - purin-8-one (compound 1d) to prepare compound 41c. Was obtained as a white solid of 6-amino-9 - [(4-chlorophenyl) methyl] -2- (ethyl sulfonylurea acyl imine) -7 H - purin-8-one (217 mg, Example 41c ). 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 = 7.4 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 367.0.

化合物 41c-A ： ¹ H NMR (400 MHz, DMSO-d₆ )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 = 7.4 Hz, 3H)。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 367.0。

化合物 41c-B ： ¹ H NMR (400 MHz, DMSO-d₆ )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 = 7.4 Hz, 3H)。MS觀測值 (ESI⁺ ) [(M+H)⁺ ]: 367.0。Using methanol 5%-40% (0.05% DEA)/CO ₂ on a ChiralPak IC-3 column to separate compound 41c by palm HPLC, compound 41c-A was obtained as a white solid (faster dissolution, 31.8 mg) and compound 41c-B (slow dissolution, 10 mg).

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 = 7.4 Hz, 3H). MS observation (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 = 7.4 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 367.0.

類似於實例 1 、方法 A 、 步驟 6 ，藉由使用化合物 41c-B 而非6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7H -嘌呤-8-酮(化合物 1e )來製備實例 41-A 。獲得呈白色固體狀之6-胺基-9-[(4-氯苯基)甲基]-2-[S(R )-乙基磺醯亞胺醯基]-N -甲基-8-側氧基-N -丙基-嘌呤-7-甲醯胺(實例 41-A ，78 mg)。¹ H NMR (400 MHz, DMSO-d₆ )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 = 7.28 Hz, 3H), 0.95 - 0.66 (m, 3H)。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 466.1。 Step 4 : 6- amino- 9-[(4- chlorophenyl ) methyl ]-2-[S(R) -ethylsulfonylimide ] -N - methyl -8 -oxo -N - propyl - purine -7- carboxamide ( Example 41-A) and 6- amino- 9-[(4- chlorophenyl ) methyl ]-2-[S(S) -ethylsulfonate Acetylimidyl ] -N - methyl -8 -pentoxy - N - propyl - purine -7- methylamide ( Example 41-B)

Similar to Example 1, Method A, Step 6, compound 41c-B by using not-9- benzyl-2-6- (propylsulfonyl (PEI) acyl) -7 H - purin-8 Ketone ( Compound 1e ) to prepare Example 41-A . Obtain 6-amino-9-[(4-chlorophenyl)methyl]-2-[S( R )-ethylsulfonylimidoamide]- N -methyl-8- as a white solid Pendant- N -propyl-purine-7-carboxamide ( Example 41-A , 78 mg). 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 = 7.28 Hz, 3H), 0.95-0.66 (m, 3H ). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 466.1.

Similar to Example 1 , Method A , Step 6 , by using compound 41c-A instead of 6-amino-9-benzyl-2-(propylsulfonylimide)-7H-purin-8-one ( Compound 1e ) to prepare Example 41-B (125 mg). 6-Amino-9-[(4-chlorophenyl)methyl]-2-[S( S )-ethylsulfonylimidoamide]- N -methyl-8- was obtained as a white solid Pendant- N -propyl-purine-7-carboxamide ( Example 41-B , 38 mg). 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 466.2.

The stereochemistry of Example 41-B was determined by the single crystal X-ray diffraction shown in FIG. 1.

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

Similar to Example 1 , Method A , Step 6 , by using compound 41c-A and chloride N- ethyl- N -methyl-aminoformamide instead of 6-amino-9-benzyl-2-(propylene sulfonic imine acyl group) -7 H - purin-8-one (compound 1e) and N- methyl -N--propyl chloride - methyl acyl amine (intermediate AA) prepared by example 42-A. 6-Amino-9-[(4-chlorophenyl)methyl] -N -ethyl-2[S( S )-ethylsulfonylimide] -N -methyl was obtained as a white solid Yl-8-oxo-purine-7-carboxamide ( Example 42-A , 40 mg). 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 452.2.

Similar to Example 1 , Method A , Step 6 , by using compound 41c-B and chloride N- ethyl- N -methyl-aminoformamide instead of 6-amino-9-benzyl-2-(propylene Sulfoimidamide)-7H-purin-8-one ( Compound 1e ) and N -methyl- N -propyl-aminecarboxamide ( intermediate product AA ) chloride were used to prepare Example 42-B . Was obtained as a white solid of 6-amino-9 - [(4-chlorophenyl) methyl] - N - ethyl -2- [S (R) - ethyl sulfonylurea imine acyl] - N - Methyl-8-oxo-purine-7-carboxamide ( Example 42- B, 38 mg). 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 452.2.

The stereochemistry of Example 42-A was determined by the single crystal X-ray diffraction shown in FIG. 2.

Example 43-A and Example 43-B 6- amino -2-[S( R ) -ethylsulfonylimide ] -N - methyl -8 -oxo - N - propyl -9- ( P-tolylmethyl ) purine -7- carboxamide ( Example 43-A) and 6- amino -2-[S( S ) -ethylsulfonylimide ] -N - methyl- 8 - oxo - N - propyl-9- (methyl p-tolyl) purin-7-acyl-amine (example 43-B)

類似於實例 1 、方法 A 、步驟 1 ，藉由使用異氰酸4-甲基苯甲酯而非異氰酸苯甲酯來製備化合物 43a 。獲得呈灰色固體狀之4-胺基-2-側氧基-3-(對甲苯基甲基)-1H -咪唑-5-甲腈(26.6 g，化合物 43a )且不經進一步純化直接用於下一步驟。MS觀測值 (ESI⁺ ) [(M+H)⁺ ]: 229.2。 Step 1 : Preparation of 4- amino -2 -oxo- 3-( p-tolylmethyl )-1H- imidazole -5 -carbonitrile ( Compound 43a)

Similar to Example 1 , Method A , Step 1 , compound 43a was prepared by using 4-methylbenzyl isocyanate instead of benzyl isocyanate. Was obtained as a gray solid of 4-amino-2-oxo-3- (p-ylmethyl) -1 H - imidazole-5-carbonitrile (26.6 g, compound 43a) used without further purification To the next step. MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 229.2.

類似於實例 1 、方法 A 、 步驟 2 ，藉由使用4-胺基-2-側氧基-3-(對甲苯基甲基)-1H -咪唑-5-甲腈(化合物 43a )而非4-胺基-3-苄基-2-側氧基-1H -咪唑-5-甲腈(化合物 1a )來製備化合物 43b 。獲得呈黃色固體狀之6-胺基-9-(對甲苯基甲基)-2-磺醯基-7H -嘌呤-8-酮(20.0 g，化合物 43b )。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 288。 Step 2: amino -9-6- (p-tolyl) -2-sulfo acyl -7 H - purin-8-one (Compound 43b) of

Similar to Example 1, Method A, Step 2, by using 4-amino-2-oxo-3- (p-ylmethyl) -1 H - imidazole-5-carbonitrile (Compound 43a) instead of 4-Amino-3-benzyl-2-oxo- 1H -imidazole-5-carbonitrile ( compound 1a ) to prepare compound 43b . Was obtained as a yellow solid of 6-amino-9- (p-tolyl) -2-sulfo acyl -7 H - purin-8-one (20.0 g, compound 43b). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 288.

類似於實例 1 、方法 A 、步驟 3 ，藉由使用6-胺基-9-(對甲苯基甲基)-2-磺醯基-7H -嘌呤-8-酮(化合物 43b )及碘乙烷而非6-胺基-9-苄基-2-磺醯基-7H-嘌呤-8-酮(化合物 1b )及溴丙烷來製備化合物 43c 。獲得呈黃色固體狀之6-胺基-2-乙基磺醯基-9-(對甲苯基甲基)-7H -嘌呤-8-酮(13 g，化合物 43c )。 MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 316。 Step 3: 6-amino-2-ethyl-sulfonic acyl-9- (p-ylmethyl) -7 H - purin-8-one (Compound 43c) of

Similar to Example 1, Method A, Step 3, by using 6-amino-9- (p-tolyl) -2-sulfo acyl -7 H - purin-8-one (Compound 43b) and iodoacetamide Alkane instead of 6-amino-9-benzyl-2-sulfonyl-7H-purin-8-one ( compound 1b ) and bromopropane to prepare compound 43c . Was obtained as a yellow solid of 6-amino-2-ethyl-sulfonic acyl-9- (p-ylmethyl) -7 H - purin-8-one (13 g, compound 43c). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 316.

類似於實例 1 、方法 A 、 步驟 4 ，藉由使用6-胺基-2-乙基磺醯基-9-(對甲苯基甲基)-7H -嘌呤-8-酮(化合物 43c )而非6-胺基-9-苄基-2-甲基磺醯基-7H -嘌呤-8-酮(化合物 1c )來製備化合物 43d 。獲得呈黃色固體狀之6-胺基-2-乙基亞磺醯基-9-(對甲苯基甲基)-7H -嘌呤-8-酮6(3.5 g，化合物 43d )。MS觀測值 (ESI⁺ ) [(M+H)⁺ ]: 332。 Step 4: 6-amino-2-ethyl methylsulfoximide acyl-9- (p-ylmethyl) -7 H - purin-8-one (Compound 43d) of

Similar to Example 1, Method A, Step 4, by using 6-amino-2-ethyl-sulfonic acyl 9- (toluene-yl methyl) -7 H - purin-8-one (Compound 43c) and non-6- benzyl-2-methyl-9- sulfo acyl -7 H - purin-8-one (compound 1c) to prepare compound 43d. Was obtained as a yellow solid of 6-amino-acyl-2-ethyl methylsulfoximide 9- (p-ylmethyl) -7 H - purin-6 (3.5 g, compound 43d). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 332.

類似於實例 1 、方法 A 、 步驟 5 ，藉由使用6-胺基-2-乙基亞磺醯基-9-(對甲苯基甲基)-7H -嘌呤-8-酮(化合物 43d )而非6-胺基-9-苄基-2-丙基亞磺醯基-7H -嘌呤-8-酮(化合物 1d )來製備化合物 43e 。獲得呈黃色固體狀之6-胺基-2-(乙基磺醯亞胺醯基)-9-(對甲苯基甲基)-7H -嘌呤-8-酮(530 mg，化合物 43e )。¹ H NMR (400 MHz, DMSO-d₆ )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 = 7.28 Hz, 3H)。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 347。 Step 5: -9-6- amino-2- (ethyl sulfonylurea acyl imine) (p-ylmethyl) -7 H - purin-8-one (Compound 43e) of

Similar to Example 1, Method A, Step 5, by using 6-amino-2-ethyl methylsulfoximide acyl-9- (p-ylmethyl) -7 H - purin-8-one (Compound 43d) instead of 6- benzyl-2-propyl-9- alkylsulfinyl acyl -7 H - purin-8-one (compound 1d) to prepare compound 43e. Was obtained as a yellow solid of 6-amino-2- (ethyl-acyl imine sulfonylurea) -9- (p-ylmethyl) -7 H - purin-8-one (530 mg, compound 43e). 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 = 7.28 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 347.

化合物 43e-A ：¹ H NMR (400 MHz, DMSO-d₆ )δ ppm: 10.52 (br. s., 1H), 7.23 (d,J = 8.0 Hz, 2H), 7.13 (d,J = 7.9 Hz, 2H), 6.94 (br. s., 2H), 4.90 (s, 2H), 4.03 (s, 1H), 3.42 - 3.33 (m, 2H), 2.25 (s, 3H), 1.17 (t,J = 7.3 Hz, 3H)。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 347。

化合物 43e-B ：¹ H NMR (400 MHz, DMSO-d₆ )δ ppm: 10.56 (br. s., 1H), 7.23 (d,J = 8.0 Hz, 2H), 7.13 (d,J = 8.0 Hz, 2H), 6.95 (br. s., 2H), 4.90 (s, 2H) 4.03 (s, 1H), 3.44 - 3.29 (m, 2H), 2.25 (s, 3H), 1.17 (t,J = 7.3 Hz, 3H)，MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 347。Using methanol 5%-40% (0.05% DEA)/CO ₂ on a ChiralPak AD-3 column to separate compound 43e by palm HPLC, compound 43e-A was obtained as a white solid (faster dissolution, 56.8 mg) and compound 43e-B (slow dissolution, 56.7 mg).

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 = 7.9 Hz , 2H), 6.94 (br. s., 2H), 4.90 (s, 2H), 4.03 (s, 1H), 3.42-3.33 (m, 2H), 2.25 (s, 3H), 1.17 (t, J = 7.3 Hz, 3H). MS observation (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 = 8.0 Hz , 2H), 6.95 (br. s., 2H), 4.90 (s, 2H) 4.03 (s, 1H), 3.44-3.29 (m, 2H), 2.25 (s, 3H), 1.17 (t, J = 7.3 Hz, 3H), MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 347.

類似於實例 1 、方法 A 、 步驟 6 ，藉由使用化合物 43e-A 而非6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7H -嘌呤-8-酮(化合物 1e )來製備實例 43-A 。獲得呈白色固體狀之6-胺基-2-[S(R )-乙基磺醯亞胺醯基]-N -甲基-8-側氧基-N -丙基-9-(對甲苯基甲基)嘌呤-7-甲醯胺(實例 43-A ，58.1 mg，較快溶離，5%至40%異丙醇(0.05% DEA)/CO₂ 於ChiralPak AD-3管柱上)。¹ H NMR (400 MHz, DMSO-d₆ )δ ppm: 7.28 (d,J = 7.8 Hz, 2H), 7.15 (d,J = 7.8 Hz, 2H), 6.88 (br. s., 2H), 5.03 - 4.87 (m, 2H), 4.19 (s, 1H), 3.61 - 3.36 (m, 4H), 3.11 - 2.96 (m, 3H), 2.26 (s, 3H), 1.72 - 1.45 (m, 2H), 1.20 (t,J = 7.2 Hz, 3H), 0.97 - 0.65 (m, 3H)。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 446。 Step 6 : 6- amino -2-[S(R) -ethylsulfonylimide ] -N - methyl -8 -oxo - N - propyl -9-( p-tolylmethyl ) Purine -7- carboxamide ( Example 43-A) and 6- amino -2-[S(S) -ethylsulfonylimide ] -N - methyl -8 -oxo - N ---9- preparation of propyl (methyl p-tolyl) purin-7-acyl-amine (example 43-B) of

Similar to Example 1 , Method A , Step 6 , by using compound 43e-A instead of 6-amino-9-benzyl-2-(propylsulfonylimide)-7 H -purine-8- Ketone ( Compound 1e ) to prepare Example 43-A . Obtained as a white solid 6-amino-2-[S( R )-ethylsulfonylimide] -N -methyl-8-oxo- N -propyl-9-(p-toluene Methylmethyl)purine-7-carboxamide ( Example 43-A , 58.1 mg, faster dissolution, 5% to 40% isopropanol (0.05% DEA)/CO ₂ on ChiralPak AD-3 column). 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 = 7.2 Hz, 3H), 0.97-0.65 (m, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 446.

Similar to Example 1 , Method A , Step 6 , by using compound 43e-B instead of 6-amino-9-benzyl-2-(propylsulfonylimide)-7 H -purine-8- Ketone ( Compound 1e ) to prepare Example 43-B . Obtained as a white solid 6-amino-2-[S( S )-ethylsulfonylimide] -N -methyl-8-oxo- N -propyl-9-(p-toluene Methyl)purine-7-carboxamide ( Example 43-B , 40.1 mg, slower dissolution, 5% to 40% isopropanol (0.05% DEA)/CO ₂ on ChiralPak AD-3 column): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm: 7.28 (d, J = 7.5 Hz, 2H), 7.15 (d, J = 7.5 Hz, 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 = 7.2 Hz, 3H), 0.95-0.71 (m, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 446.3.

The stereochemistry of Example 43-B was determined by the single crystal X-ray diffraction shown in FIG. 3.

類似於實例 1 、方法 A 、步驟 6 ，藉由使用化合物 43e-B 及氯化N -乙基-N -甲基-胺甲醯而非6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7H -嘌呤-8-酮(化合物 1e )及氯化N -甲基-N -丙基-胺甲醯(中間產物 AA )來製備實例 44-A 。獲得呈白色固體狀之6-胺基-N -乙基-2[S(S )-乙基磺醯亞胺醯基]-N -甲基-8-側氧基-9-(對甲苯基甲基)嘌呤-7-甲醯胺(實例 44-A ，73.1 mg)。¹ H NMR (400 MHz, DMSO-d₆ )δ ppm: 7.28 (d,J = 7.8 Hz, 2H), 7.15 (d,J = 7.8 Hz, 2H), 6.90 (br. s., 2H), 4.95 (s, 2H), 4.19 (br. 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觀測值 (ESI⁺ ) [(M+H)⁺ ]: 432。 Example 44-A and Example 44-B 6- amino - N - ethyl- 2[S( S ) -ethylsulfonylimido ] -N - methyl -8 -oxo -9-( methyl p-tolyl) purin-7-acyl-amine (example 44-A) and 6- amino - N - ethyl -2- [S (R) - ethyl sulfonylurea imine acyl] - N - Methyl -8 -oxo -9-( p-tolylmethyl ) purine -7- carboxamide ( Example 44-B)

Similar to Example 1 , Method A , Step 6 , by using compound 43e-B and N -ethyl- N -methyl-aminoformamide chloride instead of 6-amino-9-benzyl-2-(propylene Examples 44-A were prepared by sulfamoylimidamide)-7 H -purin-8-one ( compound 1e ) and N -methyl- N -propyl-aminecarboxamide ( intermediate product AA ). Obtained as a white solid 6-amino- N -ethyl-2[S( S )-ethylsulfonylimido] -N -methyl-8-oxo-9-(p-tolyl Methyl)purine-7-carboxamide ( Example 44-A , 73.1 mg). 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 432.

Similar to Example 1 , Method A , Step 6 , by using compound 43e- A and N -ethyl- N -methyl-aminoformamide chloride instead of 6-amino-9-benzyl-2-(propylene Examples 44-B were prepared by sulfamoylimidamide)-7 H -purin-8-one ( Compound 1e ) and N -methyl- N -propyl-aminecarboxamide chloride ( intermediate product AA ). Obtained as a white solid 6-amino- N -ethyl-2-[S( R )-ethylsulfonylimido] -N -methyl-8-oxo-9-(p-toluene Methyl)purine-7-carboxamide ( Example 44-B , 46.7 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm: 7.28 (d, J = 7.9 Hz, 2H), 7.15 (d, J = 7.9 Hz, 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 432.

Example 45-A and 45-B 6- amino example -2- [S (R) ethyl sulfonylurea acyl imine] -9 - [(4-fluorophenyl) methyl] - N - methyl - 8 -Penoxy - N - propyl - purine -7- carboxamide and 6- amino -2-[S( S ) ethylsulfonylimide ]-9-[(4- fluorophenyl ) Methyl ] -N - methyl -8- pendant - N - propyl - purine -7- carboxamide

類似於實例 1 、方法 A 、步驟 1 ，藉由使用異氰酸4-氟苯甲酯而非異氰酸苯甲酯來製備化合物 45a 。獲得呈淡黃色固體狀之4-胺基-3-[(4-氟苯基)甲基]-2-側氧基-1H -咪唑-5-甲腈(48 g，化合物 45a )且其未經進一步純化即直接用於下一步驟。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 233。 Step 1 : Preparation of 4- amino- 3-[(4- fluorophenyl ) methyl ]-2 -oxo - 1H - imidazole -5 -carbonitrile ( Compound 45a)

Similar to Example 1 , Method A , Step 1 , compound 45a was prepared by using 4-fluorobenzyl isocyanate instead of benzyl isocyanate. 4-Amino-3-[(4-fluorophenyl)methyl]-2-oxo- 1H -imidazole-5-carbonitrile (48 g, compound 45a ) was obtained as a light yellow solid and it It was used directly in the next step without further purification. MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 233.

類似於實例 1 、方法 A 、 步驟 2 ，藉由使用4-胺基-3-[(4-氟苯基)甲基]-2-側氧基-1H -咪唑-5-甲腈(化合物 45a )而非4-胺基-3-苯基甲基-2-側氧基-1H-咪唑-5-甲腈(化合物 1a )來製備化合物 45b 。獲得呈黃色固體狀之6-胺基-9-[(4-氟苯基)甲基]-2-磺醯基-7H -嘌呤-8-酮(32.0 g，化合物 45b )。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 292。 Step 2: 6-amino--9-- purin-8-one (Compound 45b) of - [(4-fluorophenyl) methyl] -2-sulfonamide acyl -7 H

Similar to Example 1 , Method A , Step 2 , by using 4-amino-3-[(4-fluorophenyl)methyl]-2-oxo- 1H -imidazole-5-carbonitrile ( compound 45a ) instead of 4-amino-3-phenylmethyl-2-oxo-1H-imidazole-5-carbonitrile ( compound 1a ) to prepare compound 45b . Was obtained as a yellow solid of 6-amino-9 - [(4-fluorophenyl) methyl] -2-sulfonamide acyl -7 H - purin-8-one (32.0 g, compound 45b). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 292.

類似於實例 1 、方法 A 、步驟 3 ，藉由使用6-胺基-9-[(4-氟苯基)甲基]-2-磺醯基-7H -嘌呤-8-酮(化合物 45b )及碘乙烷而非6-胺基-9-苄基-2-磺醯基-7H-嘌呤-8-酮(化合物 1b )及溴丙烷來製備化合物 45c 。獲得呈黃色固體狀之6-胺基-2-乙基磺醯基-9-[(4-氟苯基)甲基]-7H -嘌呤-8-酮(5.6 g，化合物 45c )。MS觀測值 (ESI⁺ ) [(M+H)⁺ ]: 320。 Step 3: 6-amino-2-ethyl-sulfonic acyl -9 - [(4-bromophenyl) methyl] -7 H - purin-8-one (Compound 45c) Preparation of

Similar to Example 1, Method A, Step 3, by using 6-amino-9 - [(4-fluorophenyl) methyl] -2-sulfonamide acyl -7 H - purin-8-one (Compound 45b ) And iodoethane instead of 6-amino-9-benzyl-2-sulfonyl-7H-purin-8-one ( compound 1b ) and bromopropane to prepare compound 45c . Was obtained as a yellow solid of 6-amino-2-ethyl-sulfonic acyl -9 - [(4-fluorophenyl) methyl] -7 H - purin-8-one (5.6 g, compound 45c). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 320.

類似於實例 1 、方法 A 、 步驟 4 ，藉由使用6-胺基-2-乙基磺醯基-9-[(4-氟苯基)甲基]-7H -嘌呤-8-酮(化合物 45c )而非6-胺基-9-苄基-2-丙基磺醯基-7H -嘌呤-8-酮(化合物 1c )來製備化合物 45d 。獲得呈黃色固體狀之6-胺基-2-乙基亞磺醯基-9-[(4-氟苯基)甲基]-7H -嘌呤-8-酮(4.8 g，化合物 45d )。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 332。 Step 5: 6-amino-2-ethyl methylsulfoximide acyl -9 - -7 H [(4- fluorophenyl) methyl] - purin-8-one (Compound 45d) of

Similar to Example 1, Method A, Step 4, by using 6-amino-2-ethyl-sulfonic acyl -9 - [(4-fluorophenyl) methyl] -7 H - purin-8-one ( compound 45c) instead of 6-amino-sulfo-2-propyl-benzyl -9- acyl -7 H - purin-8-one (compound 1c) to prepare compound 45d. Was obtained as a yellow solid of 6-amino-acyl-2-ethyl methylsulfoximide 9 - [(4-fluorophenyl) methyl] -7 H - purin-8-one (4.8 g, compound 45d). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 332.

類似於實例 1 、方法 A 、 步驟 5 ，藉由使用6-胺基-2-乙基亞磺醯基-9-[(4-氟苯基)甲基]-7H -嘌呤-8-酮(化合物 45d )而非6-胺基-9-苄基-2-丙基亞磺醯基-7H -嘌呤-8-酮(化合物 1d )來製備化合物 45e 。獲得呈黃色固體狀之6-胺基-2-(乙基磺醯亞胺醯基)-9-[(4-氟苯基)甲基]-7H -嘌呤-8-酮(2.9 g，化合物 45e )。¹ H NMR (400 MHz, DMSO-d₆ )δ ppm: 10.57 (br. s., 1H), 7.40 (dd,J = 8.5, 5.5 Hz, 2H), 7.16 (t,J = 8.9 Hz, 2H), 6.97 (br. s., 2H), 4.94 (s, 2H), 4.07 (s, 1H), 3.43 - 3.36 (m, 2H), 1.17 (t,J = 7.4 Hz, 3H)。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 351。 Step 6: -96- amino-2- (ethyl-acyl imine sulfonylurea) - Preparation purin-8-one (Compound 45e) of - [(4-fluorophenyl) methyl] -7 H

Similar to Example 1, Method A, Step 5, by using 6-amino-2-ethyl methylsulfoximide acyl -9 - [(4-fluorophenyl) methyl] -7 H - purin-8-one (compound 45d) instead of 6- benzyl-2-propyl-9- alkylsulfinyl acyl -7 H - purin-8-one (compound 1d) to prepare compound 45e. Was obtained as a yellow solid of 6-amino-2- (ethyl-acyl imine sulfonylurea) -9 - [(4-fluorophenyl) methyl] -7 H - purin-8-one (2.9 g, Compound 45e ). 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 = 8.9 Hz, 2H) , 6.97 (br. s., 2H), 4.94 (s, 2H), 4.07 (s, 1H), 3.43-3.36 (m, 2H), 1.17 (t, J = 7.4 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 351.

Using methanol 5%-40% (0.05% DEA)/CO ₂ on a ChiralPak AD-3 column to separate compound 45e by palm HPLC, compound 45e-A was obtained as a white solid (faster dissolution, 85.4 mg) and compound 45e-B (slow dissolution, 36.4 mg). 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 = 8.9 Hz, 2H), 6.98 (br. s., 2H), 4.95 (s, 2H), 4.07 (s, 1H), 3.45-3.36 (m, 2H), 1.17 (t, J = 7.3 Hz, 3H) . MS observation (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 = 8.9 Hz, 2H), 6.98 (br. s., 2H), 4.95 (s, 2H), 4.07 (s, 1H), 3.44-3.37 (m, 2H) 1.17 (t, J = 7.3 Hz, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 351.

(實例 45)

Step 7 : 6- Amino -2-( ethylsulfonylimide )-9-[(4- fluorophenyl ) methyl ] -N - methyl -8 -oxo - N - propyl - purin-7-acyl-amine (example 45), 6-amino--2- [S (R) ethyl sulfonylurea acyl imine] -9 - [(4-fluorophenyl) methyl] - N - methyl-8-oxo - N - propyl - purin-7-amine and 6-amino-acyl -2- [S (S) -ethyl sulfonylurea acyl imine] -9 - [(4 - fluorophenyl) methyl] - N - methyl-8-oxo - N - propyl - methyl acyl-7-amine (example 45-A and example 45-B) of purine.

( Example 45)

( Example 45-A and Example 45-B ) Similar to Example 1 , Method A , Step 6 , by using 6-amino-2-(ethylsulfonylimide)-9-[(4-fluoro Phenyl)methyl]-7 H -purin-8-one ( Compound 45e ) instead of 6-amino-9-benzyl-2-(propylsulfonylimide)-7 H- purin-8 -Ketone ( Compound 1e ) to prepare Example 45 . Obtained as a white solid 6-amino-2-(ethylsulfonylimide)-9-[(4-fluorophenyl)methyl] -N -methyl-8-oxo- N -Propyl-purine-7-carboxamide (162.4 mg, Example 45 ).

Using methanol 5%-40% (0.05% DEA)/CO ₂ on a ChiralPak AD-3 column to separate the compound of Example 45 by palm HPLC, Example 45-A was obtained as a white solid (faster dissolution, 85.3 mg) and Example 45-B (slower dissolution, 52 mg). Example 45-A : 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 450. Example 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 450.

(實例46)

(實例46-A及實例46-B) Example 46-A and Example 46-B 6- amino - N - ethyl -2-( ethylsulfonylimide )-9-[(4- fluorophenyl ) methyl ] -N - methyl -8 -Penoxy - purine -7- methylamide ( Example 46) , 6- amino - N - ethyl -2-[S( S )-( ethylsulfonylimideamide )]-9 -[(4- fluorophenyl ) methyl ] -N - methyl -8 -oxo - purine -7- carboxamide and 6- amino - N - ethyl -2-[S( R )- ( Ethylsulfonylimide amide )]-9-[(4- fluorophenyl ) methyl ] -N - methyl -8 -oxo - purine -7- methylamide ( Example 46-A and Example 46-B) .

(Example 46)

(Example 46-A and Example 46-B)

Similar to Example 1, Method A, Step 6, by using 6-amino-2- (ethyl-acyl imine sulfonylurea) -9 - [(4-fluorophenyl) methyl] -7 H - purin -8-keto ( Compound 45e ) and N -ethyl- N -methyl-aminoformamide chloride instead of 6-amino-9-benzyl-2-(propylsulfonylimide amide)-7 Example 46 was prepared by H -purin-8-one ( Compound 1e ) and N -methyl- N -propyl-aminecarboxamide ( intermediate product AA ). Obtained as a white solid 6-amino- N -ethyl-2-(ethylsulfonylimide)-9-[(4-fluorophenyl)methyl] -N -methyl-8- Pendyloxy-purine-7-carboxamide (51 mg, Example 46 ). 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 436.

Using methanol 5%-40% (0.05% DEA)/CO ₂ on a ChiralPak AD-3 column to separate the compound of Example 46 by palm HPLC, Example 46-A was obtained as a white solid (faster dissolution, 72 mg) and Example 46-B (slower dissolution, 45 mg). Example 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 436. Example 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 436.

(實例47)

(實例47-A及實例47-B) Example 47-A and Example 47-B 6- amino- 9-[(4- bromophenyl ) methyl ]-2-( ethylsulfonylimide ) -N -methyl -8- side oxygen yl - N - propyl - purin-acyl-7-amine (example 47), 6-amino--2- [S (R) - ethyl sulfonylurea acyl imine] -9 - [(4-bromophenyl Yl ) methyl ] -N - methyl -8 -oxo - N - propyl - purine -7- carboxamide and 6- amino -2-[S( S ) -ethylsulfonylimide amide Group ]-9-[(4- bromophenyl ) methyl ] -N - methyl -8- pendant - N - propyl - purine -7- carboxamide

(Example 47)

(Example 47-A and Example 47-B)

類似於實例 1 、方法 A 、步驟 1 ，藉由使用異氰酸4-溴苯甲酯而非異氰酸苯甲酯來製備化合物 47a 。獲得呈淡黃色固體狀之4-胺基-3-[(4-溴苯基)甲基]-2-側氧基-1H-咪唑-5-甲腈(500 mg，化合物 47a )且其未經進一步純化即直接用於下一步驟。¹ H NMR (400 MHz, DMSO-d₆ )δ ppm: 9.94 (S, 1H), 7.55-7.53 (d,J = 8.0 Hz, 2H), 7.20-7.18 (d, J = 8.0 Hz, 2H), 6.52 (br. s., 2H), 4.74 (s, 2H)。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 293。 Step 1 : Preparation of 4- amino- 3-[(4- bromophenyl ) methyl ]-2 -oxo - 1H - imidazole -5 -carbonitrile ( Compound 47a)

Similar to Example 1 , Method A , Step 1 , compound 47a was prepared by using 4-bromobenzyl isocyanate instead of benzyl isocyanate. 4-Amino-3-[(4-bromophenyl)methyl]-2-oxo-1H-imidazole-5-carbonitrile (500 mg, compound 47a ) was obtained as a pale yellow solid and it was not After further purification, it was directly used in the next step. 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 = 8.0 Hz, 2H), 6.52 (br. s., 2H), 4.74 (s, 2H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 293.

類似於實例 1 、方法 A 、 步驟 2 ，藉由使用4-胺基-3-[(4-溴苯基)甲基]-2-側氧基-1H -咪唑-5-甲腈(化合物 47a )而非4-胺基-3-苯基甲基-2-側氧基-1H -咪唑-5-甲腈(化合物 1a )來製備化合物 47b 。獲得呈黃色固體狀之6-胺基-9-[(4-溴苯基)甲基]-2-磺醯基-7H -嘌呤-8-酮(300 mg,化合物 47b )。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 352。 Step 2: 6-amino--9-- purin-8-one (Compound 47b) of - [(4-bromophenyl) methyl] -2-sulfonamide acyl -7 H

Similar to Example 1 , Method A , Step 2 , by using 4-amino-3-[(4-bromophenyl)methyl]-2-oxo- 1H -imidazole-5-carbonitrile ( compound 47a ) instead of 4-amino-3-phenylmethyl-2-oxo- 1H -imidazole-5-carbonitrile ( compound 1a ) to prepare compound 47b . Was obtained as a yellow solid of 6-amino-9 - [(4-bromophenyl) methyl] -2-sulfonamide acyl -7 H - purin-8-one (300 mg, compound 47b). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 352.

類似於實例 1 、方法 A 、步驟 3 ，藉由使用6-胺基-9-[(4-溴苯基)甲基]-2-磺醯基-7H -嘌呤-8-酮(化合物 45b )及碘乙烷而非6-胺基-9-苄基-2-磺醯基-7H-嘌呤-8-酮(化合物 1b )及溴丙烷來製備化合物 47c 。獲得呈黃色固體狀之6-胺基-2-乙基磺醯基-9-[(4-溴苯基)甲基]-7H -嘌呤-8-酮(5.6 g，化合物 47c )。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 380。 Step 3: 6-amino-2-ethyl-sulfonic acyl -9 - [(4-bromophenyl) methyl] -7 H - purin-8-one (Compound 47c) Preparation of

Similar to Example 1, Method A, Step 3, by using 6-amino-9 - [(4-bromophenyl) methyl] -2-sulfonamide acyl -7 H - purin-8-one (Compound 45b ) And iodoethane instead of 6-amino-9-benzyl-2-sulfonyl-7H-purin-8-one ( compound 1b ) and bromopropane to prepare compound 47c . Was obtained as a yellow solid of 6-amino-2-ethyl-sulfonic acyl -9 - [(4-bromophenyl) methyl] -7 H - purin-8-one (5.6 g, compound 47c). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 380.

類似於實例 1 、方法 B 、 步驟 6 ，藉由使用6-胺基-9-[(4-溴苯基)甲基]-2-乙基磺醯基-7H -嘌呤-8-酮(化合物 47c )而非6-胺基-9-苄基-2-(2-丙基磺醯基)-7H -嘌呤-8-酮(化合物 1c )來製備化合物 47d 。獲得呈白色固體狀之6-胺基-9-[(4-溴苯基)甲基]-2-乙基亞磺醯基-7H -嘌呤-8-酮(3.2 g，化合物 47d )。MS觀測值 (ESI⁺ ) [(M+H)⁺ ]: 396。 Preparation of [(4-bromophenyl) methyl] -2-ethyl methylsulfoximide acyl -7h- purin-8-one (Compound 47D) - A 6-amino--9: Step 4

Similar to Example 1, Method B, Step 6, by using 6-amino-9 - [(4-bromophenyl) methyl] -2-ethyl sulfonic acyl -7 H - purin-8-one ( compound 47c) instead of 6-amino-benzyl-2- -9- (2-propyl sulfo acyl) -7 H - purin-8-one (compound 1c) to prepare compound 47d. Was obtained as a white solid of 6-amino-9 - [(4-bromophenyl) methyl] -2-ethyl methylsulfoximide acyl -7 H - purin-8-one (3.2 g, compound 47d). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 396.

類似於實例 1 、方法 B 、 步驟 7 ，藉由使用6-胺基-9-[(4-溴苯基)甲基]-2-乙基亞磺醯基-7H -嘌呤-8-酮(化合物 47d )而非6-胺基-9-苄基-2-丙基亞磺醯基-7H -嘌呤-8-酮(化合物 1d )來製備化合物 47e 。 獲得呈白色固體狀之6-胺基-9-[(4-溴苯基)甲基]-2-(乙基磺醯亞胺醯基)-7H -嘌呤-8-酮(4.0 g，化合物 47e )。MS 觀測值(ESI⁺ ) [(M+H)⁺ ]: 411。

化合物 47e-A 及化合物 47e-B Preparation of [(4-bromophenyl) methyl] -2- (ethyl sulfonylurea acyl imine)-7H-purin-8-one (Compound 47e) - A 6-amino--9: Step 5

Similar to Example 1, Method B, Step 7, by using 6-amino-9 - [(4-bromophenyl) methyl] -2-ethyl methylsulfoximide acyl -7 H - purin-8-one (compound 47D) instead of 6- benzyl-2-propyl-9- alkylsulfinyl acyl -7 H - purin-8-one (compound 1d) to prepare compound 47e. 6-Amino-9-[(4-bromophenyl)methyl]-2-(ethylsulfonylimide)-7 H -purin-8-one (4.0 g, Compound 47e ). Observed MS (ESI ⁺ ) [(M+H) ⁺ ]: 411.

Compound 47e-A and Compound 47e-B

Using methanol 5%-40% (0.05% DEA)/CO ₂ on a ChiralPak AD-3 column to separate compound 47e by palm HPLC, compound 47e-A was obtained as a white solid (faster dissolution, 112 mg) and compound 47e-B (slow dissolution, 99 mg). 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 = 8.0 Hz, 2H), 6.54 (br. s., 2H), 4.93 (s, 2H), 4.05 (s, 1H), 3.42-3.31 (m, 2H), 1.15 (t, J = 7.3 Hz, 3H ). MS observation (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 = 8.0 Hz, 2H), 6.98 (br. s., 2H), 4.93 (s, 2H), 4.06 (s, 1H), 3.40-3.37 (m, 2H), 1.15 (t, J = 7.3 Hz, 3H ). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 411.

(實例47)

(實例47-A及實例47-B) 類似於實例 1 、方法 A 、 步驟 6 ，藉由使用6-胺基-9-[(4-溴苯基)甲基]-2-(乙基磺醯亞胺醯基)-7H -嘌呤-8-酮(化合物 47e )而非6-胺基-9-苄基-2-(丙基磺醯亞胺醯基)-7H-嘌呤-8-酮(化合物 1e )來製備實例 47 。獲得呈白色固體狀之6-胺基-9-[(4-溴苯基)甲基]-2-(乙基磺醯亞胺醯基)-N- 甲基-8-側氧基-N -丙基-嘌呤-7-甲醯胺(570 mg，實例 47 )。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 = 8.0 Hz, 3H), 0.93-0.75 (m, 3H)。MS觀測值 (ESI⁺ ) [(M+H)⁺ ]: 510。 使用甲醇5%-40% (0.05% DEA)/CO₂ 於ChiralPak AD-3管柱上藉由對掌性HPLC分離實例 47 之化合物，得到呈白色固體狀之實例 47-A (較快溶離，260 mg)及實例 47-B (較慢溶離，266 mg)。實例 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 = 8,0 Hz, 2H), 6.90 (br. s., 2H), 4.97 (s, 2H), 4.21 (s, 1H), 3.46 - 3.41 (m, 4H), 3.05 - 3.02 (m, 3H),1.65-1.54 (m, 2H), 1.24-1.16 (m, 3H), 0.93-0.75 (m, 3H)。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 510。實例 47-B ：¹ H NMR (400 MHz, DMSO-d₆ )δ ppm: 7.54 - 7.53 (d,J = 8.0 Hz, 2H), 7.36-7.33 (d,J = 8,0 Hz, 2H), 6.90 (br. s., 2H), 4.97 (s, 2H), 4.21 (s, 1H), 3.46 - 3.41 (m, 4H), 3.06 - 3.02 (m, 3H), 1.65-1.54 (m, 2H), 1.20-1.16 (m, 3H), 0.93-0.75 (m, 3H)。MS觀測值(ESI⁺ ) [(M+H)⁺ ]: 510。 Step 6 : 6- Amino- 9-[(4- bromophenyl ) methyl ]-2-( ethylsulfonylimide ) -N - methyl -8 -oxo - N - propyl - purin-7-acyl-amine (example 47), 6-amino-9 - [(4-bromophenyl) methyl] -2- [S (R) - ethyl sulfonylurea imine acyl] - N - methyl -8 -oxo - N - propyl - purine -7- carboxamide and 6- amino- 9-[(4- bromophenyl ) methyl ]-2-[S( S ) - ethyl sulfonylurea imine acyl] - purin-7-acyl-amine (example 47-A and example 47-B) of - N - methyl-8-oxo - N - propyl.

(Example 47)

(Example 47-A and Example 47-B) Similar to Example 1 , Method A , Step 6 , by using 6-amino-9-[(4-bromophenyl)methyl]-2-(ethylsulfonate (PEI) acyl) -7 H - purin-8-one (compound 47e) instead of 6-amino--9- benzyl-2- (propylsulfonyl (PEI) acyl) -7H- purin-8 Ketone ( Compound 1e ) to prepare Example 47 . Obtained as a white solid 6-amino-9-[(4-bromophenyl)methyl]-2-(ethylsulfonylimide) -N -methyl-8-oxo- N -Propyl-purine-7-carboxamide (570 mg, Example 47 ). 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 = 8.0 Hz, 3H), 0.93-0.75 ( m, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 510. Using methanol 5%-40% (0.05% DEA)/CO ₂ on a ChiralPak AD-3 column, the compound of Example 47 was separated by palm HPLC to obtain Example 47-A as a white solid (faster dissolution, 260 mg) and Example 47-B (slower dissolution, 266 mg). Example 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, 0 Hz, 2H), 6.90 (br. s., 2H), 4.97 (s, 2H), 4.21 (s, 1H), 3.46-3.41 (m, 4H), 3.05-3.02 (m, 3H), 1.65-1.54 (m, 2H) , 1.24-1.16 (m, 3H), 0.93-0.75 (m, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 510. Example 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 = 8,0 Hz, 2H), 6.90 (br. s., 2H), 4.97 (s, 2H), 4.21 (s, 1H), 3.46-3.41 (m, 4H), 3.06-3.02 (m, 3H), 1.65-1.54 (m, 2H) , 1.20-1.16 (m, 3H), 0.93-0.75 (m, 3H). MS observation (ESI ⁺ ) [(M+H) ⁺ ]: 510.

(實例48)

(實例48-A及實例48-B)

Example 48-A and Example 48-B 6- amino- 9-[(4- bromophenyl ) methyl ] -N - ethyl -2-( ethylsulfonylimide ) -N -methyl -8 -oxo - purine -7- carboxamide ( Example 48) , 6- amino- 9-[(4- bromophenyl ) methyl ] -N - ethyl -2-[S(S) -( Ethylsulfonylimide )]- N - methyl -8 -oxo - purine -7- carboxamide and 6- amino- 9-[(4- bromophenyl ) methyl ] -N - ethyl -2-[S( R )-( ethylsulfonylimide )]- N - methyl -8 -oxo - purine -7- methylamide ( Example 48-A and Example 48-B) .

(Example 48)

(Example 48-A and Example 48-B)

Similar to Example 1 , Method A , Step 6 , by using 6-amino-9-[(4-bromophenyl)methyl]-2-(ethylsulfonylimide)-7 H -purine -8-one ( compound 47e ) and N -ethyl- N -methyl- aminoformamide chloride instead of 6-amino-9-benzyl-2-(propylsulfonylimide amide)-7H -Purine-8-one ( Compound 1e ) and N-methyl-N-propyl-aminoformamide chloride ( intermediate product AA ) to prepare Example 48 . Obtain 6-amino-9-[(4-bromophenyl)methyl]-2-(ethylsulfonylimidoamide) -N -methyl-8-oxo- N as a white solid -Propyl-purine-7-formamide (469 mg, Example 48 ). 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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 496.

Using methanol 5%-40% (0.05% DEA)/CO ₂ on a ChiralPak AD-3 column to separate the compound of Example 48 by palm HPLC, Example 48-A was obtained as a white solid (faster dissolution, 198 mg) and Example 48-B (slower dissolution, 202 mg). Example 48-A : 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), 6.92 (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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 496. Example 48-B : 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), 6.92 (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 observation (ESI ⁺ ) [(M+H) ⁺ ]: 496.

Examples 49 Compounds and examples HEK293-hTLR-7 Activity in analysis

HEK293-Blue-hTLR-7 cell analysis: The stable HEK293-Blue-hTLR-7 cell line was purchased from InvivoGen (catalog number: hkb-htlr7, San Diego, California, USA). These cells are designed to study the stimulation of human TLR7 by monitoring the activation of NF-κB. The secreted embryonic alkaline phosphatase (SEAP) 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 induced by activating NF-κB and AP-1 by stimulating HEK-Blue hTLR7 cells with TLR7 ligand. Therefore, after 20 hours of human TLR7 stimulation, the reporter performance is regulated by the NF-κB promoter. The SEAP reporter activity of the cell culture supernatant was measured at 640 nm using the QUANTI-Blue™ kit (catalog number: rep-qb1, Invivogen, San Diego, Ca, USA). The kit is alkaline phosphatase. Detection medium that turns purple or blue in the presence.

HEK293-Blue-hTLR7 cells at a density of 250,000 to 450,000 cells/ml in a volume of 180 µL in a 96-well dish containing 4.5 g/L glucose, 50 U/mL penicillin, 50 mg/mL streptomycin, 100 mg/mL Normocin, 2 mM L-glutamic acid, 10% (V/V) heat-inactivated fetal bovine serum in Dulbecco's Modified Eagle's medium (DMEM) Incubate for 24 hours. Subsequently, 20 μL of a serial dilution of the test compound was added, HEK293-Blue-hTLR-7 cells were incubated in the presence of 1% final DMSO, and incubated at 37° C. in a CO ₂ incubator for 20 hours. Subsequently, 20 µL of supernatant from each well was incubated with 180 µL Quanti-blue substrate solution for 2 hours at 37°C and the absorbance was read using a spectrophotometer at 620 to 655 nm. TLR7 activation leads to the signaling pathway of downstream NF-κB activation, and therefore, similar reporter analysis is also widely used to evaluate TLR7 agonists (Tsuneyasu Kaisho and Takashi Tanaka, Trends in Immunology, Volume 29, Page 7 Issue, July 2008, p. 329. sci; Hiroaki Hemmi et al., Nature Immunology 3, 196-200 (2002)).

The compounds and examples of the invention were tested for TLR7 agonistic activity in the HEK293-hTLR-7 assay as described herein and the results are listed in Table 1. Examples of prodrugs were found to have an EC _{50 of} about 2.1 µM to about 1000 µM, and compounds in the active form were found to have an EC _{50 of} less than 0.2 µM. The calculated ratio of EC _{50 ( prodrug )} /EC _{50 ( active form )} is in the range of 32 to about 7600. Table 1. Examples of the present invention and the activity of compounds in HEK293-hTLR-7 analysis

Examples 50 formula (I) Compound Prodrug Metabolism

Studies are conducted to evaluate the metabolic conversion of the prodrug, compound of formula (I), to its corresponding active form. The compound of formula (I) can be metabolized in the body as the active compound of the present invention or other compounds when charged as a medicine. Human liver microsomes are commonly used to assess the degree of metabolic transformation in prodrug animals or humans. material

The NADPH cofactor system including β-nicotinamide adenine dinucleotide phosphate (NADP), isocitrate and isocitrate dehydrogenase was purchased from Sigma-Aldrich Co. (St. Louis, MO, USA). Human liver microsomes (catalog number 452117, lot number 38290) were purchased from Corning (Woburn, MA, USA). Mouse liver microsomes (catalog number M1000, batch number 1310028) were purchased from Xenotech.

Working and other solutions of the compound Dissolve the compound in DMSO to prepare a 10 mM stock solution. Dilute the 10 µL stock solution with acetonitrile (990 µL) to obtain a 100 µM working solution.

Incubation The microsomes were preincubated with the test compound in 100 mM potassium phosphate buffer pH 7.4 at 37°C for 10 minutes. The reaction was started by adding a NADPH regeneration system, resulting in a final incubation volume of 200 μL and shaken in a water bath at 37°C. The incubation mixture consists of liver microsomes (0.5 mg microsomal protein/ml), substrate (1.0 μM) and NADP (1 mM), isocitrate dehydrogenase (1 unit/ml), isocitrate (6 mM) .

Preparation of samples for analysis At 30 minutes, the reaction was quenched by adding 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 are prepared as follows. Dispense 100 microliters/well of liver microsomes and 98 microliters/well of NADPH regeneration system solution into a 96-well dish. First 600 μL of quenching solution was added, and then 2 μL of standard curve and QC working solution were added.

Biological analysis The compounds were quantified on the API4000 LC-MC/MC instrument in ESI-Positive MRM (ESI-Positive MRM) mode.

Research in the presence of human liver microsomes to evaluate prodrugs (1µM): Example 1 , Example 1-A , Example 1-B , Example 2 , Example 2-A , Example 2-B , Example 3 , Example 4 , Example 5. Example 6 , Example 7 , Example 8 , Example 9 , Example 10 , Example 11 , Example 12 , Example 13 , Example 14 , Example 15 , Example 16 , Example 17 , Example 21 , Example 22 , Example 23 , Example 25 , Example 26 , Example 27 , Example 28 , Example 29 , Example 30 , Example 31 , Example 32 , Example 33 , Example 34-A , Example 34-B , Example 36-A , Example 36-B , Example 37-A , Example 37-B , Example 38-A , Example 38-B , Example 39 , Example 40 , Example 41 , Example 41-A , Example 41-B , Example 42 , Example 42-A , Example 42-B , Example 43 , Example 43-A , Example 43-B , Example 44 , Example 44-A , Example 44-B and Example 45-A , Example 46-A , Example 46-B , Example 47-A , Example 47-B , Example 48- A. Examples 48-B correspond to the 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 , Metabolic transformation of compound 41c-B , compound 41c-A , compound 43e , compound 43e-A , compound 43e-B , compound 45e-A , compound 45e-B , compound 47e-A and compound 47e-B . The results are summarized and shown in Table 2. Table 2. Metabolic transformation of prodrugs in human liver microsomes

Examples 51 Compound of the invention ( Chemical compound 41-A) Former drug form and in vivo combined efficacy of sorafenib in a highly invasive model of hepatocellular carcinoma ( Tumor-free mice )

In iAST mice, by intravenous injection of 5×10 ⁸ IFU adenoviruses expressing Cre recombinase (Ad-CMV-iCre vector in vivo application, Vector Biolabs) into hepatocyte-specific albumin promoter (loxP-side termination cassette) and SV40 larger T-antigen transgenic mice to induce tumor formation (Runge A, et al., Cancer Res. 74 (2014) 4157-69). Cre recombinase excises the termination cassette in the transduced cells and causes transient viral hepatitis and causes multi-nodular tumor formation within 8 weeks. Female mice daily vehicle (7.5% gelatin/0.22% NaCl for sorafenib; or 2% Klucel® hydroxypropyl cellulose LF (Asland), 0.5% D-α-fertility for 41-A Phenol polyethylene glycol 1000 succinate (TPGS, Sigma), 0.09% methyl paraben (Sigma), 0.01% propyl paraben (Sigma) in water), or 90 mg/kg sorafen (Nexavar®, Bayer HealthCare) treatment or oral gavage compound 41-A (10mg/kg) once a week. The treatment with vehicle or sorafenib was started at 7.5 weeks after adenovirus administration and 3 days before administration of compound 41-A. The animals were sacrificed on the 12th day after the start of treatment and the total liver and tumor weights were measured. Each group was analyzed by one-way ANOVA with n=10 and Tukey correction was plotted using GraphPad Prism software version 6 as individual points with mean±SEM. Although sorafenib is highly effective as a monotherapy, in this highly invasive hepatocellular carcinoma model, the surface form of the liver combined with the active form of the compound of the present invention (Compound 41-A) resulted in even 2/10 tumor-free Mice. The results are shown in the table below and in Figures 1A and 1B. Synergistic effect of compound 41-A and sorafenib on tumor burden ( tumor-free mice )

Examples 52 With the compound of the invention ( Chemical compound 41-A) Prodrug treatment is induced on tumor cells in hepatocellular carcinoma PD-L1 which performed

The tumors of iAST mice were treated as described in Figure 1. Animals were sacrificed on the 12th day after the start of treatment and tumors were analyzed by flow cytometry. For flow cytometry, the tumor was excised and a single cell suspension was obtained by mechanical treatment and enzymatic digestion (DNase 0.01%, collagenase IV 1 mg/ml). A 2.4G2 antibody pure line (1:200 dilution, BD Bioscience) was used to start the staining procedure with Fc receptor blockade, and the following antibodies (pure line) were used to analyze leukocyte infiltration: CD45-FITC (30-F11, BioLegend) and CD11b-BUV737 (M1/70, BD Bioscience). Samples were obtained using LSR Fortessa machine (BD Bioscience) and analyzed by FlowJo version 10 (Treestar). The data is presented with n=5/group, by one-way ANOVA analysis and Tukey correction using GraphPad Prism software version 6 as a single point with mean±SEM. Although absolute immune cell infiltration in iAST tumors was not altered by any of the treatments described (Figure 2A), significant changes were observed in total lymphocytes and bone marrow components of the tumor (Figure 2C and D). Here, the change is clearly driven by sorafenib, and its previous display also works on immune cells (Martin del Campo, et al., J Immunol. 195 (2015) 1995-2005). However, 41-A treatment induced PD-L1 expression on tumor cells with monotherapy and in combination with sorafenib (Figure 2B).

Examples 53 41-A , Sorafenib and anti -PD-1 The triple combination in vivo produces increased median survival.

As described for Figure 1, multi-nodular tumors were induced in iAST mice (see Example 51). Female transgenic mice received daily vehicle at week 7.5 after virus injection (7.5% gelatin/0.22% NaCl for sorafenib; or 2% Klucel® hydroxypropylcellulose LF for 41-A (Asland), 0.5% D-α-tocopherol polyethylene glycol 1000 succinate (TPGS, Sigma), 0.09% methylparaben (Sigma), 0.01% propylparaben (Sigma) Water), or 90 mg/kg sorafenib treatment or oral gavage compound 41-A (10 mg/kg) once a week. The treatment with vehicle or sorafenib was started at 7.5 weeks after adenovirus administration and 3 days before administration of compound 41-A. Anti-mouse PD-1 antibody (pure line RPM1-14, BioXCell) was administered intraperitoneally at 250 μg/mouse every 3 days. The total treatment period is 2 weeks (and 3 days + 2 weeks for sorafenib) and iAST mice are monitored for survival. The mice were sacrificed after showing signs of pain, such as >20% weight gain, ruffled fur, and or hatching position. The Kaplan-Meier curve was analyzed by Pairwise log rank test (see table). In the context of survival, sorafenib or 41-A were not effective with monotherapy. Compared to the VEH control, anti-PD-1 monotherapy even resulted in a significantly reduced survival period. The median survival time of iAST mice was significantly improved in the combination group of sorafenib and anti-PD-1 antibody. However, the triple combination of 41-A with sorafenib and anti-PD-1 resulted in a median survival period from 71 days (VEH) to 104 days (41-A+PD-1+ in this highly invasive HCC model Sorafenib) has the largest and obvious increase. The results are shown in Figure 3 and the table below.table: Pairwise Log level test ( Multiple test levels =0.00179)

Examples 54 Transplantation of hepatocellular carcinoma Hep55.1c Compounds of the invention used in mouse models ( Chemical compound 41-A) Former medication

Female C57BL/6N mice (Jackson Laboratories) were injected intrahepatic with 5×10 ⁵ Hep55.1c tumor cell lines with a total volume of 20 µl and Matrigel (Matrigel Basement Membrane Matrix, Corning catalog number 354234) (10 µl cell suspension plus 10 µl Martigel). Tumor volume was monitored weekly using µCT (TomoScope Synergy Twin, CT Imaging GmbH) after a single intravenous administration of the contrast agent Exitron 6000 (Viscovert). The TomoScope software reconstructs the image data and analyzes it using Osirix software. Once the tumor reaches 80 mm ³ , weekly oral gavage of 10 mg/kg 41-A compound or vehicle (containing 2% Klucel® hydroxypropyl cellulose LF (Asland), 0.5% D-α-tocopherol The mice were treated with polyethylene glycol 1000 succinate (TPGS, Sigma), 0.09% methylparaben (Sigma), 0.01%propylparaben (Sigma) in water). For comparison with another agonistic immunostimulant, a single dose of anti-CD40 antibody (4 mg/kg; pure line FGK.45, BioXCell) was given. The data depicted is the average ±SEM of at least n=9 animals in each group.

When compared to vehicle treatment, compound 41-A was administered weekly to inhibit tumor growth in Hep55.1c tumor-bearing mice. As previously published, a single dose of anti-CD40 antibody can cause tumor eradication of subcutaneous MC38 tumors and it has been shown that anti-CD40 antibodies have an inflammatory effect in the liver (Hoves S, et al., J Exp Med, DOI: 10.1084/jem.20171440 ; Released on February 7, 2018). However, no beneficial therapeutic effect by anti-CD40 antibody was observed in Hep55.1c tumor-bearing mice. The results are shown in Figure 5A.

Examples 55 Chemical compound 42-A (6- Amine -9-[(4- Chlorophenyl ) methyl ] -N- Ethyl - 2[S(S)- Ethylsulfonylimide ]- N- methyl - 8- Pendant - Purine -7- Formamide ) Alone and with -PD-1 combination In vivo efficacy in hepatocellular carcinoma Hep55.1c Survival benefits are produced in mouse models.

Female C57BL/6N mice (Jackson Laboratories) were injected intrahepatic with 5×10 ⁵ Hep55.1c tumor cell lines with a total volume of 20 µl and Matrigel (Matrigel Basement Membrane Matrix, Corning catalog number 354234) (10 µl cell suspension plus 10 µl Martigel). The investigative animals were sacrificed to determine the time to start treatment at a tumor volume of approximately 80 mm ³ . Mice by oral gavage of compound 42-A 10 mg/kg or vehicle (containing 2% Klucel® hydroxypropyl cellulose LF (Asland), 0.5% D-α-tocopherol polyethylene glycol 1000 succinate (TPGS, Sigma), 0.09% methyl paraben (Sigma), 0.01% propyl paraben (Sigma) in water) or intraperitoneal administration of 250 µg anti-PD-1 antibody (pure RPM1-14 , BioXCell), or compound 42-A plus anti-PD-1 combination for treatment. 42-A was given weekly (a total of 3 times) and anti-PD-1 antibody treatment was started on the same day. A total of 6 doses of antibody treatment are continued every three to four days. Compared with VEH control and PD-1 monotherapy, 42-A monotherapy produces smaller tumor volume. Combined treatment with 42-A and anti-PD-1 also reduced tumor volume, with 3/9 mice free of tumors. The results are shown in Figure 5B and the table below. The combined effect of compound 42-A and anti- PD-1 on tumor burden ( tumor-free mice )

Examples 56 Hepatocellular carcinoma Hep55.1c Compounds of the invention in mouse models ( Chemical compound 41-A) Former drugs and resistance -PD-1 Antibody combinations

Female C57BL/6N mice (Jackson Laboratories) were injected intrahepatic with 5×10 ⁵ Hep55.1c tumor cell lines with a total volume of 20 µl and Matrigel (Matrigel Basement Membrane Matrix, Corning catalog number 354234) (10 µl cell suspension plus 10 µl Martigel). After 3 weeks, the animals were sacrificed and tumors were excised from the liver. The excised tumor was cut into 1×1 mm ³ pieces and transplanted into the liver of female C57BL/6N mice. The investigative animals were sacrificed to determine the time to start treatment at a tumor volume of approximately 80 mm ³ . Mice were administered by oral gavage of 41-A or vehicle (containing 2% Klucel® hydroxypropyl cellulose LF (Asland), 0.5% D-α-tocopherol polyethylene glycol 1000 succinate (TPGS, Sigma ), 0.09% methyl paraben (Sigma), 0.01% propyl paraben (Sigma) in water) or intraperitoneal administration of 250 µg anti-PD-1 antibody (pure RPM1-14, BioXCell) or 41 -1 plus a combination of anti-PD-1 to treat 41-A given weekly, while starting anti-PD-1 antibody treatment one day after 41-A treatment and continuing a total of 8 doses every three to four days. The treatment with the two agents was stopped after the last anti-PD-1 administration. Compared to vehicle control (1/10), 41-A monotherapy resulted in longer survival mice (5/10). The combination treatment of 41-A and anti-PD-1 increased the survival period of mice, and even significantly increased to 8/10 mice survived on the 94th day after tumor fragment transplantation.

Example 57 Treatment with the active form of the compound of the present invention ( Compound 41c-B) does not induce tumor cell proliferation enhancement of cell lines derived from hepatocellular carcinoma and cholangiocarcinoma Cell lines were maintained and tested in the following media: 4.5 g/L glucose in DMEM (Gibco, catalog number 31966-021), 10% FCS (GIBCO, catalog number 10500-064 batch number 07G3690K), 2 mM L-glutamic acid (Thermo Fischer, catalog number 25030081) and 1 mM sodium pyruvate (GIBCO catalog number 11360-039) were used to cultivate Huh7 and EGI1. Hep3B and Hep3B were incubated in Eagles MEM + Earle's BSS (PAN, catalog number P04-08510), 10% FCS, 2 mM L-glutamic acid, 0.1 mM NEAA (PAN catalog number P08-32100), and 1 mM sodium pyruvate HepG2. JHH1, JHH5, JHH6 and OZ were cultivated in Williams'E (PAN catalog number P04-29050), 10% FCS and 2 m ML-glutamic acid. JHH2 was incubated with Williams'E, 10% FCS and 2 m ML-glutamic acid. HLE was incubated in DMEM 4.5 g/L glucose, 10% FCS, and 2 mM L-glutamic acid. HLF was incubated in DMEM 4.5 g/L glucose, 5% FCS, 0.1 mM NEAA, and 2 mM L-glutamic acid. JHH4 was grown in Eagles MEM + Earle's BSS, 10% FCS and 2 mM L-glutamic acid. SkHep1 was incubated in Eagles MEM + Earle's BSS, 10% FCS, 2 mM L-glutamic acid, 0.1 mM NEAA, and 1 mM sodium pyruvate. SNU449 was incubated with RPMI 1640 (PAN catalog number P04-18047) 10% FCS and 2 mM L-glutamic acid. Cells were seeded in individual media overnight at a density of 5,000 cells/well in 96-well plates with transparent bottom black polystyrene TC-treated microplates (Corning, catalog number 3904). The next day, add 41c-B log dilution from 27 µM to 270 pM and incubate for 72, 120, and 148 hours, respectively. Perkin Elmer Operetta imaging system and Harmony software were used to determine the number of tumor cells by counting the nuclei stained for 20 minutes in complete medium using Hoechst 33342 dye (2 µg/ml, Sigma catalog number B2261). The data presented is the mean + SD from three replicate wells, which is based on the analysis of 9 images per well relative to the DMSO control.

At the depicted time point, none of the tested cell lines showed significantly increased proliferation after direct treatment with 41c-B. The results are shown in Figure 6A.

Examples 58 With the compound of the present invention ( Chemical compound 41C-A) The active form of treatment does not induce enhanced tumor cell proliferation derived from hepatocellular carcinoma and cholangiocarcinoma cell lines

Cell lines derived from hepatocellular carcinoma and cholangiocarcinoma (EGI1) were maintained and tested in the following media: 4.5 g/L glucose in DMEM (Gibco, catalog number 31966-021), 10% FCS (GIBCO, catalog number 10500-064 Batch No. 07G3690K), 2 mM L-glutamic acid (Thermo Fischer, catalog number 25030081), and 1 mM sodium pyruvate (GIBCO catalog number 11360-039) were used to cultivate Huh7 and EGI1. Hep3B and Hep3B were incubated in Eagles MEM + Earle's BSS (PAN, catalog number P04-08510), 10% FCS, 2 mM L-glutamic acid, 0.1 mM NEAA (PAN catalog number P08-32100), and 1 mM sodium pyruvate HepG2. JHH2 was incubated with Williams'E, 10% FCS and 2 mM L-glutamic acid. HLF was incubated in DMEM 4.5 g/L glucose, 5% FCS, 0.1 mM NEAA, and 2 mM L-glutamic acid. SkHep1 was incubated in Eagles MEM + Earle's BSS, 10% FCS, 2 mM L-glutamic acid, 0.1 mM NEAA, and 1 mM sodium pyruvate. Cells were seeded in individual medium overnight at a density of 5,000 cells/well in a 96-well plate transparent bottom black polystyrene TC-treated microwell plate (Corning, catalog number 3904). The next day, a log dilution of compound 41c-A from 27 µM down to 270 pM was added and incubated for 72 hours. Perkin Elmer Operetta imaging system and Harmony software were used to determine the number of tumor cells by counting the nuclei stained for 20 minutes in complete medium using Hoechst 33342 dye (2 µg/ml, Sigma catalog number B2261). The data presented is the mean + SD from three replicate wells, which is based on the analysis of 9 images per well relative to the DMSO control.

None of the tested cell lines showed significantly increased proliferation after 72 hours of treatment with 41c-A directly. The results are shown in Figure 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 results in the inhibition of tumor cell proliferation. Heparinized whole blood of 3 different donors was diluted 1:1 in RPMI medium (PAN catalog number P04-18047) plus 10% FCS (GIBCO catalog number 10500-064, batch number 07G3690K) and at 37°C and 5% Incubate with 2.7µM compound 41c-B under CO ₂ for 24 hours. The supernatant was collected and centrifuged at 600×g for 8 minutes to remove residual white blood cells, platelets and red blood cells. The supernatant was stored at -80°C until further use and was gradually thawed at room temperature before being added to the cell line. Cell lines Huh7, JHH2, HLE, HLF, JHH4, Hep3B, HepG2, JHH1, EGI1, JHH5, JHH6, OZ in 96-well flat transparent bottom black polystyrene TC-treated microplates (Corning, catalog number 3904) , SkHep1, and SNU449 were seeded at a density of 5,000 cells/well in 100 µl of individual medium (as described in Example 57) overnight. The next day, 100 µl of whole blood supernatant was added to the cell line. Whole blood supernatant without addition of 41c-B compound ("whole blood w/o") or pure RPMI medium plus FCS ("medium CTRL") was added as a control. The cell line was incubated for 72 hours. The Perkin Elmer Operetta imaging system and Harmony software were used to determine the number of tumor cells by counting the nuclei stained for 20 minutes in a complete medium using Hoechst33342 (2µg/ml, Sigma Cat# B2261) and by Propidium Iodine (PI, 1µg/ml , Sigma catalog number P4864) additional detection to assess survival rate. The data presented is the mean + SD from three replicate wells, which is based on the analysis of 9 images per well.

The results are shown in FIGS. 7A and 7B. For some cell lines (SNU449, JHH2 and SkHep), the addition of non-stimulated whole blood supernatant induces proliferation above the medium control level, while other reactions have reduced proliferation (OZ, JHH1, HepG2, JHH4, JHH6, JHH5 And EGI1). However, compared to the individual "whole blood w/o" control, treatment with whole blood supernatant derived from 41c-B resulted in a reduced number of cells in all tested cases. The reduction in cell number was mainly due to the termination of proliferation, and only the cell lines JHH2, JHH4, JHH6, Hep3B, and EGI1 did undergo cell death, as determined by a large number of PI positives (data not shown).

Examples 60 Compound of the invention ( Chemical compound 41C-A) Factors released in the peripheral blood after treatment in the active form result in inhibition of the proliferation of tumor cell lines.

Heparinized whole blood of 2 different donors was diluted 1:1 in RPMI medium (PAN catalog number P04-18047) plus 10% FCS (GIBCO catalog number 10500-064, batch number 07G3690K) and at 37°C and 5% CO ₂ and 24 hours of incubation at 2.7μM compound 41c-A together. The supernatant was collected and centrifuged at 600×g for 8 minutes to remove residual white blood cells, platelets and red blood cells. The supernatant was stored at -80°C until further use and was gradually thawed at room temperature before being added to the cell line. Cell lines Huh7, JHH2, HLF, Hep3B, HepG2, EGI1 and SkHep1 were seeded at a density of 5,000 cells/well in 96-well flat transparent bottom black polystyrene TC-treated microplates (Corning, catalog number 3904) Overnight in 100 µl of individual medium (as described in Figure 6). The next day, 100 µl of whole blood supernatant was added to the cell line. Whole blood supernatant without addition of 41c-A compound ("whole blood w/o") or pure RPMI medium plus FCS ("medium CTRL") was added as a control. The cell line was incubated for 72 hours. The Perkin Elmer Operetta imaging system and Harmony software were used to determine the number of tumor cells by counting the nuclei stained for 20 minutes in a complete medium using Hoechst33342 (2µg/ml, Sigma Cat# B2261) and by Propidium Iodine (PI, 1µg/ml , Sigma catalog number P4864) additional detection to assess survival rate. The data presented is the mean + SD from three replicate wells, which is based on the analysis of 9 images per well.

The results are shown in Figure 7C. Compared with individual "whole blood w/o" controls, treatment with whole blood supernatant from 41c-A resulted in a reduction or reduction in all tested cases. Stable cell count. In Hep3B only, the supernatant of donor 5 increased the proliferation of this cell line, while the supernatant from donor 4 did not affect the proliferation of tumor cells.

Examples of dose PK study in 61 male Wister-Han rats in the single

A single dose PK of male Wister-Han rats was performed to evaluate the pharmacokinetic properties of the tested compounds. The two groups of animals were administered individual compounds via gavage (POE). Blood samples (approximately 20 μL) were collected via the jugular vein or replacement site at 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 24 h in the post-dose group. The blood sample was placed in a test tube containing EDTA-K2 anticoagulant and centrifuged at 5000 rpm for 6 min at 4°C to separate plasma from the sample. After centrifugation, the resulting plasma was transferred to clean test tubes for bioanalysis of prodrugs and active forms on LC/MS/MS. In the prodrug group, the concentration of prodrug in the plasma sample was below the detection limit. The "tested compound" in Table 8 was used as an internal standard for testing metabolites (active forms) of "dose compounds" in vivo. Pharmacokinetic parameters were calculated using the non-compartment module of WinNonlin® Professional Edition 6.2. Record the peak concentration ( _Cmax ) directly according to the experimental observation. Use the linear trapezoidal rule to calculate the area under the plasma concentration-time curve (AUC _0-t ) until the last detectable concentration.

C _max and AUC _0-last are two important PK parameters related to the in vivo efficacy of the tested compounds. Compounds with higher C _max and AUC _0-last will produce better in vivo efficacy. The results of the PK parameters after oral administration of the active form and competing compounds are given in Table 7. The PK parameters of the prodrug are listed in Table 8.

*對於化合物41c-A、化合物41c-B及化合物43e-A採用7小時 表8.以5 mg/kg經口給藥之後前藥之PK參數

After oral administration of the prodrug, the active form is observed in the plasma and the active form is therefore tested. Compared to the reference compounds ( GS9620 , S-2 and S-3 ) and the compounds mentioned in the present invention which are all active forms ( compounds 41c-A , 41c-B and 43e-A ), the exemplification of the present invention Prodrugs ( Examples 41-B , 42-A , 42-B , 43-A , 45-A, and 45-B ) unexpectedly showed greatly improved C _max (an increase of 5-175 times) and AUC _0-last (An increase of 2.5-56 times). The results clearly demonstrate the unexpected superiority of the prodrug over the active form in terms of PK parameters, which produces better in vivo efficacy. Table 7. Average plasma concentration and PK parameters of the active form after oral administration at 5 mg/kg

*For compound 41c-A, compound 41c-B, and compound 43e-A, use 7 hours Table 8. PK parameters of prodrug after oral administration at 5 mg/kg

Examples 62 LYSA Solubility studies

The LYSA study is used to determine the water solubility of the tested compounds. Samples were prepared in duplicate from 10 mM DMSO stock solution. After evaporating DMSO with a vacuum centrifugal evaporator, the compound was dissolved in 0.05 M phosphate buffer (pH 6.5), stirred for one hour and shaken for two hours. After one night, the solution was filtered using a microtiter filter plate. The filtrate and its 1/10 dilution were subsequently analyzed by HPLC-UV. In addition, a four-point calibration curve was prepared from a 10 mM stock solution and used for the determination of compound solubility. The result is in µg/mL. If the percentage of the sample measured in the solution after evaporation divided by the calculated maximum sample amount is greater than 80%, the solubility is reported to be greater than this value.

The results of LYSA are shown in Table 9. It is clear that the solubility of the active form unexpectedly increases by 10 to more than 200 times when converted to various prodrugs. Table 9. Solubility data of specific compounds

Examples 63 Portal vein study

The goal of this study is to understand whether the prodrug remains unchanged when it is absorbed into the portal vein circulation through the intestine and shows the main site of transformation.

Portal vein cannulation method (Portal vein cannulation; PVC) and carotid cannulation method (Carotid artery cannulation; CAC) of surgical procedures surgery under pentobarbital (pentobarbital) / isoflurane anesthesia. Briefly, after disinfecting the abdominal area with betadine and 70% isopropyl alcohol, a small midline abdominal incision was made. The cecum was pulled out and the mesenteric vein was identified and separated for approximately 5 mm blood vessels. Place a loose ligature at the proximal end and ligate the end of the vein. A small incision is made in the separated vein (only enough to allow catheter insertion) and the PU catheter is inserted toward the liver at a suitable length. Secure the catheter in place by tying loose ligatures around the cannula. Reposition the cecum in the abdominal cavity. A hole is created in the right abdominal wall to allow the end of the catheter to pass freely. Fix the catheter to the abdominal wall with sutures. The abdominal muscle incision was closed with sutures. A small incision is made in the scapular region to serve as the exit site of the catheter. The catheter was inserted subcutaneously and removed through a scapular incision. Place the fixed suture on the scapular area. Check the patency of the catheter and then remove it from the subcutaneous space to the dorsal neck area. After gently wiping the area, the abdominal cavity was sutured. The left carotid artery was then cannulated by inserting a PE50 catheter. The two removed catheters are firmly tied to the dorsal neck area and fixed. The animals were then recovered in their cages and used for research at least 3 days after surgery. All catheters were flushed with heparinized saline once a day to maintain patency.

Oral PK study in PVC/CAC double-intubated rats Animals were fasted overnight (n=3) and administered via oral gavage (10 mg/kg, 10 mL/kg). Blood samples (60 μL) were collected from portal vein catheter and carotid artery catheter at 0.083, 0.25, 0.5, 1, 2, 4, 7, and 24h. All blood samples were transferred to microcentrifuge tubes containing 2 μL of K ₂ EDTA (0.5 M) as anticoagulant and placed on wet ice. Subsequently, to obtain plasma, a blood sample will be processed by centrifugation at about 4°C, and 3000 g will be collected within half an hour. Plasma samples will be stored in polypropylene test tubes, quickly frozen on dry ice and stored at -70±10°C until LC/MS/MS analysis.

Detect and analyze the pharmacokinetic parameters of prodrugs and active forms in portal vein samples and carotid artery samples (mean ± SD, n) after oral administration of prodrug (10 mg/kg) =3). The test results of Example 1 -B , 41-A , 41-B , 42-A and 43-A are summarized as follows.

表11.在門靜脈插管大鼠中經口投與實例43-A (10 mg/kg)之後，在門靜脈樣品及頸動脈樣品中實例43-A及其對應活性形式化合物43e-A之藥物動力學參數

表12.在門靜脈插管大鼠中經口投與實例1-B (10 mg/kg)之後，在門靜脈樣品及全身性樣品中實例1-B及其對應活性形式化合物1e-A之藥物動力學參數

表13.在門靜脈插管大鼠中經口投與實例42-A (10 mg/kg)之後，在門靜脈樣品及頸動脈樣品中實例42-A及其對應活性形式化合物41c-A之藥物動力學參數

表14.在門靜脈插管大鼠中經口投與實例41-B (10 mg/kg)之後，在門靜脈樣品及頸動脈樣品中實例41-B及其對應活性形式化合物41c-A之藥物動力學參數

Table 10. Pharmacokinetics of Example 41-A and its corresponding active form compound 41c-B in portal vein samples and carotid artery samples after oral administration of Example 41-A (10 mg/kg) in portal vein cannulated rats Academic parameters

Table 11. Pharmacokinetics of Example 43-A and its corresponding active form compound 43e-A in portal vein samples and carotid artery samples after oral administration of Example 43-A (10 mg/kg) in portal vein cannulated rats Academic parameters

Table 12. Pharmacokinetics of Example 1-B and its corresponding active form compound 1e-A in portal vein samples and systemic samples after oral administration of Example 1-B (10 mg/kg) in portal vein cannulated rats Academic parameters

Table 13. Pharmacokinetics of Example 42-A and its corresponding active form compound 41c-A in portal vein samples and carotid artery samples after oral administration of Example 42-A (10 mg/kg) in portal vein cannulated rats Academic parameters

Table 14. Pharmacokinetics of Example 41-B and its corresponding active form compound 41c-A in portal vein samples and carotid artery samples after oral administration of Example 41-B (10 mg/kg) in portal vein cannulated rats Academic parameters

Based on these findings, concluded that the major portion of converting a prodrug to the liver, rather than the intestinal system, because this system than in the AUC in the portal vein sampling AUC _active / AUC _total sampling carotid high _active / AUC _total.

Figure 1 : The combination of the prodrug form of the compound of the present invention (Compound 41-A) and sorafenib produces 2 tumor-free mice in the iAST mouse model of hepatocellular carcinoma, and FIG. 1A: Compound 41-A And Sorafenib's synergistic effect on tumor burden (mice without tumor); Figure 1B: combined liver and tumor weight after treatment:

Figure 2 : PD-L1 expression on tumor cells in an iAST mouse model of hepatocellular carcinoma induced by treatment with the prodrug form of the compound of the present invention (Compound 41-A). Figure 2A: CD45+ total immune cell infiltration, Figure 2B: PD-L1 on CD45-, Figure 2C: CD11b lymphocytes, Figure 2D: CD11b+ bone marrow cells

Figure 3 : The triple combination of the prodrug form of the compound of the invention (Compound 41-A), sorafenib and anti-PD-1 results in increased median survival.

Figure 4 : Treatment with a prodrug form of the compound of the present invention (Compound 41-A) causes tumor stasis in a transplanted Hep55.1c mouse model of hepatocellular carcinoma.

Figure 5A : The combination of the prodrug form of the compound of the invention (Compound 41-A) and the anti-PD-1 antibody produces survival benefits in a Hep55.1c mouse model of hepatocellular carcinoma.

Figure 5B : Compound 42-A (6-amino-9-[(4-chlorophenyl)methyl]-N-ethyl-2[S(S)-ethylsulfonylimide acetyl]-N -Methyl-8- pendoxy-purine-7-carboxamide) alone and in combination with anti-PD-1 in vivo efficacy in hepatocellular carcinoma.

Figure 6 : Treatment with the active form of the compounds of the invention does not induce enhanced tumor cell proliferation in cell lines derived from hepatocellular carcinoma and cholangiocarcinoma. Figure 6A: Compound 41c-B, Figure 6B: Compound 41c-A

Figure 7 : 7A and 7B: After treatment with the active form of the compound of the present invention ( compound 41c-B ), the factors released in the peripheral blood cause the inhibition of the proliferation of tumor cell lines. Figure 7A: Cell lines Hep3B, SNU449, HLF, JHH2, Huh7, OZ, JHH1, HepG2, Figure 7B: Cell lines JHH4, HLE, JHH6, JHH5, SkHep1, EGI1. 7C: Compound of the present invention ( Compound 41c-A ) After the active form of treatment, the factors released in the peripheral blood inhibit the proliferation of tumor cell lines.

Figure 8 : Single crystal X-ray diffraction of Example 41-B.

Figure 9 : Single crystal X-ray diffraction of Example 42-A. Figure 10 : Single crystal X-ray diffraction of Example 43-B.

Claims (34)

A compound of formula (I),

, Or a pharmaceutically acceptable salt, enantiomer, or diastereomer, wherein R ¹ is C _1-6 alkyl; R ² is benzyl, which is unsubstituted or , Two or three substituents independently selected from halogen and C _1-6 alkyl substituents; 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 NCOOC _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 alkylcarbonyl (C _1-6 alkyl) amine C _1-6 alkyl or pyrrolidinyl Amidomethyloxy C _1-6 alkyl; or R ⁴ and R ⁵ together with the nitrogen to which they are attached form a heterocyclic group; it is used in the treatment or prevention of liver cancer; its limitation is that it does not include 6-amino- 9-benzyl-2-(propylsulfonyliminamide)-7-(pyrrolidin-1-carbonyl)purin-8-one; 6-amino-9-benzyl-7-(piperidin- 1-carbonyl)-2-(propylsulfonylimideamide)purin-8-one; 6-amino-9-benzyl-7-(morpholin-4-carbonyl)-2-(propylsulfonate Amidimide)purine-8-one; 6-amino-9-benzyl-7-(3,3-dimethylpyrrolidin-1-carbonyl)-2-(propylsulfonylimideamide) Group) purine-8-one; 1-[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide)purine-7-carbonyl]pyrrolidine-2- Ethyl formate; 6-amino-7-(2-azaspiro[3.3]heptane-2-carbonyl)-9-benzyl-2-(propylsulfonylimide)purin-8-one ; 6-amino-9-benzyl-7-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-2-(propylsulfonylamidoimido)purine-8 -Ketone; 6-amino-9-benzyl-7-(3,3-difluoropyrrolidin-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; 6- Amino-9-benzyl-7-(3-fluoro-3-methyl-pyrrolidine-1-carbonyl)-2-(propylsulfonylimide)purin-8-one; and its enantiomers Isomers or diastereomers. If the compound of claim 1 or its pharmaceutically acceptable salt, enantiomer or diastereomer, wherein R ¹ is C _1-6 alkyl; R ² is benzyl, the benzyl is not Substituted or substituted by halogen or C _1-6 alkyl; R ³ is azetidinyl; piperazinyl substituted by C _1-6 alkyl; piperidinyl substituted by piperidinyl; pyrrolidinyl; Or -NR ⁴ R ⁵ , wherein R ⁴ is C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl; R ⁵ is (C _1-6 alkyl) ₂ NCOOC _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 (benzene Group) 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} alkylcarbonyl (C _1-6 alkyl) amine C _1-6 alkyl or pyrrolidinyl amine methyloxy C _1-6 alkyl. If the compound of claim 1 or 2 or its pharmaceutically acceptable salt, enantiomer or diastereomer, wherein R ¹ is ethyl or propyl; R ² is benzyl, bromobenzyl , Chlorobenzyl, fluorobenzyl or methylbenzyl; R ³ is azetidinyl; 4-methylpiperazinyl; piperidinyl piperidinyl; pyrrolidinyl; or -NR ⁴ R ⁵ , where R ⁴ is methyl, ethyl, propyl or methoxyethyl; R ⁵ is acetyl(methyl)aminoethyl, butyl, butyl(methyl)aminomethyloxyethyl, Diethylamine methyloxyethyl, ethoxycarbonyl (methyl)aminoethyl, ethoxycarbonylethyl, ethoxycarbonyl isobutyl, ethoxycarbonyl isopentyl, ethoxy Carbonylcarbonylmethyl, ethoxycarbonyloxyethyl, ethoxycarbonyl (phenyl) ethyl, ethyl, isobutyl, isopropoxycarbonyl isopentyl, isopropoxycarbonyl (phenyl) Ethyl, isopropyl, methoxycarbonyl (methyl)aminoethyl, methoxyethyl, methoxypropyl, propyl, propyl (methyl)aminomethyloxyethyl, Pyrrolidinylamine methyloxyethyl, third butoxycarbonyl (methyl)aminoethyl, third butoxycarbonyl ethyl, third butoxycarbonyl isopentyl or third butoxy Carbonyl (phenyl) ethyl. The compound of claim 3 or its pharmaceutically acceptable salt, enantiomer or diastereomer, wherein R ³ is azetidinyl, 4-methylpiperazinyl, piperidinyl Piperidinyl, pyrrolidinyl, acetyl(methyl)aminoethyl(methyl)amino, bis(methoxyethyl)amino, butyl(ethyl)amino, butyl(methyl Group) amine group, butyl (methyl) amine, methyl oxyethyl (methyl) amine group, diethyl amine, methyl oxy ethyl (methyl) amine group, ethoxycarbonyl group (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, ethylpropoxycarbonylisopentyl(methyl)amino, isopropoxycarbonyl(phenyl)ethyl(methyl)amino , Isopropyl (methyl) amino, methoxycarbonyl (methyl) amino ethyl (methyl) amino, methoxy ethyl (ethyl) amino, methoxy ethyl (methyl ) Amino, methoxyethyl (propyl) amine, methoxypropyl (methyl) amine, propyl (ethyl) amine, propyl (methyl) amine, propyl (methyl Group) amine methyloxyethyl (methyl) amino group, pyrrolidinyl amine methyl oxyethyl (methyl) amino group, third butoxycarbonyl (methyl) amino ethyl group ( Methyl)amino, third butoxycarbonyl ethyl (methyl) amino, third butoxycarbonyl isopentyl (methyl) amino or third butoxycarbonyl (phenyl) ethyl ( Methyl) amine group. A compound as claimed in claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein R ¹ is ethyl. A compound as claimed in claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein R ² is benzyl substituted with halogen or C _1-6 alkyl. If the compound of claim 1 or 2 or its pharmaceutically acceptable salt, enantiomer or diastereomer, wherein R ² is bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl . The compound according to claim 7 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein R ² is bromobenzyl, chlorobenzyl or fluorobenzyl. If the compound of claim 1 or 2 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein R ³ is -NR ⁴ R ⁵ , wherein R ⁴ is C _1-6 alkyl Radical, R ⁵ is C _1-6 alkyl. The compound of claim 9 or its pharmaceutically acceptable salt, enantiomer or diastereomer, wherein R ³ is propyl(methyl)amino or ethyl(methyl)amino . If the compound of claim 1 or 2 or its pharmaceutically acceptable salt, enantiomer or diastereomer, wherein R ¹ is C _1-6 alkyl; R ² is benzyl, the benzyl The group 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 as claimed in claim 11 or its pharmaceutically acceptable salt, enantiomer or diastereomer, wherein R ¹ is ethyl; R ² is methylbenzyl, bromobenzyl, chlorobenzyl Or fluorobenzyl; R ³ is propyl (methyl) amine or ethyl (methyl) amine. A compound or its pharmaceutically acceptable salt, enantiomer or diastereomer, which is used for the treatment or prevention of liver cancer and is selected from: 6-amino-9-benzyl-N- Methyl-8-oxo-N-propyl-2-(propylsulfonylimide)purine-7-methylamide; 6-amino-9-benzyl- N- (2-methyl Oxyethyl) -N -methyl-8-oxo-2-(propylsulfonylimide)purine-7-methylamide; 6-amino-9-benzyl- N -ethyl Yl-8-pendoxy- N -propyl-2-(propylsulfonylimide)purine-7-formamide; 6-amino-9-benzyl-7-[4-(1 -Piperidinyl)piperidin-1-carbonyl]-2-(propylsulfonylimide)purin-8-one; 6-amino-9-benzyl- N -ethyl- N-( 2 -Methoxyethyl)-8- pendant-2-(propylsulfonylimide) purine-7-methylamide; 6-amino-9-benzyl- N -butyl- N -Ethyl-8-oxo-2-(propylsulfonylimide acetyl) purine-7-methylamide; 6-amino-9-benzyl- N- (2-methoxyethyl )-8-Penoxy- N -propyl-2-(propylsulfonylimide) purine-7-methylamide; 6-amino-9-benzyl- N,N -bis(2 -Methoxyethyl)-8- pendant-2-(propylsulfonylimide)purine-7-formamide; 6-amino-7-(azetidine-1- Carbonyl)-9-benzyl-2-(propylsulfonylimide)purin-8-one; 6-amino-9-benzyl- N -isopropyl- N -methyl-8-side Oxo-2-(propylsulfonylimide) purine-7-carboxamide; 6-amino-9-benzyl-7-(4-methylpiperazine-1-carbonyl)-2- (Propylsulfonylimide) purin-8-one; 6-amino-9-benzyl- N- (3-methoxypropyl) -N -methyl-8-oxo-2 -(Propylsulfonylimide)purine-7-methylamide; 6-amino-9-benzyl- N -isobutyl- N -methyl-8-oxo-2-(propylene Sulfamoylimidamide)purine-7-carboxamide; 2-[[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide acetyl)purine- 7-carbonyl]-methyl-amino] ethyl acetate; 3-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7 -Carbonyl]-methyl-amino] ethyl propionate; 3-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide)purine-7 -Carbonyl]-methyl-amino] propionic acid third butyl ester; (2 S )-2-[[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonamide Aminyl)purine-7-carbonyl]-methyl-amino] ethyl propionate; (2 S )-2-[[6-amino-9-benzyl-8-oxo-2-( (Propylsulfonylimide) purine-7 -Carbonyl]-methyl-amino]-4-methyl-valeric acid third butyl ester; (2 S )-2-[[6-amino-9-benzyl-8-oxo-2- (Propylsulfonylimide) purine-7-carbonyl]-methyl-amino]-4-methyl-valeric acid isopropyl ester; (2 S )-2-[[6-amino-9 -Benzyl-8-oxo-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]-3-methyl-butyric acid ethyl ester; (2 S ) -2-[[6-Amino-9-benzyl-8- pendant-2-(propylsulfonylimido)purine-7-carbonyl]-methyl-amino]-4-methyl Ethyl-valerate; (2 S )-2-[[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide acetyl)purine-7-carbonyl] -Methyl-amino]-3-phenyl-propionic acid ethyl ester; (2 S )-2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonamide Imidyl)purine-7-carbonyl]-methyl-amino]-3-phenyl-propionic acid isopropyl ester; (2 S )-2-[[6-amino-9-benzyl-8 -Penoxy-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]-3-phenyl-propionic acid third butyl ester; N- [2-[B Acetyl(methyl)amino]ethyl]-6-amino-9-benzyl- N -methyl-8-oxo-2-(propylsulfonylimide)purine-7- Formamide; N- [2-[[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide acetyl)purine-7-carbonyl]-methyl-amine Yl]ethyl] -N -methyl-carbamic acid methyl ester; N- [2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide) Group) purine-7-carbonyl]-methyl-amino]ethyl] -N -methyl-aminocarbamic acid third butyl ester; N- [2-[[6-amino-9-benzyl-8 -Pentoxy-2-(propylsulfonylimide)purine-7-carbonyl]-methyl-amino]ethyl] -N -methyl-ethyl carbamate; N -butyl- N -Methyl-carbamic acid 2-[[6-amino-9-benzyl-8-pentoxy-2-(propylsulfonylimide acetyl)purine-7-carbonyl]-methyl- Amino] ethyl ester; pyrrolidine-1-carboxylic acid 2-[[6-amino-9-benzyl-8- pendant-2-(propylsulfonylimide acetyl)purine-7-carbonyl] -Methyl-amino]ethyl ester; N- methyl- N -propyl-carbamic acid 2-[[6-amino-9-benzyl-8-oxo-2-(propylsulfonamide Imidyl)purine-7-carbonyl]-methyl-amino]ethyl; N,N -diethylaminocarboxylic acid 2-[[6-amino-9-benzyl-8- pendant -2-(propylsulfonylimide acetyl)purine-7-carbonyl]-methyl-amino]ethyl; 2-[[6-amino-9-benzyl-8-oxo-carbonate carbonate] 2-(propylsulfonylimide)purine-7-carbonyl ]-Methyl-amino]ethyl ethyl; 6-amino-N-butyl-9-[(4-chlorophenyl)methyl]-N-methyl-8-oxo-2- [S(R)-propylsulfonylimide acetyl] purine-7-methylamide; 6-amino-N-butyl-9-[(4-chlorophenyl)methyl]-N-methyl 8-Penoxy-2-[S(S)-propylsulfonylimide]purine-7-methylamide; 6-amino-9-[(4-chlorophenyl)methyl ] -N -ethyl- N- methyl-8-oxo-2-(propylsulfonylimide)purine-7-methylamide; 6-amino- N -methyl-8- Pendant- N -propyl-2[S( S )-propylsulfonylimide]-9-(p-tolylmethyl)purine-7-methylamide; 6-amino- N- Methyl-8-oxo- N -propyl-2[S( R )-propylsulfonylimide]-9-(p-tolylmethyl)purine-7-methylamide; 6- Amino-2-[S (S) -propylsulfonyliminyl]-9-(p-tolylmethyl)-7-(pyrrolidin-1-carbonyl)purin-8-one; 6-amine Yl-2-[S( R )-propylsulfonylimide acetyl]-9-(p-tolylmethyl)-7-(pyrrolidin-1-carbonyl)purin-8-one; 6-amino -N -(2-methoxyethyl)- N- methyl-8-oxo-2-[S(S)-propylsulfonyliminyl]-9-(p-tolylmethyl ) Purine-7-methylamide; 6-amino- N- (2-methoxyethyl) -N- methyl-8-oxo-2-[S( R )-propylsulfonamide Aminyl]-9-(p-tolylmethyl)purine-7-carboxamide; 6-amino- N -ethyl- N -methyl-8-oxo-2-(propylsulfonamide Iminyl)-9-(p-tolylmethyl)purine-7-carboxamide; 6-amino- N -butyl- N -methyl-8-oxo-2-(propylsulfonate Acetamidoamide)-9-(p-tolylmethyl)purine-7-formamide; 6-amino-9-[(4-chlorophenyl)methyl]-2-[S( R ) -Ethylsulfonylimide] -N -methyl-8-pentoxy- N -propyl-purine-7-methylamide; 6-amino-9-[(4-chlorophenyl) Methyl]-2-[S( S )-ethylsulfonylimide]- N -methyl-8-oxo- N -propyl-purine-7-methylamide; 6-amino -9-[(4-chlorophenyl)methyl] -N -ethyl-2[S( S )-ethylsulfonylimide] -N -methyl-8-oxo-purine- 7-formamide; 6-amino-9-[(4-chlorophenyl)methyl]- N -ethyl-2-[S( R )-ethylsulfonylimide]- N- Methyl-8-oxo-purine-7-formamide; 6-amino-2-[S( S )-ethylsulfonylimide] -N -methyl- 8-Penoxy- N -propyl-9-(p-tolylmethyl)purine-7-carboxamide; 6-amino-2-[S( R )-ethylsulfonylimide] -N -methyl-8-oxo- N -propyl-9-(p-tolylmethyl)purine-7-carboxamide; 6-amino- N -ethyl-2[S(S) -Ethylsulfonylimide] -N -methyl-8-pentoxy-9-(p-tolylmethyl)purine-7-methylamide; 6-amino- N -ethyl-2 -[S( R )-ethylsulfonylimide]- N -methyl-8-oxo-9-(p-tolylmethyl)purine-7-methylamide; 6-amino- 2-[S( S )ethylsulfonylimide]-9-[(4-fluorophenyl)methyl]- N -methyl-8-oxo- N -propyl-purine-7 -Methamide; 6-amino-2-[S( R )ethylsulfonylimide]-9-[(4-fluorophenyl)methyl] -N -methyl-8-side oxygen -N -propyl-purine-7-methylamide; 6-amino- N -ethyl-2-(ethylsulfonylimideamide)-9-[(4-fluorophenyl)methyl ]- N -Methyl-8-oxo-purine-7-carboxamide; 6-amino- N -ethyl-2-[S( S )-(ethylsulfonylimide amide)] -9-[(4-fluorophenyl)methyl] -N -methyl-8-oxo-purine-7-carboxamide; 6-amino- N -ethyl-2-[S( R )-(Ethylsulfonylimide)]-9-[(4-fluorophenyl)methyl] -N -methyl-8-oxo-purine-7-methylamide; 6-amine Yl-9-[(4-bromophenyl)methyl]-2-(ethylsulfonylimide) -N- methyl-8-oxo- N -propyl-purine-7-methyl Acylamine; 6-amino-2-[S( R )-ethylsulfonylimide]-9-[(4-bromophenyl)methyl]- N -methyl-8-oxo -N -propyl-purine-7-carboxamide; 6-amino-2-[S( S )-ethylsulfonylimide]-9-[(4-bromophenyl)methyl] -N -methyl-8-oxo- N -propyl-purine-7-carboxamide; 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2 -(Ethylsulfonylimide) -N- methyl-8-oxo-purine-7-formamide; 6-amino-9-[(4-bromophenyl)methyl]- N -ethyl-2-[S( S )-(ethylsulfonylimide)]- N -methyl-8-oxo-purine-7-methylamide; and 6-amino- 9-[(4-Bromophenyl)methyl] -N -ethyl-2-[S( R )-(ethylsulfonylimide)]- N -methyl-8-oxo- Purine-7-formamide. The compound according to claim 13 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, which is selected from: 6-amino-9-[(4-chlorophenyl)methyl ]- N -ethyl-2[S( S )-ethylsulfonylimide]- N -methyl-8-oxo-purine-7-carboxamide; 6-amino-9- [(4-chlorophenyl)methyl] -N -ethyl-2-[S( R )-ethylsulfonylimide] -N -methyl-8-oxo-purine-7- Formamide; 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-(ethylsulfonylimide) -N -methyl-8-side oxygen -Purine-7-methylamide; 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2-[S( S )-(ethylsulfonylimideamide Group)]- N -methyl-8-oxo-purine-7-carboxamide; and 6-amino-9-[(4-bromophenyl)methyl] -N -ethyl-2- [S( R )-(Ethylsulfonylimide)]- N -methyl-8-oxo-purine-7-methylamide. The compound according to claim 13 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein the compound is 6-amino-9-[(4-chlorophenyl)methyl ] -N -ethyl-2[S( S )-ethylsulfonylimide] -N -methyl-8-oxo-purine-7-carboxamide. 2 and any of the compounds or pharmaceutically acceptable salts, enantiomers or diastereomers of any one of 13 to 15, wherein the liver cancer is hepatocellular carcinoma, liver cancer, cholangiocarcinoma, hepatoblastoma , Liver cancer, hepatic angiosarcoma or metastatic liver cancer. 2 and the compound or pharmaceutically acceptable salt, enantiomer or diastereomer of any one of 13 to 15, wherein the liver cancer is hepatocellular carcinoma. A pharmaceutical composition or medicament comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, an enantiomer or a diastereomer, and a therapeutically inert carrier, It is used for the treatment or prevention of liver cancer. Use of a compound as claimed in any one of claims 1 to 15 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof for the preparation of liver cancer treatment or prevention Pharmacy. Use of a compound as claimed in any one of claims 1 to 15 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, or a pharmaceutical composition or medicament as claimed in claim 18, It is used to prepare medicaments, This medicine is used a) Combination with antagonistic PD1 antibody or antagonistic PD-L1 antibody to treat or prevent liver cancer, or b) Treatment of patients with liver cancer in combination with antagonistic PD1 antibody or antagonistic PD-L1 antibody. Use of a compound as claimed in any one of claims 1 to 15 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof or a pharmaceutical composition or medicament as claimed in claim 18, It is used to prepare a medicament for the treatment or prevention of liver cancer The treatment is combined with antagonistic PD1 antibody or antagonistic PD-L1 antibody. Use according to claim 20 or 21, wherein the treatment is combined with an antagonistic PD1 antibody. The use according to claim 22, wherein the antagonistic PD1 antibody is nivolumab or peclizumab. The use according to claim 23, wherein the compound is 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl-2[S( S )-ethylsulfonylimide amide ] -N -methyl-8-oxo-purine-7-carboxamide. The use according to claim 22, wherein the antagonistic PD1 antibody comprises a heavy chain variable domain VH having an amino acid sequence SEQ ID NO: 5 and a light chain variable domain having an amino acid sequence SEQ ID NO: 6 VL. Use according to claim 20 or 21, wherein the treatment is combined with an antagonistic PD-L1 antibody. The use according to claim 26, wherein the antagonist PD-L1 antibody used in the combination therapy is attuzumab or devarizumab or avilumumab (in a preferred embodiment, att Zolimumab). The use as claimed in claim 27, wherein the compound is 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl-2[S (S )-ethylsulfonylimide amide ] -N -methyl-8-oxo-purine-7-carboxamide. The use according to claim 20 or 21, wherein the agent is additionally used in combination with an anti-angiogenic agent. The use according to claim 20 or 21, wherein the agent is additionally used in combination with an anti-angiogenic agent selected from the group consisting of: sorafenib: regofenib, sunitinib or bevacizumab (in a preferred embodiment In an example, the anti-angiogenic agent is sorafenib; in a preferred embodiment, the anti-angiogenic agent is bevacizumab). Use of a compound as claimed in any one of claims 1 to 15 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, or a pharmaceutical composition or medicament as claimed in claim 18, It is used to prepare medicament a) Combined with anti-angiogenic agents to treat or prevent liver cancer, or b) Treatment of patients with liver cancer in combination with anti-angiogenic agents. Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof or a pharmaceutical composition or medicament according to claim 18, which It is used to prepare medicament for the treatment or prevention of liver cancer, Wherein the treatment is combined with anti-angiogenic agents. The use according to claim 31 or 32, wherein the anti-angiogenic agent is selected from the group consisting of sorafenib, regofenib, sunitinib or bevacizumab (in a preferred embodiment, the anti-angiogenic agent Is sorafenib; in a preferred embodiment, the anti-angiogenic agent is bevacizumab). The use as claimed in claim 33, wherein the compound is 6-amino-9-[(4-chlorophenyl)methyl] -N -ethyl-2[S( S )-ethylsulfonylimideamide ] -N -methyl-8-oxo-purine-7-carboxamide.

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