阅读说明：本技术 用于治疗和预防肝癌的7-取代的磺亚氨酰基嘌呤酮化合物和衍生物 (7-substituted sulfoxy-purinone compounds and derivatives for the treatment and prevention of liver cancer ) 是由 T·珀施因格 C·里斯 沈宏 贠红英 S·霍弗斯 C·哈格 于 2019-02-26 设计创作，主要内容包括：本发明涉及式(I)的化合物,其中R<Sup>1</Sup>、R<Sup>2</Sup>和R<Sup>3</Sup>如本文所述,及它们的前药或药学上可接受的盐、其对映异构体或非对映异构体,用于(用以)肝癌的治疗和/或预防。<Image he="465" wi="644" file="DDA0002653921470000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to compounds of formula (I), wherein R 1 、R 2 And R 3 As described herein, and their prodrugs or pharmaceutically acceptable salts, enantiomers or diastereomers thereof, for use in the treatment and/or prevention of liver cancer.)

1. A compound of the formula (I),

wherein

R¹Is C_1-6An alkyl group;

R²is benzyl which is unsubstituted or substituted by one, two or three independently selected from halogen and C_1-6Alkyl substituent substitution;

R³is-NR⁴R⁵Wherein

R⁴Is C_1-6Alkyl or C_1-6Alkoxy radical C_1-6An alkyl group;

R⁵is (C)_1-6Alkyl radical)₂NCOOC_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (C) _1-6Alkyl) amino C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (phenyl) C_1-6Alkyl radical, C_1-6Alkoxycarbonyl radical C_1-6Alkyl radical, C_1-6Alkoxy carbonyl oxygen radical C_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Alkylcarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl or pyrrolidinylcarbamoyloxy C_1-6An alkyl group; or

R⁴And R⁵Together with the nitrogen to which they are attached form a heterocyclic group;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, for use in the treatment or prevention of liver cancer;

with the proviso that the following compounds are excluded:

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

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

6-amino-9-benzyl-7- (morpholine-4-carbonyl) -2- (propylsulfonimidoyl) purin-8-one;

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

1- [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] pyrrolidine-2-carboxylic acid ethyl ester;

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

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

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

6-amino-9-benzyl-7- (3-fluoro-3-methyl-pyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one;

and enantiomers or diastereomers thereof.

2. The compound for use according to claim 1, wherein

R¹Is C_1-6An alkyl group;

R²is benzyl which is unsubstituted or substituted by halogen or C_1-6Alkyl substitution;

R³is azetidinyl;

quilt C_1-6Alkyl-substituted piperazinyl;

piperidinyl substituted with piperidinyl;

a pyrrolidinyl group; or

-NR⁴R⁵Wherein

R⁴Is C_1-6Alkyl or C_1-6Alkoxy radical C_1-6An alkyl group;

R⁵is (C)_1-6Alkyl radical)₂NCOOC_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (phenyl) C_1-6Alkyl radical, C_1-6Alkoxycarbonyl radical C_1-6Alkyl radical, C_1-6Alkoxy carbonyl oxygen radical C_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Alkylcarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl or pyrrolidinylcarbamoyloxy C_1-6An alkyl group.

3. The compound for use according to claim 1 or 2, wherein

R¹Is ethyl or propyl;

R²is benzyl, bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl;

R³is azetidinyl;

4-methylpiperazinyl;

a piperidinyl group;

A pyrrolidinyl group; or

-NR⁴R⁵Wherein

R⁴Is methyl, ethyl, propyl or methoxyethyl;

R⁵is acetyl (methyl) aminoethyl, butyl (methyl) carbamoyloxyethyl, diethylcarbamoyloxyethyl, ethoxycarbonyl (methyl) aminoethyl, ethoxycarbonylethyl, ethoxycarbonylisobutyl, ethoxycarbonylisopentyl, ethoxycarbonylmethyl, ethoxycarbonyloxyethyl, ethoxycarbonyl (phenyl) ethyl, isobutyl, isopropoxycarbonylisoamyl, isopropoxycarbonyl (phenyl) ethyl, isopropyl, methoxycarbonyl (methyl) aminoethyl, methoxyethyl, methoxypropyl, propyl (methyl) carbamoyloxyethyl, pyrrolidinylcarbamoyloxyethyl, tert-butoxycarbonyl (methyl) aminoethyl, tert-butoxycarbonylethyl, tert-butoxycarbonylisopentyl, or tert-butoxycarbonyl (phenyl) ethyl.

4. The compound for use according to claim 3, wherein R³Is azetidinyl, 4-methylpiperazinyl, piperidinyl, pyrrolidinyl, acetyl (methyl) aminoethyl (methyl) amino,Bis (methoxyethyl) amino, butyl (ethyl) amino, butyl (methyl) carbamoyloxyethyl (methyl) amino, diethylcarbamoyloxyethyl (methyl) amino, ethoxycarbonyl (methyl) aminoethyl (methyl) amino, ethoxycarbonylethyl (methyl) amino, ethoxycarbonylisobutyl (methyl) amino, ethoxycarbonylisopentyl (methyl) amino, ethoxycarbonylmethyl (methyl) amino, ethoxycarbonyloxyethyl (methyl) amino, ethoxycarbonyl (phenyl) ethyl (methyl) amino, isobutyl (methyl) amino, isopropoxycarbonylisopentyl (methyl) amino, isopropoxycarbonyl (phenyl) ethyl (methyl) amino, isopropyl (methyl) amino, methoxycarbonyl (methyl) aminoethyl (methyl) amino, Methoxyethyl (ethyl) amino, methoxyethyl (methyl) amino, methoxyethyl (propyl) amino, methoxypropyl (methyl) amino, propyl (ethyl) amino, propyl (methyl) carbamoyloxyethyl (methyl) amino, pyrrolidinylcarbamoyloxyethyl (methyl) amino, tert-butoxycarbonyl (methyl) aminoethyl (methyl) amino, tert-butoxycarbonylethyl (methyl) amino, tert-butoxycarbonylisopentyl (methyl) amino, or tert-butoxycarbonyl (phenyl) ethyl (methyl) amino.

5. The compound for use according to any one of claims 1 to 4, wherein R¹Is ethyl.

6. The compound for use according to claim 1 or 2, wherein R²Is by halogen or C_1-6Alkyl-substituted benzyl.

7. The compound for use according to any one of claims 2 to 6, wherein R²Is bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl.

8. The compound for use according to claim 7, wherein R²Is bromobenzyl, chlorobenzyl or fluorobenzyl.

9. The compound for use according to claim 1 or 2, wherein R³is-NR⁴R⁵Wherein R is⁴Is C_1-6Alkyl radical, R⁵Is C_1-6An alkyl group.

10. The compound for use according to claim 9, wherein R³Is propyl (methyl) amino or ethyl (methyl) amino.

11. The compound for use according to any one of claims 1, 2, 6 and 9, wherein

R¹Is C_1-6An alkyl group;

R²is benzyl, said benzyl being substituted by halogen or C_1-6Alkyl substitution;

R³is-NR⁴R⁵Wherein R is⁴Is C_1-6Alkyl radical, R⁵Is C_1-6An alkyl group.

12. The compound for use according to claim 11, wherein

R¹Is an ethyl group;

R²is methylbenzyl, bromobenzyl, chlorobenzyl or fluorobenzyl;

R³is propyl (methyl) amino or ethyl (methyl) amino.

13. A compound for use in the treatment or prevention of liver cancer selected from:

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

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

6-amino-9-benzyl-N-ethyl-8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-7- [4- (1-piperidinyl) piperidine-1-carbonyl ] -2- (propylsulfonimidoyl) purin-8-one;

6-amino-9-benzyl-N-ethyl-N- (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-N-butyl-N-ethyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

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

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

6-amino-9-benzyl-7- (4-methylpiperazine-1-carbonyl) -2- (propylsulfoximine) purin-8-one;

6-amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

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

2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] acetic acid ethyl ester;

3- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] propanoic acid ethyl ester;

3- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] propionic acid tert-butyl ester;

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

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -4-methyl-pentanoic acid tert-butyl ester;

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -4-methyl-pentanoic acid isopropyl ester;

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

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

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -3-phenyl-propionic acid ethyl ester;

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

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -3-phenyl-propionic acid tert-butyl ester;

n- [2- [ acetyl (methyl) amino ] ethyl ] -6-amino-9-benzyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

n- [2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] ethyl ] -N-methyl-carbamic acid methyl ester;

n- [2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] ethyl ] -N-methyl-carbamic acid tert-butyl ester;

n- [2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] ethyl ] -N-methyl-carbamic acid ethyl ester;

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

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

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

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

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

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

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

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

6-amino-N-methyl-8-oxo-N-propyl-2 [ s(s) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N-methyl-8-oxo-N-propyl-2 [ s (r) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-2- [ S (S) -propylsulfoxy ] -9- (p-tolylmethyl) -7- (pyrrolidine-1-carbonyl) purin-8-one;

6-amino-2- [ S (R) -propylsulfoxy ] -9- (p-tolylmethyl) -7- (pyrrolidine-1-carbonyl) purin-8-one;

6-amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [ S (S) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [ S (R) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

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

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

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

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

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2- [ s (r) -ethylsulfoxy ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-2- [ s(s) -ethylsulfonylimidoyl ] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;

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

6-amino-N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N-ethyl-2- [ s (r) -ethylsulfoximidoyl ] -N-methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-2- [ s(s) ethylsulfonylimidoyl ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s (r) ethylsulfonylimidoyl ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-N-ethyl-2- (ethylsulfonylimidoyl) -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-N-ethyl-2- [ s (r) - (ethylsulfoximine) ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s (r) -ethylsulfonylimidoyl ] -9- [ (4-bromophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s(s) -ethylsulfonylimidoyl ] -9- [ (4-bromophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide; and

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s (r) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

14. The compound for use according to claim 13, selected from:

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2- [ s (r) -ethylsulfoxy ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide; and

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s (r) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

15. The compound for use according to claim 13, wherein said compound is 6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

16. The compound or pharmaceutically acceptable salt, enantiomer or diastereomer for use according to any one of claims 1 to 15, wherein the liver cancer is hepatocellular carcinoma, hepatoma, cholangiocarcinoma, hepatoblastoma, liver tumor, hepatic angiosarcoma or metastatic liver cancer.

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

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

19. Use of a compound according to any one of claims 1 to 15 in the manufacture of a medicament for the treatment or prevention of liver cancer.

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

21. A compound as defined in any one of claims 1 to 15, or a pharmaceutical composition or medicament comprising the compound, for use in therapy

a) Treating or preventing liver cancer in combination with antagonistic PD1 antibody or antagonistic PD-L1 antibody, or

b) Treating a patient having liver cancer in combination with an antagonistic PD1 antibody or an antagonistic PD-L1 antibody.

22. A compound as defined in any one of claims 1 to 15, or a pharmaceutical composition or medicament comprising the compound,

can be used for treating or preventing liver cancer,

wherein the treatment is in combination with an antagonistic PD1 antibody or an antagonistic PD-L1 antibody.

23. A compound as defined in any one of claims 1 to 15

The use in the preparation of a medicament for the treatment or prevention of liver cancer;

wherein the treatment is in combination with an antagonistic PD1 antibody or an antagonistic PD-L1 antibody.

24. The compound, composition, medicament, or use according to any one of claims 21 to 23, wherein the treatment is in combination with an antagonistic PD1 antibody.

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

26. The compound, composition, medicament, or use according to claim 25, wherein the compound is 6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximine ] -N-methyl-8-oxo-purine-7-carboxamide.

27. The compound, composition, medicament or use according to claim 24, wherein the antagonistic PD1 antibody comprises a heavy chain variable domain VH having the amino acid sequence of SEQ ID No. 5 and a light chain variable domain VL having the amino acid sequence of SEQ ID No. 6.

28. The compound, composition, medicament, or use according to claim 26, wherein the compound is 6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide.

29. The compound, composition, medicament, or use according to any one of claims 21 to 23, wherein the treatment is in combination with an antagonistic PD-L1 antibody.

30. The compound, composition, medicament or use according to claim 29, wherein the antagonistic PD-L1 antibody used in the combination therapy is astuzumab or bevacizumab or avizumab (in a preferred embodiment, astuzumab).

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

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

33. The compound, composition, medicament or use according to any one of claims 21 to 31, wherein the additional anti-angiogenic agent is selected from sorafenib, regorafenib, 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 combination therapy.

34. A compound as defined in any one of claims 1 to 15, or a pharmaceutical composition or medicament comprising the compound, for use in therapy

a) In combination with an anti-angiogenic agent for the treatment or prevention of liver cancer,

or

b) In combination with an anti-angiogenic agent, treat patients with liver cancer.

35. A compound as defined in any one of claims 1 to 15, or a pharmaceutical composition or medicament comprising the compound, for use in the treatment or prevention of liver cancer;

Wherein the treatment is in combination with an anti-angiogenic agent.

36. Use of a compound as defined in any one of claims 1 to 15 in the manufacture of a medicament for the treatment or prevention of liver cancer;

wherein the treatment is in combination with an anti-angiogenic agent.

37. The compound, composition, medicament or use according to any one of claims 34 to 36, wherein the anti-angiogenic agent is selected from sorafenib, regorafenib, 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 claim 37, wherein the compound is 6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide.

Background

Liver cancer is the fifth most common cancer. Approximately 75000 cases are diagnosed each year, and approximately 700000 people die from the disease, thus it becomes the third leading cause of cancer death worldwide (Ferlay et al, int.J. cancer 127:2893-2917 (2010)). In the united states, the incidence of primary liver Cancer is on the rise, and despite some progress in detecting and treating localized disease, the five-year survival rate of advanced liver Cancer is still well below 10% (American-Cancer-society.2012.Cancer Facts & regulations 2012.Atlanta: American Cancer Society).

Established treatments for liver cancer include surgical resection of the liver portion containing the tumor (partial hepatectomy), liver transplantation, Transcatheter Arterial Chemoembolization (TACE), in situ tumor destruction by various methods such as radiofrequency ablation (RFA) or cryosurgery, and administration of Sorafenib (Sorafenib). Treatment options for patients with advanced liver disease are limited. Thus, the medical need for effective treatment of liver cancer remains significantly unmet.

The invention relates to compounds of formula (I),

wherein R is¹To R³As will be described hereinafter in greater detail,

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Toll-like receptors (TLRs) detect a variety of conserved pathogen-associated molecular patterns (PAMPs). They play an important role in sensing invading pathogens and subsequently initiating innate immune responses. There are 10 known members of the TLR family in humans, which are type I transmembrane proteins characterized by an extracellular leucine-rich domain and a cytoplasmic tail containing a conserved Toll/Interleukin (IL) -1 receptor (TIR) domain. Within this family, TLR3, TLR7, TLR8 and TLR9 are located in endosomes.

TLR7 can be activated by binding to a specific small molecule ligand (i.e., TLR7 agonist) or its natural ligand (i.e., single stranded RNA, ssRNA). Upon binding of ssRNA to TLR7, it is believed that the receptor in its dimeric form undergoes a structural change, resulting in subsequent recruitment of the adaptor protein to its cytoplasmic domain, which includes the myeloid differentiation primary response gene 88(MyD 88). Upon initiation of the receptor signaling cascade via the MyD88 pathway, cytoplasmic transcription factors such as interferon regulatory factor 7(IRF-7) and nuclear factor κ B (NF- κ B) are activated. These transcription factors are then translocated to the nucleus and initiate transcription of various genes (e.g., IFN- α and other antiviral cytokine genes).

WO201772662 relates to TLR7 agonist-anti-HER 2 conjugates for the treatment of HER2 positive cancer. Hottex et al, Oncoimmunology 2012,227-. However, to date, no TLR7 agonist has been used systemically to treat cancer. Only the local TLR7 agonist imiquimod (imiquimod) is known to induce immune-mediated rejection of skin metastases in breast cancer patients (Adams s., Kozhaya l., Martiniuk f., Meng t.c., Chiriboga l., Liebes l., Hochman t., Shuman n., Axelrod d., Speyer j., et al.

Disclosure of Invention

The invention relates to a series of novel 6-amino-2-sulfimidoyl (sulfimidoyl) -9-substituted-7-purine-8-ketone compounds with Toll-like receptor agonistic activity and prodrugs thereof, which are used for treating or preventing (preventing) liver cancer.

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

The present invention provides a series of novel 6-amino-2-sulfoxy-acyl-9-substituted-7-purin-8-one compounds having Toll-like receptor agonistic activity and prodrugs thereof. The invention also provides the biological activity of such compounds to induce cytokine/chemokine release, increased SEAP levels, metabolic conversion of prodrugs to the parent compound in the presence of human hepatocytes by activation of Toll-like receptors, such as TLR7 receptors, and the use of such compounds and pharmaceutical compositions comprising them in the treatment or prevention of liver cancer. The present invention also provides a compound having excellent activity. In addition, the compounds of formula (I) also show good solubility and PK profiles.

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

R¹is C_1-6An alkyl group;

R²is benzyl which is unsubstituted or substituted by one, two or three independently selected from halogen and C_1-6Alkyl substituent substitution;

R³is-NR⁴R⁵Wherein

R⁴Is C_1-6Alkyl or C_1-6Alkoxy radical C_1-6An alkyl group;

R⁵is (C)_1-6Alkyl radical)₂NCOOC_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (phenyl) C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,C_1-6Alkoxycarbonyl radical C_1-6Alkyl radical, C_1-6Alkoxy carbonyl oxygen radical C_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Alkylcarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl or pyrrolidinylcarbamoyloxy C_1-6An alkyl group; or

R⁴And R⁵Together with the nitrogen to which they are attached form a heterocyclic group;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, for use in the treatment or prevention of liver cancer;

with the proviso that the following compounds are excluded:

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

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

6-amino-9-benzyl-7- (morpholine-4-carbonyl) -2- (propylsulfonimidoyl) purin-8-one;

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

1- [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] pyrrolidine-2-carboxylic acid ethyl ester;

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

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

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

6-amino-9-benzyl-7- (3-fluoro-3-methyl-pyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one;

and enantiomers or diastereomers thereof.

These prodrug compounds are particularly useful in the treatment of liver cancer as they are activated (converted to their active form) in the liver. They show valuable in vivo anti-tumor efficacy and in vitro anti-hepatoma cells (by activating peripheral blood cells and/or factors) in models of hepatoma cells (alone or in combination with anti-PD 1/PD1 antibodies or with anti-angiogenic agents).

The invention also relates to their use for the preparation of a medicament for the treatment or prevention of liver cancer, based on the compounds according to the invention for the treatment or prevention of liver cancer. Therefore, the compounds of formula (I) are useful for the treatment or prevention of liver cancer, in particular for the treatment or prevention of hepatocellular carcinoma, hepatoma, cholangiocarcinoma, hepatoblastoma, liver tumor, hepatic angiosarcoma or metastatic liver cancer.

Drawings

FIG. 1: the combination of the prodrug form of the compound of the invention (compound 41-a) and sorafenib resulted in two tumor-free mice in an iAST mouse model of hepatocellular carcinoma. FIG. 1A: synergistic effect of compound 41-a and sorafenib on tumor burden (tumor-free mice), fig. 1B: combined liver and tumor weight after treatment.

FIG. 2: treatment with the prodrug form of the compound of the invention (compound 41-a) induces expression of PD-L1 on tumor cells in an iAST mouse model of hepatocellular carcinoma. FIG. 2A: CD45+ total immune cell infiltration, fig. 2B: PD-L1 on CD45-, fig. 2C: CD11 b-lymphoid cells, fig. 2D: CD11b + myeloid cells

FIG. 3: the triple combination of prodrug form of the compounds of the present invention (compound 41-a), sorafenib, and anti-PD-1 resulted in increased median survival.

FIG. 4: treatment with the prodrug form of the compound of the present invention (compound 41-a) resulted in tumor arrest in the hep55.1c mouse model of transplantation of hepatocellular carcinoma.

FIG. 5A: the combination of a prodrug form of the compound of the invention (compound 41-a) and an anti-PD-1 antibody produced a survival benefit in a hep55.1c mouse model of hepatocellular carcinoma.

FIG. 5B: the in vivo efficacy of compound 42-a (6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide) alone or in combination with anti-PD-1 in hepatocellular carcinoma.

FIG. 6: treatment with active forms of the compounds of the present invention does not induce enhanced tumor cell proliferation in cell lines derived from hepatocellular carcinoma and cholangiocarcinoma. FIG. 6A: compound 41c-B, fig. 6B: compound 41 c-A.

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

FIG. 8: single crystal X-ray diffraction of example 41-B.

FIG. 9: single crystal X-ray diffraction of example 42-A.

FIG. 10: single crystal X-ray diffraction of example 43-B.

Detailed Description

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

The term "C_1-6Alkyl "denotes a saturated straight-chain or branched alkyl group containing 1 to 6, especially 1 to 4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. In particular "C_1-6Alkyl "groups are methyl, ethyl and n-propyl.

The term "C_1-6Alkoxy "is of the formula C_1-6alkyl-O-groups. C_1-6Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. In particular "C_1-6Alkoxy "is methoxy, ethoxy and isopropoxy. More particularly C_1-6Alkoxy is ethoxy.

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

The term "heterocyclyl" denotes a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 3 to 10 ring atoms comprising 1 to 5 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. In particular embodiments, heterocyclyl is a monovalent saturated monocyclic ring system of 4 to 7 ring atoms, comprising 1, 2 or 3 ring atoms selected from N, O and S Ring heteroatoms, the remaining ring atoms being carbon. Examples of monocyclic saturated heterocyclic groups are: aziridinyl (aziridinyl), oxetanyl, azetidinyl (azetidinyl), oxetanyl, pyrrolidinyl, dimethylpyrrolidinyl, ethoxycarbonylpyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, azepanyl (azepanyl), diazepanyl, homopiperazinyl or oxazepanyl (oxazepanyl). The monocyclic saturated heterocyclic group can also be independently selected from 1 to 3 of halogen and C_1-6Alkyl and C_1-6Substituent of alkoxycarbonyl. Examples of substituted monocyclic saturated heterocyclic groups are 4-methylpiperazinyl, dimethylpyrrolidinyl, ethoxycarbonylpyrrolidinyl, difluoropyrrolidinyl, 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, oxazabicyclo [3.3.1]Nonyl, thiazabicyclo [3.3.1 ]Nonyl, azaspiro [3.3]Heptyl and oxaza [3.3]A heptyl group. Examples of partially unsaturated heterocyclyl groups are: dihydrofuranyl, imidazolinyl, dihydrooxazolyl, tetrahydropyridinyl and dihydropyranyl.

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

The term "C_1-6Alkylcarbonyl "means a radical C_1-6alkyl-C (O) -, in which "C" is_1-6Alkyl "is as defined above. In particular "C_1-6The alkylcarbonyl "group is acetyl.

The term "enantiomer" refers to two stereoisomers of a compound that are mirror images of each other.

The term "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities.

The term "pharmaceutically acceptable salt" refers to salts that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid addition salts and base addition salts.

The term "pharmaceutically acceptable acid addition salts" denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and organic acids selected from the group consisting of aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic organic 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, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid (embonic acid), phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.

The term "pharmaceutically acceptable base addition salts" denotes those 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 the following salts: primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tris (hydroxymethyl) aminomethane, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine and polyamine resins.

The compounds of formula (I) and prodrugs thereof containing one or more chiral centers may exist as racemates, mixtures of diastereomers or as optically active single isomers. The racemates can be separated into enantiomers according to known methods. In particular, diastereoisomeric salts which can be separated by crystallization are formed from the racemic mixture by reaction with an optically active acid such as, for example, D-or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.

The term "prodrug" means a form or derivative of a compound that is metabolized in vivo, e.g., by a biological fluid or enzyme of the subject, into a pharmacologically active form of the compound following administration to produce a desired pharmacological effect. Prodrugs are described, for example, in Richard B.Silverman, "The Organic Chemistry of Drug Design and Drug Action", Academic Press, San Diego,2004, Chapter 8 prodrug and Drug delivery systems, page 497 558.

"pharmaceutically active metabolite" refers to a pharmaceutically active product produced by the metabolism of a particular compound or salt thereof in vivo. Most drugs are substrates for chemical reactions that may alter their physical properties and biological effects upon entry into the human body. These metabolic transformations, which generally affect the polarity of the compounds of the present invention, alter the way in which drugs are distributed and excreted from the body. However, in some cases, metabolism of the drug is necessary for therapeutic effect.

The term "therapeutically effective amount" means an amount of a compound or molecule of the invention that achieves, when administered to a subject: (i) treating or preventing a particular disease, condition, or disorder, (ii) alleviating, ameliorating, or eliminating one or more symptoms of the particular disease, condition, or disorder, or (iii) preventing or delaying the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The therapeutically effective amount will vary with the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

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

TLR7 agonists and prodrugs

The invention relates to a compound of formula (I),

wherein

R¹Is C_1-6An alkyl group;

R²is benzyl which is unsubstituted or substituted by one, two or three independently selected from halogen and C_1-6Alkyl substituent substitution;

R³is-NR⁴R⁵Wherein

R⁴Is C_1-6Alkyl or C_1-6Alkoxy radical C_1-6An alkyl group;

R⁵is (C)_1-6Alkyl radical)₂NCOOC_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (phenyl) C_1-6Alkyl radical, C_1-6Alkoxycarbonyl radical C_1-6Alkyl radical, C_1-6Alkoxy carbonyl oxygen radical C_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Alkylcarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl or pyrrolidinylcarbamoyloxy C_1-6An alkyl group; or

R⁴And R⁵Together with the nitrogen to which they are attached form a heterocyclic group;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, for use in the treatment or prevention of liver cancer;

with the proviso that the following compounds are excluded:

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

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

6-amino-9-benzyl-7- (morpholine-4-carbonyl) -2- (propylsulfonimidoyl) purin-8-one;

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

1- [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] pyrrolidine-2-carboxylic acid ethyl ester;

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

6-amino-9-benzyl-7- (2-oxo-6-azaspiro [3.3] heptane-6-carbonyl) -2- (propylsulfinyl) purin-8-one;

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

6-amino-9-benzyl-7- (3-fluoro-3-methyl-pyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one;

and enantiomers or diastereomers thereof.

Another embodiment of the invention is (ii) a compound of formula (I),

wherein

R¹Is C_1-6An alkyl group;

R²is benzyl which is unsubstituted or substituted by halogen or C_1-6Alkyl substitution;

R³is azetidinyl;

quilt C_1-6Alkyl-substituted piperazinyl;

piperidinyl substituted with piperidinyl;

a pyrrolidinyl group; or

-NR⁴R⁵Wherein

R⁴Is C_1-6Alkyl or C_1-6Alkoxy radical C_1-6An alkyl group;

R⁵is (C) _1-6Alkyl radical)₂NCOOC_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (phenyl) C_1-6Alkyl radical, C_1-6Alkoxycarbonyl radical C_1-6Alkyl radical, C_1-6Alkoxy carbonyl oxygen radical C_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Alkylcarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl or pyrrolidinylcarbamoyloxy C_1-6An alkyl group, a carboxyl group,

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, for use in the treatment or prevention of liver cancer.

Another embodiment of the present invention are (iii) the compounds of formula (I),

wherein

R¹Is ethyl or propyl;

R²is benzyl, bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl;

R³is azetidinyl;

4-methylpiperazinyl;

a piperidinyl group;

a pyrrolidinyl group; or

-NR⁴R⁵Wherein

R⁴Is methyl, ethyl, propyl or methoxyethyl;

R⁵is acetyl (methyl) aminoethyl, butyl (methyl) carbamoyloxyethyl, diethylcarbamoyloxyethyl, ethoxycarbonyl (methyl) aminoethyl, ethoxycarbonylethyl, ethoxycarbonylisobutyl, ethoxycarbonylisopentyl, ethoxycarbonylmethyl, ethoxycarbonyloxyethyl, ethoxycarbonyl (phenyl) ethyl, isobutyl, isopropoxycarbonylisoamyl, isopropoxycarbonyl (phenyl) ethyl, isopropyl, methoxycarbonyl (methyl) aminoethyl, methoxyethyl, methoxypropyl, propyl (methyl) carbamoyloxyethyl, pyrrolidinylcarbamoyloxyethyl, tert-butoxycarbonyl (methyl) aminoethyl, tert-butoxycarbonylethyl, tert-butoxycarbonylisoamyl or tert-butoxycarbonyl (phenyl) ethyl,

Or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, for use in the treatment or prevention of liver cancer.

Another embodiment of the present invention are (iii-1) compounds of formula (I),

wherein

R¹Is ethyl or propyl;

R²is benzylA radical, chlorobenzyl, fluorobenzyl or methylbenzyl radical;

R³is azetidinyl;

4-methylpiperazinyl;

a piperidinyl group;

a pyrrolidinyl group; or

-NR⁴R⁵Wherein

R⁴Is methyl, ethyl, propyl or methoxyethyl;

R⁵is acetyl (methyl) aminoethyl, butyl (methyl) carbamoyloxyethyl, diethylcarbamoyloxyethyl, ethoxycarbonyl (methyl) aminoethyl, ethoxycarbonylethyl, ethoxycarbonylisobutyl, ethoxycarbonylisopentyl, ethoxycarbonylmethyl, ethoxycarbonyloxyethyl, ethoxycarbonyl (phenyl) ethyl, isobutyl, isopropoxycarbonylisoamyl, isopropoxycarbonyl (phenyl) ethyl, isopropyl, methoxycarbonyl (methyl) aminoethyl, methoxyethyl, methoxypropyl, propyl (methyl) carbamoyloxyethyl, pyrrolidinylcarbamoyloxyethyl, tert-butoxycarbonyl (methyl) aminoethyl, tert-butoxycarbonylethyl, tert-butoxycarbonylisoamyl or tert-butoxycarbonyl (phenyl) ethyl,

Or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, for use in the treatment or prevention of liver cancer.

Another embodiment of the present invention are (iv) compounds of formula (I), wherein R³Is azetidinyl, 4-methylpiperazinyl, piperidinyl, pyrrolidinyl, acetyl (methyl) aminoethyl (methyl) amino, bis (methoxyethyl) amino, butyl (ethyl) amino, butyl (methyl) carbamoyloxyethyl (methyl) amino, diethylaminocarbamoyloxyethyl (methyl) amino, ethoxycarbonyl (methyl) aminoethyl (methyl) amino, ethoxycarbonylethyl (methyl) amino, ethoxycarbonylisobutyl (methyl) amino, ethoxycarbonylisopentyl (methyl) amino, ethoxycarbonylmethyl (methyl) amino, ethoxycarbonyloxyethyl (methyl) amino, ethoxycarbonyloxy (methyl) amino(phenyl) ethyl (methyl) amino, isobutyl (methyl) amino, isopropoxycarbonylisopentyl (methyl) amino, isopropoxycarbonyl (phenyl) ethyl (methyl) amino, isopropyl (methyl) amino, methoxycarbonyl (methyl) aminoethyl (methyl) amino, methoxyethyl (ethyl) amino, methoxyethyl (methyl) amino, methoxyethyl (propyl) amino, methoxypropyl (methyl) amino, propyl (ethyl) amino, propyl (methyl) carbamoyloxyethyl (methyl) amino, pyrrolidinylcarbamoyloxyethyl (methyl) amino, tert-butoxycarbonyl (methyl) aminoethyl (methyl) amino, tert-butoxycarbonylethyl (methyl) amino, tert-butoxycarbonylisoamyl (methyl) amino, or tert-butoxycarbonyl (phenyl) ethyl (methyl) amino;

Or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, for use in the treatment or prevention of liver cancer.

Another embodiment of the present invention are (v) compounds of formula (I), wherein R¹Is ethyl, and can be used for treating or preventing hepatocarcinoma.

Another embodiment of the present invention are (vi) compounds of formula (I), wherein R²Is by halogen or C_1-6Alkyl-substituted benzyl for the treatment or prevention of liver cancer.

Another embodiment of the present invention are (vii) the compounds of formula (I), wherein R²Is bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl, and can be used for treating or preventing hepatocarcinoma.

Another embodiment of the present invention are (vii-1) the compounds of formula (I), wherein R²Is chlorobenzyl, fluorobenzyl or methylbenzyl, and can be used for treating or preventing hepatocarcinoma.

Another embodiment of the present invention are (viii) the compounds of formula (I), wherein R²Is bromobenzyl, chlorobenzyl or fluorobenzyl, and can be used for treating or preventing hepatocarcinoma.

Another embodiment of the present invention are (viii-1) compounds of formula (I), wherein R²Is chlorobenzyl or fluorobenzyl, and can be used for treating or preventing hepatocarcinoma.

Another embodiment of the inventionIs (ix) a compound of formula (I) wherein R³is-NR⁴R⁵Wherein R is⁴Is C_1-6Alkyl radical, R ⁵Is C_1-6Alkyl for the treatment or prevention of liver cancer.

Another embodiment of the present invention are (x) compounds of formula (I), wherein R³Is propyl (methyl) amino or ethyl (methyl) amino, and can be used for treating or preventing hepatocarcinoma.

Another embodiment of the invention are (xi) compounds of formula (I),

wherein

R¹Is C_1-6An alkyl group;

R²is benzyl, said benzyl being substituted by halogen or C_1-6Alkyl substitution;

R³is-NR⁴R⁵Wherein R is⁴Is C_1-6Alkyl radical, R⁵Is C_1-6An alkyl group, a carboxyl group,

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, for use in the treatment or prevention of liver cancer.

Another embodiment of the invention are (xii) compounds of formula (I),

wherein

R¹Is an ethyl group;

R²is methylbenzyl, bromobenzyl, chlorobenzyl or fluorobenzyl;

R³is propyl (methyl) amino or ethyl (methyl) amino,

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, for use in the treatment or prevention of liver cancer.

Another embodiment of the present invention is (xii-1) a compound of formula (I),

wherein

R¹Is an ethyl group;

R²is methylbenzyl, chlorobenzyl or fluorobenzyl;

R³is propyl (methyl) amino or ethyl (methyl) amino,

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, for use in the treatment or prevention of liver cancer.

Another embodiment of the present invention is (xiii) a specific compound of formula (I) as follows:

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

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

6-amino-9-benzyl-N-ethyl-8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-7- [4- (1-piperidinyl) piperidine-1-carbonyl ] -2- (propylsulfonimidoyl) purin-8-one;

6-amino-9-benzyl-N-ethyl-N- (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-N-butyl-N-ethyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

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

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

6-amino-9-benzyl-7- (4-methylpiperazine-1-carbonyl) -2- (propylsulfoximine) purin-8-one;

6-amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

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

2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] acetic acid ethyl ester;

3- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] propanoic acid ethyl ester;

3- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] propionic acid tert-butyl ester;

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

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -4-methyl-pentanoic acid tert-butyl ester;

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -4-methyl-pentanoic acid isopropyl ester;

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

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

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -3-phenyl-propionic acid ethyl ester;

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

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -3-phenyl-propionic acid tert-butyl ester;

n- [2- [ acetyl (methyl) amino ] ethyl ] -6-amino-9-benzyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

n- [2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] ethyl ] -N-methyl-carbamic acid methyl ester;

n- [2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] ethyl ] -N-methyl-carbamic acid tert-butyl ester;

n- [2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] ethyl ] -N-methyl-carbamic acid ethyl ester;

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

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

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

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

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

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

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

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

6-amino-N-methyl-8-oxo-N-propyl-2 [ s(s) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N-methyl-8-oxo-N-propyl-2 [ s (r) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-2- [ S (S) -propylsulfoxy ] -9- (p-tolylmethyl) -7- (pyrrolidine-1-carbonyl) purin-8-one;

6-amino-2- [ S (R) -propylsulfoxy ] -9- (p-tolylmethyl) -7- (pyrrolidine-1-carbonyl) purin-8-one;

6-amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [ S (S) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [ S (R) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

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

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

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

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

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2- [ s (r) -ethylsulfoxy ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-2- [ s(s) -ethylsulfonylimidoyl ] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;

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

6-amino-N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N-ethyl-2- [ s (r) -ethylsulfoximidoyl ] -N-methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-2- [ s(s) ethylsulfonylimidoyl ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s (r) ethylsulfonylimidoyl ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-N-ethyl-2- (ethylsulfonylimidoyl) -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-N-ethyl-2- [ s (r) - (ethylsulfoximine) ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s (r) -ethylsulfonylimidoyl ] -9- [ (4-bromophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s(s) -ethylsulfonylimidoyl ] -9- [ (4-bromophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide; and

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

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, for use in the treatment or prevention of liver cancer.

Another embodiment of the invention is (xiv) a more specific compound of formula (I) as follows:

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

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

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

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2- [ s (r) -ethylsulfoxy ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-2- [ s(s) -ethylsulfonylimidoyl ] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;

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

6-amino-N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N-ethyl-2- [ s (r) -ethylsulfoximidoyl ] -N-methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-2- (ethylsulfonylimidoyl) -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s(s) ethylsulfonylimidoyl ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s (r) ethylsulfonylimidoyl ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-N-ethyl-2- (ethylsulfonylimidoyl) -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-N-ethyl-2- [ s (r) - (ethylsulfoximine) ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s (r) -ethylsulfonylimidoyl ] -9- [ (4-bromophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s(s) -ethylsulfonylimidoyl ] -9- [ (4-bromophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide; and

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s (r) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, for use in the treatment or prevention of liver cancer.

Another embodiment of the invention is (xv) more particular compounds of formula (I) as follows:

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2- [ s (r) -ethylsulfoxy ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide; and

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

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, for use in the treatment or prevention of liver cancer.

In some embodiments, the compounds of the present invention are tested and compared to the following reference compounds. Gilead, the most successful biopharmaceutical company focused on finding and developing TLR7 agonists for the treatment of liver disease, has the most advanced TLR7 agonist production line with lead compounds such as GS-9620 that have entered phase II studies. In the present application, Gilead compound GS-9620 disclosed as example 49 in US20100143301, compound S-2 and compound S-3 disclosed in JP1999193282 were all selected as reference compounds:

Synthesis of

The compounds of the present invention may be prepared by any conventional method. Suitable methods for synthesizing these compounds and their starting materials are provided in the schemes and examples below. Unless otherwise indicated, all substituents, in particular R¹To R¹⁴Are as defined above. In addition, unless otherwise expressly stated, all reactions, reaction conditions, abbreviations and symbols have the meaning well known to those of ordinary skill in the art of organic chemistry.

Scheme 1

The compound of formula VI is prepared by cyclization of isocyanate VII with amino malononitrile p-toluenesulfonate. 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. In a base such as K₂CO₃NaH or Cs₂CO₃With an alkyl halide to give the compound of formula IV. By using oxidizing agents such as m-chloroperoxybenzoic acid, urea-hydroperoxide adducts and HIO₄Oxidizing the compound of formula IV to produce the compound of formula III. The compound of formula II is obtained by imidizing the compound of formula III with an imidizing agent such as sodium azide in an acid (the acid is, for example, Eaton's reagent or PPA). The compound of formula I is obtained by reacting a compound of formula II with a carbamoyl chloride in the presence of a mixed base such as pyridine and triethylamine, pyridine and DIPEA, DMAP and triethylamine or DMAP and DIPEA.

Scheme 2

The compounds of formula II may also be prepared according to scheme 2.

By reacting a compound of formula XI with R²NH₂Reacting to prepare the compound of formula X. Reduction of compound X with a reducing agent such as zinc dust or iron powder in AcOH affords a compound of formula IX. Cyclizing the compound of formula IX with a cyclizing reagent such as phosgene, carbonyldiimidazole, diethyl carbonate and triphosgene to give the compound of formula VIII. By using PMBNH₂Treating the compound of formula VIII to prepare the compound of formula IVa. By using acids such as CF₃Deprotection of the compound of formula IVa with COOH, followed by oxidation with oxidizing agents such as m-chloroperoxybenzoic acid, urea-hydroperoxide adducts and HIO₄Oxidation to produce the compound of formula III. The compound of formula II is obtained by imidizing the compound of formula III with an imidizing agent such as sodium azide in an acid (e.g., eaton's reagent or PPA).

Also described is a process for preparing a compound of formula (I), which process comprises the following reaction:

reacting a compound of formula (II) with a carbamoyl chloride in the presence of a mixed base,

wherein R is¹And R²As 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 compounds of formula (I) for use in the treatment or prevention of liver cancer, when manufactured according to the above process, are also an object of the present invention.

Pharmaceutical compositions and administration

Another embodiment provides a pharmaceutical composition or medicament for the treatment or prevention of liver cancer comprising a compound of the invention and a therapeutically inert carrier, diluent or excipient, and methods of using the compounds of the invention for the preparation of such compositions and medicaments. In one embodiment, the compounds of formula (I) may be formulated by mixing at ambient temperature and at an appropriate pH and in the required purity with a physiologically acceptable carrier, i.e. a carrier that is non-toxic to the recipient at the dosages and concentrations applied to the galenic administration form. The pH of the formulation depends primarily on the particular use and concentration of the compound, but is preferably in any range from about 3 to about 8. In one embodiment, the compound of formula (I) is formulated in acetate buffer at pH 5. In another embodiment, the compounds of formula (I) are sterile. The compounds may be stored, for example, in the form of solid or amorphous compositions, in lyophilized formulations or in aqueous solution.

The compositions are formulated, administered and administered in a manner consistent with good medical practice. Factors to be considered in this context include the particular condition being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the condition, the site of delivery of the agent, the method of administration, the schedule of administration, and other factors known to the physician. An "effective amount" of the compound to be administered will be determined by such considerations and is the minimum amount required to activate the TLR7 receptor and result in the production of INF-alpha and other cytokines useful in, but not limited to, treating or preventing hepatitis b and/or c virus infected patients.

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

The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and if required for topical treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

The compounds of the invention may be administered in any convenient form of administration, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. Such compositions may contain ingredients conventional in pharmaceutical formulations, such as diluents, carriers, pH adjusting agents, sweeteners, fillers and other active agents.

Typical formulations are prepared by mixing a compound of the invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in the following: ansel, Howard c, et al,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia:Lippincott,Williams&wilkins, 2004; gennaro, Alfonso RRemington:The Science and Practice of Pharmacy.Philadelphia:Lippincott,Williams&Wilkins, 2000; and Rowe, Raymond C.Handbook of Pharmaceutical ExcipientsChicago, Pharmaceutical Press, 2005. The formulations may also contain one or more buffering agents, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents and other known additives that provide a pleasing appearance to the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or aid in the manufacture of the pharmaceutical product (i.e., a drug).

An example of a suitable oral dosage form is a tablet containing about 20mg to 1000mg of a compound of the invention admixed with about 30mg to 90mg of anhydrous lactose, about 5mg to 40mg of croscarmellose sodium, about 5mg to 30mg of polyvinylpyrrolidone (PVP) K30 and about 1mg to 10mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of PVP. The resulting composition may be dried, granulated, mixed with magnesium stearate and compressed into tablet form using conventional equipment. Examples of aerosol formulations may be prepared by dissolving, for example, from 20mg to 1000mg of a compound of the invention in a suitable buffer solution, for example phosphate buffer, if desired with the addition of a strong penetration agent such as a salt of sodium chloride. The solution may be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

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

In another embodiment, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or enantiomer or diastereomer thereof and a pharmaceutically acceptable carrier or excipient is included.

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

Indications and treatment methods

The present invention provides methods of treating or preventing liver cancer in a patient in need thereof. In some embodiments, the liver cancer is hepatocellular carcinoma, hepatoma, cholangiocarcinoma, hepatoblastoma, liver cancer, hepatic angiosarcoma, or metastatic liver cancer. In some embodiments, the liver cancer is a refractory cancer.

The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by uncontrolled cell growth/proliferation. Examples of liver cancers include, but are not limited to: hepatocellular carcinoma, hepatoma, hepatoblastoma, cholangiocarcinoma, hepatoblastoma, liver cancer, sarcoma, lymphoma, hepatic tumor and hepatic angiosarcoma. In various embodiments, the liver cancer (e.g., HCC) can be intermediate, advanced, or terminal. Liver cancer (e.g., HCC) can be metastatic or non-metastatic. Liver cancer (e.g., HCC) may or may not be resected. Liver cancer (e.g., HCC) may include a single tumor, multiple tumors, or poorly defined tumors with invasive growth patterns (into the portal or hepatic veins). Liver cancer (e.g., HCC) may include a fibrolamellar, pseudoglandular (adenoid), pleomorphic (giant cells), or clear cell pattern. Liver cancer (e.g., HCC) may include a highly differentiated form, and tumor cells, like hepatocytes, form trabeculae, spinal cord, and nests, and/or contain bile pigments in the cytoplasm. Liver cancer (e.g., HCC) may include poorly differentiated forms, and malignant epithelial cells are loose, polymorphic, anaplastic, and/or giant. In some embodiments, the liver cancer (e.g., HCC) is associated with hepatitis b, hepatitis c, cirrhosis, or type 2 diabetes. The terms "cell proliferative disease" and "proliferative disease" refer to a condition associated with some degree of abnormal cell proliferation. In one embodiment, the cell proliferative disease is cancer.

In one embodiment of the present invention, the compounds described herein (and pharmaceutical compositions and medicaments thereof) are used for preventing/preventing liver cancer in patients with a high risk of developing liver cancer.

In a preferred embodiment of the invention, the compounds described herein are particularly useful as prodrugs that are converted to the active drug primarily in the liver. One embodiment of the present invention is a prodrug compound for use in the treatment of liver cancer as described herein, wherein the compound is a prodrug of formula (I),

wherein

R¹Is C_1-6An alkyl group;

R²is benzyl which is unsubstituted or substituted by one, two or three independently selected from halogen and C_1-6Alkyl substituent substitution;

R³is-NR⁴R⁵Wherein

R⁴Is C_1-6Alkyl or C_1-6Alkoxy radical C_1-6An alkyl group;

R⁵is (C)_1-6Alkyl radical)₂NCOOC_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (phenyl) C_1-6Alkyl radical, C_1-6Alkoxycarbonyl radical C_1-6Alkyl radical, C_1-6Alkoxy carbonyl oxygen radical C_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Alkylcarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl or pyrrolidinylcarbamoyloxy C_1-6An alkyl group; or

R⁴And R⁵Together with the nitrogen to which they are attached form a heterocyclic group;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, for use in the treatment or prevention of liver cancer;

With the proviso that the following compounds are excluded:

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

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

6-amino-9-benzyl-7- (morpholine-4-carbonyl) -2- (propylsulfonimidoyl) purin-8-one;

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

1- [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] pyrrolidine-2-carboxylic acid ethyl ester;

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

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

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

6-amino-9-benzyl-7- (3-fluoro-3-methyl-pyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one;

and enantiomers or diastereomers thereof,

and wherein the prodrug compound of formula I is converted in the human liver to the active drug of formula II

Wherein R is¹And R²As defined above.

Exemplary conversions using human liver microsomes are shown in example 50. Example 61 also demonstrates that liver is the primary site for conversion of a prodrug to its active form.

A preferred embodiment of the present invention is a (prodrug) compound as described herein, wherein said compound is susceptible to conversion to its active form by the liver enzymes CYP2C9 and CYP2C 19. A preferred embodiment of the present invention is a (prodrug) compound as described herein, wherein the compound shows a conversion of ≥ 10nmol/min/mg protein in human hepatocytes into the active compound and ≤ 2nmol/min/mg protein in human intestinal epithelial cells into the active compound (as measured in a suitable assay using human hepatocytes and human intestinal epithelial cells).

Combination therapy

One aspect of the invention is the treatment (combination therapy) of patients with liver cancer with a compound of formula I in combination with anti-PD-L1/PD 1 axis therapy.

Surprisingly, we have found that the combination treatment of a compound of formula I and an anti-PD-L1/PD 1 axis therapy is very effective against liver tumors.

Accordingly, one aspect of the present invention is a compound of formula (I) (or a medicament or pharmaceutical composition comprising such a compound),

R¹is C_1-6An alkyl group;

R²Is benzyl which is unsubstituted or substituted by one, two or three independently selected from halogen and C_1-6Alkyl substituent substitution;

R³is-NR⁴R⁵Wherein

R⁴Is C_1-6Alkyl or C_1-6Alkoxy radical C_1-6An alkyl group;

R⁵is (C)_1-6Alkyl radical)₂NCOOC_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (phenyl) C_1-6Alkyl radical, C_1-6Alkoxycarbonyl radical C_1-6Alkyl radical, C_1-6Alkoxy carbonyl oxygen radical C_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Alkylcarbonyl (C)_1-6Alkyl) ammoniaRadical C_1-6Alkyl or pyrrolidinylcarbamoyloxy C_1-6An alkyl group; or

R⁴And R⁵Together with the nitrogen to which they are attached form a heterocyclic group;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof;

with the proviso that the following compounds are excluded:

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

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

6-amino-9-benzyl-7- (morpholine-4-carbonyl) -2- (propylsulfonimidoyl) purin-8-one;

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

1- [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] pyrrolidine-2-carboxylic acid ethyl ester;

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

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

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

6-amino-9-benzyl-7- (3-fluoro-3-methyl-pyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one;

and enantiomers or diastereomers thereof,

for

a) Treating liver cancer in combination with antagonistic PD1 or antagonistic PD-L1 antibody,

or

b) Treating a patient having liver cancer in combination with antagonistic PD1 or an antagonistic PD-L1 antibody.

One embodiment of the invention is a compound of formula (I) (or a medicament or pharmaceutical composition comprising the compound),

wherein

R¹Is C_1-6An alkyl group;

R²is benzyl which is unsubstituted or substituted by one, two or three independently selected from halogen and C_1-6Alkyl substituent substitution;

R³is-NR⁴R⁵Wherein

R⁴Is C_1-6Alkyl or C_1-6Alkoxy radical C_1-6An alkyl group;

R⁵is (C)_1-6Alkyl radical)₂NCOOC_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (phenyl) C_1-6Alkyl radical, C_1-6Alkoxycarbonyl radical C _1-6Alkyl radical, C_1-6Alkoxy carbonyl oxygen radical C_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Alkylcarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl or pyrrolidinylcarbamoyloxy C_1-6An alkyl group; or

R⁴And R⁵Together with the nitrogen to which they are attached form a heterocyclic group;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof;

with the proviso that the following compounds are excluded:

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

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

6-amino-9-benzyl-7- (morpholine-4-carbonyl) -2- (propylsulfonimidoyl) purin-8-one;

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

1- [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] pyrrolidine-2-carboxylic acid ethyl ester;

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

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

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

6-amino-9-benzyl-7- (3-fluoro-3-methyl-pyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one;

and enantiomers or diastereomers thereof,

for preventing or treating liver cancer

Wherein the antagonist PD1 or antagonist PD-L1 antibody is co-administered (wherein the treatment is in combination with the antagonist PD1 or antagonist PD-L1 antibody).

One embodiment of the present invention are compounds of formula (I)

Wherein

R¹Is C_1-6An alkyl group;

R²is benzyl which is unsubstituted or substituted by one, two or three independently selected from halogen and C_1-6Alkyl substituent substitution;

R³is-NR⁴R⁵Wherein

R⁴Is C_1-6Alkyl or C_1-6Alkoxy radical C_1-6An alkyl group;

R⁵is (C)_1-6Alkyl radical)₂NCOOC_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (phenyl) C_1-6Alkyl radical, C_1-6Alkoxycarbonyl radical C_1-6Alkyl radical、C_1-6Alkoxy carbonyl oxygen radical C_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Alkylcarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl or pyrrolidinylcarbamoyloxy C_1-6An alkyl group; or

R⁴And R⁵Together with the nitrogen to which they are attached form a heterocyclic group;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof;

with the proviso that the following compounds and their enantiomers or diastereomers are excluded:

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

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

6-amino-9-benzyl-7- (morpholine-4-carbonyl) -2- (propylsulfonimidoyl) purin-8-one;

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

1- [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] pyrrolidine-2-carboxylic acid ethyl ester;

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

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

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

6-amino-9-benzyl-7- (3-fluoro-3-methyl-pyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one,

the application in preparing the medicament for treating or preventing liver cancer,

wherein the antagonist PD1 or antagonist PD-L1 antibody is co-administered (wherein the treatment is in combination with the antagonist PD1 or antagonist PD-L1 antibody).

In another embodiment of the invention, the particular compound of formula (I) for use in combination therapy with antagonistic PD1 or antagonistic PD-L1 antibody is selected from the group consisting of:

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

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

6-amino-9-benzyl-N-ethyl-8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-7- [4- (1-piperidinyl) piperidine-1-carbonyl ] -2- (propylsulfonimidoyl) purin-8-one;

6-amino-9-benzyl-N-ethyl-N- (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-N-butyl-N-ethyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

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

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

6-amino-9-benzyl-7- (4-methylpiperazine-1-carbonyl) -2- (propylsulfoximine) purin-8-one;

6-amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

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

2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] acetic acid ethyl ester;

3- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] propanoic acid ethyl ester;

3- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] propionic acid tert-butyl ester;

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

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -4-methyl-pentanoic acid tert-butyl ester;

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -4-methyl-pentanoic acid isopropyl ester;

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

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

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -3-phenyl-propionic acid ethyl ester;

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

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -3-phenyl-propionic acid tert-butyl ester;

n- [2- [ acetyl (methyl) amino ] ethyl ] -6-amino-9-benzyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

n- [2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] ethyl ] -N-methyl-carbamic acid methyl ester;

n- [2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] ethyl ] -N-methyl-carbamic acid tert-butyl ester;

n- [2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] ethyl ] -N-methyl-carbamic acid ethyl ester;

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

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

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

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

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

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

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

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

6-amino-N-methyl-8-oxo-N-propyl-2 [ s(s) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N-methyl-8-oxo-N-propyl-2 [ s (r) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-2- [ S (S) -propylsulfoxy ] -9- (p-tolylmethyl) -7- (pyrrolidine-1-carbonyl) purin-8-one;

6-amino-2- [ S (R) -propylsulfoxy ] -9- (p-tolylmethyl) -7- (pyrrolidine-1-carbonyl) purin-8-one;

6-amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [ S (S) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [ S (R) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

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

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

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

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

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2- [ s (r) -ethylsulfoxy ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-2- [ s(s) -ethylsulfonylimidoyl ] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;

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

6-amino-N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N-ethyl-2- [ s (r) -ethylsulfoximidoyl ] -N-methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-2- [ s(s) ethylsulfonylimidoyl ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s (r) ethylsulfonylimidoyl ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-N-ethyl-2- (ethylsulfonylimidoyl) -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-N-ethyl-2- [ s (r) - (ethylsulfoximine) ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s (r) -ethylsulfonylimidoyl ] -9- [ (4-bromophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s(s) -ethylsulfonylimidoyl ] -9- [ (4-bromophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide; and

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s (r) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

In another embodiment of the invention, the particular compound of formula (I) for use in combination therapy with antagonistic PD1 or antagonistic PD-L1 antibody is selected from the group consisting of:

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2- [ s (r) -ethylsulfoxy ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide; and

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s (r) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide;

Or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

In another embodiment of the invention, the specific compound of formula (I) for use in combination therapy with antagonistic PD1 or antagonistic PD-L1 antibodies is: 6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ S (S) -ethylsulfoxy ] -N-methyl-8-oxo-purine-7-carboxamide.

In one embodiment, the co-administration (either combination therapy or combination therapy with … …) of the compound of formula I with antagonistic PD1 or antagonistic PD-L1 antibody is simultaneous. In one embodiment, the co-administration (either combination therapy or combination therapy with … …) of the compound of formula I with antagonistic PD1 or antagonistic PD-L1 antibody is sequential.

The terms "administered in combination with … …" or "co-administered", "co-administered with", "combination therapy", "treatment in combination with … …" or "combination therapy" refer to the administration of a compound of formula I as described herein and an antagonistic PD1 or PD-L1 antibody as described herein, e.g., as separate formulations/applications (or as one single formulation/application). Co-administration can be simultaneous or in any order, where there is a period of time during which both (or all) active agents exert their biological activities simultaneously. Co-administration is simultaneous or sequential (e.g., by continuous infusion intravenous (iv)). In one embodiment, the co-administration is simultaneous. In one embodiment, the co-administration is sequential. Co-administration is simultaneous or sequential (e.g., by continuous infusion intravenous (iv)).

It is understood that the antibody is administered to a patient in a "therapeutically effective amount" (or simply "effective amount") or "effective amount" which is the amount of the corresponding compound or combination that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.

The amount and time of co-administration will depend on the type (species, sex, age, weight, etc.) and condition of the patient being treated and the severity of the disease or condition being treated. The compound of formula I and the antibody are suitably co-administered to the patient at once or within a series of treatments, e.g. (on the same day or after the day).

PD-1/PD-L1/PD-L2 pathway:

the important negative co-stimulatory signals that regulate T-cell activation are provided by the programmed death-1 receptor (PD-1) (CD279) and its ligand binding partners PD-L1(B7-H1, CD 274; SEQ ID NO:13) and PD-L2(B7-DC, CD 273). The negative regulatory role of PD-1 was revealed by the PD-1 knockout (Pdcd1-/-), which is prone to autoimmunity. Nishimuraet al, Immunity 11:141-51 (1999); nishimuraet al, Science 291:319-22 (2001). PD-1 is associated with CD28 and CTLA-4, but lacks a membrane-proximal cysteine that allows for homodimerization. The cytoplasmic domain of PD-1 contains an immunoreceptor tyrosine-based inhibitory motif (ITIM, V/IxYxxL/V). PD-1 binds only to PD-L1 and PD-L2. Freeman et al, J.exp.Med.192:1-9 (2000); donget al, Nature Med.5: 1365-; latchmanet, 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 monocytes, and Dendritic Cells (DCs). PD-1 is expressed by activated human CD4+ and CD8+ T cells, B cells, and myeloid cells, but not by unstimulated human CD4+ and CD8+ T cells, B cells, and myeloid cells. This is in contrast to the more restricted expression of CD28 and CTLA-4. Nishimuraet al, int.Immunol.8:773-80 (1996); boettleret al, J.Virol.80:3532-40 (2006). At least 4 PD-1 variants have been cloned from activated human T cells, including transcripts lacking (i) exon 2, (ii) exon 3, (iii) exons 2 and 3, or (iv) exons 2 to 4. Nielseneet al, cell. Immunol.235:109-16 (2005). With the exception of PD-1ex3, all variants were expressed at similar levels in resting Peripheral Blood Mononuclear Cells (PBMCs) as full-length PD-1. Expression of all variants was significantly induced after activation of human T cells with anti-CD 3 and anti-CD 28. The PD-1ex3 variant lacks a transmembrane domain and, like soluble CTLA-4, plays an important role in autoimmunity. Uedaet al, Nature 423:506-11 (2003). The variant is enriched in synovial fluid and serum of patients with rheumatoid arthritis. Wanet al, J.Immunol.177:8844-50 (2006).

The expression patterns of the two PD-1 ligands differ. PD-L1 is constitutively expressed on mouse T and B cells, CD, 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 (e.g., cornea, lung, vascular epithelium, liver parenchymal cells, mesenchymal stem cells, pancreatic islets, placental trophoblasts, keratinocytes, etc.) [ Keir et al, annu. rev. immunol.26: 677-. Both type I and type II interferons IFN up-regulate PD-L1. Eppihimer et al, Microcirculation 9:133-45 (2002); schreiner et al, J.Neuropimunol.155: 172-82 (2004). PD-L1 expression was reduced in cell lines when MyD88, TRAF6 and MEK were inhibited. Liu et al, Blood 110: 296-. JAK2 is also involved in PD-L1 induction. Lee et al, FEBS Lett.580:755-62 (2006); liu et al, Blood 110: 296-. Loss or inhibition of phosphatase and tensin homolog (PTEN), a cellular phosphatase that modifies phosphatidylinositol 3-kinase (PI3K) and Akt signaling), increases post-transcriptional PD-L1 expression in cancer. Parsa et al, nat. med.13:84-88 (2007).

The expression of PD-L2 was more restricted than that of PD-L1. PD-L2 was induced to be expressed on DCs, macrophages and bone marrow mast cells. PD-L2 can also be expressed on about half to two thirds of resting peritoneal B1 cells, but not on conventional B2B cells. Zhong et al, eur.j.immunol.37:2405-10 (2007). PD-L2+ B1 cells bind phosphatidylcholine and may be important for innate immune responses against bacterial antigens. The induction of PD-L2 by IFN- γ depends in part on NF-. kappa.B. Liang et al, eur.j.immunol.33:2706-16 (2003). PD-L2 is also induced on monocytes and macrophages by GM-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 generally has a greater effect on cytokine production than on cell proliferation, with significant effects on IFN- γ, TNF- α and IL-2 production. PD-1 mediated inhibitory signaling also depends on the strength of TCR signaling, delivering greater inhibition at low levels of TCR stimulation. This reduction can be overcome by co-stimulation via CD28 [ Freeman et al, j.exp.med.192:1027-34(2000) ], or in the presence of IL-2 [ Carter et al, eur.j.immunol.32:634-43(2002) ].

There is increasing evidence that signaling through PD-L1 and PD-L2 may be bidirectional. That is, in addition to modifying TCR or BCR signaling, signaling can be transmitted back to cells expressing PD-L1 and PD-L2. While the treatment of dendritic cells with native human anti-PD-L2 antibody isolated from patients with Waldenstrom's macroglobulinemia was not found to upregulate MHC II or B7 co-stimulatory molecules, such cells do produce greater amounts of pro-inflammatory cytokines, particularly TNF-a 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) enhanced resistance to transplanted b16 melanoma and rapidly induced tumor-specific CTLs, radhakurishn et al, j.immunol.170:1830-38(2003), radhakurishn et al, Cancer res.64:4965-72(2004), Heckman et al, eur.j.immunol.37:1827-35(2007), (2) blocked progression of airway inflammatory disease in a mouse model of allergic asthma, radhakurishn et al, j.immunol.173:1360-65 (2004); radhakrishnan et al, J.allergy Clin.Immunol.116:668-74 (2005).

Additional evidence for reverse signaling into dendritic cells ("DCs") came from studies of bone marrow-derived DCs cultured with soluble PD-1 (PD-1 EC domain fused to Ig constant region- "s-PD-1"). Kuipers et al, Eur.J. Immunol.36:2472-82 (2006). The sPD-1 inhibits DC activation and increases IL-10 production in a reversible manner by administering anti-PD-1.

In addition, several studies have shown receptors for PD-L1 or PD-L2 that are independent of PD-1. B7.1 has been identified as a binding partner for PD-L1. Button et al, Immunity 27:111-22 (2007). Chemical cross-linking studies have shown that PD-L1 and B7.1 can interact through their IgV-like domains. B7.1: the PD-L1 interaction may induce an inhibitory signal into T cells. PD-L1 delivered inhibitory signals on CD4+ T cells through linkage of B7.1 or B7.1 on CD4+ T cells through linkage of PD-L1. T cells lacking CD28 and CTLA-4 showed reduced proliferation and cytokine production when stimulated by anti-CD 3+ B7.1 coated beads. In T cells lacking all of the receptors for B7.1 (i.e., CD28, CTLA-4, and PD-L1), T cell proliferation and cytokine production were no longer inhibited by anti-CD 3+ B7.1-coated beads. This indicates that B7.1 acts specifically on T cells by PD-L1 in the absence of CD28 and CTLA-4. Similarly, T cells lacking PD-1 showed reduced proliferation and cytokine production when stimulated in the presence of anti-CD 3+ PD-L1 coated beads, indicating an inhibitory effect of PD-L1 ligation on B7.1 on T cells. When T cells lack all known receptors for PD-L1 (i.e. no PD-1 and B7.1), T cell proliferation is no longer impaired by anti-CD 3+ PD-L1 coated beads. Thus, PD-L1 can exert an inhibitory effect on T cells via B7.1 or PD-1.

The direct interaction between B7.1 and PD-L1 suggests that the present understanding of co-stimulation is not yet complete and underestimates the importance of expression of these molecules on T cells. Studies with PD-L1-/-T cells indicate that PD-L1 on T cells can down-regulate T cell cytokine production. Latchman et al, Proc. Natl. Acad. Sci. USA 101:10691-96 (2004). Because both PD-L1 and B7.1 are expressed on T cells, B cells, DCs, and macrophages, there may be directed interactions between B7.1 and PD-L1 on these cell types. Furthermore, PD-L1 on non-hematopoietic cells can interact with B7.1 as well as PD-1 on T cells, raising the question of whether PD-L1 is involved in its regulation. One possible explanation for the inhibition of the B7.1 PD-L1 interaction is that T-cell PD-L1 may capture or isolate APCB7.1 from interaction with CD 28.

As a result, antagonism of signaling by PD-L1 (including blocking PD-L1 from interacting with PD-1, B7.1, or both, thereby preventing PD-L1 from sending negative co-stimulatory signals to T cells and other antigen presenting cells) may enhance immunity and tumor immunity in response to infection (e.g., acute and chronic).

An exemplary PD-L1 antagonist is the anti-PD-L1 antibody atelizumab (atezolizumab). Other antagonistic PD-L1 antibodies are either dutvacizumab (durvalumab) or avilumab (avelumab).

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

The term "human PD-L1" refers to the human protein PD-L1(SEQ ID NO:13, typically PD-1 signaling). As used herein, "binds to human PD-L1" or "specifically binds to human PD-L1" or "it binds to human PD-L1" or "anti-PD-L1 antibody" or "antagonistic PD-L1" means at 1.0X10^-8KD of mol/l or lower, in one embodiment at 1.0X10^-9An antibody that specifically binds to human PD-L1 antigen with an affinity having a KD value of mol/L or lower. Binding affinity is determined using standard binding assays, such as surface plasmon resonance techniques (GE-Healthcare Uppsala, Sweden). Thus, "antibody that binds to human PD-L1" as used herein refers to the antibody with KD 1.0x10^-8mol/l or less (1.0 x10 in one embodiment)^-8mol/l to 1.0x10^-13mol/l), in one embodiment with a KD of 1.0x10^-9mol/l or less (1.0 x10 in one embodiment)^-9mol/l to 1.0x10^-13mol/L) of the binding affinity specifically binds to the antibody of human PD-L1 antigen.

The term "human PD 1" refers to the human protein PD1(SEQ ID NO:14, typically PD-1 signaling). As used herein, "binding to human PD 1" or "specifically binding to human PD 1" or "binding to human PD 1" or "anti-PD 1 antibody" or "antagonistic PD 1" means with a KD value of 1.0 × 10^-8mol/l or less, and in one embodiment 1.0X 10^-9An antibody that specifically binds to human PD1 antigen with a binding affinity of mol/l or less. Binding affinity is determined using standard binding assays, such as surface plasmon resonance techniques (GE-Heathcare Uppsala, Sweden). Thus, "antibody that binds to human PD 1" as used herein refers to the antibody with KD 1.0 × 10^-8mol/l or less (1.0X 10 in one embodiment)^-8mol/l to 1.0X 10^-13mol/l), and in one embodiment has a KD of 1.0X 10^-9mol/l or less (1.0X 10 in one embodiment)^-9mol/l to 1.0X 10^-13mol/l) of the binding affinity specifically binds to an antibody of human PD1 antigen.

As used herein, "variable domain" (variable domain of a light chain (VL), variable domain of a heavy chain (VH)) means each of a pair of light and heavy chains involved in directly binding an antibody to an antigen. The domains of variable human light and heavy chains have the same general structure, and each domain comprises four Framework (FR) regions, the sequences of which are widely conserved, connected by three "hypervariable regions" (or complementarity determining regions, CDRs). The framework regions adopt a β -sheet conformation and the CDRs may form loops connecting the β -sheet structure, the CDRs in each chain being held in their three-dimensional structure by the framework regions and forming together with the CDRs from the other chain an antigen binding site. The antibody heavy and light chain CDR3 regions play a particularly important role in the binding specificity/affinity of the antibodies according to the invention and therefore provide a further object of the invention.

The term "constant region" as used in the present application denotes the sum of the domains of an antibody excluding the variable region. The constant region is not directly involved in antigen binding, but exhibits various effector functions. Depending on the amino acid sequence of its heavy chain constant region, antibodies fall into the following categories: IgA, IgD, IgE, IgG and IgM, some of which can be further divided into subclasses such as IgG1, IgG2, IgG3, and IgG4, IgA1 and IgA 2. The heavy chain constant regions corresponding to different classes of antibodies are referred to as α, γ, and μ, respectively. The light chain constant regions that can be found in all five antibody classes are called kappa (kappa) and lambda (lambda).

The term "constant region derived from human origin" or "human constant region" as used in the present application denotes the constant heavy chain region and/or constant light chain kappa or lambda region of a human antibody of the subclass IgG1, IgG2, IgG3 or IgG 4. Such constant regions are well known in the art, for example, as described by Kabat, E.A. et al, Sequences of Proteins of immunologicals interest, 5 th edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991) (see also, e.g., Johnson, G., and Wu, T.T., Nucleic Acids Res.28(2000) 214-. In the numbering application for positions and mutations, the EU numbering system (EU Index) according to Kabat, E.A. et al, Sequences of Proteins of immunological interest, fifth edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991) was used and referred to as "numbering of the EU Index according to Kabat".

In one embodiment, the antagonistic anti-PD 1 antibody that binds to human PD1 for use in the combination therapy described herein is nivolumab or pembrolizumab characterized by comprising the following VH and VL sequences described herein:

table:

in a preferred embodiment of the invention, the compound of formula I for use in the combination therapy described herein is selected from:

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2- [ s (r) -ethylsulfoxy ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide; or

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

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof; (in a preferred embodiment, 6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ S (S) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide);

The antagonistic PD1 antibody used in the combination therapy was nivolumab or pembrolizumab.

In one embodiment, the antagonistic anti-PD 1 antibody that binds to human PD1 used in the combination therapy described herein is a monospecific or multispecific antagonistic PD1 antibody and comprises the following heavy chain variable domain VH and light chain variable domain VL sequences described herein.

Table:

preferably, such anti-PD 1 antibodies based on the heavy chain variable domain VH and light chain variable domain VL sequences of PD1-0103-0312 comprise a heavy chain constant region of the IgG1 subtype (e.g., SEQ ID NO:16 or SEQ ID NO:17, eventually also comprising further mutations, see below for the bispecific embodiments) and a human kappa light chain constant region (e.g., SEQ ID NO: 15).

In one embodiment, such an anti-PD 1 antibody based on the heavy chain variable domain VH and light chain variable domain VL sequences of PD1-0103-0312 is, for example, bispecific and i) the bispecific antibody comprises a constant heavy chain region of the human IgG1 subclass comprising the mutations L234A, L235A and P329G (numbering according to the EU Index of Kabat); and wherein ii)) in the constant heavy chain region, one CH3 domain comprises the S354C and T366W mutations, while the other CH3 domain comprises the Y349C, T366S, L368A and Y407V mutations (numbering according to the EU Index of Kabat).

In another preferred embodiment of the invention, the compound of formula I for use in the combination therapy described herein is selected from:

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2- [ s (r) -ethylsulfoxy ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide; or

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s (r) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof; (in a preferred embodiment, 6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ S (S) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide);

the antagonistic PD1 antibody used in the combination therapy comprises a heavy chain variable domain VH having the amino acid sequence SEQ ID No. 5 and a 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 use in the combination therapy described herein is atelizumab or bevacizumab or avizumab ozogamicin characterized by comprising the following VH and VL sequences described herein:

table:

in another preferred embodiment of the invention, the compound of formula I for use in the combination therapy described herein is selected from:

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2- [ s (r) -ethylsulfoxy ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide; or

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

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof; (in a preferred embodiment, 6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ S (S) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide);

The antagonistic PD-L1 antibody used in the combination therapy is atlizumab or dulvacizumab or avizumab (in a preferred embodiment, atlizumab).

Another aspect of the invention is the treatment (combination therapy) of a patient suffering from liver cancer with a compound of formula I as described above in combination with an anti-angiogenic agent. The anti-angiogenic agent may be administered with the compound of formula I alone or in addition to the combination therapy of the compound of formula I and anti-PD-L1/PD 1 axis therapy. Anti-angiogenic agents as used herein include, but are not limited to, small molecule Tyrosine Kinase Inhibitors (TKIs) that competitively bind to intracellular receptor domains for VEGF, PDGF and other angiogenic growth factors, such as sorafenib (sorafenib, 4- {4- [3- (4-chloro-3-trifluoromethylphenyl) ureido ] ureido]Phenoxy } pyridine-2-carbonamide methylamide; nexavar^TM) Regorafenib (4- [4- ({ [ 4-chloro-3- (trifluoromethyl) phenyl)]Carbamoyl } 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-indol-3-ylidene) -methyl]-2, 4-dimethyl-1H-pyrrole-3-carboxamide; sutent ^TM) But also anti-VEGF or anti-VEGF receptor antibodies, e.g. bevacizumab (Avastin)^TM)。

In a preferred embodiment of the invention, the compound of formula I in the combination therapy with an anti-angiogenic agent as described herein is selected from the group consisting of:

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

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

6-amino-9-benzyl-N-ethyl-8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-7- [4- (1-piperidinyl) piperidine-1-carbonyl ] -2- (propylsulfonimidoyl) purin-8-one;

6-amino-9-benzyl-N-ethyl-N- (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-N-butyl-N-ethyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

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

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

6-amino-9-benzyl-7- (4-methylpiperazine-1-carbonyl) -2- (propylsulfoximine) purin-8-one;

6-amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

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

2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] acetic acid ethyl ester;

3- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] propanoic acid ethyl ester;

3- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] propionic acid tert-butyl ester;

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

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -4-methyl-pentanoic acid tert-butyl ester;

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -4-methyl-pentanoic acid isopropyl ester;

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

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

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -3-phenyl-propionic acid ethyl ester;

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

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -3-phenyl-propionic acid tert-butyl ester;

n- [2- [ acetyl (methyl) amino ] ethyl ] -6-amino-9-benzyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

n- [2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] ethyl ] -N-methyl-carbamic acid methyl ester;

n- [2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] ethyl ] -N-methyl-carbamic acid tert-butyl ester;

n- [2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] ethyl ] -N-methyl-carbamic acid ethyl ester;

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

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

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

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

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

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

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

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

6-amino-N-methyl-8-oxo-N-propyl-2 [ s(s) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N-methyl-8-oxo-N-propyl-2 [ s (r) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-2- [ S (S) -propylsulfoxy ] -9- (p-tolylmethyl) -7- (pyrrolidine-1-carbonyl) purin-8-one;

6-amino-2- [ S (R) -propylsulfoxy ] -9- (p-tolylmethyl) -7- (pyrrolidine-1-carbonyl) purin-8-one;

6-amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [ S (S) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [ S (R) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

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

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

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

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

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2- [ s (r) -ethylsulfoxy ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-2- [ s(s) -ethylsulfonylimidoyl ] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;

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

6-amino-N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N-ethyl-2- [ s (r) -ethylsulfoximidoyl ] -N-methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-2- [ s(s) ethylsulfonylimidoyl ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s (r) ethylsulfonylimidoyl ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-N-ethyl-2- (ethylsulfonylimidoyl) -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-N-ethyl-2- [ s (r) - (ethylsulfoximine) ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s (r) -ethylsulfonylimidoyl ] -9- [ (4-bromophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s(s) -ethylsulfonylimidoyl ] -9- [ (4-bromophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide; and

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

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof;

and the anti-angiogenic agent used in the combination therapy is sorafenib, regorafenib, sunitinib, or bevacizumab (preferably sorafenib or bevacizumab).

In a preferred embodiment of the invention, the compound of formula I for the treatment in combination with the anti-angiogenic agents described herein is selected from the group consisting of:

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2- [ s (r) -ethylsulfoxy ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide; or

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ S (R) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide.

Or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof; (in a preferred embodiment, 6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ S (S) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide);

the anti-angiogenic agent used in the combination therapy is sorafenib, regorafenib, sunitinib or bevacizumab (preferably sorafenib or bevacizumab)

In a preferred embodiment of the invention, the compound of formula I used in the combination therapy with antagonistic PD1 or an antagonistic PD-L1 antibody and an anti-angiogenic agent as described herein is selected from:

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

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

6-amino-9-benzyl-N-ethyl-8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-7- [4- (1-piperidinyl) piperidine-1-carbonyl ] -2- (propylsulfonimidoyl) purin-8-one;

6-amino-9-benzyl-N-ethyl-N- (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-N-butyl-N-ethyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

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

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

6-amino-9-benzyl-7- (4-methylpiperazine-1-carbonyl) -2- (propylsulfoximine) purin-8-one;

6-amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

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

2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] acetic acid ethyl ester;

3- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] propanoic acid ethyl ester;

3- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] propionic acid tert-butyl ester;

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

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -4-methyl-pentanoic acid tert-butyl ester;

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -4-methyl-pentanoic acid isopropyl ester;

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

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

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -3-phenyl-propionic acid ethyl ester;

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

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -3-phenyl-propionic acid tert-butyl ester;

n- [2- [ acetyl (methyl) amino ] ethyl ] -6-amino-9-benzyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

n- [2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] ethyl ] -N-methyl-carbamic acid methyl ester;

n- [2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] ethyl ] -N-methyl-carbamic acid tert-butyl ester;

n- [2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] ethyl ] -N-methyl-carbamic acid ethyl ester;

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

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

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

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

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

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

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

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

6-amino-N-methyl-8-oxo-N-propyl-2 [ s(s) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N-methyl-8-oxo-N-propyl-2 [ s (r) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-2- [ S (S) -propylsulfoxy ] -9- (p-tolylmethyl) -7- (pyrrolidine-1-carbonyl) purin-8-one;

6-amino-2- [ S (R) -propylsulfoxy ] -9- (p-tolylmethyl) -7- (pyrrolidine-1-carbonyl) purin-8-one;

6-amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [ S (S) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [ S (R) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

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

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

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

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

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2- [ s (r) -ethylsulfoxy ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-2- [ s(s) -ethylsulfonylimidoyl ] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;

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

6-amino-N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N-ethyl-2- [ s (r) -ethylsulfoximidoyl ] -N-methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-2- [ s(s) ethylsulfonylimidoyl ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s (r) ethylsulfonylimidoyl ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-N-ethyl-2- (ethylsulfonylimidoyl) -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-N-ethyl-2- [ s (r) - (ethylsulfoximine) ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s (r) -ethylsulfonylimidoyl ] -9- [ (4-bromophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s(s) -ethylsulfonylimidoyl ] -9- [ (4-bromophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide; and

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

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof;

i) the antagonistic PD1 antibody is nivolumab or pembrolizumab, or comprises a heavy chain variable domain VH of SEQ ID NO:5 and a light chain variable domain VL of SEQ ID NO: 6;

ii) the antagonistic PD-L1 antibody is atuzumab or bevacizumab or avizumab (in a preferred embodiment, atuzumab);

and the anti-angiogenic agent used in the combination therapy is sorafenib, regorafenib, sunitinib, or bevacizumab (preferably sorafenib or bevacizumab).

In a preferred embodiment of the invention, the compound of formula I used in the combination therapy with antagonistic PD1 or antagonistic PD-L1 antibody and an anti-angiogenic agent as described herein is selected from:

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2- [ s (r) -ethylsulfoxy ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide; or

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s (r) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof; (in a preferred embodiment, 6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ S (S) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide);

i) the antagonistic PD1 antibody is nivolumab or pembrolizumab, or comprises a heavy chain variable domain VH of SEQ ID NO:5 and a light chain variable domain VL of SEQ ID NO: 6;

ii) the antagonistic PD-L1 antibody is atuzumab or bevacizumab or avizumab (in a preferred embodiment, atuzumab);

and the anti-angiogenic agent used in the combination therapy is sorafenib, regorafenib, sunitinib, or bevacizumab (preferably sorafenib or bevacizumab).

Specific embodiments of the invention are included below:

1. A compound of the formula (I),

wherein

R¹Is C_1-6An alkyl group;

R²is benzyl which is unsubstituted or substituted by one, two or three independently selected from halogen and C_1-6Alkyl substituent substitution;

R³is-NR⁴R⁵Wherein

R⁴Is C_1-6Alkyl or C_1-6Alkoxy radical C_1-6An alkyl group;

R⁵is (C)_1-6Alkyl radical)₂NCOOC_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (phenyl) C_1-6Alkyl radical, C_1-6Alkoxycarbonyl radical C_1-6Alkyl radical, C_1-6Alkoxy carbonyl oxygen radical C_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Alkylcarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl or pyrrolidinylcarbamoyloxy C_1-6An alkyl group; or

R⁴And R⁵Together with the nitrogen to which they are attached form a heterocyclic group;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof; (or a pharmaceutical composition or medicament thereof);

for treating or preventing liver cancer;

with the proviso that the following compounds are excluded:

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

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

6-amino-9-benzyl-7- (morpholine-4-carbonyl) -2- (propylsulfonimidoyl) purin-8-one;

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

1- [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] pyrrolidine-2-carboxylic acid ethyl ester;

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

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

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

6-amino-9-benzyl-7- (3-fluoro-3-methyl-pyrrolidine-1-carbonyl) -2- (propylsulfonimidoyl) purin-8-one;

and enantiomers or diastereomers thereof.

2. The compound for use according to embodiment 1, wherein

R¹Is C_1-6An alkyl group;

R²is benzyl which is unsubstituted or substituted by halogen or C_1-6Alkyl substitution;

R³is azetidinyl;

quilt C_1-6Alkyl-substituted piperazinyl;

piperidinyl substituted with piperidinyl;

a pyrrolidinyl group; or

-NR⁴R⁵Wherein

R⁴Is C_1-6Alkyl or C_1-6Alkoxy radical C_1-6An alkyl group;

R⁵is (C)_1-6Alkyl radical)₂NCOOC_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl radical, C_1-6Alkoxycarbonyl (phenyl) C_1-6Alkyl radical, C_1-6Alkoxycarbonyl radical C_1-6Alkyl radical, C_1-6Alkoxy carbonyl oxygen radical C_1-6Alkyl radical, C _1-6Alkyl radical, C_1-6Alkylcarbonyl (C)_1-6Alkyl) amino C_1-6Alkyl or pyrrolidinylcarbamoyloxy C_1-6An alkyl group.

3. A compound for use according to embodiment 1 or 2, wherein

R¹Is ethyl or propyl;

R²is benzyl, bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl;

R³is azetidinyl;

4-methylpiperazinyl;

a piperidinyl group;

a pyrrolidinyl group; or

-NR⁴R⁵Wherein

R⁴Is methyl, ethyl, propyl or methoxyethyl;

R⁵is acetyl (methyl) aminoethyl, butyl (methyl) carbamoyloxyethyl, diethylcarbamoyloxyethyl, ethoxycarbonyl (methyl) aminoethyl, ethoxycarbonylethyl, ethoxycarbonylisobutyl, ethoxycarbonylisopentyl, ethoxycarbonylmethyl, ethoxycarbonyloxyethyl, ethoxycarbonyl (phenyl) ethyl, isobutyl, isopropoxycarbonylisoamyl, isopropoxycarbonyl (phenyl) ethyl, isopropyl, methoxycarbonyl (methyl) aminoethyl, methoxyethyl, methoxypropyl, propyl (methyl) carbamoyloxyethyl, pyrrolidinylcarbamoyloxyethyl, tert-butoxycarbonyl (methyl) aminoethyl, tert-butoxycarbonylethyl, tert-butoxycarbonylisopentyl, or tert-butoxycarbonyl (phenyl) ethyl.

4. A compound for use according to embodiment 3, wherein R³Is azetidinyl, 4-methylpiperazinyl, piperidinyl-piperidinyl, pyrrolidinyl, acetyl (methyl) aminoethyl (methyl) amino, bis (methoxyethyl) amino, butyl (ethyl) amino, butyl (methyl) carbamoyloxyethyl (methyl) amino, diethylaminocarbamoyloxyethyl (methyl) amino, ethoxycarbonyl: (A), (B), (C), (Methyl) aminoethyl (methyl) amino, ethoxycarbonylethyl (methyl) amino, ethoxycarbonylisobutyl (methyl) amino, ethoxycarbonylisopentyl (methyl) amino, ethoxycarbonylmethyl (methyl) amino, ethoxycarbonyloxyethyl (methyl) amino, ethoxycarbonyl (phenyl) ethyl (methyl) amino, isobutyl (methyl) amino, isopropoxycarbonylisopentyl (methyl) amino, isopropoxycarbonyl (phenyl) ethyl (methyl) amino, isopropyl (methyl) amino, methoxycarbonyl (methyl) aminoethyl (methyl) amino, methoxyethyl (ethyl) amino, methoxyethyl (methyl) amino, methoxyethyl (propyl) amino, methoxypropyl (methyl) amino, propyl (ethyl) amino, propyl (methyl) carbamoyloxyethyl (methyl) amino, Pyrrolidinylcarbamoyloxyethyl (methyl) amino, tert-butoxycarbonyl (methyl) aminoethyl (methyl) amino, tert-butoxycarbonylethyl (methyl) amino, tert-butoxycarbonylisopentyl (methyl) amino, or tert-butoxycarbonyl (phenyl) ethyl (methyl) amino.

5. A compound for use according to any one of embodiments 1 to 4, wherein R¹Is ethyl.

6. A compound for use according to embodiment 1 or 2, wherein R²Is by halogen or C_1-6Alkyl-substituted benzyl.

7. A compound for use according to any one of embodiments 2 to 6, wherein R²Is bromobenzyl, chlorobenzyl, fluorobenzyl or methylbenzyl.

8. A compound for use according to embodiment 7, wherein R²Is bromobenzyl, chlorobenzyl or fluorobenzyl.

9. A compound for use according to embodiment 1 or 2, wherein R³is-NR⁴R⁵Wherein R is⁴Is C_1-6Alkyl radical, R⁵Is C_1-6An alkyl group.

10. The compound for use according to embodiment 9, wherein R³Is propyl (methyl) amino or ethyl (methyl) amino.

11. A compound for use according to any one of embodiments 1, 2, 6 and 9, wherein

R¹Is C_1-6An alkyl group;

R²is benzyl, said benzyl being substituted by halogen or C_1-6Alkyl substitution;

R³is-NR⁴R⁵Wherein R is⁴Is C_1-6Alkyl radical, R⁵Is C_1-6An alkyl group.

12. A compound for use according to embodiment 11, wherein

R¹Is an ethyl group;

R²is methylbenzyl, bromobenzyl, chlorobenzyl or fluorobenzyl;

R³is propyl (methyl) amino or ethyl (methyl) amino.

13. A compound for use in the treatment or prevention of liver cancer selected from the group consisting of:

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

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

6-amino-9-benzyl-N-ethyl-8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-7- [4- (1-piperidinyl) piperidine-1-carbonyl ] -2- (propylsulfonimidoyl) purin-8-one;

6-amino-9-benzyl-N-ethyl-N- (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-N-butyl-N-ethyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-N- (2-methoxyethyl) -8-oxo-N-propyl-2- (propylsulfonimidoyl) purine-7-carboxamide;

6-amino-9-benzyl-N, N-bis (2-methoxyethyl) -8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

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

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

6-amino-9-benzyl-7- (4-methylpiperazine-1-carbonyl) -2- (propylsulfoximine) purin-8-one;

6-amino-9-benzyl-N- (3-methoxypropyl) -N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

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

2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] acetic acid ethyl ester;

3- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] propanoic acid ethyl ester;

3- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] propionic acid tert-butyl ester;

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

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -4-methyl-pentanoic acid tert-butyl ester;

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -4-methyl-pentanoic acid isopropyl ester;

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

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

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -3-phenyl-propionic acid ethyl ester;

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

(2S) -2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] -3-phenyl-propionic acid tert-butyl ester;

n- [2- [ acetyl (methyl) amino ] ethyl ] -6-amino-9-benzyl-N-methyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carboxamide;

n- [2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] ethyl ] -N-methyl-carbamic acid methyl ester;

n- [2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] ethyl ] -N-methyl-carbamic acid tert-butyl ester;

n- [2- [ [ 6-amino-9-benzyl-8-oxo-2- (propylsulfonimidoyl) purine-7-carbonyl ] -methyl-amino ] ethyl ] -N-methyl-carbamic acid ethyl ester;

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

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

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

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

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

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

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

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

6-amino-N-methyl-8-oxo-N-propyl-2 [ s(s) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N-methyl-8-oxo-N-propyl-2 [ s (r) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-2- [ S (S) -propylsulfoxy ] -9- (p-tolylmethyl) -7- (pyrrolidine-1-carbonyl) purin-8-one;

6-amino-2- [ S (R) -propylsulfoxy ] -9- (p-tolylmethyl) -7- (pyrrolidine-1-carbonyl) purin-8-one;

6-amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [ S (S) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N- (2-methoxyethyl) -N-methyl-8-oxo-2- [ S (R) -propylsulfoxy ] -9- (p-tolylmethyl) purine-7-carboxamide;

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

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

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

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

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2- [ s (r) -ethylsulfoxy ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-2- [ s(s) -ethylsulfonylimidoyl ] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-2- [ s (r) -ethylsulfonylimidoyl ] -N-methyl-8-oxo-N-propyl-9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-N-ethyl-2- [ s (r) -ethylsulfoximidoyl ] -N-methyl-8-oxo-9- (p-tolylmethyl) purine-7-carboxamide;

6-amino-2- [ s(s) ethylsulfonylimidoyl ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s (r) ethylsulfonylimidoyl ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-N-ethyl-2- (ethylsulfonylimidoyl) -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-N-ethyl-2- [ s (r) - (ethylsulfoximine) ] -9- [ (4-fluorophenyl) methyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s (r) -ethylsulfonylimidoyl ] -9- [ (4-bromophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-2- [ s(s) -ethylsulfonylimidoyl ] -9- [ (4-bromophenyl) methyl ] -N-methyl-8-oxo-N-propyl-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide; and

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ S (R) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide.

14. A compound according to embodiment 13, selected from:

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2- [ s (r) -ethylsulfoxy ] -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- (ethylsulfonylimidoyl) -N-methyl-8-oxo-purine-7-carboxamide;

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s(s) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide; and

6-amino-9- [ (4-bromophenyl) methyl ] -N-ethyl-2- [ s (r) - (ethylsulfoximine) ] -N-methyl-8-oxo-purine-7-carboxamide;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

14. The compound for use according to embodiment 13, wherein said compound is 6-amino-9- [ (4-chlorophenyl) methyl ] -N-ethyl-2 [ s(s) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide.

16. The compound or pharmaceutically acceptable salt, enantiomer or diastereomer for use according to any one of embodiments 1 to 15, wherein the liver cancer is hepatocellular carcinoma, hepatoma, cholangiocarcinoma, hepatoblastoma, liver tumor, hepatic angiosarcoma or metastatic liver cancer.

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

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

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

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

21. A compound as defined in any one of embodiments 1 to 15, or a pharmaceutical composition or medicament comprising such a compound, for use in therapy

a) Treating or preventing liver cancer in combination with antagonistic PD1 antibody or antagonistic PD-L1 antibody, or

b) Treating a patient having liver cancer in combination with an antagonistic PD1 antibody or an antagonistic PD-L1 antibody.

22. A compound as defined in any one of embodiments 1 to 15, or a pharmaceutical composition or medicament comprising the compound,

can be used for treating or preventing liver cancer,

wherein the treatment is in combination with an antagonistic PD1 antibody or an antagonistic PD-L1 antibody.

23. A compound as defined in any one of embodiments 1 to 15

The use in the preparation of a medicament for the treatment or prevention of liver cancer;

wherein the treatment is in combination with an antagonistic PD1 antibody or an antagonistic PD-L1 antibody.

24. A compound, composition, medicament, or use according to any one of embodiments 21 to 23, wherein the treatment is in combination with an antagonistic PD1 antibody.

25. The compound, composition, medicament, or use of embodiment 24, wherein the antagonistic PD1 antibody is nivolumab or pembrolizumab.

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) -ethylsulfoximine ] -N-methyl-8-oxo-purine-7-carboxamide.

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

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) -ethylsulfoximine ] -N-methyl-8-oxo-purine-7-carboxamide.

29. A compound, composition, medicament, or use according to any one of embodiments 21 to 23, wherein the treatment is in combination with an antagonistic PD-L1 antibody.

30. The compound, composition, medicament, or use according to embodiment 29, wherein the antagonistic PD-L1 antibody used in the combination therapy is attentizumab or bevacizumab or avizumab (in a preferred embodiment, attentizumab).

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) -ethylsulfoximine ] -N-methyl-8-oxo-purine-7-carboxamide.

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

34. A compound as defined in any one of embodiments 1 to 15, or a pharmaceutical composition or medicament comprising such a compound, for use in therapy

a) In combination with an anti-angiogenic agent for the treatment or prevention of liver cancer,

or

b) In combination with an anti-angiogenic agent, treat patients with liver cancer.

35. A compound as defined in any one of embodiments 1 to 15, or a pharmaceutical composition or medicament comprising the compound, for use in the treatment or prevention of liver cancer;

Wherein the treatment is in combination with an anti-angiogenic agent.

36. Use of a compound as defined in any one of embodiments 1 to 15 in the manufacture of a medicament for the treatment or prevention of liver cancer;

wherein the treatment is in combination with an anti-angiogenic agent.

37. The compound, composition, medicament or use according to any one of embodiments 34 to 36, wherein the anti-angiogenic agent is selected from sorafenib, regorafenib, 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) -ethylsulfoximidoyl ] -N-methyl-8-oxo-purine-7-carboxamide.

39. The invention as hereinbefore described.

Description of the amino acid sequence

1 heavy chain variable domain of anti-PD 1 antibody nivolumab

2 anti-PD 1 antibody nivolumab light chain variable domain

3 anti-PD 1 antibody pembrolizumab heavy chain variable domain

4 anti-PD 1 antibody pembrolizumab's light chain variable domain

5 anti-PD 1 antibody PD1-0103-0312 heavy chain variable domain

6 anti-PD 1 antibody PD1-0103-0312 light chain variable domain

7 anti-PD-L1 antibody Attributab heavy chain variable domain

8 anti-PD-L1 antibody Attuzumab light chain variable domain

Heavy chain variable domain of anti-PD-L1 antibody Duvacizumab of SEQ ID NO 9

10 anti-PD-L1 antibody Duvacizumab light chain variable domain

Heavy chain variable domain of anti-PD-L1 antibody Abelluzumab of SEQ ID NO 11

12 anti-PD-L1 antibody Ablumumab light chain variable domain of SEQ ID NO

Exemplary human PD-L1 of SEQ ID NO 13

14 exemplary human PD1 of SEQ ID NO

15 human kappa light chain constant region of SEQ ID NO

16 human heavy chain constant region from IgG1

SEQ ID NO 17 is derived from the human heavy chain constant region of IgG1 mutated at L234A, L235A, P329G.