WO2019008156A1

WO2019008156A1 - Inhibitors of the pd-1/pd-l1 protein/protein interaction

Info

Publication number: WO2019008156A1
Application number: PCT/EP2018/068419
Authority: WO
Inventors: Alexander Dömling
Original assignee: Rijksuniversiteit Groningen
Priority date: 2017-07-07
Filing date: 2018-07-06
Publication date: 2019-01-10

Abstract

The present invention provides novel compounds of formula (I) that are useful as inhibitors of the PD-1/PD-L1 protein/protein interaction. The compounds may be used in the treatment of cancer, infectious diseases and neurodegenerative diseases such as schizophrenia, Alzheimer, multiple sclerosis or Parkinson.

Description

Inhibitors of the PD-l/PD-Ll protein/protein interaction

The present invention provides novel compounds that are useful as inhibitors of the PD-l/PD-Ll protein/protein interaction.

The PD-l/PD-Ll axis is hijacked by viruses, bacteria and uncontrolled fast growing cells to suppress the immune surveillance. In cancer for example, the malignant cells express PD-L1 which bind to the PD1 receptor expressed on immune T-cells. Binding of PD-1 to PD-1L determines a downregulation of T-cell effector functions in cancer patients inhibiting the antitumor immune response and leading to T-cell exhaustion. In viral and infectious diseases a similar mechanism is used by viruses and bacteria to undermine the effective immune recognitions and answer.

Current medication directed towards the PD-l/PD-Ll axis includes monoclonal antibodies. These have shown impressive clinical results in the treatment of several types of tumours . Therapeutic antibodies however exhibit several disadvantages such as limited tissue and tumour penetration, very long half life time, lacking oral bioavailability, immunogenicity, and difficult and expensive production. The current PD-l/PD-Ll axis directed monoclonal antibodies lead to a tumour response only in a fraction of cases and tumour types. Recently small molecules have been described to bind to PD-L1 in WO 2015/160641 and WO 2015/034820. The compounds described therein, however, display a high lipophilicity (cLogP) .

A high cLogP is often associated with extensive metabolism, poor water solubility, fast excretion and toxicity and reduced target selectivity. Therefore PD-1/PD-L1 axis targeted drugs are needed which overcome the above disadvantages and which further lead to a high tumour response, are fast and efficient to produce and can penetrate tumour tissue and have favourable half-life times to be able to adequately react on drug induced immunological adverse side effects. These objects are solved by the compounds of the present invention.

The present invention provides compounds of formula (I) :

(I)

wherein

R¹ and R² are independently from each other a hydrogen atom, a Ci-6 alkyl group or a group of formula - CH₂-Ar or - CH₂ - CH₂ - R³R⁴ ; wherein

Ar is an optionally substituted phenyl group or an optionally substituted heteroaryl group having 5 or 6 ring atoms and 1, 2, 3 or 4 heteroatoms which are independently selected from 0, S and N; and the groups R³ and R⁴ are independently from each other a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl , alkylcycloalkyl, heteroalkyl- cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group; all of which groups may optionally be substituted; or R³ and R⁴ together with the nitrogen atom to which they are bound are part of an optionally substituted heterocycloalkyl group containing 5, 6 or 7 ring atoms; or a pharmaceutically acceptable salt, ester, solvate or hydrate or a pharmaceutically acceptable formulation thereof.

In the following, preferred embodiments of the present invention are disclosed. It is preferred that the preferred embodiments may be combined in any manner:

Preferably, R¹ and R² are identical.

Moreover preferably, R¹ and R² are independently from each other a group of formula -C¾-Ar or -CH₂-CH2-NR³R⁴.

Further preferably, both R¹ and R² are independently from each other a group of formula -C¾-Ar.

Moreover preferably, R¹ is a hydrogen atom and R² is a group of formula -CHb-Ar.

Especially preferably, R¹ and R² are not both hydrogen atoms.

Moreover especially preferably, R¹ and R² are not both methyl groups .

Further preferably, Ar is an optionally substituted phenyl group .

Moreover preferably, Ar is substituted by a CN group or a O2 group . Especially preferably, Ar is substituted by a group of formula - (CH₂)n-NR⁵R⁶ wherein the groups R⁵ and R⁶ are independently from each other a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or hetero- aralkyl group; all of which groups may optionally be substituted; or R⁵ and R⁶ together with the nitrogen atom to which they are bound are part of an optionally substituted heterocycloalkyl group containing 5, 6 or 7 ring atoms and n is 0 , 1 , 2 , 3 or .

Moreover preferably, n is 0 or 1.

Further preferably, R⁵ and R⁶ are both hydrogen atoms.

Moreover preferably, R⁵ is a hydrogen atom or a methyl group (especially a hydrogen atom) and R⁶ is a C1-C6 alkyl group; a C1-C6 heteroalkyl group; a cycloalkyl group containing one ring having from 3 to 7 ring atoms; a heterocycloalkyl group containing one ring having from 3 to 7 ring atoms comprising 1 or 2 heteroatoms selected from S, 0 and N; an alkylcycloalkyl group containing a C1-C6 alkyl group and a cycloalkyl group containing one ring having from 3 to 7 ring atoms; a heteroalkylcycloalkyl group containing a Ci-Ce alkyl group or a Ci-Cs heteroalkyl group and a cycloalkyl group containing one ring having from 3 to 7 ring atoms or a heterocycloalkyl group containing one ring having from 3 to 7 ring atoms comprising 1 or 2 heteroatoms selected from S, O and N with the proviso that a heteroalkylcycloalkyl group contains at least one heteroatom; a phenyl group; a heteroaryl group containing 5 or 6 ring atoms comprising 1, 2, 3 or 4 heteroatoms selected from O, S and N; an aralkyl group containing a C1 - C6 alkyl group and a phenyl group; or a heteroaralkyl group containing a Ci- Cs alkyl group or a C1 - C6 heteroalkyl group and a phenyl group or a heteroaryl group containing 5 or 6 ring atoms comprising 1, 2, 3 or 4 heteroatoms selected from O, S and N with the proviso that a heteroaralkyl group contains at least one heteroatom; all of which groups may optionally be substituted.

Further preferably, R⁵ and R⁶ together with the nitrogen atom to which they are bound are part of a heterocycloalkyl group containing 5, 6 or 7 ring atoms and optionally one further heteroatom selected from O and N, which heterocycloalkyl group may optionally be substituted (especially by a C1-C4 alkyl group or a group of formula -C(=0)-CH3 or - CH2OH ) .

Further preferably, R¹ and R² are independently from each other a group of formula -CH₂-CH₂-NR³R⁴.

Moreover preferably, R³ and R⁴ are both hydrogen atoms.

Further preferably, R³ is a hydrogen atom or a methyl group (especially a hydrogen atom) and R⁴ is a C1-C6 alkyl group; a Ci- Ce heteroalkyl group; a cycloalkyl group containing one ring having from 3 to 7 ring atoms; a heterocycloalkyl group containing one ring having from 3 to 7 ring atoms comprising 1 or 2 heteroatoms selected from S, O and N; an alkylcycloalkyl group containing a C1 - C6 alkyl group and a cycloalkyl group containing one ring having from 3 to 7 ring atoms; a heteroalkylcycloalkyl group containing a C1 - C6 alkyl group or a C₁ - C6 heteroalkyl group and a cycloalkyl group containing one ring having from 3 to 7 ring atoms or a heterocycloalkyl group containing one ring having from 3 to 7 ring atoms comprising 1 or 2 heteroatoms selected from S, 0 and N with the proviso that a heteroalkylcycloalkyl group contains at least one heteroatom; a phenyl group; a heteroaryl group containing 5 or 6 ring atoms comprising 1, 2, 3 or 4 heteroatoms selected from 0, S and N; an aralkyl group containing a Q_-C6 alkyl group and a phenyl group; or a heteroaralkyl group containing a C1-C6 alkyl group or a Ci-C6 heteroalkyl group and a phenyl group or a heteroaryl group containing 5 or 6 ring atoms comprising 1, 2, 3 or 4 heteroatoms selected from 0, S and N with the proviso that a heteroaralkyl group contains at least one heteroatom; all of which groups may optionally be substituted.

Moreover preferably, R³ and R⁴ together with the nitrogen atom to which they are bound are part of a heterocycloalkyl group containing 5, 6 or 7 ring atoms and optionally one further heteroatom selected from 0 and N, which heterocycloalkyl group may optionally be substituted (especially by a C1-C4 alkyl group or a group of formula -0(=0)-Ο¾ or -CH2OH) .

Especially preferred are compounds of formula

wherein R⁷ and R⁸ are independently from each other are a group of formula - {C¾) _n-NR⁵R⁶ wherein the groups R^s and R⁶ and n are as defined above, or a pharmaceutically acceptable salt, ester, solvate or hydrate or a pharmaceutically acceptable formulation thereof . Moreover preferably, R⁷ and R⁸ are identical.

Especially preferably, R⁷ and R⁸ are both a group of formula -CH2-NH-R⁶.

Further especially preferred are compounds of formula (III) :

(III) wherein R⁷ is a group of formula - (C¾) _n-NR⁵R⁶ wherein the groups R⁵ and R⁶ and n are as defined above, or a pharmaceutically acceptable salt, ester, solvate or hydrate or a pharmaceutically acceptable formulation thereof.

Most preferred compounds of formula (I) are the compounds disclosed in the examples.

The expression alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, preferably from 1 to 12 carbon atoms, especially from 1 to 6 (e.g. 1, 2, 3 or 4) carbon atoms, for example a methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, 2 , 2-dimethylbutyl or n-octyl group. Furthermore, the term alkyl refers to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl) such as, for example, a 2 , 2 , 2-trichloroethyl or a trifluoromethyl group. The expressions alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups that contain from 2 to 20 carbon atoms, preferably from 2 to 12 carbon atoms, especially from 2 to 6 (e.g. 2, 3 or 4) carbon atoms, for example an ethenyl (vinyl) , propenyl (allyl) , iso-propenyl, butenyl, ethinyl, propinyl, butinyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group. Preferably, alkenyl groups have one or two (especially preferably one) double bond(s) , and alkynyl groups have one or two (especially preferably one) triple bond(s) . Furthermore, the terms alkenyl and alkynyl refer to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl) .

The expression heteroalkyl refers to an alkyl, alkenyl or alkynyl group in which one or more (preferably 1, 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or a group of formula SO or SO2. The expression heteroalkyl furthermore refers to a carboxylic acid or to a group derived from a carboxylic acid, such as, for example, acyl, acylalkyl, alkoxycarbonyl , acyloxy, acyloxyalkyl , carboxyalkylamide or alkoxycarbonyloxy.

Preferably, a heteroalkyl group contains from 1 to 12 carbon atoms and from 1 to 4 hetero atoms selected from oxygen, nitrogen and sulphur (especially oxygen and nitrogen) . Especially preferably, a heteroalkyl group contains from 1 to 6 (e.g. 1, 2, 3 or 4) carbon atoms and 1, 2 or 3 (especially 1 or 2) hetero atoms selected from oxygen, nitrogen and sulphur (especially oxygen and nitrogen) . The term Ci-Cs heteroalkyl refers to a heteroalkyl group containing from 1 to 6 carbon atoms and 1, 2 or 3 heteroatoms selected from O, S and/or N (especially O and/or N) . The term Ci-C₄ heteroalkyl refers to a heteroalkyl group containing from 1 to 4 carbon atoms and 1, 2 or 3 heteroatoms selected from 0, S and/or N (especially 0 and/or N) . Furthermore, the term heteroalkyl refers to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or CI) .

Examples of heteroalkyl groups are groups of formulae: R^a-0-Y^a-, R^a-S-Y^a-, R^a-SO-Y^a-, R^a-S0₂-Y^a-, R^a-N (R^b) -Y^a- , R^a-CO-Y^a-, R^a-0-CO-Y^a-, R^a-C0-0-Y^a-, R^a-CO-N(R^b) -Y^a-, R^a-N (R^b) -CO-Y^a- , R^a-0-CO-N(R^b) -Y^a- , R^a-N(R^b) -C0-0-Y^a-, R^a-N (R^b) -CO-N (R^c) -Y^a- ,

R^a-0-C0-0-Y^a-, R^a-N(R^b) -C(=NR^d) -N(R^C) -Y^a-, R^a-CS-Y^a-, R^a-0-CS-Y^a-, R^a-CS-0-Y^a-, R^a-CS-N(R^b) -Y^a- , R^a-N (R^b) -CS-Y^a- , R^a-0-CS-N (R^b) -Y^a- , R^a-N(R^b) -CS-0-Y^a- , R^a-N (R^b) -CS-N (R^c) -Y^a- , R^a-0-CS-0-Y^a- ,

R^a-S-CO-Y^a-, R^a-CO~S-Y^a-, R^a-S-CO-N(R^b) -Y^a-, R^a-N (R^b) -CO-S-Y^a- , R^a-S-C0-0-Y^a-, R^a-0-C0-S-Y^a- , R^a-S-CO-S-Y^a- , R^a-S-CS-Y^a-, R^a-CS-S-Y^a-, R^a-S-CS-N(R^b) -Y^a-, R^a-N (R^b) -CS-S-Y^a- , R^a-S-CS-0-Y^a- , R^a-0-CS-S-Y^a- , wherein R^a being a hydrogen atom, a Ci-C₆ alkyl, a C2- C6 alkenyl or a C2-C6 alkynyl group; R^b being a hydrogen atom, a Ci-Ce alkyl, a C2- C6 alkenyl or a Q.1 - Q.& alkynyl group; R^c being a hydrogen atom, a C1- C6 alkyl, a C2-C₆ alkenyl or a C2- C6 alkynyl group; R^d being a hydrogen atom, a Ci-Ce alkyl, a C2- C6 alkenyl or a C2-C6 alkynyl group and Y^a being a direct bond, a C1- C6 alkylene, a C₂-C6 alkenylene or a C2- C6 alkynylene group, wherein each heteroalkyl group contains at least one carbon atom and one or more hydrogen atoms may be replaced by fluorine or chlorine atoms. Specific examples of heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy, isopropyloxy, butoxy, tert-butyloxy, methoxymethyl, ethoxymethyl, -CH₂CH₂OH, -CH₂OH, methoxyethyl, 1-methoxyethyl , 1-ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, isopropyl- ethylamino, methylamino methyl, ethylamino methyl, diiso- propylamino ethyl, methylthio, ethylthio, isopropylthio, enol ether, dimethylamino methyl, dimethylamino ethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl , ethoxy- carbonyl, propionyloxy, acetylamino or propionylamino, carboxymethyl , carboxyethyl or carboxypropyl , N-ethyl-N- methylcarbamoyl or N-methylcarbamoyl . Further examples of heteroalkyl groups are nitrile, isonitrile, cyanate, thio- cyanate, isocyanate, isothiocyanate and alkylnitrile groups.

The expression cycloalkyl refers to a saturated or partially unsaturated (for example, a cycloalkenyl group) cyclic group that contains one or more rings (preferably 1 or 2) , and contains from 3 to 14 ring carbon atoms, preferably from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms. The expression cycloalkyl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, Ν¾, =NH, N3 or NO2 groups, thus, for example, cyclic ketones such as, for example, cyclohexanone, 2-cyclohexenone or cyclopenta- none. Further specific examples of cycloalkyl groups are a cyclopropyl, cyclobutyl, cyclopentyl, spiro [4 , 5] decanyl , norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl , decalinyl, bicyclo [4.3.0] nonyl, tetraline, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2 -enyl group . The expression heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (preferably 1, 2, 3 or 4) ring carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) . A heterocycloalkyl group has preferably 1 or 2 ring(s) containing from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms (preferably secected from C, O, N and S) . The expression heterocycloalkyl refers furthermore to groups that may be substituted by one or more fluorine, chlorine, bromine or iodine atoms or by one or more OH, =0, SH, =S, NH₂, =NH, N₃ or N0₂ groups. Examples are a piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl , tetrahydrofuryl or 2-pyrazolinyl group and also lactames, lactones, cyclic imides and cyclic anhydrides.

The expression alkylcycloalkyl refers to groups that contain both cycloalkyl and also alkyl, alkenyl or alkynyl groups in accordance with the above definitions, for example alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl , alkenylcycloalkyl and alkynylcycloalkyl groups . An alkylcycloalkyl group preferably contains a cycloalkyl group that contains one or two rings having from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms, and one or two alkyl, alkenyl or alkynyl groups (especially alkyl groups) having 1 or 2 to 6 carbon atoms .

The expression heteroalkylcycloalkyl refers to alkylcycloalkyl groups as defined above in which one or more (preferably 1, 2, 3, 4 or 5) carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) . A hetero- alkylcycloalkyl group preferably contains 1 or 2 rings having from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms, and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups (especially alkyl or heteroalkyl groups) having from 1 or 2 to 6 carbon atoms (the heteroalkyl groups having preferably 1, 2 or 3 heteroatoms selected from 0, S and N) . Examples of such groups are alkylheterocycloalkyl , alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, hetero- alkylcycloalkyl, heteroalkylheterocycloalkyl and hetero- alkylheterocycloalkenyl, the cyclic groups being saturated or mono-, di- or tri-unsaturated.

The expression aryl refers to an aromatic group that contains one or more rings containing from 5 or 6 to 14 ring carbon atoms, preferably from 5 or 6 to 10 (especially 6) ring carbon atoms. The expression aryl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH2, N3 or NO2 groups. Examples are the phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group .

The expression heteroaryl refers to an aromatic group that contains one or more rings containing from 5 to 14 ring atoms, preferably from 5 to 10 (especially 5 or 6 or 9 or 10) ring atoms, and contains one or more (preferably 1, 2, 3, 4 or 5) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N) . The expression heteroaryl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, SH, N3, NH₂ or NO2 groups. Examples are pyridyl (e.g. 4-pyridyl) , imidazolyl (e.g. 2-imidazolyl) , phenylpyrrolyl (e.g. 3- phenylpyrrolyl) , thiazolyl, isothiazolyl , 1, 2, 3-triazolyl, 1, 2 , -triazolyl, oxadiazolyl , thiadiazolyl , indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, pyridazinyl, quinolinyl, isoguinolinyl, pyrrolyl , purinyl , carbazolyl , acridinyl , pyrimidyl , 2,3'- bifuryl, pyrazolyl (e.g. 3-pyrazolyl) and isoquinolinyl groups .

The expression aralkyl refers to groups containing both aryl and also alkyl, alkenyl, alkynyl and/or cycloalkyl groups in accordance with the above definitions, such as, for example, arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, aryl- cycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl groups. Specific examples of aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, lH-indene, tetraline, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl , fluorene and indane. An aralkyl group preferably contains one or two aromatic ring systems (1 or 2 rings) containing from 6 to 10 carbon atoms and one or two alkyl, alkenyl and/or alkynyl groups containing from 1 or 2 to 6 carbon atoms and/or one or two cycloalkyl groups containing 5 or 6 ring carbon atoms.

The expression heteroaralkyl refers to an aralkyl group as defined above in which one or more (preferably 1, 2, 3 or 4) carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulfur atom (preferably oxygen, sulfur or nitrogen) , that is to say to groups containing both aryl or heteroaryl, respectively, and also alkyl, alkenyl, alkynyl and/or heteroalkyl and/or cycloalkyl and/or heterocycloalkyl groups in accordance with the above definitions . A heteroaralkyl group preferably contains one or two aromatic ring systems (1 or 2 rings) containing from 5 or 6 to 10 ring carbon atoms and one or two alkyl, alkenyl and/or alkynyl groups containing 1 or 2 to 6 carbon atoms and/or one or two cycloalkyl groups containing 5 or 6 ring carbon atoms, wherein 1, 2, 3, 4, 5 or 6 of these carbon atoms have been replaced by oxygen, sulfur or nitrogen atoms .

Examples are arylheteroalkyl , arylheterocycloalkyl, aryl- heterocycloalkenyl , arylalkylheterocycloalkyl , arylalkenyl- heterocycloalkyl, arylalkynylheterocycloalkyl, arylalkyl- heterocycloalkenyl, heteroarylalkyl , heteroarylalkenyl , heteroarylalkynyl, heteroarylheteroalkyl, heteroaryl- cycloalkyl, heteroarylcycloalkenyl, heteroarylhetero- cycloalkyl, heteroarylheterocycloalkenyl , heteroarylalkyl- cycloalkyl, heteroarylalkylheterocycloalkenyl , heteroarylheteroalkylcycloalkyl, heteroarylheteroalkylcycloalkenyl and heteroarylheteroalkylheterocycloalkyl groups, the cyclic groups being saturated or mono-, di- or tri-unsaturated. Specific examples are a tetrahydroisoquinolinyl, benzoyl, 2- or 3-ethylindolyl, -methylpyridino, 2-, 3- or -methoxyphenyl , 4-ethoxyphenyl, 2-, 3- or 4-carboxy- phenylalkyl group.

The term halogen or halogen atom refers to F, CI, Br or I.

The expression "optionally substituted" preferably refers to groups in which one, two, three or more hydrogen atoms may have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =0 , SH, =S, NH₂, =NH, N₃ or N0₂ grou s. This expression refers furthermore to groups that may be substituted by one, two, three or more preferably unsubstituted Ci- Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 heteroalkyl, C3-C18 cycloalkyl, C₂-Ci7 heterocycloalkyl , C4-C20 alkylcycloalkyl, C2-C19 heteroalkylcycloalkyl, C6-C18 aryl, C1-C17 heteroaryl, C7-C20 aralkyl or C2-C19 heteroaralkyl groups. This expression refers furthermore especially to groups that may be substituted by one, two, three or more preferably unsubstituted Ci - Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C7-C12 alkylcycloalkyl, C2-C11 heteroalkylcycloalkyl, C6-C10 aryl, C1-C9 heteroaryl, C7-C12 aralkyl or C2-C11 heteroaralkyl groups.

The expression "optionally substituted" further preferably refers to a group which may be substituted by a group of formula - (C¾) _n-NR⁵R^s wherein R⁵, R⁶ and n are as defined above.

If a substituent contains a ring, this ring may be bonded to the respective substituted group via a single or double bond (especially a single bond) or, if the substituted group also contains a ring, the ring of the substituent may also be annulated to the ring of the substituted group.

Preferred substituents are F, CI, Br, I, OH, =0 , NH₂, NO2, C1-4 alkyl (e.g. methyl, ethyl, t-butyl ) , Me₂, NHMe, CONH₂, CH₂NMe₂, NHS0₂Me, C(CH₃)₂CN, COMe, OMe, SMe, COOMe, COOEt, CH₂C00H, OCH2COOH, COOH, SOMe, S0₂Me, cyclopropyl, S0₂NH₂, S0₂NHMe, SO2CH2CH2OH, SF₅, S0₂NMe₂, CHO, OCF₃, SO2CF3, COMe, CH₂OH, CN or CF₃. Especially preferred substituents are F, CI, Br, OH, N¾, CH2NH2, N0₂, Me, Ethyl, NMe₂, CONH2 , OMe, CN or CF₃.

According to a preferred embodiment, all alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl , alkylcycloalkyl , heteroalkylcycloalkyl, aralkyl and heteroaralkyl groups described herein may optionally be substituted.

When an aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl group contains more than one ring, these rings may be bonded to each other via a single or double bond or these rings may be annulated.

The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) or (II) as defined herein or a pharmaceutically acceptable ester, prodrug, hydrate, solvate or salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

It is a further object of the present invention to provide a compound of formula (I) or (II) as defined herein or a pharmaceutical composition as defined herein for the preparation of a medicament for the treatment of one or more diseases mentioned herein.

Preferably the compounds of the present invention may be used for the treatment and/or prevention of cancer, viral diseases and infectious diseases. Further preferably, the compounds of the present invention may be used for the treatment and/or prevention of neurodegenerative diseases such as: Schizophrenia, Alzheimer, Multiples Sclerosis, Parkinson, Corea Huntington,

Spinocerebellar ataxia type 1 (SCA1) , Amyotrophic lateral sclerosis, Batten disease.

A therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.

The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage may be adjusted to the individual requirements in each particular case including the specific compound being administered, the route of administration, the condition being treated, as well as the patient being treated.

Examples of pharmacologically acceptable salts of sufficiently basic compounds of formula (I) or (II) are salts of physiologically acceptable mineral acids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; or salts of organic acids like methanesulfonic, p-toluenesulfonic , lactic, acetic, trifluoroacetic , citric, succinic, fumaric, maleic and salicylic acid. Further, a sufficiently acidic compound of formula (I) or (II) may form alkali or earth alkali metal salts, for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine , trimethylamine , triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris-(2- hydroxyethyl ) amine , lysine or arginine salts; all of which are also further examples of salts of formula (I) or (II) . Compounds of formula (I) or (II) may be solvated, especially hydrated. The hydratization/hydration may occur during the process of production or as a consequence of the hygroscopic nature of the initially water free compounds of formula (I) or (II) . The solvates and/or hydrates may e.g. be present in solid or liquid form.

It should be appreciated that certain compounds of formula (I) or (II) may have tautomeric forms from which only one might be specifically mentioned or depicted in the following description, different geometrical isomers (which are usually denoted as cis/trans isomers or more generally as (E) and (Z) isomers) or different optical isomers as a result of one or more chiral carbon atoms (which are usually nomenclatured under the Cahn-Ingold-Prelog or R/S system) . All these tautomeric forms, geometrical or optical isomers (as well as racemates and diastereomers) and polymorphous forms are included in the invention. Since the compounds of formula (I) or (II) may contain asymmetric C-atoms, they may be present either as achiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds. The present invention comprises both all pure enantiomers and all pure diastereomers, and also the mixtures thereof in any mixing ratio.

The therapeutic use of compounds according to formula (I) or (II) , their pharmacologically acceptable salts, solvates and hydrates, respectively, as well as formulations and pharmaceutical compositions also lie within the scope of the present invention.

The pharmaceutical compositions according to the present invention comprise at least one compound of formula (I) or (II) as an active ingredient and, optionally, carrier substances and/or adjuvants.

The present invention also relates to pro-drugs which are composed of a compound of formula (I) or (II) and at least one pharmacologically acceptable protective group which will be cleaved off under physiological conditions, such as an alkoxy- , arylalkyloxy- , acyl-, acyloxymethyl group (e.g. pivaloyloxymethyl) , an 2-alkyl-, 2-aryl- or 2-arylalkyl- oxycarbonyl-2-alkylidene ethyl group or an acyloxy group as defined herein, e.g. ethoxy, benzyloxy, acetyl or acetyloxy or, especially for a compound of formula (I) or (II) , carrying a hydroxy group (-OH) : a sulfate, a phosphate (-OPO3 or - OCH2OPO3) or an ester of an amino acid.

Preferably, the present invention also relates to a prodrug, a biohydrolyzable ester, a biohydrolyzable amide, a polymorph, tautomer, stereoisomer, metabolite, N-oxide, biohydrolyzable carbamate, biohydrolyzable ether, physiologically functional derivative, atropisomer, or in vivo-hydrolysable precursor, diastereomer or mixture of diastereomers, chemically protected form, affinity reagent, complex, chelate and a stereoisomer of the compounds of formula (I) or (II) .

As used herein, the term pharmaceutically acceptable ester especially refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof . Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates .

As mentioned above, therapeutically useful agents that contain compounds of formula (I) or (II) , their solvates, salts or formulations are also comprised in the scope of the present invention. In general, compounds of formula (I) or (II) will be administered by using the known and acceptable modes known in the art, either alone or in combination with any other therapeutic agent .

For oral administration such therapeutically useful agents can be administered by one of the following routes: oral, e.g. as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, for example soft and hard gelatine capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral including intravenous, intramuscular and subcutaneous injection, e.g. as an injectable solution or suspension, rectal as suppositories, by inhalation or insufflation, e.g. as a powder formulation, as microcrystals or as a spray (e.g. liquid aerosol), transdermal, for example via an transdermal delivery system (TDS) such as a plaster containing the active ingredient or intranasal . For the production of such tablets, pills, semisolids, coated tablets, dragees and hard, e.g. gelatine, capsules the therapeutically useful product may be mixed with pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like. For the production of soft capsules one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat, polyols. For the production of liquid solutions, emulsions or suspensions or syrups one may use as excipients e.g. water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable, petroleum, animal or synthetic oils. Especially preferred are lipids and more preferred are phospholipids (preferred of natural origin; especially preferred with a particle size between 300 to 350 nm) preferred in phosphate buffered saline (pH = 7 to 8, preferred 7.4). For suppositories one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat and polyols . For aerosol formulations one may use compressed gases suitable for this purpose, as are e.g. oxygen, nitrogen and carbon dioxide . The pharmaceutically useful agents may also contain additives for conservation, stabilization, e.g. UV stabilizers, emulsifiers, sweetener, aromatizers, salts to change the osmotic pressure, buffers, coating additives and antioxidants .

In general, in the case of oral or parenteral administration to adult humans weighing approximately 80 kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 20 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion or subcutaneous injection.

The present invention moreover provides a method of inhibiting growth, proliferation, or metastasis of cancer cells in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (II) , or a pharmaceutically acceptable salt . In one embodiment the cancer is selected from melanoma, renal cell carcinoma, squamous non-small cell lung cancer (NSCLC) , non-squamous NSCLC, colorectal cancer, castration-resistant prostate cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, squamous cell carcinoma of the head and neck, carcinomas of the esophagus, gastrointestinal tract and breast, cancer of the genital organs, penis and vagina, and a hematological malignancy.

Further the present invention provides a method of treating an infectious disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (II) , or a pharmaceutically acceptable salt thereof . In one embodiment the infectious disease is caused by a virus . In a further embodiment the virus is selected from HIV, Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, herpes viruses, papillomaviruses and influenza.

In one embodiment, a method is provided for treating cancer comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of formula (I) or (II) or a salt thereof. Examples of cancers include those whose growth may be inhibited using compounds of the disclosure include cancers typically responsive to immunotherapy. Non-limiting examples of preferred cancers for treatment include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormone refractory prostate adenocarcinoma), breast cancer, colon cancer and lung cancer (e.g. non-small cell lung cancer) . Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the present invention.

Examples of other cancers that may be treated using the methods of the present invention include bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin' s lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or urethra, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS) , primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers. The present invention is also useful for treatment of metastatic cancers, especially metastatic cancers that express PD-L1.

Some examples of pathogenic viruses causing infections treatable by methods of the present invention include HIV, hepatitis (A, B, C, or D) , herpes viruses (e.g., VZV, HSV-1 , HAV-6, HHv-7, HHV-8, HSV-2, CMV, and Epstein Barr virus), adenovirus, influenza virus, fiaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial viras, mumps viras, rotaviras, measles viras, rabella viras, parvovirus, vaccinia virus, HTLV viras, dengue viras, papillomavirus, molluscum viras, poliovirus, rabies viras, JC viras and arboviral encephalitis viras.

Some examples of pathogenic bacteria causing infections treatable by methods of the present invention include chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, lebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lymes disease bacteria.

Some examples of pathogenic fungi causing infections treatable by methods of the present invention include Candida (albicans, krasei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus) , Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis , Coccidioides immitis and Histoplasma capsulatum. Some examples of pathogenic parasites causing infections treatable by methods of the present invention include Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma bracei, Trypanosoma crazi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.

Examples

Synthesis of building block 3

(3-methoxy-2-methylphenyl)boronic acid (1)

To a solution of 3-bromo-2-methylanisol (5.9 g, 29.34 mmol) in anhydrous THF (80 mL) , n-BuLi in n-hexane (2.5 M, 13.8 mL, 34.5 mmol, 1.2 eq) was added at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for one hour. Triisopropylborate (8.28 mL, 26.24 mmol) was added dropwise, the mixture stirred at -78 °C for one hour, allowed to warm up to room temperature and stirred for another hour. IN HC1 (125 mL) was added. The solvent (THF) was removed in vacuum and the products extracted with ethyl acetate (3x 100 mL) . The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the product as white solid (4.22g, 25.42 mmol, 87%). ¾ MR (300 MHz, CDC1₃) : δ 7.79 (d, J^" = 7.5 Hz, 1H) , 7.29 (t, J = 7.8 Hz, 1H) , 7.06 (d, J^" = 8.4 Hz, 1H) , 3.87 (s, 3H) , 2.67 (s, 3H) ppm. MS (ESI) m/z: calc. for C₈HuB0₃, [M+H]⁺: 167.09; found: 167.05.

3,3' -dimethoxy-2, 2 · -dimethyl-1, 1 ' -biphenyl (2)

To a solution solution of 3-bromo-2-methylanisol (3.94g, 19.7 mmol) and boronic acid (3.78 g, 23 mmol) in 1,4-dioxane (150 ml.) , [1,1' -Bis (diphenylphosphino) ferrocene] dichloropalladium

(II) (0.821 g, 0.99 mmol) was added under nitrogen atmosphere followed by addition of 2M aq. Solution of potassium carbonate

(19.7 mL, 39.4 mmol). The reaction mixture was heated at 95 °C under nitrogen atmosphere overnight. After cooling to room temperature, water (300 mL) was added and the product was extracted with ethyl acetate (3x400 mL) . The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate/heptane) yielding the product as white solid (4.62g, 19.06 mmol, 97%). ¾ NMR (300 MHz, CDCI3) : δ 7.23 (t, J = 8.0 Hz, 2H) , 6.87 (d, J = 8.4 Hz, 2H) , 6.77 (d, J^" = 7.8 Hz, 2H) , 3.90 (s, 6H) , 1.95 (s, 6H) ppm. MS (ESI) m/z: calc. for Ci₆Hi₈0₂, [M+H]⁺: 243.14; found: 243.20.

2,2 ^» -dimethyl- [1,1· -biphenyl] -3,3 ' -diol (3) To a cold (-78 °C) solution of the di-methyl ester (4.56g, 18.82 mmol) in dichloromethane (120 mL) , boron tribromide (93 mL, 98.2 mmol) was added dropwise under nitrogen atmosphere. The reaction was stirred at -78 °C for one hour, allowed to warm up to room temperature and stirred overnight. Ethyl acetate (100 mL) was added and the mixture was quenched with ice water. Dichloromethane was removed under reduced pressure and the phases were separated. The aqueous phase was extracted with ethyl acetate (2x) . The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate/heptane) yielding the product 3 as white solid (2.73g, 12.74 mmol, 68%). ¾ NMR (300 MHz, d-MeOH) : δ 6.99 (t, J^" = 7.7 Hz, 2H) , 6.73 (d, J = 7.5 Hz, 2H) , 6.55 (d, J = 7.6 Hz, 2H) , 1.86 (s, 6H) ppm. MS (ESI) m/z: calc . for C14H14O2, [M-H] - : 213.09; found: 213.05.

4,4 · - ( ( (2,2 ' -dimethyl- [1, 1^■ -biphenyl] -3,3 ' - diyl) bis (oxy) ) bis (methylene) ) dibenzonitrxle (4)

A solution of alpha-bromo-p-tolunitrile (918 mg, 5.68 mmol), building block 3 (500 mg, 2.34 mmol) and Cs₂C0₃ (4.57g, 14.04 mmol) in DMF (20 mL) was stirred virtuously at room temperature overnight. Water (20 mL) was added and the mixture was stirred for one hour at room temperature. The precipitate was filtered off and washed with water. The white solid dissolved in ethyl acetate (200 mL) and the solution was dried over sodium sulfate and concentrated to give product 4 as white solid (770 mg, 1.73 mmol, 74%). ¾ NMR (500 MHz, CDC1₃) : δ 7.70 (d, J = 8.1 Hz, 4H) , 7.59 (d, J = 8.4 Hz, 4H) , 7.19 (t, J^" = 7.94 Hz, 2H) , 6.87 (d, J^" = 8.1 Hz, 2H) , 6.79 (d, J = 7.8 Hz, 2H) , 5.18 (s, 4H) , 2.01 (s, 6H) ppm. MS (ESI) m/z: calc. for C₃oH2_{4 2}0₂, [M+Na]⁺: 467.17; found: 467.20.

3,3 · - < ( (2,2^■ -dimethyl- [1, 1 ^« -biphenyl] -3,3 ' - diyl) bis (oxy) ) bis (methylene) ) dibenzonxtrxle (5)

Was synthesized according to the procedure as described for compound 4 using 3 equiv. of alpha-bromo-m-tolunitrile . Compound 5 was obtained as white solid (208 mg, 0.47 mmol, quant.). MS (ESI) m/z: calc. for C30H24N2O2 , [M+Na]⁺: 467.17; found: 467.20.

2,2· -dimethyl-3 , 3¹ -bis ( (4-nitrobenzyl) oxy) -1,1* -biphenyl (6)

Was synthesized according to the procedure as described for compound 4 using 2 equiv. of p-nitrobenzyl bromide. Compound 6 was obtained as white solid (660 mg, 1.36 mmol, 97%) . MS (ESI) m/z: calc. for C28H24N2C-6, [M+Na]⁺: 507.14; found: 507.20, [M-H] ^" : 483.16; found: 483.20.

2,2" -dimethyl -3, 3¹ -bis ( (3 -nitrobenzyl) oxy) -1,1' -biphenyl (7)

Was synthesized according to the procedure as described for compound 4 using 3 equiv. of 3 -nitrobenzyl bromide. Compound 7 was obtained as white solid (226 mg, 0.47 mmol, quant.). MS (ESI) m/z: calc . for C28H24N2O6, [M+Na]⁺: 507.14; found: 507.20.

di-tert-butyl ((2,2· -dimethyl- [1, 1 · -biphenyl] -3,3'- diyDbis (oxy) )bis (ethane-2, 1-diyl) ) dxcarbamate (8)

Was synthesized according to the procedure as described for compound 4 using 4 equiv. of 2- (Boc-amino) -ethyl bromide and 6 equiv. of base. Compound 8 was obtained as white solid (563 mg, 1.12 mmol, 80%). MS (ESI) m/z: calc. for C₂8H4oN₂0₆, [M+Na]⁺: 523.28; found: 523.40.

2,2' -dimethyl-3 * - (pyridin-4-ylmethoxy) - [1,1· -biphenyl] -3 -ol (9)

Was synthesized according to the procedure as described for compound 4 using 3 equiv. of 4- (chloromethyl) yridine hydrochloride and 8 equiv. of base. Compound 9 was obtained as white solid (60 mg, 0.20 mmol, 97%). ¾ NMR (500 MHz , d- MeOH) : δ 8.54 (d, J = 4.5 Hz, 2H) , 7.56 (d, J = 5.4 Hz, 2H) , 7.16 (t, J = 8.0 Hz, 1H) , 7.01 (t, J = 7.7 Hz, 1H) , 6.93 (d, J = 8.1 Hz, 1H) , 6.77-6.70 (m, 2H) , 6.55 (d, J^" = 7.2 Hz, 1H) , 5.24 (s, 2H) , 2.00 (s, 3H) , 1.86 (s, 3H) ppm. MS (ESI) calc. for C₂₀Hi₉NO₂, [M-H] " : 304.13; found: 304.05.

4,4¹ - ( { (2,2 ' -dimethyl- [1, 1 · -biphenyl] -3 , 3 · -diyl) bis (oxy) )bis- (methylene) ) dipyridine (10)

A solution of 4- (chloromethyl) pyridine hydrochloride (161 mg, 0.99 mmol) , compound 9 (100 mg, 0.33 mmol) and Cs₂C0₃ (645 mg, 2.97 mmol, 6 eq.) in (5 mL) was stirred virtuously at room temperature overnight. Water (10 mL) was added and the mixture was stirred for one hours at room temperature. The precipitate was filtered off and washed with water. The white solid dissolved in ethyl acetate (100 mL) and the solution was dried over sodium sulfate and concentrated to give compound 10 as white solid (129 mg, 0.33 mmol, quant). ^XH MR (500 MHz, CDCla) : δ 8.64 (d, J^" = 4.2 Hz, 4H) , 7.41 (d, J = 5.1 Hz, 4H) , 7.19 (t, J = 8.0 Hz, 2H) , 6.87-6.79 (m, 4H) , 5.15 (s, 4H) , 2.04 (s, 6H) ppm. MS (ESI) m/z: calc. for C₂6H24N₂0₂, [M+H]⁺: 397.19; found: 397.20, [M+Na]⁺: 419.17; found: 419.20.

Reduction of nitrile groups into amino methyl groups

Raney-Ni, H₂

( ( ( (2,2 ' -dimethyl- [1, 1 ' -biphenyl] -3,3 · -diyDbis (oxy) )bis- (methylene) )bis (4, 1-phenylene) ) dimethanamine (11)

Raney-Nickel (1.4 mL, 50% in water, slurry) was transferred into a round bottom flask flushed with nitrogen. Methanolic ammonia (7N, 40 mL) and compound 4 (0.63 g, 1.42 mmol) were added to the mixture. The resulting suspension was stirred under hydrogen atmosphere overnight. The reaction was filtered over celite and the celite pad was washed with acetone. The filtrate was concentrated in vacuo. The resulting oil was co- evaporated and recrystallized in a mixture of heptane and ethyl acetate to give compound 11 as white solid (0.46 g, 1.03 mmol, 73%). ^XH NMR (500 MHz , d₆-DMS0) : δ 7.39 (d, J = 7.8 Hz, 4H) , 7.33 (d, J = 8.1 Hz, 4H) , 7.14 (t, J^" = 7.5 Hz, 2H) , 7.02 (d, J = 8.1 Hz, 2H) , 6.64 (d, J^" = 7.2 Hz, 2H) , 5.08 (s, 4H) , 3.69 (s, 4H) , 1.83 (s, 6H) ppm. MS (ESI) m/z: calc. for C30H32N2O2, [M+H]⁺: 453.25; found: 453.40.

(({(2,2' -dimethyl- [1,1' -biphenyl] -3,3 · -diyDbis (oxy) ) - bis (methylene) ) bis (3 , 1-phenylene) ) dimethanamine hydrochloride (12)

Was synthesized according to the procedure as described for compound 11. Compound 12 was obtained as hydrochloride salt after treating the crude product with 4N HC1 in dioxane, evaporation of the volatile and precipitation by shaking the residue in tert-butyl methyl ether. Compound 12 was obtained as white solid (234 mg, 0.43 mmol, 76%) . MS (ESI) m/z: calc. for C30H32N2O2 , [M+H]⁺: 453.25; found: 453.40.

( { ( (2,2 ^» -dimethyl- [1,1' -biphenyl] -3,3' -diyDbis (oxy) )bis- (methylene) ) bis (2 , 1-phenylene) ) dimethanamxne dihydrochloride (13)

Was synthesized according to the procedure as described for compound 12. MS (ESI) m/z: calc. for C30H32N2O2, [M+H]⁺: 453,25; found: 453.20.

Reductio of nitro groups into amino groups

3,3¹ - ( ( (2,2 ' -dimethyl- [1, 1 ' -biphenyl] -3,3 ^« -diyDbis (oxy) )bis- (methylene) ) dxanxlxne (14)

Compound 7 (241 mg, 0.50 mmol) was dissolved in a mixture of isopropanol and THF (25 mL, 2:3) and heated to 70 °C. Catalytic amounts of Raney-Nickel (0.5 ml, 50 % in water, slurry) and hydrazine hydrate (1 mL, 1.03 g, 20.61 mmol, 15 eq.) were added. After stirring at 70°C for two hours all starting material was converted (TLC, EtOAc/heptane 1:1). The catalyst was removed by filtration over a pad of celite, which was washed with THF. The filtrate was concentrated and the crude was purified by column chromatography (EtOAc/he tane) to give compound 14 as white solid (69 mg, 0.516 mmol, 33%). ¹H NMR (500 MHz , CDCI₃) : δ 7.18 (m, 4H) , 6.92-6.75 (m, 8H) , 6.65 (d, J = 8.1, 2H) , 5.04 (s, 4H) , 2.01 (s, 6H) ppm. MS (ESI) m/z: calc. for C₂₈H₂₈N₂0₂, [M+Na]⁺: 447.20; found: 447.20.

4, 4 ' - ( ( (2 , 2 ' -dimethyl- [1,1· -biphenyl] -3,3" -diyDbis (oxy) )bis- (methylene) ) dianiline (15) and 3 '-{ (4-aminobenzyl) oxy) -2 , 2 · - dimethyl- [1, 1 ' -biphenyl] -3-ol (16)

were synthesized according to the procedure as described for compound 14 as a mixture that was separated by column

chromatography (EtOAc/he tane) . Compound 15 (280 mg, 0.66 mmol, 49%) and compound 16 (120 mg, 0.38 mmol, 28%) were both obtained as white solid.

4,4^» -(((2,2" -dimethyl- [1,1· -biphenyl] -3,3" -diyl) bis (oxy) )bis- (methylene) ) dianiline (15)

MS (ESI) m/z: calc. for C₂8H28N₂0₂, [M+Na]⁺: 447.20; found: 447.20.

3¹ - ( (4-aminobenzyl) oxy) -2,2' -dimethyl- [1,1' -biphenyl] -3

(16)

MS (ESI) m/z: calc. for C21H21NO2, [M+H]⁺: 320.16;

320.20. Deprotection of amino roups

2, 2 ' - { (2, 2 · -dimethyl- [1,1· -biphenyl] -3,3' -diyUbis (oxy) )bis- (ethan-1-amine) hydrochloride (17)

Compound 8 (563 mg, 1.12 mmol) was stirred in 4N HC1 in dioxane (20 mL) at room temperature. After six hours the reaction mixture was concentrated under reduced pressure and the product was precipitated by shaking the residue in tert- butyl methyl ether. The precipitate was filtered and dried to yield compound 17 as white solid (388 mg, 1.09 mmol, 97%). ¾ NMR (500 MHz , d-MeOH) : δ 7.21 (t, J^" = 8.0, 2H) , 6.98 (d, J = 8.1, 2H) , 6.73 (d, J^" = 6.9, 2H) , 4.29 (t, J = 5.1 Hz, 4H) , 3.42 (t, J = 5.0 Hz, 4H) , 1.95 (s, 6H) ppm. MS (ESI) m/z: ca2c. for C18H26CI2 2O2 , [M+H]⁺: 301.19; found: 301.20.

General Procedure for the Reductive amination

Compound 11 (50 mg, 0.11 mmol) was dissolved in DCM (1 mL) and diluted with MeOH (1 mL) . The appropriate aldehyde or ketone (0.24 mmol) was added dropwise and the reaction mixture was stirred at room temperature until full conversion of the bis- amine was observed. Sodium borohydride (13 mg, 0.33 mmol) or sodium cyanoborohydride (21 mg, 0.33 mmol) was then added and the bubbling mixture stirred until full conversion of the imine was observed. The reaction mixture was then partitioned between water and DCM (total volume: 4 mL) and the DCM layer filtered over sodium sulfate. The aqueous layer was extracted with further DCM (3 x 1 mL) . The combined organic layers were filtered over sodium sulfate and concentrated by rotary evaporation. The crude material was purified by ISCO (MeOH/DCM gradient) or RP-ISCO (MeOH/water gradient) to give the products below.

1,1· - ( ( ( (2,2 ' -dimethyl- [1, 1 · -biphenyl] -3,3 ' -diyDbis (oxy) )bis- (methylene) ) bis (4, 1-phenylene) )bis(N- (pyridin-3 -ylmethyl) - methanamine) (18)

¾ NMR (300 MHz , CDC1₃) : δ 2.00 (s, 6H) , 3.85 (s, 8H) , 5.12 (br s, 4H) , 6.78 (d, 2H) , 6.92 (d, 2H) , 7.18 (t, 2H) , 7.26 (t, 2H, overlaps with CHCI3) , 7.38 (d, 4H) , 7.48 (d, 4H) , 7.73 (d, 2H) , 8.51 (d, 2H) , 8.61 (br s, 2H) ppm. MS (ESI) m/z: calc. for C42H42N4O2, [M+H]⁺: 635,34; found: 635.40.

1,1' - ( ( ( (2,2 ' -dimethyl- [1, 1 · -biphenyl] -3 , 3 · -diyl) bis (oxy) )bis- (methylene) ) bis (4, 1-phenylene) )bis(N- (pyridin-4 - ylmethyl) methanamine) (19)

MS (ESI) m/z: calc. for C42H42N4O2, [M+H]⁺: 635,34; found: 635.40.

Ν,Ν' - ( ( ( ( (2,2 ' -dimethyl- [1, 1 ' -biphenyl] -3,3 ' -diyUbis- (oxy) )bis (methylene) )bis ( , 1-phenylene) )bis (methylene) ) - dieye1ohexanamine (20)

MS (ESI) m/z: calc. for C₄₂H₅₂N₂0₂, [M+H]⁺: 617.41;

617.40.

Ν,Ν' - ( ( ( ( (2,2 ' -dimethyl- [1, 1 ' -biphenyl] -3,3 ' -diyDbis- (oxy) )bis (methylene) )bis (4, 1-phenylene) )bis (methylene) )bis- (tetrahydro-2H-pyran-4 -amine) (21)

MS (ESI) m/z: calc. for C₄oH48N₂0₄, [M+H]⁺: 621.37; found: 621.40.

Ν,Ν' - ( ( ( ( (2,2 · -dimethyl- [1, 1 · -biphenyl] -3,3 ^« -diyDbis- (oxy) )bis (methylene) )bis (4, 1-phenylene) )bis (methylene) )bis (3- methylbutan-1-amine) (22)

MS (ESI) m/z: calc. for C₄oH52N₂0_2i [M+H]⁺: 593.41; found: 593.40.

Ν,Ν' - ( ( ( ( (2,2 ' -dimethyl- [1,1· -biphenyl] -3, 3 · -diyDbis- (oxy) )bis (methylene) )bis (4 , 1-phenylene) )bis (methylene) )bis (2- methylpropan-1-amine) (23)

MS (ESI) m/z: calc. for C₃8H48N₂0₂, [M+H]⁺: 565.38; found: 565.40.

Ν,Ν' - ( ( ( ( (2,2 ' -dimethyl- [1,1· -biphenyl] -3,3 ' -diyDbis- (oxy) ) bis (methylene) ) bis (4, 1-phenylene) ) bis (methylene) )bis- (tetrahydro-2H-1hiopyran-4 -amine) (24)

MS (ESI) m/z: calc. for C40H48N2O2S2 , [M+H]⁺: 653.32; found: 653.40.

1, 1 ' - ( ( ( (2, 2¹ -dimethyl- [1,1· -biphenyl] -3,3' -diyDbis (oxy) )bis- (methylene) ) bis (4 , 1-phenylene) )bis(N- ( (3-methyloxetan-3- yl) methyl)methanamine) (25)

MS (ESI) m/z: calc. for C40H48N2O4, [M+H]⁺: 621.37; found: 621.40.

3' - ( (4- ( ( (cyclopropylmethyl) amino) methyl) benzyl) oxy) -2,2'- dimethyl- [1,1' -biphenyl] -3 -ol (26)

MS (ESI) m/z: calc. for C26H29NO2, [M+H]⁺: 388.23; found: 388.25. [M-H]-: 386.21; found: 386.20.

3 ' - ( (4- ( (isopentylamino) methyl) benzyl) oxy) -2,2 ' -dimethy1- [1,1· -biphenyl] -3-0I (27)

MS (ESI) m/z: calc. for C₂₇H₃3N0₂, [M+H]⁺: 404.26;

404.20. [M-H]": 402.24; found: 402.20.

3¹ - ( (4- ( (isobutylamino) methyl) benzyl) oxy) -2,2· -dimethyl- [1,1·- biphenyl] -3-0I (28)

MS (ESI) m/z: calc. for C26H₃iN0_2i [M+H]⁺: 390,24; found: 390.20. [M-H]^": 388,23; found: 388.20.

2,2¹ -dimethyl-3 * - ( (4- ( ( (tetrahydro-2H-thiopyran-4-yl) amino) - methyl) benzyl) oxy) - [1,1' -biphenyl] -3-ol (29) MS (ESI) m/z: calc. for C27H31NO2S, [M+H]⁺: 434.22; found: 434.20. [M-H]-: 432.20; found: 432.20.

2,2 ' -dimethyl -3 * - ( (4- ( ( (pyridin-2 -ylmethyl) amino) methyl) - benzyl) oxy) - [1,1· -biphenyl] -3-ol (30)

MS (ESI) m/z: calc. for CssHbeNaOa, [M+H]⁺: 425.22; found: 425.25. [M-H]^": 423.21; found: 423.10.

2,2 ' -dimethyl-3¹ - ( (4- ( ( (3- (methylthio) propyl) amino)methyl) - benzyl) oxy) -[1,1· -biphenyl] -3-ol (31)

MS (ESI) m/z: calc. for C26H31NO2S, [M+H]⁺:; found: 422.20. [M- H]-: 420.20; found: 420.15.

Screening :

Expression and purification of recombinant PD-L1, PD-L2 and PD-1

The gene encoding human PD-L1 (amino acids 18-134) was cloned into the pET-21b, the gene encoding human PD-L2 (20-220) was cloned into pET28a and that of human PD-1 (33-150, Cys93 exchanged to serine) into pET-24d. Proteins were expressed in the E. coli BL21 (DE3) . Cells were cultured in LB at 37°C. The protein production was induced with 1 mM IPTG at OD600 of 1.0 and the cells were cultured for additional 5h. For hPD-1, after induction the temperature was lowered to 30°C. Proteins were expressed as inclusion bodies which were collected by centrifugation, washed twice with 50 mM Tris-HCl pH 8.0 containing 200 mM NaCl, 0.5% Triton X-100, 10 mM EDTA and 10 mM 2-mercaptoethanol and once more with the same buffer with no detergent. The inclusion bodies were stirred overnight in 50 mM Tris pH 8.0 containing 6M GuHCl, 200 mM NaCl and 10 mM 2-mercaptoethanol. Solubilized fraction was clarified by high speed centrifugation. hPD-Ll and hPD-L2 were refolded by drop- wise dilution into 0.1 M Tris pH 8.0 containing 1 M L-Arg hydrochloride, 0.25 mM oxidized glutathione and 0.25 mM reduced glutathione for hPD-Ll and 0.1 M Tris pH 8.5 containing 1 M NDSB201, 0.2 M NaCl, 5 mM cysteamine and 0.5 mM cystamine for hPD-L2. hPD-1 was refolded in similar manner in 0.1 M Tris pH 8.0 containing 0.4 M L-Arg hydrochloride, 2 mM EDTA, 5 mM cystamine and 0.5 mM cysteamine. After refolding, the proteins were dialyzed 3 times against 10 mM Tris pH 8.0 containing 20 mM NaCl, and purified by size exclusion chromatography on Superdex 75 (GE Healthcare) in 10 mM Tris pH 8.0 containing 20 mM NaCl. The purity and protein folding were evaluated by SDS-PAGE and NMR, respectively.

Analytical size-exclusion chromatography

The oligomeric state of tested proteins was analyzed by size exclusion chromatography. Superdex 75 10/30 HR (GE Healthcare) was equilibrated with PBS pH 7.4 and calibrated using globular proteins of known molecular weight. Approximate molecular weight of apo-hPD-Ll and hPD-Ll-small molecule complex (3:1 compound : protein molar ratio) were estimated using the calibration curve .

Differential scanning fluorimetry (DSF) DSF analysis was performed according to Niesen and colleagues (24). In brief hPD-Ll and hPD-L2 (both 12.5 μΜ) were incubated alone, with compound BMS-202 or compound 8 (both at 37.5 μΜ) in the presence of SYPRO Orange Dye (Life Technologies, final concentration 20x) . Constant temperature gradient of 0.2°C/min was applied and changes in fluorescence were monitored using real time thermocycler (BioRad) . Melting temperature (Tm) was estimated from first derivative of fluorescence intensity as a function of temperature .

NMR methods

Uniform ¹⁵N labeling was obtained by expressing the protein in the M9 minimal medium containing ¹⁵NH₄C1 as the sole nitrogen source. Unlabeled proteins were prepared as for crystallization. For NMR measurements the buffer was exchanged by gel filtration to PBS pH 7.4 (hPD-Ll) or 25 mM sodium phosphate containing 100 mM NaCl pH 6.4 (hPD-1) . 10% (v/v) of D₂0 was added to the samples to provide lock signal. All spectra were recorded at 30OK using a Bruker Avance 600 MHz spectrometer .

Binding of the compounds was analyzed by titrating the ¹⁵N- labeled PD-L1 (0.3 mM) and recording the ^-H-^N HMQC spectra prior and after addition of the compound (Supplementary Figs. SI, S2 and S3) .

The ability of tested compounds to dissociate hPD-Ll / hPD-1 was evaluated using AIDA (27) . ¹⁵N-labeled hPD-1 (0.2 mM) was slightly overtitrated with unlabeled hPD-Ll. Compound was aliquoted into the resulting mixture. During the experiment the ¹H-¹⁵N signals were monitored by HMQC experiment. Changes in the oligomeric state of hPD-Ll in the presence of tested compounds were monitored by titration of unlabeled hPD- Ll (0.3 mM) while recording 1H spectra prior and after addition of the compound. The approximate molecular weights of protein populations present in the sample were determined by analyzing the linewidth (relaxation time) of well separated NMR signals.

All compounds showed activity (IC50) in the range of from 0.001 to 1000 μΜ.

Screening for PD-Ll binders using Microscale Thermophoresis

MST (Microscale Thermophoresis) using the Monolith NT.115 (NanoTemper technologies, Munchen) is a technique that allows measuring of the interaction between biomolecules and the designed inhibitors. It can be used in several ways in the hit discovery and lead identification process. It can be used to determine if the designed compounds show binding to PD-Ll and determine their KD for PD-Ll. In addition, it allows measuring of the dissociation of the PDl/PD-Ll complex upon addition of the compounds and it permits rapid screening of compounds using two point measurements.

Protein preparation, labeling and compound preparation:

Refolded PD-Ll and PD-1 proteins were used for all experiments. The PD-1 construct is a 13.2 kDa protein. While PD-Ll is 14.5 kDa containing a His6-tag. Labeling of PD-Ll can be performed in several ways, for example, by attaching a fluorescent label to free amine groups, cysteine's or by binding to the His6-tag. PD-Ll was labeled using the Monolith NTtm His-tag labeling kit RED-tris-NTA (Nano temper technologies, Munchen) . The RED-tris-NTA dye (100 nm) was mixing with PD-Ll (200 nM) in a 1:1 ratio and incubated for 30 min at room temperature followed by centrifugation at 13k rpm for 15 min. Binding of the dye to the PD-Ll His6-tag was confirmed by measuring the KD (~8 nm) .

Compound stocks were prepared at 100 mM in 100% DMSO and were subsequently diluted in PBS-t buffer to a concentration of 2- 0.25 mM, depending on their solubility, while keeping the DMSO concentration at 2%.

PD-Ll vs compounds:

For determining affinity of the test compounds to PD-Ll a 2- fold dilution series was made using the compound stocks and dilution with PBS-t buffer with 2% DMSO. The labeled PD-Ll was added to a final concentration of 50 nm and the samples were loaded into Monolith NT115 standard treated capillaries (NanoTemper technologies, Miinchen) and measured using the Monolith NT.115. The obtained binding curves were analyzed using the MO. Affinity analysis software (NanoTemper technologies, Miinchen) .

Dissociation of the PD-1/ PD-Ll complex:

The PD-l/PD-Ll complex is prepared by mixing PD-Ll and PD-1 in a 1:10 ratio the complex was labeled a described above for PD- Ll. The dissociation of the PD-1/ PD-Ll complex is measured by adding the labeled complex to a final PD-Ll concentration of 50 nm to a 2-fold dilution series of the compound and measuring using the Monolith NT.115.

Screening of compounds using two point measurements :

Rapid screening of PD-Ll binding without a full KD determination is also possible using MST. This requires preparation of two samples, one at low compound concentration and one at high compound concentration. If the MST measurements shows a significant change in fluorescence signal between the two samples after the temperature jump it is a good indication if the compound is binding or not. Subsequently, a full KD determination as described above can be performed on the hits .

Claims

A compound of formula

(I)

wherein

R¹ and R² are independently from each other a hydrogen atom, a Ci-6 alkyl group or a group of formula -CH2-Ar or -CH₂-CH₂-NR³R⁴; wherein

Ar is an optionally substituted phenyl group or an optionally substituted heteroaryl group having 5 or 6 ring atoms and 1, 2, 3 or 4 heteroatoms which are independently selected from 0, S and N; and the groups R³ and R⁴ are independently from each other a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl , hetero- alkylcycloalkyl , aryl, heteroaryl, aralkyl or hetero- aralkyl group; all of which groups may optionally be substituted; or R³ and R⁴ together with the nitrogen atom to which they are bound are part of an optionally substituted heterocycloalkyl group containing 5, 6 or 7 ring atoms; or a pharmaceutically acceptable salt, ester, solvate or hydrate or a pharmaceutically acceptable formulation thereof .

2. A compound according to claim 1, wherein both R¹ and R² are independently from each other a group of formula -C¾- Ar or wherein R¹ is a hydrogen atom and R² is a group of formula -CEb-Ar.

3. A compound according to claim 1 or 2 , wherein wherein Ar is substituted by a CN group or a NO2 group.

4. A compound according to claim 1 or 2, wherein Ar is substituted by a group of formula - (CH₂) _n-NR⁵R⁶ wherein the groups R⁵ and R⁶ are independently from each other a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl , hetero- alkylcycloalkyl, aryl, heteroaryl, aralkyl or hetero- aralkyl group; all of which groups may optionally be substituted; or R⁵ and R⁶ together with the nitrogen atom to which they are bound are part of an optionally substituted heterocycloalkyl group containing 5, 6 or 7 ring atoms and n is 0, 1, 2, 3 or 4.

5. A compound according to claim 4 , wherein n is 0 or 1.

6. A compound according to claim 4 or 5 , wherein R⁵ and R^s are both hydrogen atoms .

7. A compound according to claim 4 or 5, wherein R⁵ is a hydrogen atom or a methyl group and R⁶ is a C1-C6 alkyl group; a Ci-Ce heteroalkyl group; a cycloalkyl group containing one ring having from 3 to 7 ring atoms; a heterocycloalkyl group containing one ring having from 3 to 7 ring atoms comprising 1 or 2 heteroatoms selected from S, O and N; an alkylcycloalkyl group containing a Ci- Ce alkyl group and a cycloalkyl group containing one ring having from 3 to 7 ring atoms; a heteroalkylcycloalkyl group containing a C1-C6 alkyl group or a C1-C6 heteroalkyl group and a cycloalkyl group containing one ring having from 3 to 7 ring atoms or a heterocycloalkyl group containing one ring having from 3 to 7 ring atoms comprising 1 or 2 heteroatoms selected from S, O and N with the proviso that a heteroalkylcycloalkyl group contains at least one heteroatom; a phenyl group; a heteroaryl group containing 5 or 6 ring atoms comprising 1, 2, 3 or 4 heteroatoms selected from O, S and N; an aralkyl group containing a C1-C6 alkyl group and a phenyl group; or a heteroaralkyl group containing a Ci-Ce alkyl group or a Ci-Ce heteroalkyl group and a phenyl group or a heteroaryl group containing 5 or 6 ring atoms comprising 1, 2, 3 or 4 heteroatoms selected from 0, S and N with the proviso that a heteroaralkyl group contains at least one heteroatom; all of which groups may optionally be substituted.

8. A compound according to claim 4 or 5 , wherein R⁵ and R⁶ together with the nitrogen atom to which they are bound are part of a heterocycloalkyl group containing 5, 6 or 7 ring atoms and optionally one further heteroatom selected from O and N, which heterocycloalkyl group may optionally be substituted (especially by a C1-C4 alkyl group or a group of formula -C(=0)-CH₃ or -CH₂OH) .

9. A compound according to claim 1, wherein R¹ and R² are independently from each other a group of formula -CH2-CH2- NR³R⁴.

10. A compound according to claim 1 or 9, wherein R³ and R⁴ are both hydrogen atoms .

11. A compound according to claim 1 or 9, wherein R³ is a hydrogen atom or a methyl group (especially a hydrogen atom) and R⁴ is a Ci-Cs alkyl group; a Ci-Cs heteroalkyl group; a cycloalkyl group containing one ring having from 3 to 7 ring atoms; a heterocycloalkyl group containing one ring having from 3 to 7 ring atoms comprising 1 or 2 heteroatoms selected from S, O and N; an alkylcycloalkyl group containing a C1-C6 alkyl group and a cycloalkyl group containing one ring having from 3 to 7 ring atoms; a heteroalkylcycloalkyl group containing a Ci-Ce alkyl group or a Ci-Ce heteroalkyl group and a cycloalkyl group containing one ring having from 3 to 7 ring atoms or a heterocycloalkyl group containing one ring having from 3 to 7 ring atoms comprising 1 or 2 heteroatoms selected from S, 0 and N with the proviso that a heteroalkylcycloalkyl group contains at least one heteroatom; a phenyl group; a heteroaryl group containing 5 or 6 ring atoms comprising 1, 2, 3 or 4 heteroatoms selected from O, S and N; an aralkyl group containing a C1-C6 alkyl group and a phenyl group; or a heteroaralkyl group containing a C1-C6 alkyl group or a C1-C6 heteroalkyl group and a phenyl group or a heteroaryl group containing 5 or 6 ring atoms comprising 1, 2, 3 or 4 heteroatoms selected from O, S and N with the proviso that a heteroaralkyl group contains at least one heteroatom; all of which groups may optionally be substituted.

12. A compound according to claim 1 or 9, wherein R³ and R⁴ together with the nitrogen atom to which they are bound are part of a heterocycloalkyl group containing 5, 6 or 7 ring atoms and optionally one further heteroatom selected from O and N, which heterocycloalkyl group may optionally be substituted (especially by a C1- C4 alkyl group or a group of formula -C(=0)-CH₃ or -CH2OH) .

13. A compound according to claim 1 of formula (II) or (III):

(III) wherein R⁷ and R⁸ are independently from each other are a group of formula - (CH₂) _n-NR⁵R⁶ wherein the groups R⁵ and R⁶ and n are as defined in any one of claims 4 to 8.

A pharmaceutical composition comprising a compound according to anyone of the preceding claims or a pharmaceutically acceptable ester, prodrug, hydrate, solvate or salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

A compound or a pharmaceutical composition according to anyone of the preceding claims for use in the treatment of cancer, viral diseases and infectious diseases and neurodegenerative diseases such as Schizophrenia, Alzheimer, Multiples Sclerosis, Parkinson, Corea Huntington, Spinocerebellar ataxia type 1 (SCA1) , Amyotrophic lateral sclerosis, Batten disease.